Breast Cancer Prevention Watch:  Evidence-based Prevention of Breast Cancer
Compiled by:
Constantine Kaniklidis, medical researcher

[ Breast Cancer Prevention Watch is a member of the Evidencewatch portal of evidence-based medicine sites ]

:: what's new
  • Alcohol, Breast Cancer and Hormone-Responsiveness
  • Update on the Status of Resveratrol and Wine
  • COX-2 Inhibitory Breast Cancer Chemoprevention
  • Potential Interference of Vitamin E on Tamoxifen
  • EGCG Antitumor and Chemopreventive Activity
  • Pesticides / Environmental Toxins
  • New Findings on Soy Phytoestrogens
  • Further Concerns about I3C / DIM

Issues in Prevention and Risk Reduction

  • Hormone Replacement Therapy/Hormone Therapy:
    Risk factors for breast cancer such as age at menarche, first birth, and menopause strongly suggest hormonal influences for the development of breast cancer, and it is known that both estrogen and progestin can induce growth and proliferation of breast cells (women with breast cancer tend to have higher endogenous circulating levels of estrogen and androgens).

    Combination hormone replacement therapy, (hereafter, HRT, estrogen-progestin, and hormone therapy (HT) will be used interchangeably unless finer distinction is called for) has been shown to be associated with an increased risk of breast cancer development. Numerous studies have found higher levels of endogenous estrogen and androgen levels in women who develop breast cancer than in those who do not (see the Endogenous Hormones and Breast Cancer Collaborative Group in J Natl Cancer Inst:
    Endogenous Sex Hormones and Breast Cancer in Postmenopausal Women: Reanalysis of Nine Prospective Studies.

    The WHI (Women’s Health Initiative), an randomized controlled trial (RCT) which examined the impact of HRT and dietary interventions on women’s health, terminated early one arm of the study, that investigating the effect of combination estrogen/progestin therapy on health risks (Writing Group for the Women's Health Initiative Investigators in JAMA:
    Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women), due to the fact that the trial showed an excess risk of invasive breast cancer, but not in situ breast cancer, associated with combination therapy compared with placebo, and within 1 year on the trial, women on HRT evidenced a higher percentage of abnormal mammograms, persisting throughout the trial. In addition, later applications, with which Evidencewatch concurs, have weighed all findings and in the light of potential benefits and countervailing adverse effects, concluded that "the risk of breast cancer outweighs the benefits of osteoporosis prevention from HRT" (Deady in J Manag Care Pharm (2004): Clinical Monograph: Hormone Replacement Therapy [pdf]).

    The trial, and subsequent confirming studies, demonstrated in addition the adverse effects of hormone therapy on atherosclerotic and thrombotic cerebrovascular effects. Later studies have further shown, settling uncertainty, an adverse effect on cognition in women 65 and older using HRT (Espeland et al. in JAMA:
    Conjugated Equine Estrogens and Global Cognitive Function in Postmenopausal Women and Shumaker et al. in JAMA: Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women), in contrast to a number of earlier observational studies which suggested a putatively protective role for exogenous estrogen in cognitive function in postmenopausal women.

    Note, however, that the evidence of an association between estrogen-only therapy and incidence of breast cancer is not determinative: some observational data suggest a small increase of risk, but the only completed RCT (randomized controlled trial) to date actually (and surprisingly) suggests a decreased risk of breast cancer.

    In conclusion, it is important to articulate and exploit methods known to decrease endogenous estrogen:

    (1) maintenance of ideal body weight (see section on obesity, below),

    (2) adoption of a low-fat diet in postmenopausal women (see Prentice et al. in J Natl Cancer Inst:
    Dietary fat reduction and plasma estradiol concentration in healthy postmenopausal women. The Women's Health Trial Study Group) , and

    (3) moderate exercise in adolescent girls (see Morimoto et al. in Cancer Causes Control:
    Obesity, body size, and risk of postmenopausal breast cancer: the Women's Health Initiative)). It is to be hoped that such interventions will decrease breast cancer risk, although further study is required to conclude this definitively.

  • Oral Contraceptives:
    Some studies suggest that oral contraceptives are associated with a small increased risk of breast cancer, although some controversy and uncertainty continued in this arena. First, in 1996 the Collaborative Group on Hormonal Factors in Breast Cancer reviewed and reanalyzed the worldwide epidemiological evidence (pooled analysis of more than 50 studies with more than 150,000 patients) on the relation between breast cancer risk and use of hormonal contraceptives (Collaborative Group on Hormonal Factors in Breast Cancer, Lancet (1996): Breast cancer and hormonal contraceptives: Collaborative reanalysis of individual data on 53297 women with breast cancer and 100239 women without breast cancer from 54 epidemiological studies), finding a slight increase in the risk of breast cancer with previous oral contraceptive use, with no evidence of an increase in the risk of having breast cancer diagnosed 10 or more years after cessation of use; we note that the included studies were of variable methodological quality.

    Against this, a later high-quality case-control study and failed to find such an association between breast cancer risk and oral contraceptive use (Marchbanks et al. in N Engl J Med:
    Oral Contraceptives and the Risk of Breast Cancer; see also Farquhar's commentary on this study in CMAJ: Oral Contraceptives and the Risk of Breast Cancer), even when taken for in excess of 25 years. Furthermore, the estrogen-only WHI study found an almost statistically significant reduction in breast cancer incidence in the estrogen-only arm (compared with placebo), although such an effect is possible to have come about by chance.

    However, recently Milne et al. (Cancer Epidemiol Biomarkers Prev (2005): Oral Contraceptive Use and Risk of Early-Onset Breast Cancer in Carriers and Noncarriers of BRCA1 and BRCA2 Mutations) examined the narrow question of whether oral contraceptive use is associated with increased risk for women with germ line mutations in BRCA1 or BRCA2, finding no evidence that use of current low-dose oral contraceptive formulations increases risk of early-onset breast cancer for either type of mutation carrier, and that furthermore there may actually be a reduced risk for BRCA1 mutation carriers (in the case of OC use for at least 12 months) was associated with decreased breast cancer risk for BRCA1 mutation carriers ). They conclude from this that given that current OC formulations may reduce, or at least not exacerbate, ovarian cancer risk for mutation carriers, OCs should not be contraindicated for women with a germ line mutation in BRCA1 or BRCA2.

    Finally, Dumeaux et al. (Cancer Epidemiol Biomarkers Prev (2004): Use of Oral Contraceptives, Alcohol, and Risk for Invasive Breast Cancer) have recently helped to untangle a complex interaction, namely that between breast cancer risk on the one hand and OC use and alcohol consumption, either jointly or singly. They found
    (1) that long-term users of OCs (10 years) who consumed 10.0 g/daily or more of alcohol had almost a two-fold increase in breast cancer risk compared with nonconsumers of alcohol who never used OCs; (2) the increased risk was roughly the same when nondrinkers used OCs during a long time or when nonusers of OCs drank 10.0 g/daily or more of alcohol; (3) among women consuming less than 5.0 g/daily of alcohol, the risk of breast cancer increased significantly with the total duration of OC use or with the estrogen dose from OCs; (4) in contrast, among women consuming 5.0 g/daily or more of alcohol, duration of OC use and estrogen dose from OCs did not add any excess risk of breast cancer compared with women consuming the same amount of alcohol and who never used OCs; (5) a negative interaction between alcohol and duration of OC use (or estrogen dose from OCs) was observed; and (6) the association between high alcohol intake and breast cancer was more prominent among postmenopausal women than among premenopausal women, with no significant interaction between alcohol and duration of OC use was observed after stratification on menopausal status. This suggest strongly that alcohol and OCs have antagonistic effects on breast cancer risk through a common pathway.

  • A Critique of the Kahlenborn / Mayo OC Study
    Recently there appeared a widely-cited study of Kahlenborn et al. (Kahlenborn et al., Mayo Clin Proc (2006): Oral Contraceptive Use as a Risk Factor for Premenopausal Breast Cancer: A Meta-analysis [pdf]) on OC (oral contraceptive) use and breast cancer risk.
    The principle author is Chris Kahlenborn, who is a former US Congressman and physician, the author of Breast cancer: its link to abortion and the birth control pill (2000) in which the author acknowledges that he is an opponent of all forms of artificial contraception (on the author's political and ideological stance in this arena, see Patricia Jasen's Breast Cancer and the Politics of Abortion in the United States; in addition, C Kahlenborn is on the advisory board of the national (self-acknowledged) right-wing Christian organization Concerned Women for America which defines itself as anti-gay, anti-choice, anti-feminism and anti-sex education, and actively lobbies for legislation recognizing the abortion-breast cancer link. Despite the clear potential for significant bias consequent to all this, no conflict of interest in declared either in the article itself, nor on the associated Mayo site.

    Some Confounding Factors:

    • Changing patterns of contraceptive use in the population (larger numbers of younger women are OC users, with usage of increasing duration),

    • the newly introduced use of low-dose and ultra-low-dose formulations delivering dramatically lower estrogen dose levels,

    • along with new progestin agents such desogestrel (Marvelon / Mercilon / Mircette / Apri / Desogen / Ortho-Cept / Cyclessa) and norgestimate (Ortho-Prefest, often along with shorter hormone-free intervals,

    • the epidemiology of breast cancer, with associated steady increase in the incidence of breast cancer,

    • the studies meta-analysis of 39 independent case-control studies failed to even attempt to explain for the significant heterogeneity across the individual studies;

    All of which may entail divergent results in future cohort studies (thus, AA Kubba's comprehensive review (J R Soc Med (2003): Breast cancer and the pill), among many others, and which includes the results of the Oxford Collaborative Group Study, concluded that although OCs may have some small potential to promote the growth of preexisting tumors in some women (and note that the cancers diagnosed in women who had used combined oral contraceptives were less advanced clinically than those diagnosed in women who had never used these contraceptives for ever-users compared with never-users), "It does not increase the lifetime risk of breast cancer. Women over 35, whether current or past users, do not show an increased incidence. In women in their 20s the absolute risk of breast cancer is very low, and any excess attributable to the pill is small (around 1 in 10 000)".

  • Absolute Risk

    • Although OCs may be carcinogenic, the relative risk is small, and the absolute risk, meaning the excess breast cancers due to OC exposure, is barely perceptible: the most comprehensive relevant data from the pooled analysis (from the Oxford Collaborative Group) estimates that the excess number of cases of breast cancer expected up to 10 years after discontinuation of OC use among a population of 10,000 is:

    • a half a case (0.5 cases) for OC use from age 16 to 19 years,

    • 1.5 cases for OC use from age 20 to 24 years, and

    • 4.7 cases for OC use from 25 to 29 years, and

    • with increasing duration, risk becomes insignificant (there was no significant excess risk of having breast cancer diagnosed 10 or more years after stopping use - there was no excess risk in women aged over 45

    as found by the Collaborative Group on Hormonal Factors in Breast Cancer (Oxford Collaborative Study Group), Lancet (1997): Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer); such risk is dwarfed, for instance, by the much larger risks associated with even modest social alcohol consumption.

    Risk-Benefit Ratio

    • Furthermore, a risk-benefit analysis must be weighed in any such considerations: so for instance, the IARC (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol 72 (1999): Hormonal Contraception and Post-menopausal Hormonal Therapy [pdf]) concluded that there is convincing evidence that OCs decrease the risk of both ovarian and endometrial cancer (see also the confirming findings of Medard Lech and Lucyna Ostrowska's recent review (Lech & Ostrowska, Eur J Contracept Reprod Health Care (2006): Risk of cancer development in relation to oral contraception), where it was concluded that "The risk of developing ovarian cancer in women using COCs is at least 40% smaller than in other women; the degree of protection given by COCs is directly proportional to the duration of use of this form of contraception. Reliable scientific data prove convincingly that the risk of endometrial cancer is smaller in women who used COCs than in women who never took them".

    • there is accumulating evidence that they may lower the risk of colorectal cancer.

    • Noncontraceptive health benefits associated with OCs:
      (see IARC review, cited above), including:

      • relief from menstrual disorders;

      • reduced risk of:

      • pelvic inflammatory disease,

      • benign breast disease,

      • uterine leiomyomas, and

      • ovarian cysts; and

      • improved bone mineral density/BMD (see the recent systematic review of Lee & Lebrun, Br J Sports Med (2006): Effect of oral contraceptives and hormone replacement therapy on bone mineral density in premenopausal and perimenopausal women: a systematic review).

  • Progesterone Cream:
    As progesterone can be absorbed through the skin, progesterone creams have common into increasing use, especially in the OTC (over-the-counter) marketplace, primarily for treatment of menopausal vasomotor symptoms, osteoporosis and for skin antiaging and skin-firming treatment. [Note: a widely promoted OTC product, Mexican yam, although claimed to either contain progesterone, or to be convertible into progesterone via one of its constituents, diosgenin, actually contains no progesterone whatever, and diosgenin conversion into progesterone can only be effected industrially, but by any body-intrinsic mechanisms.] Its efficacy in these conditions has to date not been convincingly well established by consistent and methodologically sound evidence, but the primary issue under focus here is its safety in oncologic settings, especially problematic given its well-known highly unpredictable dermal absorption.

    In this context, Hermann et al. (J Clin Pharmacol (2005): Over-the-Counter Progesterone Cream Produces Significant Drug Exposure Compared to a Food and Drug Administration–Approved Oral Progesterone Product) compared 200-mg oral progesterone (once daily) with a 40 mg OTC progesterone cream (twice daily), both given for 12 days, finding that the progesterone cream delivered a measured dose-normalized 24-hour progesterone exposure equivalent to the powerful oral preparation (a finding prompting the authors to question whether topical progesterone products should be available OTC). At these levels, therefore, it is not impossible that even if it promoted an anti-proliferative on uterine/ endometrial tissue, it could like progesterone deployed in HRT regimens exert a proliferative effect on breast tissue.

  • Alcohol:
    Alcohol, currently listed as a known human carcinogen by several agencies - IARC (International Agency for Research on Cancer) and the US National Toxicology Program, among others - is a known risk factor for several cancers, including those of the mouth, larynx, esophagus and liver; it has been conjectured that the mechanism for causing cancer may be through alcohol's alteration of estrogen levels (themselves known to be associated with breast cancer risk), and/or its interference with DNA repair, and as B Macmahon has observed (Int J Cancer (2005): Epidemiology and the causes of breast cancer), the three known causes of human breast cancer are (1) ionizing radiation, (2) exogenous ovarian hormones, and (3) beverage alcohol consumption. And Kroman et al. (Ugeskr Laeger (2005): Is the rising incidence of breast cancer a consequence of lifestyle? [in Danish]
    ) that the observed increase in the incidence of breast cancer is attributable in terms of modifiable lifestyle factors primarily to obesity and alcohol use.

    Many epidemiological studies have shown an increased risk of breast cancer associated with alcohol consumption. Individual data from 53 case-control and cohort studies were included in a British meta-analysis (Hamajima et al. in Br J Cancer:
    Alcohol, tobacco and breast cancer — collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Collaborative Group on Hormonal Factors in Breast Cancer) which found alcohol to be an independent risk factor for breast cancer. There was a 7% increase in risk with each 10 g (about 1 drink) of alcohol per day and this finding argues against the previous conception of a threshold effect for alcohol. This translates to the outcome that consumption of 15 g/day of alcohol raised breast cancer risk by 2.5-fold so that women who average 1.5 drinks per day have a 30% increase in risk. Given that alcohol consumption is one of rare known risk factors for breast cancer that is a potentially modifiable behavior, it would be prudent for women in general, and certainly for any woman at especial risk, to refrain from regular alcohol consumption (in agreement, see the conclusions of Kristan Aronson at Queens University, Ontario in her thoughtful commentary (CMAJ: Alcohol: a recently identified risk factor for breast cancer)).

    These findings are further validated by the NIAAA State of the Science Report (National Institute on Alcohol Abuse and Alcoholism (12/19/2003):
    State Of The Science Report On The Effects Of Moderate Drinking) which found that women with a family history of breast cancer are as a group at substantially increased risk even at low doses of alcohol consumption which found that, compared with nondrinkers, women who consume an average of 1 drink per day appear to have a 10% increase in breast cancer risk. See the confirmative findings on this by Vachon et al. (Cancer (2001): Investigation of an interaction of alcohol intake and family history on breast cancer risk in the Minnesota Breast Cancer Family Study) who found a risk ratio of 2.45 in daily drinkers who were first-degree relatives of breast cancer probands, as compared with never-drinkers (risk for second degree relatives was not significant, and there was no association for women who were not biologically related); see also Go et al. (J Nutr (2004): Diet and cancer prevention: evidence-based medicine to genomic medicine).

    Suzuki et al. (J Natl Cancer Inst (2005): Alcohol and Postmenopausal Breast Cancer Risk Defined by Estrogen and Progesterone Receptor Status: A Prospective Cohort Study) have valuably clarified the association of alcohol with the estrogen receptor (ER) and progesterone receptor (PR) status of the breast tumors, finding that alcohol consumption was associated with an increased risk for the development of ER-positive tumors, irrespective of PR status, a serious negative impact given that because the majority of breast tumors among postmenopausal women overexpress ER. Even more importantly perhaps is their secondary finding of a statistically significant interaction between alcohol intake and the use of postmenopausal hormones on the risk for ER+PR+ tumors.

    And although some evidence exists for a potential cardiovascular benefit for modest alcohol consumption (as wine), note that (1) for most women it would prove easier and probably more desirable to achieve a comparable cardiovascular benefit through other techniques (for example, diet, supplements, exercise) than to attempt to gain a proportionate reduction in risk of breast cancer, (2) most women probably find the prospect of breast cancer more viscerally intimidating than that of cardiovascular disease, regardless of mortality statistics, and (3) it is not at all clear whether drinking's potential cardiovascular benefit is due to resveratrol and polyphenol components, independent of the alcohol content itself, in which case separate supplementation minus the alcoholic content may again be more prudent. (See the recent study of Irene Mattison and her colleagues at Lund University, Sweden (Int J Cancer: High fat and alcohol intakes are risk factors of postmenopausal breast cancer: a prospective study from the Malmo diet and cancer cohort) which concluded that "high wine intake was associated with a significantly elevated breast cancer risk".

    Finally, on a positive note, there is some evidence that alcohol and folate consumption interact to affect risk, with differences in associations for those with or without p53 mutations, and that causal pathways may vary for pre- and postmenopausal women (Freudenheim, Carcinogenesis:
    Diet and alcohol consumption in relation to p53 mutations in breast tumors). And adequate folate supplementation may protect against alcohol related increased risk of breast cancer, as found in the prospective cohort study (population of 17,000 Australian women over 10 years) of Baglietto and colleagues ((BMJ (2005): Does dietary folate intake modify effect of alcohol consumption on breast cancer risk? Prospective cohort study). They found that women who regularly consumed more than 40 g (5 units) a day of alcohol had a 40% greater risk of invasive breast cancer than lifetime abstainers, but that a daily folate intake of 400 µg (micrograms) in this drinking group was however associated with a significant reduction in risk, when compared with a lower daily intake of 200 µg. This is an important preventive message, as it demonstrates that the known adverse effect of alcohol consumption may be reduced by sufficient dietary intake of folate.

    Furthermore, the findings of Tjonneland et al. (Eur J Clin Nutr (2005): Folate intake, alcohol and risk of breast cancer among postmenopausal women in Denmark) also support the evidence that adequate folate intake may attenuate the risk of breast cancer associated with high alcohol intake, and confirming the conclusion from other studies that alcohol intake and risk of breast cancer are associated mainly among women with low folate intake; they note that among women with a folate intake higher than 350 micrograms, there was no association between the alcohol intake and the breast cancer incidence.

    Some genotype influence does appear to play a role: individuals differ in their ability to metabolize alcohol, through genetic differences in the enzyme, alcohol dehydrogenase (ADH), that catalyzes the oxidation of about 80% of ethanol to acetaldehyde, which is a known carcinogen; there is individual variation in the ADH genotype, with one locus, ADH3, being polymorphic in Caucasians The question whether fast metabolizers of alcohol, as measured by the a refined measure of the ADH3 genotype, have a higher risk of breast cancer from alcohol intake compared to those individuals who are slow metabolizers, but consume comparable amounts of alcohol, and Terry et al. (Carcinogenesis (2005): ADH3 genotype, alcohol intake, and breast cancer risk) evaluated just this scenario, finding that fast metabolizers of alcohol have a higher risk of breast cancer risk, especially premenopausally, from alcohol intake than slow metabolizers.

    [new] Alcohol, Breast Cancer and Hormone-Responsiveness
    It appears on the balance of the evidence that the association of alcohol consumption and breast cancer risk is primarily if not exclusively in hormone-responsive populations: Huiyan Ma at the USC/Norris Comprehensive Cancer Center and coresearchers (Breast Cancer Res (2006):
    Hormone-Related Risk Factors for Breast Cancer in Women Under Age 50 Years by Estrogen and Progesterone Receptor Status: Results From a Case-Control and a Case-Case Comparison) found that the average number of alcoholic drinks per week in the recent 5 years was positively associated with ER+/PR+ breast cancer and weakly associated with all types of cancer together but not associated with ER-/PR- breast cancer.

    [updated: 1/19/07] Update on the Status of Resveratrol and Wine
    Resveratrol, a non-flavonoid polyphenol, and a natural constituent of both grapes and therefore wine, has been studied as a potential anticancer agent in vitro and in vivo. Yun Wang and coresearchers (Toxicol Sci (2006): The Red Wine Polyphenol Resveratrol Displays Bilevel Inhibition on Aromatase in Breast Cancer Cells) reasoned that given that the rate-limiting reaction of estrogen biosynthesis is catalyzed by cytochrome P450 CYP19 enzyme or aromatase, the polyphenolic compound resveratrol, derived from grape peel, with known structural resemblance to estrogen and demonstrated agonistic and antagonistic properties on the estrogen receptor, may exert aromatase-inhibitory effect on the expression and enzyme activity of the aromatase enzyme, finding that testosterone-induced cell proliferation of MCF-7 breast cancer cells was significantly reduced by a pharmacological dose (10µM) of resveratrol, while a higher 50µM dose significantly reduced CYP19-encoding mRNA; thus pharmacological dose levels of resveratrol can inhibit aromatase at both the enzyme and mRNA levels.

    Breast Cancer Prevention Watch notes that other anticancer benefits of resveratrol may be via indirect enhancement activity on other agents. Thus J Wietzke and colleagues at the University of Notre Dame (J. Steroid Biochem. Mol. Biol (2003):
    Phytoestrogen regulation of a vitamin D3 receptor promoter and 1.25-dihydroxyvitamin D3 actions in human breast cancer cells) have shown that resveratrol increases the effects of vitamin D in breast tumor cells, and it also blocks the growth-promoting effects of linoleic acid in the Western diet, which converts to arachidonic acid (and ultimately to proliferative factors such as prostaglandin E2 and leukotriene B4) that promote inflammatory processes stimulative of cancer cell growth (see Nakagawa et al., J Cancer Res Clin Oncol (2001): Resveratrol inhibits human breast cancer cell growth and may mitigate the effect of linoleic acid, a potent breast cancer cell stimulator who demonstrated that resveratrol inhibited the breast cancer cell growth and blocked linoleic acid's growth-promoting activity).

    In addition, Austrian researchers have shown that resveratrol blocks the ability of cancer cells to metastasize to bone, especially for breast, renal, and pancreatic cancer (Ulsperber et al. Int J Oncol (1999):
    Resveratrol pretreatment desensitizes AHTO-7 human osteoblasts to growth stimulation in response to carcinoma cell supernatants)

    Recently Swiss researchers Levi et al. (Eur J Cancer Prev (2005): Resveratrol and breast cancer risk) have examined epidemiological data, analyzing the relation between dietary resveratrol intake and breast cancer risk using data from a case-control study (conducted between 1993 - 2003), finding a significant inverse association for resveratrol from grapes, but not for wine. Given what is already known about the hazards of alcohol intake on breast cancer risk, this study suggests that an overall positive benefit of resveratrol on breast cancer risk reduction can be still be made when that component is consumed through grapes directly, and research is underway to examine whether a comparable scenario exist vis a vis the cardiac benefits of resveratrol. In addition, Masala et al. (Int J Cancer (2005): Dietary and lifestyle determinants of mammographic breast density. A longitudinal study in a Mediterranean population) found a positive association between increasing consumption of wine and high mammographic breast density, which is known to be associated with increased breast cancer risk, even after adjustment for established BC risk factors. This has been cross-confirmed by Maskarinec et al. (Int Journal Cancer (2005): Alcohol consumption and mammographic density in a multiethnic population) who found that alcohol consumers had higher percent breast densities than did abstainers.

    [new: 1/19/07] Why Wine is Irrelevant as a Source of Resveratrol
    Finally, Breast Cancer Prevention Watch noted that although it is often cited that organic red wines from certain areas of Europe contain the highest level of resveratrol, nonetheless given standard pesticidal treatment of grapes and other factors, most wines contain either no resveratrol whsoever, or non-therapeutic trace amounts (usually a few micrograms per glass). Thus, contrary to popular opinion, although wine is a dietary source, the amounts of resveratrol are both widely variant, and therapeutically negligible (Pennington Biomedical Research Center, Pennington Nutrition Series: Resveratrol [pdf]), with an average of 1.5 micrograms of resveratrol/ml, so that for a full glass of wine - which is about 5 fluid ounces (= 150 ml.), total resveratrol content would be 225 micrograms, or just above 2 tenths of one milligram, and similarly for grapes and grape juice. But it appears that pharmacological dose ranges between a minimum of 10 mg. to about 32 mg. to 40 mg. at typical optimal level, so to ingest just the lower range amount of 10 mg. would require approximately 50 glasses of wine or an indigestible amount of grapes. Hence the only feasible source for pharmaceutical / therapeutic levels of resveratrol therefore is by standardized supplementation.

    Breast Cancer Watch Commentary:
    The Facts on Alcohol and Breast Cancer Risk

    (1) Alcohol is incontrovertibly both a known and recognized human carcinogen and a significant breast cancer risk factor, with each 10 grams = 1 drink consumption being associated with at least 7% - 10% increase in risk.
    (2) There is no safe minimum consumption, with each drink adding an additional 7% to 10% risk increase linearly, and statements made to the effect that increased risk begins only at 2 or more drinks daily are in error and wholly without evidentiary support.
    (3) A family history of breast cancer influences further increases the risk factor above these levels: in first-degree relatives of breast cancer probands, there is a risk ratio of 2.45 in daily drinkers
    as compared with never-drinkers.
    (4) Alcohol consumption is associated with an increased risk for the development of ER-positive tumors, irrespective of PR status, and there is a statistically significant interaction between alcohol intake and the use of postmenopausal hormones on the risk for ER+ PR+ tumors.
    (5) Resveratrol, a non-flavonoid polyphenol, and a natural constituent of both grapes and therefore wine, appears to be a potential anticancer agent. In terms of dietary resveratrol intake and breast cancer risk, there is a significant inverse association for resveratrol from grapes, but not for wine.
    (6) There is a positive association between increasing consumption of wine and high mammographic breast density, which is known to be associated with increased breast cancer risk.
    (7) A high daily folate intake may attenuate the risk of breast cancer associated with high alcohol intake, to the extent that folate intake higher than 350 - 400 µg (micrograms), but not lower, showed no association between the alcohol intake and the breast cancer incidence.

    Warning: However, at least one recent study failed to support the hypothesis that high folate intake reduces breast cancer risk; Stolzenberg-Solomon et al. (Am J Clin Nutr (2006):
    Folate intake, alcohol use, and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial) instead found that a high intake may actually increase the risk in postmenopausal women.

  • Pesticides / Environmental Toxins:
    The role of pesticides and other environmental toxins in the promotion of human breast carcinoma has not been fully settled, however there is reasonable evidence of probable role that dioxin, polycyclic aromatic hydrocarbons (PAHs), the organochlorine pesticide DDT, PCBs (polychlorinated biphenyls), and ethylene oxide in the development of breast cancer (see the latest Breast Cancer Fund report: State of the Evidence 2006: What Is the Connection Between the Environment and Breast Cancer? [pdf].).

    With respect to PCBs. note that although the majority of early reports did not find sufficient evidence of a role of PCB exposure in breast cancer, these studies failed to consider and control for individual genetic susceptibility to PCB effects determined partially by polymorphisms in the gene encoding the biotransformation enzyme cytochrome CYP1A1: the seminal study of Francine Laden at the Brigham and Women’s Hospital and Harvard Medical School and her colleagues demonstrated that PCBs and other xenobiotics can be metabolized to carcinogenic intermediates in the presence of the variant genotype, and although among postmenopausal case-control pairs, there was no evidence of an association of either the variant CYP1A1 genotype or exposure to PCBs with breast cancer risk, nonetheless the risk for women with high plasma PCB levels and at least one variant (of the CYP1A1-exon 7 allele) was elevated, and there is furthermore some suggestion that PCBs may enhance the metabolism of PAHs, and finally high levels of PCBs may yet be associated with breast cancer risk in the subgroup of women who have the variant CYP1A1-exon7 polymorphism (Laden et al., Cancer Epidemiol Biomarkers Prev (2002): Polychlorinated Biphenyls, Cytochrome P450 1A1, and Breast Cancer Risk in the Nurses’ Health Study). Furthermore, adipose PCB concentrations were significantly associated with breast tumor recurrence, also affected by smoking (as demonstrated by Joshua Muscat at the Institute for Cancer Prevention and coresearchers, Cancer Epidemiol Biomarkers Prev (2003): Adipose Concentrations of Organochlorine Compounds and Breast Cancer Recurrence in Long Island, New York). However, in contrast to the Muscat data for New York, Ole Raaschou-Nielsen with the Danish Cancer Society / Institute of Cancer Epidemiology failed to find that higher organochlorine body levels increase the risk of breast cancer in postmenopausal women (Cancer Epidemiol Biomarkers Prfev (2005): Adipose Organochlorine Concentrations and Risk of Breast Cancer Among Postmenopausal Danish Women), but we note that this study found an inverse association between concentrations of some organochlorines and the risk of breast cancer, most evident for estrogen receptor-negative breast cancer, and the authors prudently note that the interpretation of these results is currently unclear and will require confirmation in further trials (and Lindsey Mason and colleagues at the University of Aberdeen found no consistent associations between breast cancer and CYP1A1 polymorphisms (Am J Epidemiol (2005): Cytochrome P-450 1A1 Gene Polymorphisms and Risk of Breast Cancer: A HuGE Review); see also the thoughtful commentary of Peter Shield of the Lombardi Comprehensive Cancer Center, Cancer Epidemiol Biomarkers prev (2006): Understanding Population and Individual Risk Assessment: The Case of Polychlorinated Biphenyls).

    Polybrominated diphenyl ethers (PBDEs) are a class of brominated flame retardants (BFRs) with some structural similarities to PCBs, and despite legislative curtailment both here and in Europe, are environmental contaminants still detected in soil, sediment, sludge, air, and in fish, wildlife and other biota, including in human tissues and fluids such as blood, breast milk, and adipose tissue, with evidence of accumulation of specific PBDEs in humans (as shown by Andreas Sjödin and colleagues at the CDC in Environ Health Perspec (2004): Retrospective Time-Trend Study of Polybrominated Diphenyl Ether and Polybrominated and Polychlorinated Biphenyl Levels in Human Serum from the United States).

    In the issue of the role of PBDEs in breast cancer is a complicated one. Early studies suggested that PCDEs were inductors of the p450 cytochrome CYP1A1 enzyme which, along with CYP1A2 and CYP2B2, is a carcinogen-activating enzyme (metabolizing many of these chemicals into mutagenic and toxic intermediates), with the induction it was thought via the aryl hydrocarbon receptor (AhR), which is a ligand-activated transcription factor, regulating the transcription of diverse genes through binding to the xenobiotic-responsive element (XRE). AhR may be activated by a variety of environmental contaminants including polycyclic aromatic hydrocarbons (PAH), planar chlorinated biphenyls (PCB), and halogenated aromatic hydrocarbons (HAH) such as TCDD (2, 3, 7, 8, -tetrachlorodibenzo-p-dioxin), dibenzofurans (PCDFs) and dibenzo-p-dioxins (PCDDs), among other dioxin-like contaminants, although it is now known that AhR plays important roles in normal development and physiology, including that of reproduction and growth, and cell cycle, cell growth, cell differentiation, and apoptosis, not just in toxicity, or the defense from toxicity, of xenobiotic / environmental chemicals (see Nathalie Tijet at the University of Toronto and her coresearchers, Mol Pharmacol (2006): Aryl Hydrocarbon Receptor Regulates Distinct Dioxin-Dependent and Dioxin-Independent Gene Batteries, and also the review of Paola Pocar of the Martin Luther University Halle-Wittenberg and coresearchers, Reproduction (2005): Molecular interactions of the aryl hydrocarbon receptor and its biological and toxicological relevance for reproduction of the molecular cross-talk of AhR across multiple signal transduction pathways affecting female reproduction). If correct, that these contaminant are CYP1A1-inductors via AhR-mediated activity, these studies would have direct relevance to breast cancer given the stipulated role of AhR in mammary gland tumorigenesis (Jennifer Schlezinger and colleagues at Boston University School of Public Health, Biol Chem (2006): A role for the aryl hydrocarbon receptor in mammary gland tumorigenesis).

    However, these earlier studies suggesting CYP1A1-induction by PBDEs via AhR competitive binding appear now to have been largely if not wholly an artifact of an impurity effect of low-level contamination of these tested compounds by PCDFs and PBDDs and possibly other AhR-active CYP1A1 inducers, as first shown by Annelieke Peters with the Institute for Risk Assessment Sciences (IRAS) at Utrecht University and coresearchers (Toxicol Sci (2004): Effects of Polybrominated Diphenyl Ethers on Basal and TCDD-Induced Ethoxyresorufin Activity and Cytochrome P450-1A1 Expression in MCF-7, HepG2, and H4IIE Cells), and more recently and decisively by Annelieke Peters again in her doctoral study (AK Peters, University of Utrecht (2006): Polybrominated Diphenyl Ethers, Aspects of the mechanism of action [pdf]) where no CYP1A1 induction was observed in the AhR responsive MCF-7 (human breast carcinoma), HepG2 (human hepatoma) and H4IIE (rat hepatoma) cell lines, nor in cynomolgas monkey hepatocytes. Thus it must now be concluded that PBDE-mediated toxicity is consequent to AhR-independent mechanisms given that when tested PBDE congeners are subjected to rigorous purification techniques removing possible contamination with dioxin-like compounds such as PBDFs and other AhR-active compounds, AhR-mediated activation of CYP1A1 induction is not evidenced (see also the same author's study in Toxicol Sci (2006): Interactions of Polybrominated Diphenyl Ethers with the Aryl Hydrocarbon Receptor Pathway).

    The question then shifts to what mechanisms and pathways underlie PBDE toxicity and to what extent if any are these connected to breast cancer promotion (or its opposite). Part of the puzzle's solution is provided by recent research examining the potential alteration of expression of several CYP P450 enzymes, including CYP2B and CYP3A, and especially in particular CYP3A4, involved as it is in the metabolism of a large number (over 50%) of clinically deployed drugs including oncotherapeutic agents (both endocrine, and chemotherapeutic), given that dioxin-like chemicals are able to induce CYP3A4 gene expression, indicating that there exists some essential interaction between the AhR and the human pregnane X receptor (hPXR), as discussed by Peters (AK Peters, University of Utrecht (2006): Polybrominated Diphenyl Ethers, Aspects of the mechanism of action [pdf]). Such interference of xenobiotics with CYP3A4 if confirmed would have broad implications for drug-drug and drug-CAM (complimentary and alternative medicine) agent interactions, since CYP3A4 is the predominant drug metabolizing enzyme in the human liver. What Peters found was that the observed in vitro effects by PBDEs occurred at medium concentrations that usually exceed the average European human blood levels, so that it would not be expected that human concentrations would be sufficiently high enough to initiate a possible PBDE-induced CYP3A4 interaction, although given that levels in North America are typically higher than European levels by some order of magnitude, the potential for significant interaction in these latter populations cannot be excluded, in concurrence also with the findings of Johnny Sanders at North Carolina State University in his doctoral study (JM Sanders, North Carolina State University (2006): Mechanisms of Toxicity of Polybrominated Diphenyl Ethers [pdf]) who concluded that PBDEs appear to pose little carcinogenic risk to humans through phenobarbital-like (that is, via CYP2B and CYP3A gene induction) epigenetic mechanisms at current exposure levels, although here too we note again as with Peters that this conclusion may be geographically constrained (see also his earlier study in Toxicol Sci (2005): Differential Expression of CYP1A, 2B, and 3A Genes in the F344 Rat following Exposure to a Polybrominated Diphenyl Ether Mixture or Individual Components).

    In this connection, Rocío F. Cantón at the Institute for Risk Assessment Sciences, IRAS Utrecht University and colleagues (Toxicol ASci (2005): Inhibition and Induction of Aromatase (CYP19) Activity by Brominated Flame Retardants in H295R Human Adrenocortical Carcinoma Cells) explored the endocrine-disruptive potential of several brominated flame retardants (BFRs) in a human adrenocortical carcinoma cell line (H295R), an effect apparently regulated by aromatase (CYP19), which in addition to mediating the conversion of androgens to estrogens through the bioconversion process of aromatization, is of course intimately involved in estrogen-dependent carcinogenesis. They found that PBDEs or their structural analogs exerted an inhibiting or inducing effect on aromatase activity, with the brominated triphenol TBP (brominated phenols/anisols 2,4,6-tribromophenol) capable of strongly inducing aromatase in vitro, and this is consonant with other studies showing that TBP can bind to the estrogen receptor as well as to the thyroid hormone transport protein transthyretin (Cristel Olsen and colleagues at the National Institute of Public Health, Norway, in Toxicol. Lett (2002): Brominated phenols: Characterization of estrogen-like activity in the human breast cancer cell-line MCF-7), although for other than TBP, most BFRs studied demonstrated an antiestrogenic effect via aromatase inhibition. Thus, at least in vitro TBP can interfere in steroidogenesis by aromatase induction, suggesting that this PBDE is an in vivo endocrine disruptor requiring further investigation. given that such induction enables hormone-dependent carcinogenesis, although the authors speculate that in vivo aromatase interaction by these PBDE metabolites would not easily be achieved for required concentration levels.

    Building on this and pushing further, and closer to the breast carcinoma arena, Jonathan Barber and colleagues at Lancaster University examined the activities of low-dose PBDEs in MCF-7 cells, finding elevations in micronucleus formation and also significant elevations in growth kinetics even at levels of reported concentrations measured in UK serum samples (J Barber et al., Mutagenesis (2006): Low-dose treatment with polybrominated diphenyl ethers (PBDEs) induce altered characteristics in MCF-7 cells). And notice that this is singly, yet we know that endocrine-disruptors can act and react together, allowing small, apparently non-significant quantities of individual agents to exert major cumulative effect (as noted by Julia Brody and Ruthann Rudel (Environ Health Perspect (2003): Environmental Pollutants and Breast Cancer); see also the report from the UK Working Group on the Primary Prevention of Breast Cancer (2005): Breast Cancer: an environmental disease).

    Again in this connection, of interest is the recent finding from Yasmeen Barnes-Nkrumah and colleagues at Florida A&M University (Proc Amer Assoc Cancer Res, Volume 47, 2006: Diallyl sulfide inhibits 2,2'4,4'-tetra brominated biphenyl ether (BDE-47) induced DNA strand breaks and cell proliferation in MCF10A breast epithelial cells) that the most abundant PBDE congener in human, animal and environmental samples, BDE-47, induces cell proliferation via genotoxicity (DNA strand breakage), but that DAS (diallyl sulfide, an organosulfur compound found in garlic), both inhibits such DNA damage and promotes apoptosis in affected cells. The authors speculate that DAS action contrary to that of BDE-47 can thus prevent cancer formation. However, Breast Cancer Prevention Watch in these pages has put forth evidence that suggests the potential of garlic and other Allium components to exert adverse interaction with the efficacy of certain oncotherapeutic agents via activity over the CYP3A4 and CYP2D6 metabolic pathways; see our own Issues in Drug Interactions in Oncology coverage for fuller discussion and supporting research.

    Breast Cancer Prevention Watch Summary
    On the balance of the evidence we find that it is plausible given in particular the recent cell studies of Barber and those of Barnes-Nkrumah, cited above, with the further evidence concerning cytochrome p450 system interaction, especially in respect to CYP3A4, that at least certain PBDE congeners, especially BDE-47 and TBD, may exert a cell proliferative effect on human breast carcinoma cells, either singly or in combination with other xenobiotics, but further studies of high methodological quality are needed to determine both whether this activity is at levels that are clinically significant in human trials, and whether the aggregate effect is either enhanced by other xenobiotics, or in the contrary, muted by dietary or other coadministered non-pharmaceutical interventions in the natural human setting, and it is imperative as we have seen above that laboratory testing be conducted under rigorous standards for sample purification to assure no significant contamination by other xeniobiotics.

  • Smoking:
    Collaborative Group on Hormonal Factors in Breast Cancer (see above, Alcohol) found that among women who reported drinking no alcohol there was little or no effect on breast cancer risk of having ever smoked tobacco, compared with having never smoked.

    However, a recent assessment of 10 studies with breast cancer incidence as the outcome concluded that there may indeed be an association between passive smoking and breast cancer (see Morabia in Environ Mol Mutagen:
    Smoking (active and passive) and breast cancer: epidemiologic evidence up to June 2001; see also Terry et al. in Int J Cancer: Cigarette smoking and breast cancer risk: a long latency period? and Kropp et al. in Am J Epidemiol: Active and passive smoking and risk of breast cancer by age 50 years among German women). In addition, several studies have begun to assess gene–environment interactions re smoking (Zheng et al. in Cancer Causes Control: Cigarette smoking, glutathione-s-transferase M1 and t1 genetic polymorphisms, and breast cancer risk (United States), and Chang-Claude et al. in Cancer Epidemiol Biomarkers: Differential effect of NAT2 on the association between active and passive smoke exposure and breast cancer risk).

    Furthermore, Reynolds et al. (J Natl Cancer Inst (2004): Active Smoking, Household Passive Smoking, and Breast Cancer: Evidence From the California Teachers Study), reporting on the California Teachers Study (CTS) found (1) that irrespective of inclusion of passive smokers in the reference category, the incidence of breast cancer among current smokers was higher than that among never smokers, (2) among active smokers, breast cancer risks were statistically significantly increased, compared with all never smokers, among women (a) who started smoking at a younger age, (b) who began smoking at least 5 years before their first full-term pregnancy, or (c) who had longer duration or greater intensity of smoking, (3) current smoking was associated with increased breast cancer risk relative to all nonsmokers in women without a family history of breast cancer but not among women with such a family history, and (4) breast cancer risks among never smokers reporting household passive smoking exposure were not greater than those among never smokers reporting no such exposure. In sum, therefore, this large prospective analysis found an elevated risk of breast cancer associated with active smoking that increased with smoking intensity and, to a lesser extent, duration.

    Evidencewatch Commentary:
    Passive Smoking and Breast Cancer Risk

    However, the CTS trial would appear to suggest little or no risk from exposure to passive smoking, a conclusion critically questioned by KC. Johnson in his commentary (J Natl Cancer Inst (2004): Re: Active Smoking, Household Passive Smoking, and Breast Cancer: Evidence From the California Teachers Study) on the original paper, who notes correctly the CTS trial does not include degree of exposure or occupational exposure, being based only on a binary evaluation of household passive smoking exposure (yes/no) and the timing of that exposure (childhood, adult, or both), especially problematic given that, as Reynolds et al. themselves concede in their response (J Natl Cancer Inst (2004): RESPONSE: Re: Active Smoking, Household Passive Smoking, and Breast Cancer: Evidence From the California Teachers Study), during the 1980s, the workplace replaced the home as the primary source of passive smoking exposures in this cohort, and in any case, such a conclusion is against the balance of the evidence of high-quality studies (Morabia et al., Am J Epidemiol (1996): Relation of breast cancer with passive and active exposure to tobacco smoke; Johnson et al., Cancer Causes Control (2000): Passive and active smoking and breast cancer risk in Canada, 1994–97); Terry & Rohan, Cancer Epidemiol Biomarkers Prev (2002): Cigarette smoking and the risk of breast cancer in women: a review of the literature; kropp & Chang-Claude, Am. J. Epidemiol (2002): Active and Passive Smoking and Risk of Breast Cancer by Age 50 Years among German Women.

  • Radiation:
    The relationship between exposure to ionizing radiation and the risk of developing breast cancer is by now well-established: increased breast cancer risk is consistently associated with a variety of exposures such as tuberculosis fluoroscopy, dermatologic radiation treatments for acne and tinea, or radiation treatment for Hodgkin’s lymphoma (NCI:
    Breast Cancer (PDQ): Prevention). The risk of breast cancer associated with medical radiology is estimated to be less than 1% of the total, although it may be that certain populations, such as AT (ataxia telangiectasia) heterozygotes (AT is a rare, progressive, neurodegenerative childhood disease), may be at increased risk from typical radiation exposures.

    A natural concern is whether treatment-radiation exposure (radiotherapy), such as that involved when breast cancer patients are treated with lumpectomy and radiation therapy (so-called L-RT, or LRT), may itself place a patient at increased risk for either second breast or other malignancies, as opposed to patients treated by mastectomy alone with radiation. This question was taken up at Yale (Obedian et al, J Clin Oncol:
    Second malignancies after treatment of early-stage breast cancer: lumpectomy and radiation therapy versus mastectomy), however, and with a median follow-up of 15 years, no increased risk of second malignancies was found in patients undergoing L-RT, a finding confirmed in several other RCTs (Fisher et al, N Engl J Med: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer; Veronesi et al., N Engl J Med: Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer; Fisher et al.: N Engl J Med: Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation).

  • Abortion:
    Another issue is whether there is any association between induced abortion and subsequent breast cancer. Recently the Collaborative Group on Hormonal Factors in Breast Cancer (Beral et al., Lancet:
    Breast cancer and abortion: collaborative reanalysis of data from 53 epidemiological studies, including 83,000 women with breast cancer from 16 countries) has taken up this issue, finding that the risk of breast cancer did not differ significantly according to the number or timing of aborted pregnancies. However, researchers at the Breast Cancer Prevention Institute (BCPI: Abortion and Breast Cancer: re: "collaborative reanalysis of data" published in Lancet 3/25/04) have raised some issues of serious methodological flaws in the Beral study suggesting that the study is insufficiently powered to found their conclusions.

    Nonetheless, an Evidencewatch systematic review (summer, 2005) has discovered two methodologically sound studies that convincingly challenge the abortion / breast cancer association: (1) the prospective study of Palmer et al. (Cancer Causes Control (2004):
    A prospective study of induced abortion and breast cancer in African-American women) determined that induced abortion does not increase breast cancer risk in African-American women; and (2) the study of Brewster et al. (J Epidemiol Community Health (2005): Risk of breast cancer after miscarriage or induced abortion: a Scottish record linkage case-control study) has concluded that the data do not support the hypothesis that either miscarriage or induced abortion represents a substantive risk factor for the future development of breast cancer.

    The Issue of Breast Implants :
    A common concern expressed by many women is whether there is any association between breast implants and cancer risk, whether breast or otherwise.
    This issue was address directly by the National Cancer Institute Breast Implant Study (NCI Factsheet: National Cancer Institute Breast Implant Study) initiated in 1992 to explore the on the long-term health effects associated with silicone breast implants, with findings first reported in 2000 in a series of reports. It was determined by Brinton et al. (Cancer Causes & Control (2000): Breast cancer following augmentation mammoplasty (United States)) that there was no association between breast implants and the subsequent risk of breast cancer, nor with any particular type of implant, and no significant difference in breast cancer mortality between the implant and comparison patients. In addition, neither was there any increased risk for cancers of the stomach, large intestine, cervix, uterus, ovary, bladder or thyroid, connective tissue nor immune system cancers (such as soft tissue sarcomas, lymphoma, and multiple myeloma).

    However, the same researchers in another report (Brinton et al., Ann Epidemiol (2000): Cancer Risk at Sites Other than the Breast Following Augmentation Mammoplasty) from the same initiative did find that cancer rates for brain and respiratory cancers were higher in the implant patients compared to other plastic surgery patients, although only the rates of respiratory cancers were statistically significant. And a later report (Brinton et al., Epidemiol (2001): Mortality among Augmentation Mammoplasty Patients) explored the broader issue of mortality in general in breast implant populations, finding a higher overall mortality among the implant patients which reflected increases for respiratory tract and brain cancers, and for suicide. Nonetheless, it is not clear if this is truly causal: the researchers themselves cautiously note that "It is possible that the higher risks observed for respiratory and brain cancers are not related to exposure to silicone, but are due to either chance findings or to factors common to women who choose to have implants" and in addition many of the cancers showing excesses in the study were defined on the basis of death certificates, a foundation that always requires some caution in interpretation.

    But more recent research has shown that the putative association with brain cancer however is neither confirmable nor supportable under later more methodologically sound scrutiny: McLaughlin (Ann Plast Surg (2004): Brain cancer and cosmetic breast implants: a review of the epidemiologic evidence) reviewed the epidemiologic evidence, concluding that the epidemiologic evidence overall failed to support an association between breast implants and brain cancer incidence.

    Similarly, on the balance of the evidence, there is no excess of connective tissue disease (rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus and Sjogren's syndrome) among women with cosmetic silicone breast implants (Lipworth et al, Ann Plast Surg (2004): Silicone Breast Implants and Connective Tissue Disease: An Updated Review of the Epidemiologic Evidence), nor any association with subsequent fibromyalgia (Lipworth et al., Ann Plast Surg (2004): Breast Implants and Fibromyalgia: A Review of the Epidemiologic Evidence).

  • Environmental Factors :
    Evidence of the effect of occupational, environmental, or chemical exposures on breast cancer risk is not to date wholly conclusive. Laden et al. (Int J Cancer:
    Plasma organochlorine levels and the risk of breast cancer: An extended follow-up in the Nurses' Health Study) found no support for the hypothesis that exposure to DDT and PCBs increases the breast cancer risk, and the latest NCI: Breast Cancer (PDQ) concludes that "the possibility that such substances, some of which are known to have weak estrogenic effects, influence breast cancer risk remains unproven".

    Evidencewatch Commentary:
    However, Evidencewatch disagrees with such a clear repudiation as that of the NCI. The recent comprehensive review of Mitra et al. (J Environ Health:
    Breast cancer and environmental risks: where is the link?) has concluded that many environmental factors are significantly associated with breast cancer:
    (1) the evidence is mixed re organochlorine exposure and breast cancer risk;
    (2) dieldrin and lindane are associated with breast cancer risk, atrazine is not; (3) evidence of a link between benzene and breast cancer is inconclusive;
    (4) risk of breast cancer with smoking is strong in families with a history of breast cancer, ovarian cancer, or both;
    (5) there is a positive association of breast cancer with heterocyclic amines in women who eat well-done meat (see our Evidencewatch section on
    Heterocyclic Amines (HCAs) and Cooked Meats).

    In addition Coyle (Breast Cancer Res Treat:
    The effect of environment on breast cancer risk) concluded that "Although, most of the environmental factors discussed in this review have not been convincingly found to influence breast cancer risk, research suggests that environmental exposure in combination with genetic predisposition, age at exposure, and hormonal milieu have a cumulative effect on breast cancer risk", finding, among other things, that (1) passive smoke exposure is associated with increased breast cancer risk, (2) solar radiation is associated with reduced breast cancer risk, supporting the hypothesis that vitamin D is a protective agent in breast cancer reduction. Other studies are also in substantial agreement (see Mitra & Faruque, South Med J: Breast cancer incidence and exposure to environmental chemicals in 82 counties in Mississippi; O'Leary et al., Environ Res: Pesticide exposure and risk of breast cancer: a nested case-control study of residentially stable women living on Long Island;

    Note also the work of Schernhammer and Schulmeister (Photochem Photobiol:
    Light at night and cancer risk) on environmental lighting and breast cancer risk, who concluded that "environmental lighting powerfully suppresses the physiologic release of melatonin, which typically peaks in the middle of the night. This decreased melatonin production has been hypothesized to increase the risk of cancer. Evidence from experimental studies supports a link between melatonin and tumor growth. There is also fairly consistent indirect evidence from observational studies for an association between melatonin suppression, using night work as a surrogate, and breast cancer risk". (On environmental lighting, see also our Evidencewatch discussion of melatonin under the section Radioprotection).

  • SERMS (Selective Estrogen Receptor Modulators):
    The role of SERMs in breast cancer prevention and treatment is examined critically in the separate Evidencewatch Evidence Report Breast Cancer: Treatment.

  • Genetics:
    There is known to be some underlying genetic susceptibility of individuals influencing the carcinogenic process, but this account for only a small proportion of breast cancers (approx. 5%), although research in this arena may help identify high-risk populations who are more likely to need and benefit from preventive intervention.

    The BRCA gene is a tumor suppressor gene, with two types well studied in this connection: BRCA1 and the less common BRCA2, and it is well established that women who inherit a deleterious BRCA1 or BRCA2 mutation have an increased lifetime risk of breast and ovarian cancer (possibly also colon cancer), with several mutations in BRCA1 and BRCA2 observed to occur more frequently among those of Ashkenazi Jewish descent. BRCA2 deleterious mutations are associated with an increased risk of breast cancer in men and possibly prostate cancer, as well as other cancers (for example, pancreatic cancer and lymphoma). Among women with BRCA1 or BRCA2, estimates of lifetime risk of breast cancer vary from 56% to as high as 80% to 85%, with BRCA2 carriers typically exhibiting lower risk than BRCA1, although there are some considerations suggesting that these figures may be overestimates, and present knowledge of other factors influencing when and if a deleterious-mutation carrier develops cancer is still relatively primitive.

    Other genes may also be implicated in inherited breast cancers, among which are:
    (1) the ATM (ataxia-telangiectasia mutation) gene, responsible for repairing damaged DNA; some families with a high rate of breast cancer appear to have an ATM gene mutation;
    (2) the CHEK-2 gene also appears to increase breast cancer risk under mutation;
    (3) the p53 tumor suppressor gene; inherited mutations of this gene can also increase risk of breast cancer development, as well as leukemia, brain cancer, and/or sarcomas (bone or connective tissue cancer);
    (4) the HER2 (human epidermal growth factor receptor 2) oncogene: HER2, a key component in regulating cell growth, represents a protein found on the surface of cells; altered HER2 protein leads to the production of extra HER2 protein receptors (HER2 over-expression), causing increased cell growth and reproduction, which frequently results in more aggressive breast cancer cells (women with HER2 over-expression may not be as responsive to certain standard breast cancer treatments including certain chemotherapy regimens).

    Although the goal is to use such genetic information to identify and target women who may especially benefit from enhanced early detection or from preventive intervention, nonetheless the latest NCI:
    Breast Cancer (PDQ): Prevention guidelines conclude that "at this time, there is little scientific evidence to support or quantify this potential beneficial effect". See also Pichert et al. (Ann Oncol: Evidence-based management options for women at increased breast/ovarian cancer risk).

  • Breast Size:
    Kusano et al. (Epidemiol (2005): A prospective study of breast size and premenopausal breast cancer incidence) found that larger bra cup size at a young age is associated with a higher incidence of premenopausal breast cancer, though this association is limited to leaner women.

  • Prophylactic Mastectomy and Breast Reduction:
    The role of prophylactic mastectomy in breast cancer prevention has been recently and comprehensively examined by Hartman et al (J Clin Oncol:
    Prophylactic mastectomy for BRCA1/2 carriers: progress and more questions) where it is argued that the procedure results in a marked decrease in the risk of breast cancer, although they sensibly conclude that there are many substantive questions remaining. The latest NCI (NCI: Breast Cancer (PDQ)) concludes that "although this study provides the best evidence available to date that prophylactic surgery offers benefits despite the fact that some breast tissue remains following surgery, some factors may bias the estimate of benefit", also the conclusion of Klaren et al. (J Natl Cancer Inst: Potential for bias in studies on efficacy of prophylactic surgery for BRCA1 and BRCA2 mutation), who argue that several potential biases may result in an overestimation of the benefit from such prophylactic surgery. (See also Pichert et al. (Ann Oncol: Evidence-based management options for women at increased breast/ovarian cancer risk)). Clearly, therefore, the option of prophylactic mastectomy must be done in association with mature cancer risk assessment and individual counseling regarding all available preventive options, including tamoxifen and possibly also various aromatase inhibitors (AIs) as a emergent preventive agents.

    An interesting question arises here as to whether a far less radical option than prophylactic mastectomy, breast reduction surgery, would also appreciably reduce risk of breast cancer. This question was taken up by Tarone et al. (Plast Reconstr Surg: Breast reduction surgery and breast cancer risk: does reduction mammaplasty have a role in primary prevention strategies for women at high risk of breast cancer?) who review the literature and conclude that "evidence from these studies is sufficiently strong to warrant the evaluation of breast reduction surgery as an option for primary prevention in clinical studies of women at increased risk of breast cancer".

  • Prophylactic Oophorectomy:
    The studies of Rebbeck et al. (N Engl J Med:
    Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations and Kauff et al. (N Engl J Med: Risk-Reducing Salpingo-oophorectomy in Women with a BRCA1 or BRCA2 Mutation) found that oophorectomy (Salpingo or bilateral) in carriers of BRCA mutations can decrease the risk of breast cancer and BRCA-related gynecologic cancer (coelomic epithelial cancer). However, The latest NCI (NCI: Breast Cancer (PDQ)) soberly observes that "these observational studies, however, are confounded by selection bias, family relationships between patients and controls, indications for oophorectomy, and inadequate information about hormone use" (see also the discussion of Garber and Hartman, J Clin Oncol: Prophylactic Oophorectomy and Hormone Replacement Therapy: Protection at What Price?), Pichert et al. (Ann Oncol: Evidence-based management options for women at increased breast/ovarian cancer risk), and McKelvey & Evans, J. Nutr: Cancer Genetics in Primary Care).

  • Antibiotic Use:
    The study of Dr. Christine Velicer (Department of Epidemiology, University of Washington, Seattle) et al. (JAMA (2004):
    Antibiotic Use in Relation to the Risk of Breast Cancer) suggests that long-term use of antibiotics may increase the risk of breast cancer, although the study was not sufficiently powered to determine whether such antibiotic use is causally related to breast cancer, rather than more narrowly associated with breast cancer; the study found an increase in the incidence of breast cancer associated with cumulative increase in the number of days of antibiotic use, and number of antibiotic prescriptions. Soberly the authors note that the association may be due to whatever might be the indication for antibiotic use, or possibly overall weakened immune function, or still other factors, but legitimately conclude nonetheless that "these findings reinforce the need for prudent long-term use of antibiotics". (See also NCI: Questions and Answers: Study Shows Link Between Antibiotic Use and Increased Risk of Breast Cancer, and NeLH, Hitting the Headlines: Antibiotics linked to risk of breast cancer).

    In the aftermath of the Velcier study (cited above), Kay & Jick (Epidemiol (2005): Antibiotics and the Risk of Breast Cancer) reviewed the UK General Practice Research Database, and concluded that the data do not support the hypothesis that antibiotic use is associated with an increased risk of breast cancer. Rodríguez & González-Pérez (Am J Epidemiol (2005): Use of Antibiotics and Risk of Breast Cancer) then attempted to replicate the Velcier findings, again using General Practice Research Database in the United Kingdom, failing to find a clear association between breast cancer and antibiotic use.

    Breast Cancer Prevention Watch concludes on the basis of systematic review of the literature to date (August 2006) that there is on the balance of the evidence no compelling data to suggest a causal link between antibiotic use and increased breast cancer risk. However we note that it is still possible that there may be be an association that is receptor status dependent: Rossini et al. (Cancer Res (2006): Influence of Antibiotic Treatment on Breast Carcinoma Development in Proto-neu Transgenic Mice) examined the effect of prolonged antibiotic treatments on tumor development in a model of HER-2-neu transgenic mice, finding such prolonged exposure affects the mammary glands in terms of increased tumor growth rate and increased lobulization, but these preclinical findings await further exploration and confirmation.

  • Aspirin, NSAIDs, and Acetaminophen/Paracetamol:
    Aspirin and other NSAIDs may be effective chemoprotective agents for breast cancer, it is speculated due aspirin's inhibition of either prostaglandin synthesis or inhibition of cyclooxygenase or both, which could result in lower concentrations of estrogen and the inhibition of estrogen production in the breast. The most recent study, that of Rodríguez & González-Pérez (Br J Cancer:
    Risk of breast cancer among users of aspirin and other anti-inflammatory drugs) suggests that aspirin at cardioprophylactic doses (75mg) used for one year or longer is associated with a reduced risk of breast cancer, while NSAID use showed no such association, confirming similar findings of several previous studies; however, the effect may be limited only to receptor-positive tumors (see the study led by Mary Beth Terry, Columbia University, NY - Terry et al., JAMA: Association of Frequency and Duration of Aspirin Use and Hormone Receptor Status With Breast Cancer Risk).

    More recently, the study of Cook et al. (JAMA (2005):
    Low-Dose Aspirin in the Primary Prevention of Cancer - The Women’s Health Study: A Randomized Controlled Trial) suggested that low-dose aspirin for an average 10 years of treatment does not lower risk of breast cancers (nor colorectal or other site-specific cancers). However, Breast Cancer Prevention Watch believes that the studies implications are clouded by the uncommon regimen deployed, that of alternate day 100mg aspirin; it would have been interesting to have seen the results of the more typical low-dose daily aspirin regimen, especially as the study of Swede et al. (Oncology (2005): Association of Regular Aspirin Use and Breast Cancer Risk) corroborated the growing body of observational evidence that regular aspirin use may be associated with reduced risk of breast cancer, in finding that both regular (1 tablet per week for 1 year) and occasional use were inversely associated with breast cancer, and that among regular users, an inverse trend was found for number of tablets consumed per week (1, 2-6, or 7) with corresponding better overall survival; finally, daily use spanning 10 or more years was associated with a more pronounced reduction in risk.

    Less noticed and reported, was the finding that acetaminophen / paracetamol at analgesic doses (up to 2000mg) was also associated with significant breast cancer risk reduction. This appears to be in conflict with earlier studies that find no effect for NSAIDs and acetaminophen / paracetamol, so additional studies are needed to clarify their role. Again, only an association, not a causal relationship, has been demonstrated for aspirin consumption (the greatest risk reduction was for a regimen of once-daily use or greater per week) and risk reduction of breast cancer, although the findings of aspirin's benefit in in other cancers like colorectal cancer is strongly suggestive, in the cumulative, of a chemopreventive activity.

    Coxibs (COX-2 Inhibitors)
    Coxibs (COX-2 Inhibitors), such as rofecoxib (Vioxx), celecoxib (Celebrex), and valdecoxib (Bextra), selectively inhibit pro-inflammatory cyclooxygenase (COX)-2, and unlike traditional NSAIDs (non-steroidal anti-inflammatory drugs), most coxibs do not significantly inhibit COX-1, suggesting a potential less toxicity to the gastrointestinal tract, but due to several postulated mechanisms, in many, but not all, clinical studies, the coxibs became associated with higher risks of myocardial infarction (MI) and stroke (E. Fosslein, Ann Clin Lab Sci (2005): Cardiovascular complications of non-steroidal anti-inflammatory drugs), leading to the removal of two of the three coxibs, rofecoxib (Vioxx) and valdecoxib (Bextra) from US and European markets; note, however, as we observe below, there are clinically significant intra-class differences among the coxibs.

    An earlier insight connecting the Coxibs with oncotherapy and potential chemoprevention was that cyclooxygenase-2 (COX-2) is overexpressed in several epithelial tumors, including breast cancer, and COX-2-positive tumors tend to be larger, higher grade, node-positive and HER-2/neu-positive, yielding the association of high COX-2 expression with poor prognosis and directly suggesting COX-2 inhibition as a pathway to tumor reduction, probably consequent to increased apoptosis, reduced angiogenesis and/or proliferation (Bundred & Barnes, Br J Cancer (2005): Potential use of COX-2-aromatase inhibitor combinations in breast cancer). This study found evidence to suggest that combining Coxibs with AIs (aromatase inhibitors), growth factor receptor blockers, or chemo- or radiotherapy may be particularly effective. They cite preliminary results from combination therapy with celecoxib (Celebrex) and exemestane (Aromasin) in postmenopausal women with advanced breast cancer yielding increased the time to recurrence. Given, as they note, that up to 80% of DCISs (ductal carcinomas in situ) express COX-2, COX-2 inhibition may be of particular use in the DCIS setting, and that furthermore, as COX-2 expression correlates strongly with expression of HER-2/neu, the combination of aromatase inhibitors and coxibs may be particularly useful in both DCIS and invasive cancer, especially in patients with HER-2/neu-positive tumors (see also Chow et al., Biomed Pharmacother (2005): Current directions for COX-2 inhibition in breast cancer). This was further confirmed by Chow et al. (med Pharmacother (2005):
    Study of COX-2, Ki67, and p53 expression to predict effectiveness of 5-flurouracil, epirubicin and cyclophosphamide with celecoxib treatment in breast cancer patients) who demonstrated the efficacy of a preoperative FECC regimen (5-fluorouracil, epirubicin, and cyclophosphamide, with celecoxib in breast invasive ductal carcinomas.

    The same authors (Chow et al., Biomed Pharmacother (2005):
    Serum lipid profiles in patients receiving endocrine treatment for breast cancer—the results from the Celecoxib Anti-Aromatase Neoadjuvant (CAAN) Trial) in the CAAN trial performed a proof of principle study to investigate the efficacy and side effects including changes in lipid profiles of an Coxib+AI regimen combining anti-aromatase therapy and COX-2 inhibitor (exemestane (Aromasin) 25 mg daily and celecoxib (Celebrex) 400 mg twice-daily) preoperatively in hormone sensitive postmenopausal breast cancers, finding that after 18 weeks of treatment cholesterol levels for patients on Coxib+AI dropped progressively, with significantly lowered cholesterol and LDL levels compared to patients on exemestane or letrozole (Femara) alone, suggesting that combination of AIs with celecoxib may have a beneficial effects on the serum lipid profiles. And the Ohio State University Comprehensive Cancer Center is also conducting a clinical trial of this Coxib+AI combination (Clinical Trials: Exemestane With Celecoxib as Neoadjuvant Treatment in Postmenopausal Women With Stage II, III, and IV Breast Cancer), and the same combination is also being investigated in an NCI-sponsored trial (Clinical Trials: Exemestane and Celecoxib in Postmenopausal Women at High Risk for Breast Cancer), while another open-label, multicenter study is examining the benefit of celecoxib (Celebrex) in ER-negative populations (Clinical Trials: Phase II Chemoprevention Study of Celecoxib in Premenopausal Women at High Risk For Estrogen Receptor-Negative Breast Cancer).

    The first results from these Coxib+AI studies was recently (June 20 2006) reported by the French researchers G. Freyer et al. from the Oncology Service of Cedntre Hospitalier Lyon Sud, at the Annual ASCO meeting (ASCO Annual Meeting Proceedings (Post-Meeting Edition) Abstract 565), J Clin Oncol (2006): Celecoxib (Ce) + exemestane (Ex) versus placebo + Ex in post-menopausal (PM) metastatic breast cancer (MBC) patients (pts): A double-blind phase III GINECO study) who noted from their RCT that previous in vitro and in vivo studies suggest that COX-2 inhibitors not only demonstrate antitumor activity but may enhance the activity of aromatase inhibitors (AIs), and on this foundation examined celecoxib (400 mg bid) + exemestane (Aromasin) (25mg/d) compared to exemestane alone, finding that overall response rate was significantly higher (35% versus 20%) with the Ce (celecoxib ) + Ex (exemestane) regimen, with PFS significantly longer PFS (progression free survival) in the subgroup of patients who developed MBC (metastatic breast cancer) under tamoxifen or within 12 months after its termination; in terms of adverse events, the CE + Ex patients was better tolerated, and experienced less pain, arthralgias, asthenia, and grade 1–3 insomnia, but more hypersensitivity reactions and edema, although promisingly no increase in gastrointestinal toxicity was experienced. The 66 subjects were all menopausal hormone-responsive (ER+ and/or PR+) patients with metastatic breast cancer (MBC) and measurable lesions. The trial was prematurely stopped in December 2004 in the wake of of other trials reporting celecoxib cardiovascular toxicity; however, no cardiac toxicity was observed in this trial (except a single case of arrhythmia in a patient with arrhythmia history).

    This benefit appears to be consequent to the fact that COX-2 overexpression in breast cancer activates prostaglandin E2 (PGE2) activity, which then induces a cascade of processes: the aromatase gene promoter, immunosuppression, EGFR activation, inhibition of apoptosis, and secretion of angiogenic factor, processes all known to be involved in breast tumor development, and we may conclude that both the aromatase inhibitors, including exemestane, and celecoxib (Celebrex), share a common target, the aromatase enzyme.

    Coxibs and Cardiovascular Risk
    Although the cardiovascular risk associated with rofecoxib (Vioxx) and valdecoxib (Bextra) are by now well established, some studies, notably the APC (Adenoma Prevention with Celecoxib) study (Solomon et al., N Engl J Med (2005): Cardiovascular Risk Associated with Celecoxib in a Clinical Trial for Colorectal Adenoma Prevention) have suggested that this may also be true for celecoxib (Celebrex). However this has been challenged (in the same issue, JM Brophy, N Eng J Med (2003): Cardiovascular Risk Associated with Celecoxib) and appears on the balance of the evidence to be in error (but see also the editorials of Juni et al., BMJ (2005): COX 2 inhibitors, traditional NSAIDs, and the heart; Dieppe et al., BMJ (2005): Lessons from the withdrawal of rofecoxib, and the observational study of Hippisley-Cox & Coupland (2005): Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis). JM Brophy systematically reviewed (Expert Opin Drug Saf (2005): Celecoxib and cardiovascular risks) the evidence surrounding COX-2 inhibitors and cardiovascular risk, finding that although the evidence suggests a fairly consistent cardiovascular risk with rofecoxib (Vioxx), the evidence for cardiovascular risk with celecoxib (Celebrex) is more equivocal, and although isolated studies have suggested some cardiovascular risk for celecoxib, the totality of the evidence suggests that any risk is likely to be small and comparable to traditional NSAIDs. Indeed, the cardiovascular risk of celecoxib may actually be less than NSAIDs: in a retrospective cohort study, Hudson et al. (BMJ (2005): Differences in outcomes of patients with congestive heart failure prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs: population based study) found that the combined risk of death and recurrent congestive heart failure was higher in patients prescribed NSAIDs or rofexocib (Vioxx) than in those prescribed celecoxib (Celebrex), so that celecoxib currently seems to be the safest choice for treating elderly patients with congestive heart failure. See also the review on coxibs and cardiovascular risk by Antman et al. (Circulation (2005): Cyclooxygenase Inhibition and Cardiovascular Risk).

    The risk of cardiovascular complications during long-term coxib therapy can be reduced with concurrent low-dose aspirin supplementation (E. Fosslein, Ann Clin Lab Sci (2005): Cardiovascular complications of non-steroidal anti-inflammatory drugs).

    [new] Breast Cancer Prevention Watch:
    COX-2 Inhitory Breast Cancer Chemoprevention

    In sum, the positive findings cited above, coupled with the fact as concluded in their recent review by Randall Harris and colleagues (BMC Cancer (2006): Reduction in the risk of human breast cancer by selective cyclooxygenase-2 (COX-2) inhibitors) from the Ohio State University College of Medicine and Public Health that even in the short window of exposure to these compounds, the selective COX-2 inhibitors produced a significant (71%) reduction in the risk of breast cancer suggests a high potential for their deployment in the chemoprevention of breast cancer when any potential cardiovascular concerns are recognized, monitored and addressed.

    NSAIDs (nonsteroidal anti-inflammatory drugs) such as ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn), and indomethacin (Indocin), among many others, also appear to have some beneficial activity in breast cancer: Rahme et al. (BMC Cancer (2005): Association between frequent use of nonsteroidal anti-inflammatory drugs and breast cancer) found that women who use NSAIDs, or doses of aspirin > 100 mg, frequently may have a lower risk of breast cancer; it is important to note they a corollary of these findings is that use of aspirin at doses <= 100 mg/day did not have any association with breast cancer. Also Zhang et al. (Am J Epidemiol (2005): Use of nonsteroidal antiinflammatory drugs and risk of breast cancer: the Case-Control Surveillance Study revisited) found that long-term regular use of NSAIDs was associated with decreased risk of breast cancer, and this was independent of the type of NSAID used or the hormone receptor status of the tumor.

    Antiperspirant/Deodorant Use
    On the one hand, McGrath (Eur J Cancer Prev (2003): An earlier age of breast cancer diagnosis related to more frequent use of antiperspirants/deodorants and underarm shaving [pdf]) found the age of breast cancer diagnosis was significantly lower in women who used these products and shaved their underarms more frequently, and that in addition, women who began both of these underarm hygiene habits before 16, were diagnosed with breast cancer at an earlier age than those who began these habits later. Although raising suspicion, a small retrospective study such as this, the researchers admit, cannot conclusively link a woman’s underarm habits to breast cancer. On the other hand, Mirick (J Natl Cancer Inst (2002): Antiperspirant Use and the Risk of Breast Cancer) found on the basis of epidemiologic evidence that the risk for breast cancer did not increase with any of the following activities: 1) antiperspirant or deodorant use; 2) product use among subjects who shaved with a blade razor; or 3) application of products (antiperspirant or deodorant) within 1 hour of shaving. See also the NCI Factsheet (updated: 10/04/2004): Antiperspirants/Deodorants and Breast Cancer: Questions and Answers commentary on the issue and these two contradictory studies. The suspicion of an association in part hinges on the fact that aluminum, a component common in antiperspirants and deodorants, is known to have a genotoxic profile, capable of causing both DNA alterations and epigenetic effects, consistent with a potential role in breast cancer if such effects occurred in breast cells (Dabre, J Inorg Biochem (2005): Aluminium, antiperspirants and breast cancer); this study of Dabre's demonstrated that aluminum in the form of aluminum chloride or aluminum chlorhydrate is a metalloestrogen, that is, can interfere with the function of oestrogen receptors of MCF7 human breast cancer cells, leaving open the question of degree of dermal absorption in the local area of the breast and whether long term low level absorption could play a significant role in breast cancer.

    In conclusion, our systematic review of the literature has failed to uncover any conclusive evidence linking the use of underarm antiperspirants or deodorants and the development of breast cancer, but further research is nonetheless required to be dispositive of the issue given contradictory findings.

  • Melatonin

    Melatonin Radio/Chemo-Protection

    Melatonin (at levels of 20mg/daily) may be a radioprotector agent, protecting against the harm of radiation and radiotherpy (see Weiss and Landauer, Toxicology (2003):
    Protection against ionizing radiation by antioxidant nutrients and phytochemicals; also Blask et al., Curr Top Med Chem (2002): Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy); see also Karslioglu et al. (J Radiat Res (Tokyo) (2005): Radioprotective effects of melatonin on radiation-induced cataract) who conclude that "supplementing cancer patients with adjuvant therapy of melatonin may reduce patients suffering from toxic therapeutic regimens such as chemotherapy and/or radiotherapy and may provide an alleviation of the symptoms due to radiation-induced organ injuries").

    Note that other natural agents appear to have a similar chemoprotective activity: a recent study by Branda et al. (Cancer (2005):
    Effect of vitamin B12, folate, and dietary supplements on breast carcinoma chemotherapy-induced mucositis and neutropenia) determined that the neutrophil count decrease consequent to chemotherapy was ameliorated by dietary supplementation with a multivitamin or vitamin E (but this neutrophil decrease was actually exacerbated by high serum folate levels).

    These findings are cross-validated in the review of Vijayalaxmi et al. (Int J Radiat Oncol Biol Phys (2004): Melatonin as a radioprotective agent: a review) where it was found that melatonin administration, either alone or in combination with traditional radiotherapy, results in a favorable efficacy:toxicity ratio during the treatment of human cancers.

    Melatonin Antitumor Activity
    Taking the protective role for melatonin further, Kim et al. (J Cardiovasc Pharmacol (2005):
    Modulation by Melatonin of the Cardiotoxic and Antitumor Activities of Adriamycin) have shown that given melatonin's oncolytic activity, the combination of adriamycin and melatonin improved the antitumor activity of adriamycin, as indicated by an increase in the number of long-term survivors as well as decreases in body-weight losses resulting from adriamycin treatment, suggesting that melatonin not only protects against adriamycin-induced cardiotoxicity but also enhances its antitumor activity and further suggesting that a melatonin and adriamycin combination represents a potentially useful regimen for the treatment of human neoplasms, by virtue of the fact that it allows the use of lower doses of adriamycin, thereby avoiding the toxic side effects associated with this drug.

    Furthermore, the research findings of Cos et al. J Pineal Res (2005):
    Melatonin modulates aromatase activity in MCF-7 human breast cancer cells) have demonstrated that melatonin, at physiological concentrations, decreases aromatase activity and expression in MCF-7 cells, and that this aromatase inhibitory effect of melatonin, together with its already known antiestrogenic properties interacting with the estrogen-receptor,strongly suggests a role in the prevention and treatment of hormone-dependent mammary neoplasias; see also the study of COs et al. (Int J Cancer (2005): Melatonin inhibits the growth of DMBA-induced mammary tumors by decreasing the local biosynthesis of estrogens through the modulation of aromatase activity), which investigated the in vivo aromatase-inhibitory properties of melatonin, noting that melatonin inhibits the growth of breast cancer cells by interacting with estrogen-responsive pathways, thus behaving as an antiestrogenic hormone, and concluding from their in vivo study that melatonin could exert its antitumoral effects on hormone-dependent mammary tumors by inhibiting the aromatase activity of the tumoral tissue, and phase II studies report an increase of objective responses in cancer patients using melatonin. Partially on the basis of this and related findings, Abrial et al. (Pathol Biol (Paris) (2005): Potentiel thérapeutique de la mélatonine dans la prise en charge de la pathologie cancéreuse [Therapeutic potential of melatonin in cancer treatment]) initiated a phase II randomised study of melatonin versus placebo in metastatic breast cancer patients after two lines of treatment. And Y. Touitou (Bull Acad Natl Med (2005): Melatonin: what for?) concluded that melatonin has both strong antioxidant properties - stronger than those of vitamin E - and oncostatic action. Furthermore, according to the research of Martinez-Campa et al. (Breast Cancer Res Treat (2005): Melatonin enhances the inhibitory effect of aminoglutethimide on aromatase activity in MCF-7 human breast cancer cells), melatonin may be a novel means to increase the efficacy of competitive aromatase inhibitors used in treating breast cancer.

    Melatonin as a SERM, Aromatase Inhibitor, and Anti-Estrogen
    Melatonin demonstrates an an oncostatic role on hormone-dependent mammary tumors, interacting with estrogen-signaling pathways via three antiestrogenic mechanisms:
    (1) acting through the estrogen receptor to interfere with the effects of endogenous estrogens (in keeping with selective estrogen receptor modulator (SERM) activity); and
    (2) interfering with estrogen synthesis by inhibiting the enzymes that control the interconversion from their androgenic precursors (in keeping with anti-aromatase / inhibitory activity);. and
    (3) decreasing circulating levels of estradiol (anti-estrogen activity)
    (on these melatonin mechanism, see the review of Sánchez-Barceló and colleagues (J Pineal Res (2005): Melatonin–estrogen interactions in breast cancer) who conclude that melatonin fulfills all the requirements to be considered as a true antiestrogenic agent. This is reinforced by the findings of Cos et al. (Cancer Detect Prev (2006): Estrogen-signaling pathway: A link between breast cancer and melatonin oncostatic actions) who conclude that "melatonin's direct effect on mammary tumor cells is that it interferes with the activation of the estrogen receptor, thus behaving as a selective estrogen receptor modulator", and citing the multiple activities on distinct endocrine pathways, adds "It is these action mechanisms that collectively make melatonin an interesting anticancer drug in the prevention and treatment of estrogen-dependent tumors, since it has the advantage of acting at different levels of the estrogen-signaling pathways".

    The antiestrogen activity of melatonin is further documented in the discussion of "Melatonin as an oncostatic substance" in Pandi-Perumal et al.'s review (FEBS (2006): Melatonin: Nature's most versatile biological signal?) who observe that (1) melatonin exhibits a growth inhibitory effect in estrogen-positive, MCF human breast cancer cell lines, (2) melatonin inhibits the growth of estrogen-responsive breast cancer by modulating the cell's estrogen signaling pathway, and (3) can exert its action on cell growth by modulation of estradiol receptor transcriptional activity in breast cancer cells.

    For further clarification of the complex and multiple pathways melatonin exerts activity over, see Bartsch & Bartsch,
    Pineal Gland and Cancer–An Epigenetic Approach to the Control of Malignancy: Evaluation of the Role of Melatonin (Chapter 7 in Pandi-Perumal & Cardinali (Ed.), Melatonin: Biological Basis of its Function in Health and Disease (Landes Bioscience (2005)) who observe that fresh tumors are“sensed” by the pineal gland via neuroimmunoendocrine changes, leading to a stimulation of melatonin secretion which in turn activates endogenous defense processes, and they further document the mobilization of endogenous defense mechanisms against malignant processes by melatonin, thus improving survival, suggesting that melatonin via indirect systemic mechanisms is able to favorable affect even advanced forms of malignancy, although a caution is that melatonin also exerts stimulatory effects on the hematopoietic system, thus potential aggravating a bone marrow cancer like leukemia.

    Circadian Disruption and Breast Cancer
    A new hypothesis has been postulated about the relation of melatonin, light at night, and breast cancer, known as circadian disruption. Thus there appears to be an inverse association between sleep duration and breast cancer risk, possibly due to greater overall melatonin production in longer sleepers, according to a recent population-based study (Verkasalo et al., Cancer Res (2005): Sleep Duration and Breast Cancer: A Prospective Cohort Study), and this is consonant with the recent findings of Blask et al. (Endocrine (2005): Putting cancer to sleep at night: the neuroendocrine/circadian melatonin signal) who found in their animal study that nocturnal dietary supplementation with melatonin, at levels contained in a melatonin-rich diet inhibits tumorogenesis, possibly by multiple activities: via inhibition of cell proliferation, a stimulation of differentiation and apoptosis, and melatonin-induced suppression of tumor linoleic acid (LA) uptake (note that light during darkness suppresses nocturnal melatonin production and stimulates the LA metabolism and growth of human breast cancer). These findings are the first demonstrating that tumor growth response to exposure to light-during-darkness is (1) intensity dependent and (2) that the human nocturnal circadian melatonin signal both inhibits human breast cancer growth, but also is an effect nullified by short-term ocular exposure to bright white light at night.

    And cross-confirmation exists from the animal research of Saez et al. (Mol Cell Biochem (2005): Melatonin increases the survival time of animals with untreated mammary tumours: neuroendocrine stabilization) who found that strongly suggest that melatonin per se is beneficial during advanced breast cancer, by increasing survival time, perhaps by improving the homeostatic and neuroendocrine equilibrium which is imbalanced during advanced breast cancer. And light and lighting during typical periods of darkness, as at night, of sufficient intensity can disrupt circadian rhythms, including reduction of circulating melatonin levels and resetting of the circadian pacemaker, and this reduced melatonin may increase breast cancer risk through several mechanisms, including increased estrogen production and altered estrogen receptor function (RG Stevens, Epidemiology (2005): Circadian Disruption and Breast Cancer: From Melatonin to Clock Genes). See also Mahmoud et al. (Am J Hosp Palliat Care (2005): The therapeutic application of melatonin in supportive care and palliative medicine) who concluded that circadian disruption is linked to increased cancer risk, and that the chronobiotic capacity of melatonin to reset circadian clocks may provide a verifiable strategy to reduce cancer risk and enhance quality of life by diminishing cancer-induced circadian disruption.

    And related to this, it appears that although shorter sleep duration (< 7 hours nightly) is not associated with breast cancer risk reduction, it was the case that increasing sleep duration (9 or more hours nightly) is modestly associated with an increased breast cancer risk (McElroy et al., J Sleep Res (2006): Duration of sleep and breast cancer risk in a large population-based case–control study), a finding the may hinge on melatonin and cortisol activity.

    And in addition, melatonin has the potential therapeutic value to enhance immune function in aged individuals and in patients in an immunocompromised state such as cancer disease and the immunocompromised state induced by various oncotherapies (including chemotherapy, endocrine/hormonal therapy, biological therapy and radiotherapy (Srinivasan et al., Immune Ageing (2005): Melatonin, immune function and aging).

    And the recent systematic review of randomized controlled trials and meta analysis reported the efficacy of melatonin in solid tumor cancer patient (Mills et al., J Pineal Res (21005): Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis), with the presence of melatonin prolonging both disease progression-free and overall 1-year survival in many randomized controlled trials (Indian J Med Sci (2006): Melatonin in pathogenesis and therapy of cancer). See also Paula Witt-Enderby and her colleagues at Duquesne University (J Pineal Res (2006): Therapeutic treatments potentially mediated by melatonin receptors: potential clinical uses in the prevention of osteoporosis, cancer and as an adjuvant therapy).

    Night-shift Breast Cancer
    These findings are in keeping with what is known about so-called night-shift breast cancer phenomenon: an increased risk of breast cancer is seen among subjects not sleeping during the period of the night when nocturnal melatonin levels are typically at their highest, and hence with graveyard shiftwork, with even some indication of an increased risk among subjects with the brightest bedrooms (Davis et al, J Natl Cancer Inst:
    Night Shift Work, Light at Night, and Risk of Breast Cancer, where it was concluded that "to the extent that graveyard shiftwork and nonpeak sleep reflect exposure to light at night, the results of this study add to a growing body of evidence that such exposure, for whatever reason, may be linked to breast cancer risk", speculated to be due to the fact that light at night exposure reduces nocturnal melatonin levels, which can result in increased circulating estradiol concentrations in the blood). (See also Schernhammer et al, J Natl Cancer Inst: Rotating Night Shifts and Risk of Breast Cancer in Women Participating in the Nurses' Health Study and Schernhammer et al, Cancer Epidemiol Biomarkers Prev: Epidemiology of urinary melatonin in women and its relation to other hormones and night work).

    Evidencewatch Commentary
    Although a recent study (Travis et al, J Natl Cancer Inst:
    Melatonin and Breast Cancer: A Prospective Study) found no evidence that the level of melatonin is strongly associated with the risk for breast cancer, this study measured the level of 24-hour melatonin excretion despite the fact, as pointed out by Hrushesky & Black (J Natl Cancer Inst (2004): Re: Melatonin and Breast Cancer: A Prospective Study) in their commentary that differences in the nocturnal duration of melatonin secretion and thus its distribution across the night cannot be accounted for by measuring 24-hour excretion levels, and it may be necessary to examine whether instead cancer risk is conferred not by average 24-hour melatonin exposure, but by the circadian temporal organization of melatonin availability. Hrushesky & Black also correctly point out that in those studies which have evidenced a relationship between cancer risk and melatonin excretion, have discovered the relationship based on circadian amplitude or phase (time of melatonin upswing), not on the 24-hour average amount of melatonin metabolite excreted.

    Nor did the Travis study (above) control for the potentially confounding factor of the relative nighttime light exposure of case patients and control subjects, given the well-established fact light exposure and especially nocturnal light exposure may confer cancer risk through modulation of the melatonin circadian pattern: see Schernhammer & Hankinson (J Natl Cancer Inst (2005):
    Urinary Melatonin Levels and Breast Cancer Risk) who used a prospective case–control study nested within the Nurses' Health Study II cohort, finding the prospective data supporting the hypothesis that higher melatonin levels are associated with a lower risk of breast cancer; also Schernhammer et al. (Cancer Epidemiol Biomarkers Prev (2004): Epidemiology of Urinary Melatonin in Women and Its Relation to Other Hormones and Night Work) who also concluded that women working on rotating night shifts appear to experience changes in hormone levels, as measured by urinary melatonin, that may be associated with the increased cancer risk observed among night-shift workers; and similar findings have emerged with respect to colorectal cancer (see Schernhammer et al., J Natl Cancer Inst (2003): Night-Shift Work and Risk of Colorectal Cancer in the Nurses’ Health Study who found that working a rotating night shift at least three nights per month for 15 or more years may increase the risk of colorectal cancer in women. (Although the exact mechanisms involved in noctural light, decreased melatonin levels, and increased cancer risk are still being study, the molecular mechanisms are beginning to be defined: the recent animal research of Flipski et al. (J Natl Cancer Inst (2005): Effects of Light and Food Schedules on Liver and Tumor Molecular Clocks in Mice) has found that altered light-dark modifies the expression of molecular clock genes and genes involved in carcinogenesis and tumor progression).

    In addition, Megdal et al. (Eur J Cancer (205):
    Night work and breast cancer risk: A systematic review and meta-analysis) conducted a systematic review and meta-analysis of 13 qualifying observational studies between January 1960 to January 2005 in order to assess the effects of night work on breast cancer risk, concluding that the studies to date collectively show an increased breast cancer risk among women, with publication bias unlikely to have influenced the results.

    In conclusion, therefore, Evidencewatch finds that numerous systematic reviews and meta-analyses, and their underlying research, provide in the balance compelling evidence of an increased risk of breast cancer consequent to night shift work and its known adverse impact on melatonin production.

    Radiation-induced Dermatitis: Calendula:
    Numerous agents have been proposed and tested for both symptomatic care of radiation-induced dermatitis and for potential protective activity against induced skin toxicities. The efficacy of aloe vera gel, a therapy commonly used to prevent radiation-induced dermatitis and related skin toxicity, has been rigorously evaluated in RCTs. Williams et al (Int J Radiat Oncol Biol Phys (1996): Phase III double-blind evaluation of an aloe vera gel as a prophylactic agent for radiation-induced skin toxicity) compared skin toxicity between those receiving aloe vera gel and a control group, finding that aloe vera exhibited no protective effect for those receiving breast irradiation.

    The FDA-approved preparation Biafine (Medix Pharmaceuticals) is a wound-healing product from France and has been marketed with claims to reduce radiation-related skin toxicity, via its capacity to recruit macrophages to epidermal wounds and promote granulation tissue formation. However, Fisher et al. (Int J Radiat Oncol Biol Phys (2000): Randomized phase III study comparing best supportive care to biafine as a prophylactic agent for radiation-induced skin toxicity for women undergoing breast irradiation: Radiation therapy oncology group (RTOG) 97-13) compared Biafine with best supportive care, which consisted of Aquaphor and aloe vera, in an RCT of women receiving breast irradiation, finding no statistical difference in skin toxicity between those receiving Biafine and those treated with best supportive care.

    Topical steroids are commonly used to treat radiation-induced skin inflammation and dermatitis, having been shown to inhibit the upregulation of the proinflammatory cytokine IL-6 in response to ionizing radiation. One RCT tested the efficacy of the corticosteroid cream mometasone furoate (MMF) as a prophylactic and therapeutic intervention, finding that prophylactic application of MMF combined with an emollient cream significantly decreased acute radiation dermatitis compared with emollient cream alone (as reported in NBCC (National Breast Cancer Centre) (2004): Skin Care during Radiotherapy for Breast Cancer: A summary of Key Research Findings [pdf]).

    Thus, the effectiveness of many nonsteroid topical agents for the prevention of acute dermatitis during adjuvant radiotherapy for breast carcinoma has not been demonstrated. An exception is the natural agent, calendula cream: Pommier et al. (J Clin Oncol:
    Phase III Randomized Trial of Calendula Officinalis Compared With Trolamine for the Prevention of Acute Dermatitis During Irradiation for Breast Cancer) compared the effectiveness of calendula with that of trolamine, which is considered in many institutions to be the reference topical agent. Calendula was found to be highly effective for the prevention of acute dermatitis of grade 2 or higher and may be proposed for patients undergoing postoperative irradiation for breast cancer.

    Finally the NBCC review cited above found that moisturizers containing sucralfate or hyaluronic acid were superior to those not containing one of those active ingredients, in reducing the severity of skin lesions and promoting healing of dry desquamation.

  • Endocrine Therapy: Tamoxifen, Raloxifene, and AIs
    Chemoprevention of breast cancer essentially refers to interventions for breast cancer risk reduction especially in individuals at high risk, not to true prevention. Until recently, the most widely studied chemopreventive class has been SERMs (selective estrogen receptor modulators) which includes tamoxifen (Nolvaldex) and raloxifene (Evista).

    RCTs comparing the SERMs, either tamoxifen or raloxifene, with placebo for reducing the risk of breast cancer: Fisher et al. (J Natl Cancer Inst (1998): Tamoxifen for Prevention of Breast Cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study); .

    When considered together, the tamoxifen prevention trials showed a 38% (95% CI 28-46; p<0.0001) reduction in breast-cancer incidence. There was no effect for breast cancers negative for estrogen receptor (ER; hazard ratio 1.22 [0.89-1.67]; p=0.21), but ER-positive cancers were decreased by 48% (36-58; p<0.0001) in the tamoxifen prevention trials. Age had no apparent effect. Rates of endometrial cancer were increased in all tamoxifen prevention trials (consensus relative risk 2.4 [1.5-4.0]; p=0.0005) and the adjuvant trials (relative risk 3.4 [1.8-6.4]; p=0.0002). Venous thromboembolic events were increased in all tamoxifen studies (relative risk 1.9 [1.4-2.6] in the prevention trials; p<0.0001). The evidence shows, therefore, that tamoxifen can reduce the risk of ER-positive breast cancer. It is clear from the completed trials that identification of a subgroup of high-risk, healthy women for whom the risk-benefit ratio is sufficiently positive is possible.


Prevention: Lifestyle and CAM Interventions

  • Exercise:
    Active exercise may reduce breast cancer risk particularly in young parous women. There are numerous observational studies that have examined the relationship between physical activity and breast cancer risk. Most of these studies have shown an inverse relationship between level of physical activity and breast cancer incidence. The average relative risk reduction is reportedly 30% to 40% (Thune et al., N Engl J Med:
    Physical activity and the risk of breast cancer; see also McTiernan et al., JAMA: Recreational physical activity and the risk of breast cancer in postmenopausal women. The women's health initiative cohort study), and Bernstein et al. (J Natl Cancer Inst (2005): Lifetime Recreational Exercise Activity and Breast Cancer Risk Among Black Women and White Women) who found an inverse association between physical activity and breast cancer among black women and among white women,

    Note that the McTiernan study provides the additional evidence:
    (1) that both current exercise and exercise engaged in after menopause are associated with a decreased risk of breast cancer,
    (2) that the effects appear to be induced even with a relatively small amounts of exercise (1.25–2.5 hours per week of brisk walking),
    (3) that the reduction in risk associated with exercise was seen among both women on HRT and those not on HRT. (See also the synopsis of Pritchard, in CMAJ:
    Is exercise effective in reducing the risk of breast cancer in postmenopausal women?).

    And a recent prospective observational study (Holmes et al., JAMA (2005): Physical Activity and Survival After Breast Cancer Diagnosis) concluded that physical activity after a breast cancer diagnosis may improve survival, with the greatest benefit in women who performed the equivalent of walking 3 to 5 hours per week at an average pace (absolute unadjusted mortality risk reduction was 6% at 10 years). See also Knols et al. (J Clin Oncol (2005): Physical Exercise in Cancer Patients During and After Medical Treatment: A Systematic Review of Randomized and Controlled Clinical Trials).

    However, it is not known if or to what degree the observed association is due to confounding variables, such as diet or a genetic predisposition to breast cancer, although the weight of the evidence appears to suggests that greater physical activity is associated with lower serum concentrations of estradiol, estrone, and androgens in postmenopausal women (see the review of this and other breast cancer protective factors by McTiernan, Oncologist:
    Behavioral Risk Factors in Breast Cancer: Can Risk Be Modified?). In this connection, Malin et al. (Cancer Epidemiol Biomarkers Prev (2005): Energy Balance and Breast Cancer Risk) found that that promotion of behavior patterns that optimize energy balance (weight control and increasing physical activity) may be a viable option for breast cancer prevention. See also the recent comprehensive review of Lawrence Kushi and colleagues (Kishi et al., J Nutr (2007): Lifestyle Factors and Survival in Women with Breast Cancer).

    [new] Independent of this however, it would appear that a combination of physical activity (as endurance training) couple with low intake of both low calorie and low protein dietary intake is associated with low plasma growth factors and hormones linked to increased risk of cancer, and low protein intake in particular may have the additional protective effect as it is associated with a decrease in the adverse factor of circulating IGF-I (and of the concentration ratio of IGF-I to IGF binding protein 3), independent of body fat mass (Am J Clin Nutr (2006): Long-term low-protein, low-calorie diet and endurance exercise modulate metabolic factors associated with cancer risk).

  • Obesity/Weight:
    Over a hundred studies have examined the associations between weight or BMI and incidence of breast cancer. Obesity is associated with increased breast cancer risk, especially among postmenopausal women who do not use HRT/hormone therapy. The Women’s Health Initiative Observational Study found that among women who never used hormone replacement therapy or hormone therapy, increased breast cancer risk was associated with weight as the strongest predictor, with a relative risk (RR) of 2.85 for women weighing more than 82.2 kg (180.8 lbs), compared with those weighing less than 58.7 kg (129.1 lbs). (See Morimoto et al. in Cancer Causes Control:
    Obesity, body size, and risk of postmenopausal breast cancer: the Women's Health Initiative). See also Dignam et al. (J Nat Cancer Inst (2003): Obesity, Tamoxifen Use, and Outcomes in Women With Estrogen Receptor–Positive Early-Stage Breast Cancer) and Berclaz et al. (Ann Oncol (2004): Body mass index as a prognostic feature in operable breast cancer: the International Breast Cancer Study Group experience), where jointly it was found that although obesity had no significant effect on recurrence risk or on tamoxifen efficacy, overall mortality was significantly greater for obese breast cancer patients compared with those of normal weight (Jain et al., J Natl Cancer Inst (1994): Premorbid diet and the prognosis of women with breast cancer; McTiernan et al., JAMA (2003): Recreational Physical Activity and the Risk of Breast Cancer in Postmenopausal Women: The Women's Health Initiative Cohort Study; also Enger et al. (Arch Sug (2004): Body Weight Correlates With Mortality in Early-Stage Breast Cancer) who found that body weight at diagnosis and ER status are important predictors of breast cancer death in early-stage disease. This is in essential agreement with Borugian et al. ( Am J Epidemiol (2003): Waist-to-Hip Ratio and Breast Cancer Mortality) who found that waist-to-hip ratio was directly related to breast cancer mortality in postmenopausal women but not in premenopausal women; waist-to-hip ratio (WHR) is a marker for insulin resistance and hyperinsulinemia, and high insulin levels have been associated with increased risk of breast cancer and poorer survival after a breast cancer diagnosis.

    Additional research has tended to be highly confirming of the associated between obesity and increased risk of breast cancer, especially as it is mediated through dietary habits: see Goodwin et al. (J Clin Oncol (2003): Diet and Breast Cancer: Evidence That Extremes in Diet Are Associated With Poor Survival) who suggest that the association of key dietary variables with breast cancer survival may be U-shaped rather than linear: midrange intake of most major energy sources is associated with the most favorable outcomes, and extremes are associated with less favorable outcomes. This nonlinear U-shaped association is in keeping also with the association of body size (BMI) and breast cancer risk, as overweight but also underweight status is predictive of an unfavorable prognosis of breast cancer (Suissa et al., Cancer Res (1989): Body size and breast cancer prognosis: a statistical explanation of the discrepancies, who offers this as a possible explanation for the discrepancies among previous studies on the topic).

    See also Rock & Demark-Wahnefried (J Clin Oncol (2002): Nutrition and Survival After the Diagnosis of Breast Cancer: A Review of the Evidence); Rock & Demark-Wahnefried (J Nutr (2002: Can Lifestyle Modification Increase Survival in Women Diagnosed with Breast Cancer?); Brown et al. (CA Cancer J Clin (2003): Nutrition and Physical Activity During and After Cancer Treatment: An American Cancer Society Guide for Informed Choices); Selvan et al., (J Health Manag (2004): Social and Dietary Changes Associated with Obesity and Breast Cancer Risk [pdf]); Dignam & Mamounas (Ann Oncol (2004): Obesity and breast cancer prognosis: an expanding body of evidence); Mai et al. (Int J Epidemiol (2005): Diet quality and subsequent cancer incidence and mortality in a prospective cohort of women); Whiteman et al. (Cancer Epidemiol Biomarkers Prev (2005): Body Mass and Mortality After Breast Cancer Diagnosis); Loi et al. (Cancer Epidemiol Biomarkers Prev (2005): Obesity and Outcomes in Premenopausal and Postmenopausal Breast Cancer; and Lukanova (Epidemiol (2005): Body mass index and cancer: Results from the Northern Sweden Health and Disease Cohort) found that not only was BMI (body mass index) is positively associated with cancer risk, but that up to 7% of all cancers were attributable to overweight and obesity and could be avoided by keeping BMI within the recommended range.

    Also in essential agreement, are the three papers on the CMAJ 2005 Clinical Practice Guidelines on the Care and Treatment of Breast Cancer: Grunfeld et al. (CMAJ (2005): Clinical practice guidelines for the care and treatment of breast cancer: follow-up after treatment for breast cancer (summary of the 2005 update)); Grunfeld et al. (CMAJ (2005): Clinical practice guidelines for the care and treatment of breast cancer: 9. Follow-up after treatment for breast cancer (2005 update)), and Grunfeld et al. (CMAJ (2005): Questions and answers on follow-up care after breast cancer treatment: A guide for women and their physicians); and Kroenke et al. (J Clin Oncol (2005): Weight, Weight Gain, and Survival After Breast Cancer Diagnosis) found that weight and weight gain were related to higher rates of both recurrence of and mortality from breast cancer,with the associations most apparent in never-smoking women.
    Furthermore, obese women are more likely to have higher caloric and fat intakes, and at the same time lower physical activity when compared with nonobese women, with all three factors being associated with increased breast cancer recurrence risk.

    In conclusion, the evidence from this study and dozens of others taken together, establishes:
    (1) that overweight or obese women had a 30%-50% greater risk for postmenopausal breast cancer development than leaner women. In addition, and by contrast, excess weight is associated with a somewhat lower risk of breast cancer development during premenopausal years; however, note that the study of Weiderpass et al. (Cancer Epidemiol. Biomarkers Prev:
    A Prospective Study of Body Size in Different Periods of Life and Risk of Premenopausal Breast Cancer) has clarified that the decreased risk of premenopausal breast cancer was observed only in overweight and obese women without a family history of breast cancer, no in those with breast cancer family history;
    (2) that adult weight gain is consistently associated with a greater risk for postmenopausal breast cancer;
    (3) that greater central adiposity is associated with an approximate doubling of breast cancer risk among postmenopausal women. (See McTiernan, Oncologist:
    Behavioral Risk Factors in Breast Cancer: Can Risk Be Modified?); see also Chlebowski (J Clin Oncol (2005): Obesity and Early-Stage Breast Cancer).

    Seen from a risk reduction/prevention perspective, Michels & Ekbom (JAMA: Caloric
    Restriction and Incidence of Breast Cancer), observing that in experimental animals restricting caloric intake is a highly effective way of extending lifespan and reducing spontaneous tumor occurrence, take up the question of whether similar associations hold in humans, concluding that severe caloric restriction in humans may confer protection from invasive breast cancer. Indeed, although energy restriction remains one of the most effective ways known to prevent breast cancer in animal models, until recently energy intake has not been consistently associated with risk of breast cancer in humans, but energy intake, in addition to BMI and physical activity may be independently associated with breast cancer risk, and in addition, these three aspects of energy balance may act jointly in determining breast cancer risk, according to the findings of the prospective trial of Change et al. (Cancer Epidemiol Biomarkers Prev (2006): Association of energy intake and energy balance with postmenopausal breast cancer in the prostate, lung, colorectal, and ovarian cancer screening trial).

    A final unexpected risk for overweight / obese women with breast cancer is the outgrowth of the fact that these patients often receive intentionally reduced doses of adjuvant chemotherapy, not the optimal initial and overall full weight-based doses (Griggs et al., JAMA (2005): Undertreatment of Obese Women Receiving Breast Cancer Chemotherapy), thus compromising outcome.

  • Folate:
    Although one study by Branda et al. (Cancer (2005):
    Effect of vitamin B12, folate, and dietary supplements on breast carcinoma chemotherapy-induced mucositis and neutropenia) determined that the neutrophil count decrease consequent to chemotherapy was ameliorated by dietary supplementation with a multivitamin or vitamin E, but this neutrophil decrease was actually exacerbated by high serum folate levels, Zhang et al. (J Natl Cancer Inst (2005): Plasma Folate, Vitamin B6, Vitamin B12, Homocysteine, and Risk of Breast Cancer) recently found that higher plasma levels of folate (with intake at least 600 µg/day) - and possibly vitamin B6 - may reduce the risk of breast cancer development. They concluded that "achieving adequate circulating levels of folate may be particularly important for women at higher risk of developing breast cancer because of higher alcohol consumption". Similarly, Lajous et al. (Cancer Epidemiol Biomarkers Prev (2006): Folate, Vitamin B6, and Vitamin B12 Intake and the Risk of Breast Cancer Among Mexican Women) that among postmenopausal women, intakes of folate and vitamin B12 were associated with a lower risk of breast cancer and those associations were stronger than among premenopausal women, with the inverse association of folate and breast cancer being stronger among women who consumed a high level of vitamin B12 as compared with women consuming diets low in vitamin B12. No association was observed for vitamin B6 intake

    And there is some evidence that alcohol and folate consumption interact to affect risk, with differences in associations for those with or without p53 mutations, and that causal pathways may vary for pre- and postmenopausal women (Freudenheim, Carcinogenesis:
    Diet and alcohol consumption in relation to p53 mutations in breast tumors). And adequate folate supplementation may protect against alcohol related increased risk of breast cancer, as found in the prospective cohort study (population of 17,000 Australian women over 10 years) of Baglietto and colleagues (BMJ (2005): Does dietary folate intake modify effect of alcohol consumption on breast cancer risk? Prospective cohort study). They found that women who regularly consumed more than 40 g (5 units) a day of alcohol had a 40% greater risk of invasive breast cancer than lifetime abstainers, but that a daily folate intake of 400 µg (micrograms) in this drinking group was however associated with a significant reduction in risk, when compared with a lower daily intake of 200 µg. This is an important preventive message, as it demonstrates that the known adverse effect of alcohol consumption may be reduced by sufficient dietary intake of folate.

    Furthermore, the findings of Tjonneland et al. (Eur J Clin Nutr (2005): Folate intake, alcohol and risk of breast cancer among postmenopausal women in Denmark) also support the evidence that adequate folate intake may attenuate the risk of breast cancer associated with high alcohol intake, and confirming the conclusion from other studies that alcohol intake and risk of breast cancer are associated mainly among women with low folate intake; they note that among women with a folate intake higher than 350 micrograms, there was no association between the alcohol intake and the breast cancer incidence.

    Warning: However, at least one recent study failed to support the hypothesis that high folate intake reduces breast cancer risk; Stolzenberg-Solomon et al. (Am J Clin Nutr (2006): Folate intake, alcohol use, and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial) instead found that a high intake may actually increase the risk in postmenopausal women.

    [new] Breast Cancer Prevention Watch: Folate and Breast Cancer
    A recent meta-analysis from Sarah Lewis and her colleagues (J Natl Cancer Inst (2006): Meta-analyses of Observational and Genetic Association Studies of Folate Intakes or Levels and Breast Cancer Risk) at the University of Bristol concludes that alack of dietary folate intake is not associated with the risk of breast cancer, while another meta-analysis from Susanna Larsson and coresearchers (J Natl Cancer Inst (2006):
    Folate and Risk of Breast Cancer: A Meta-analysis), although finding no clear support for an overall relationship between folate intake or blood folate levels and breast cancer risk, did conclude that adequate folate intake may reduce the increased risk of breast cancer that has been associated with moderate or high alcohol consumption. But there are inherent problems with the sampled case–control studies and the subgroup analyses, where the heterogeneity across studies with respect to lifestyle, genetic makeup, and instruments used for dietary assessment are left unexamined (as noted in the ditorial of Han-Yao Huang, J Natl Inst Cancer (2006): Customized Diets for Cancer Prevention According to Genetic Polymorphisms: Are We Ready Yet?), and in addition since nutrient intake is often associated with other lifestyle factors - and still other nutrients (methionine, betaine, choline, B vitamins) can influence the breast cancer / folate association - the variability in the extent of adjustment for lifestyle factors among the studies renders the validity of conclusions from their meta-analyses uncertain, especially given that Larsson admits that dietary folate intake was indeed statistically significantly inversely associated with risk of breast cancer in case–control studies, but not so in prospective studies, and it is well known that prospective and retrospective studies can give different estimates for associations between dietary exposures and cancer risk, and case-control studies may be affected by inaccurate recall of dietary intake. Finally the amount of folate supplementation is generally not held consistent across various sampled studies, and co-factors such as homocysteine and others cited above may influence the association critically, and are not explicitly measured or held constant in cross-study comparisons.

    However, weighing all this potential confounding factors and methodological issues together, our conclusions are that the overall association between folate intake or folate blood levels and breast cancer risk is not at present strongly evidenced from the available data base, and we still require additional methodoligically high-quality studies to draw more definitive conclusions in this arena.

  • I3C / Cruficerous Vegetables:
    Epidemiological studies provide evidence that the consumption of cruciferous vegetables protects against cancer more effectively than the total intake of fruits and vegetables. The indole-3-carbinol (I3C) component in brassica and cruciferous vegetables may may also be protective in cervical and possibly prostate cancers, probably by enhancing 2-hydroxyestrone (an estrogen receptor antagonist - non-stimulative of breast tumors - produced in estrogen breakdown) at the expense of 16-hydroxylation (an estrogen receptor agonist - promoting breast tumors - also produced in estrogen breakdown), thus shifting the ratio to the favorable estrogen breakdown product (see Keck and Fenley, Integr Cancer Ther:
    Cruciferous vegetables: cancer protective mechanisms of glucosinolate hydrolysis products and selenium). Epidemiological, laboratory, animal and translational studies increasingly indicate that dietary indole-3-carbinol (I3C) prevents the development of estrogen-enhanced cancers including breast, endometrial and cervical cancers (Auborn et al., J Nutr: Indole-3-carbinol is a negative regulator of estrogen) (see also von Poppel, Exp. Med. Biol: Brassica vegetables and cancer prevention. Epidemiology and mechanisms; Terry et al., JAMA: Brassica vegetables and breast cancer risk, where it was found that consumption of brassica vegetables was inversely associated with breast cancer risk, especially 1 to 2 servings per day, lowers the risk of breast cancer by as much as 20% to 40%, possibly by shifting the pathway of estrogen metabolism) (Ambrosone et al., J Nutr: Breast Cancer Risk in Premenopausal Women Is Inversely Associated with Consumption of Broccoli, a Source of Isothiocyanates, but Is Not Modified by GST Genotype, which found that vegetables may play an important role in decreasing the risk of premenopausal, but not postmenopausal, breast cancer) (Fowke et al., Cancer Res: Urinary isothiocyanate levels, brassica, and human breast cancer, which found that "greater Brassica vegetable consumption, as measured by the urinary ITC biomarker, was associated with significantly reduced breast cancer risk among Chinese women"; also Fowke et al., Cancer Epidemiol. Biomarkers Prev: Urinary Isothiocyanate Excretion, Brassica Consumption, and Gene Polymorphisms among Women Living in Shanghai, China) (Bell et al, Gynecol. Oncol: Placebo-controlled trial of indole-3-carbinol in the treatment of CIN) (Shukla et al., Teratog Carcinog Mutagen: Antigenotoxic potential of certain dietary constituents).

    One specific dietary regimen that has been reported to be effective is a high fiber diet including the consumption of 50 g of cabbage or 100 g of broccoli twice weekly; see Lord et al., Altern Med Rev:
    Estrogen metabolism and the diet-cancer connection: rationale for assessing the ratio of urinary hydroxylated estrogen metabolites [pdf]) (Brignall, Altern Med Rev: Prevention and treatment of cancer with indole-3-carbinol [pdf]) (Kelloff et al., J Nutr: Progress in cancer chemoprevention: development of diet-derived chemopreventive agents, where it is suggested that the anti-breast cancer activity of I3C may be exerted through modulation of cytochrome P450-dependent estradiol metabolism, by enhancing 2-hydroxyestrone (estrogen receptor antagonist) at the expense of 16-hydroxylation (estrogen receptor agonist. And Reed et al. (Cancer Epidemiol Biomarkers Prev (2005): A Phase I Study of Indole-3-Carbinol in Women: Tolerability and Effects) have recently determined with respect to I3C supplementation that no more than 400 mg I3C daily would elicit maximal protective effect.

    Issue: The Safety of I3C
    Recently, several studies have raised safety concerns for I3C consumption. One concern centers around aflatoxin-induced tumors, expressed as hepatocarcinogenesis. RH Dashwood and colleagues at the Department of Environmental Biochemistry, University of Hawaii (Dashwood et al., Cancer Res (1991): Promotion of aflatoxin B1 carcinogenesis by the natural tumor modulator indole-3-carbinol: influence of dose, duration, and intermittent exposure on indole-3-carbinol promotional potency) found that such tumors in fish (trout) are inhibited by I3C when it is given prior to aflatoxin exposure, but aflatoxin-induced tumor activity was promoted by I3C when given after aflatoxin initiation, also confirmed independently by Aram Oganesian and colleagues at Oregon State University (Organesian et al., Carcinogenesis (1991): Potency of dietary indole-3-carbinol as a promoter of aflatoxin B1-initiated hepatocarcinogenesis: results from a 9000 animal tumor study), and more recently by another team of researchers at Oregon State University headed by Susan Tilton and colleagues (Toxicol Sci (2006): Toxicogenomic Profiling of the Hepatic Tumor Promoters Indole-3-Carbinol, 17ß-Estradiol and ß-Naphthoflavone in Rainbow Trout) who also found that another compound DIM (3,3'-diindolylmethane), a major in vivo component of I3C, might be an even more potent hepatic tumor promoter than I3C itself.

    However, against this, in a somewhat more plausible rat study, MM Manson and colleagues (Manson et al., Carcinogenesis (1999): Chemoprevention of aflatoxin B1-induced carcinogenesis by indole-3- carbinol in rat liver--predicting the outcome using early biomarkers [pdf]) at the University of Leicester found that I3C inhibited the progression of aflatoxin-induced hepatocarcinogenesis at both the initiation and promotion stages, in direct contradiction of the Dashwood and Oganesian in rainbow trout, and this positive finding has been more recently confirmed by Matthew Wallig and colleagues at the University of Illinois (Wallig et al., J Nutr (2005): Synergy among Phytochemicals within Crucifers: Does It Translate into Chemoprotection). And also contradicting the studies cited above that purport to find a potential for I3C to promote hepatocarcinogenesis in certain but not all species, the animal study (on Wistar rats) of Yogeshwer Shukla and colleagues (Skukla et al., Nutr Cancer (2004):
    Chemopreventive Effect of Indole-3-Carbinol on Induction of Preneoplastic Altered Hepatic Foci) confirmed a chemopreventive effect of I3C in rat hepatocarcinogenesis through the suppression by I3C of diethylnitrosamine (DEN)- and acetylaminofluorene (AAF)-induced altered hepatic foci (AHF) development, an action opposite to hepatocarcinogenesis. And still another contradicting study is that of Aram Oganesian and coresearchers (Oganesian et al. Cancer Lett (1997): Long term dietary indole-3-carbinol inhibits diethylnitrosamine-initiated hepatocarcinogenesis in the infant mouse model) who, citing concerns raised regarding the potential tumor-promotional potency of I3C in other target organs such as liver, examined directly the hepatic tumor-modulatory properties of I3C when fed to mice (C57BL/6J) initiated with diethylnitrosamine (DEN), finding that there was actually a statistically significant inhibition of hepatocarcinogenesis observed for I3C-fed animals initiated with high dose of DEN, concluding that that long term administration of I3C in the diet inhibits DEN-initiated hepatocarcinogenesis in the infant mouse model. And in rainbow trout, where some observers claimed to find I3C promotion of hepatocarcinogenesis, other researchers failed to confirm such promotion (see the study of Takahashi and the Oregon State University team (Takahashi et al., Food Chem Toxicol (1995): Induction of hepatic CYP1A by indole-3-carbinol in protection against aflatoxin B1 hepatocarcinogenesis in rainbow trout)

    With dueling models - rainbow trout versus rat versus mouse etc. - and potentially differential confounding factors across studies and models, the safety issue is left at time of writing rather indeterminate, and there is certainly insufficient compelling evidence to propose a clear danger in the human clinical setting.

    A second concern surrounding the issue of potential adverse interactions through the P450 cytochrome family of enzymes, especially on the hepatic microsomal metabolism of tamoxifen (TAM): so Daniel Parkin and Danuta Malejka-Giganti at the University of Minnesota (Parkin et al., Cancer Detect Prev (2004): Differences in the hepatic P450-dependent metabolism of estrogen and tamoxifen in response to treatment of rats with 3,3'-diindolylmethane and its parent compound indole-3-carbinol) in another rat study found that although metabolism of TAM was unaffected by DIM, formation of N-desmethyl-TAM was increased 3-fold by I3C, and since N-desmethyl-TAM is transformed to a genotoxic metabolite, this appears to suggest that dietary exposure to I3C may enhance hepatic carcinogenicity of TAM in the rat.

    However, here again, conflicting results exists: so Dustin Leibelt and colleagues at Oregon State University (Leibelt et al., Toxicol Sci (2003): Evaluation of Chronic Dietary Exposure to Indole-3-Carbinol and Absorption-Enhanced 3,3'-Diindolylmethane in Sprague-Dawley Rats) failed to detect any direct toxicity by long-term exposure to I3C and DIM, even at doses up to approximately 5–7 times the daily dose recommended by commercial suppliers of I3C supplements, and at exposure 10 times higher than the current human dose for DIM, and the researchers concluded that data from their present study confirms results from short-term studies indicating that both I3C and DIM are relatively nontoxic compounds, and furthermore confirm earlier long-term feeding studies in other models, including the rainbow trout and the same strain of rat used in the present study, that I3C is not a complete carcinogen, a finding also confirmed by Gary Stoner and co-researchers (Stoner et al., Carcinogenesis (2002): Development of a multi-organ rat model for evaluating chemopreventive agents: efficacy of indole-3-carbinol) who nonetheless warn that I3C may not an appropriate chemoprotective agent for human use in that it appears to both inhibit (breast, colon) and promote (liver) carcinogenesis. And the Leibelt study warns of two distinct concerns: (1) that the prolonged use of I3C for cancer chemoprevention exhibits a potential for promotion of liver neoplasms, although they prudently admit that the long-term post-initiation effects of I3C in hepatocarcinogenesis are not consistent across species (trout, rats, black mice), leaving open what the real risk is, if any, in the human context; and (2) the induction of CYP enzymes by I3C, especially those of the 1A subfamily, could be a cause for concern, as these play a role in activation of polycyclic aromatic hydrocarbons (PAH) and aromatic amines with known toxicities, a concern that appears not to be shared with DIM. The reason for this may be that in the acidic conditions of the stomach after oral exposure, I3C becomes a complex mixture more than 20 different I3C-derived compounds, including DIM, all having various pharmacological/toxicological effects, while DIM is relatively more stable in acid and does not robustly undergo further condensation reactions, suggesting that the more stable DIM component may be the safer compound to deploy in the human context.

    However, I3C yielded dose-dependent increases in the hepatic P450 level according to the research of Malejka-Giganti and coresearchers at the University of Minnesota (Malejka-Giganti et al., Cancer Epidemiol Biomarkers Prev (2003): Effects of treatment of rats with indole-3-carbinol or 3,3'-diindolylmethane on the hepatic P450-dependent metabolism of estrogen and tamoxifen) who in their animal study of female Sprague-Dawley rats tested 5, 25 and 250 mg/kg body weight of I3C and DIM at 8.4 and 42 mg/kg body weight, finding that oral intake of I3C or DIM at lower dose levels did not alter CYP-mediated metabolism of tamoxifen, and hence, would not alter its therapeutic efficacy. Since for a human female weighing 140 lbs, equivalent to about 64 kilograms (kg), the CYP-mediated TAM metabolism altering dose (250/mg/kg) would map to 16,000 mg, which is easily 40 times greater than the recommended I3C dosing of 400mg/daily, and from these findings it would appear that doses up to 1600mg/daily would be without adverse interactions on tamoxifen metabolism and efficacy, assuming the same 140 lbs female. Therefore 400mg/daily IC3 ingestion is at a level to assure no oncotherapy interference with tamoxifen.

    In summary, we note the conclusions of a recent comprehensive review by EG Rogan with the Eppley Institute for Research in Cancer and Allied Diseases at the University of Nebraska Medical Center (EG Rogan, In Vivo (2006): The natural chemopreventive compound indole-3-carbinol: state of the science) who notes that "although I3C has been shown to protect against tumor induction by some carcinogens, it has also been observed to promote tumor development in animal models" and that in humans, concerns have been raised that I3C "might increase the formation of estrogen metabolites that induce or promote cancer" they nonetheless conclude that this has not been demonstrated in any way.

    Therefore given the contradictory findings of harm across divers species, and the complete lack of any human clinical data to suggest any potential promotion of hepatocarcinogenesis, we must conclude that there is no convincing evidence of such adverse potential of I3C and DIM in humans. Furthermore, the in vivo component of I3C, 3,3'-diindolylmethane (DIM) is unlike, its precursor, I3C itself, not highly enzyme-inducing, where it appears from the evidence base that it is the unwanted enzyme induction by I3C that accounts for any perceived adverse tumor promotion activity by I3C, and lacking these unwanted enzyme-inducing effects, DIM, which appears to share the positive efficacy of I3C in breast and cervical carcinomas, would be suggested as the safer compound in human use (and in keeping with the conclusion of Leibelt, cited above, that "Long-term exposure to DIM produced no observable toxicity, and comparison to I3C indicates that DIM is a markedly less efficacious inducer of CYP in the rat at doses relevant to human supplementation").

    Clinical Conclusions:
    I3C/ DIM
    However, we cannot sustain sufficient balance of evidence to suggest supplementation of I3C/DIM, given the relatively large number of  continuing serious concerns, as cited above (as in the studies of Dashwood, Tilton, Oganesian,  Parkin, Malejka-Giganti, and Rogan among others) left unresolved.  And further concerns have been voice by Frank Johnson and James Huff at the National Institute of Environmental Health Sciences (Johnson F, Huff J. Development of a multi-organ rat model for evaluating chemopreventive agents: efficacy of indole-3-carbinol. Certain health supplements may cause both carcinogenic and anticarcinogenic effects. Carcinogenesis 2002 Oct; 23(10):1767-8) concerning an I3C-induced combination of anticarcinogenic and carcinogenic effects. Likewise, Makato Suzui and colleagues in Japan have that found that I3C inhibits the growth of human colon carcinoma cells through induction of p27KIP1 and p21CIP1-mediated G1 cell-cycle arrest but that dietary I3C promotes AOM-induced rat colon carcinogenesis via inhibition of the apoptosis of colon tumors, establishing once again an ambivalent Janus-like modulatory activity from I3C (Suzui M, Inamine M, Kaneshiro T, et al. Indole-3-carbinol inhibits the growth of human colon carcinoma cells but enhances the tumor multiplicity and volume of azoxymethane-induced rat colon carcinogenesis. Int J Oncol 2005 Nov; 27(5):1391-9), disallowing based on the current evidence to date any positive guidance for supplementation.  

    Issue: The Safety of Garlic
    Furthermore, Brian Foster of Health Canada) has further help to clarify this issue (Foster, J Pharm Pharmaceut Sci (2001): An In Vitro Evaluation of Human Cytochrome P450 3A4 and P-glycoprotein Inhibition by Garlic); the study tested 6 different garlic supplements (ranging in dose from 10mg to 20mg, equivalent to 1000mg to 2000mg fresh garlic content) inhibited the cytochrome p450 CYP2C19 enzyme by 21% to 53%, and concludes that "constituents of garlic may not need to be present in high levels to elicit a pharmacological effect in order to produce a systemic or pre-systemic effect on drug disposition. The potential for the garlic products examined in this study to affect drug disposition may increase if used in combination with one or more conventional therapeutic products" and more importantly, that "that the disposition of drugs . . . could be inhibited after the co-administration with garlic or garlic products". Note that the metabolism of the widely deployed endocrine agent / aromatase inhibitor letrozole (Femara) is CYP2C19-mediated, and so potentially adversely affected by garlic coadministration.

    In contrast with these in vitro findings, David Greenblatt and his colleagues at Tufts evaluated 8 water-soluble components of aged garlic extract in order to asses potential to inhibit cytochrome-P450 (CYP) enzyme activity, for the CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A, observing that none of the 8 garlic components produced >50% inhibition even at high concentrations, except for S-methyl-L-cysteine and S-allyl-L-cysteine, which produced 20–40% inhibition of CYP3A compared to control. They conclude from this that drug interactions involving inhibition of CYP3A enzymes by aged garlic extract are very unlikely.

    However, Breast Cancer Prevention Watch notes:

    (1) that although their observation there is no available clinical evidence for CYP3A inhibition in vivo by garlic or Allium components is accurate, it should be remember that there is no such in vivo data because no in vivo trial has been conducted to settle the matter one way or the other, so the absence of data for an in vivo inhibitory effect is not to be construed as the presence of positive data that shows no such effect occurs in fact.

    (2) that they consider the two exceptions (the S-methyl-L-cysteine and S-allyl-L-cysteine garlic components) of significant 20–40% inhibition of CYP3A as "modest", but a reduction this large, were it to be evidenced in vivo with oncotherapy, would be considered quite dramatic and of grave concern given the narrow therapeutic index of oncotherapeutic agents, and this suggests at least a potential for adverse interaction with such endocrine agents as anastrozole (Arimidex) whose metabolism is CYP3A-mediated, exemestane (Aromasin) which is CYP3A4-mediated, and the CYP3A4-mediated chemotherapy agents the taxanes docetaxel (Taxotere), paclitaxel (Taxol), nab-paclitaxel (Abraxane), or any of the Vinca alkaloids vinorelbine (Navelbine), vinblastine (Velban), and vincristine (Oncovin), and the platinum agent carboplatin. Without in vivo data to demonstrate no clinically significant impact of this CYP3A/3A4-inhibitory activity, the potential for adverse interaction remains (not that although on at least one of these agents, docetaxel (Taxotere) Michael Cox and coresearchers (Cox et al., Clin Cancer Res (2006): Influence of Garlic (Allium sativum) on the Pharmacokinetics of Docetaxel) found that garlic did not significantly affect the disposition of docetaxel, nonetheless as the authors admit, it cannot be excluded that garlic decreases the clearance of docetaxel in patients carrying a CYP3A5*1A allele, and hence coadministration is still problematic, as can not typically pre-identify these populations).

    (3) the Greenblatt findings, with respect to CYP2C19 appear to be in direct contradiction to the Foster findings cited above, although Breast Cancer Prevention Watch notes this may be an artifact of the overly permissive and broad definition of significant interaction in the Greenblatt study, which is > 50% inhibition. In contrast the Foster study found that the 6 garlic supplements (ranging in dose from 10mg to 20mg, equivalent to 1000mg to 2000mg fresh garlic content) inhibited the cytochrome p450 CYP2C19 enzyme by 21% to 53%, amounts they observe correctly could "elicit a pharmacological effect in order to produce a systemic or pre-systemic effect on drug disposition".

    We see here a classical difference of disposition: for Greenblatt, potential interaction appear to have to exert very large effects (> 50%) before perceived as clinically significant, while for Foster a potential 20% or higher reduction in the activity of a drug
    (and possibly lower) is taken as significant in reductive capability; more in contrast. Greenblatt takes an optimistic approach to the issue of potential adverse interaction (based on in vitro findings), not observing a notable hazard unless there are explicit data that show an in vivo adverse interaction, while Foster takes a cautionary perspective until in vivo data were to show that the potentially adverse interaction in vitro is not also found in vivo, and absent such evidence, as here, views coadministration as problematic.

    Given the narrow therapeutic index of oncotherapy agents, and their potential impact on mortality, Breast Cancer Prevention Watch would suggest erring on the side of caution: after all, for years we have known about a well-documented potentially adverse compromise of tamoxifen efficacy when coadministered with SSRI antidepressants, but many oncologists (but not David Flockhart, a principal in these findings) argued that proactive data of a clinically adverse interaction, coadministration should continue without change (while as many said "the jury is still out".

    Others, including ourselves at Breast Cancer Prevention Watch, reasoned otherwise, noting that the absence of demonstration of harm is not equivalent to the demonstration of no harm, and that given the vital operation of tamoxifen, typically administered over years, it would be imprudent to chance coadministration with an SSRI only to learn that indeed the interaction is significant, and adverse, at the clinical level, as this may entail tamoxifen failure, and even consequent patient mortality or disease recurrence due to deployment of an efficacy-compromised endocrine agent like tamoxifen.

    On the basis therefore of the above considerations, we agree with the conclusion of Sonnichsen and colleagues (Sonnichsen et al., MMW Fortschr Med (2005): Food-drug interactions: an underestimated risk) who conclude that "Certain foodstuffs or food constituents, such as, for example, grapefruit, Seville orange juice, red wine, alcoholic drinks in general, or large quantities of caffeine and garlic should be avoided during drug treatment", in keeping also with the results of Alex Sparreboom's and colleagues at the NCI in their review, finding that garlic was one of the natural agents with the "potential to significantly modulate the activity of drug-metabolizing enzymes (notably cytochrome P450 isozymes) and/or the drug transporter P-glycoprotein" and which "participate[s] in potential pharmacokinetic interactions with anticancer drugs" and also with the results of Zhou et al. (Life Sci (2004): Herbal bioactivation: The good, the bad and the ugly) who found potentially adverse interaction of the daily sulfone component of garlic as a CYP3A4 inhibitor, although an earlier study by Markowitz et al. (Clin Pharmacol Ther (2003): Effects of garlic (Allium sativum L.) supplementation on cytochrome P450 2D6 and 3A4 activity in healthy volunteers) found in contradiction that garlic extracts were unlikely to alter the disposition of coadministered medications primarily dependent on the CYP2D6 or CYP3A4 pathway of metabolism. Such not wholly convergent findings suggest the need for caution concerning coadministration until in vivo / clinical data are available to settle the issue.

    But recent developments support our cautionary stance: the results by SK Knox and coresearchers (Knox et al., 2006 ASCO Annual Meeting Proceedings, in J Clin Oncol (2006): Cytochrome P450 2D6 status predicts breast cancer relapse in women receiving adjuvant tamoxifen (Tam)) just reported at the June 2006 ASCO meeting found that in patients that coadminister tamoxifen and an CYP2D6-inhibitory agent such as an SSRI or other inhibitory agent (fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), cimetidine(Tagamet), amiodarone (Cardarone), doxepin (Adapin/Sinnequan), ticlopidine (Ticlid) and haloperidol (Haldol) were tested), had significantly worse time to recurrence(TTR) and disease free survival (DFS), in the real human clinical setting, settling the matter. But that puts many oncologists in the embarrassing position of having countenanced significant adverse impact on patient outcome on the basis of an optimistic stance that, after all, only the potential for harm had priorly been demonstrated, not actual harm; with the Knox findings we now know retrospectively that the potential was real and did translate into adverse impact of patient outcome in terms of both disease recurrence and survival, and so this seriously degrades the value of any optimistic stance on these matters.

    Issue: The Safety of Sulforaphane
    One final issue on components of brassica vegetables concerns the component sulforaphane: as Zhou et al. (Mol Pharmacol (2006): The dietary isothiocyanate, sulforaphane is an antagonist of the human steroid and xenobiotic nuclear receptor (SXR) [pdf]) observe, this biologically active phytochemical found abundantly in broccoli, can significantly down-regulate cytochrome P450 3A4 (CYP3A4) expression in human primary hepatocytes, and although this mechanism serves as part of the foundation for its anticancer and chemopreventive activity, there may be some potential for adverse interaction with CYP3A4-mediated agents such as exemestane (Aromasin), and we await clinical studies to determine whether such interaction exerts clinically significant impact on concurrent administration (see also Maheo et al., Cancer Res (1997: Inhibition of cytochromes P-450 and induction of glutathione S-transferases by sulforaphane in primary human and rat hepatocytes, who first reported the CYP3A4 enzyme operation in sulforaphane).

    And the review of Paolini & Nestle (Mutat Res (2003): Pitfalls of enzyme-based molecular anticancer dietary manipulations: food for thought; full text (as pdf) on found that "cruciferous isothiocyanates such as sulforaphane, most often considered as beneficial phase-II detoxifying system inducers, turn out to be genotoxics or strong promoters of urinary bladder and liver carcinogenesis as well as inducing cell cycle arrest and apoptosis".

    Sulforaphane is an isothiocyanate (isothiocyanates being the family of compounds found in large amounts in cruciferous vegetables in the form of the thioglucoside precursors (glucosinolates)) that has been isolated from SAGA broccoli as the major phase II enzyme inducer present in organic solvent extracts of this vegetable. The (chemo)protective effect of sulforaphane, an isothiocyanate - - which is liberated from glucoraphanin (GRP), its glucosinolate precursor, by myrosinase hydrolysis, is believed to involve the induction of Phase-II metabolizing enzymes which are active in the detoxification of many carcinogens and ROS (reactive oxygen species), and by this protecting cells against DNA damage and subsequent malignant transformation. However, as discovered by Paolini et al (Carcinogeneis (2004): Induction of cytochrome P450, generation of oxidative stress and in vitro cell-transforming and DNA-damaging activities by glucoraphanin, the bioprecursor of the chemopreventive agent sulforaphane found in broccoli) that:
    (1) in some cases these enzymes also bioactivate several hazardous chemicals, and
    (2) that despite sulforaphane's projected benefits, overlooked is its unknown effects on the Phase-I enzyme systems involved in the bioactivation of a variety of carcinogens, where not only has sulforaphane been shown to inhibit the CYP2E1 cytochrome P-450 enzyme involved in the activation of a variety of carcinogen, but also to down-regulate CYP3A4 expression (as shown by the separate Zhou and Maheo studies, cited above), and this raises issues of potential significant and possibly adverse interaction with CYP3A4-mediated oncotherapy agents such as endocrine agent exemestane (Aromasin), taxanes (docetaxel (Taxotere), paclitaxel (Taxol)), and nab-paclitaxel (Abraxane) or any of the Vinca alkaloids (vinorelbine (Navelbine), vinblastine (Velban), vincristine (Oncovin)), and the platinum agent carboplatin (Paraplatin), suggesting caution of coadministration of high-sulforaphane-content dietary or supplemental sources with any of the CYP3A4-dependent classes of oncotherapy just notes, until further in vivo or ideally human clinically studies can demonstrate compellingly the safety ands non-problematic nature of such coadministration.

    Independent of this, there is another disturbing aspect of sulforaphanes induction of Phase-I CYP bioactivating enzymes: sulforaphane is as we noted above liberated from its glucosinolate precursor glucoraphanin (GRP), and there is some evidence that GRP may possess co-carcinogenic properties. Indeed, by inducing Phase-I CYP bioactivating enzymes, GRP may trigger the conversion of benzo[a]pyrene to carcinogenic reactive intermediates like diol-epoxides, and recent studies have shown that a cruciferase diet containing a selection of brassicaceous vegetable that includes broccoli, Brussel sprouts or cauliflower, leads to a significant increase in Phase-I enzymes such as CYP1A1/2, which can bioactivate PAHs, dioxins, aromatic amines and nitrosamines (as reported by Paolini et al (Carcinogeneis (2004): Induction of cytochrome P450, generation of oxidative stress and in vitro cell-transforming and DNA-damaging activities by glucoraphanin, the bioprecursor of the chemopreventive agent sulforaphane found in broccoli), and priorly confirmed as well in the study by Vistisen et al. (Carcinogenesis (1992): Foreign compound metabolism capacity in man measured from metabolites of dietary caffeine) who found that in nine healthy volunteers daily ingestion of 500 g of broccoli for 10 days increased the CYP1A2 ratio adversely by an average of 12% compared to a comparable diet of non-cruciferous green vegetable, see also Lampe et al. (Carcinogenesis (2000): Brassica vegetables increase and apiaceous vegetables decrease cytochrome P450 1A2 activity in humans: changes in caffeine metabolite ratios in response to controlled vegetable diets).

    The adverse impact of the brassica diet hinges on CYP1A2: CYP1A2 activity is increased by cigarette smoke, well-cooked meat, and unfortunately by cruciferous vegetables and this is adverse, since CYP1A2 metabolizes various environmental procarcinogens, such as heterocyclic amines (HCAs), nitrosamines and aflatoxin B1, in keeping with the research of Lampe et al. (Carcinogenesis (2000): Brassica vegetables increase and apiaceous vegetables decrease cytochrome P450 1A2 activity in humans: changes in caffeine metabolite ratios in response to controlled vegetable diets)), where it was found that that under controlled dietary conditions, at moderate levels of intake (428 g), brassica vegetables increased (while apiaceous vegetables decreased, and allium vegetables did not change) CYP1A2 activity by 18 - 37%, when compared with a basal, vegetable-free diet.

    A Possible Solution
    Against this adverse impact of brassica vegetables, Breast Cancer Prevention Watch finds intriguing the fact that apiaceous vegetables (carrots, parsnips, celery, dill and parsley) decreased mean CYP1A2 activity by ~13–25%, which suggest to us that the differential CYP1A2 response to the brassica and apiaceous vegetable diets may be leveraged to in largely part cancel out or nullify the adverse CYP1A2 impact of the brassica components by co-consumption with apiaceous vegetables.

  • Phytoestrogens
    Phytoestrogens are plant polyphenol compounds exhibiting structural resemblance to the mammalian estrogen hormone 17ß-oestradiol. Three classes of phytoestrogens can be distinguished:
    (1) isoflavones, found in concentrated form in soybeans and soy products and also in other legumes;
    (2) lignans, from seeds (especially flax), whole grains, fruits and berries, vegetables, and nuts;
    (3) coumestans, found in broccoli and sprouts.

    It has been observed that in Asian nations the staple consumption of phytoestrogen-rich foodstuffs correlates with a reduced incidence of breast cancer, suggesting that phytoestrogen consumption is associated with a favorable hormonal profile. It has further been observed in this connection that historically, breast cancer rates in the United States are typically as much as 4–7 times higher than those in Asia, with US isoflavone intake at less than 1% of that in Asian populations (which may range from 20 to 80 mg/daily). However, as Wu et al have noted, "it is difficult to be certain that soy intake is not a marker of other factors related to Western lifestyle that are causally associated with risk of breast cancer", so that high soy consumption may be only one of many potentially protective lifestyle factors that distinguish Asian and Western women (Wu et al, Am J Clin Nutr:
    Soy intake and risk of breast cancer in Asians and Asian Americans).

    Although several human dietary intervention trials have suggested a direct relationship between phytoestrogen ingestion and decreased breast cancer risk, such trials were not sufficiently powered to identify the exact effect of dietary phytoestrogens on mammary tissue proliferation. Epidemiological and animal studies crucially have found that the benefit of breast cancer chemoprevention by dietary phytoestrogen compounds is chronologically dependent, with pre-puberty consumption being required, as it is known that at this time the mammary gland is relatively immature, but phytoestrogen supplements are typically marketed commercially for as natural HRT alternatives in postmenopausal women.

    Therefore, the critical issue is the effect of phytoestrogens on the growth of preexisting breast tumors. Here, however, the findings to date are contradictory and not dispositive. One the one hand, cell culture studies fairly consistently report the estrogenic stimulation of estrogen receptor-positive breast cancer cell lines, as well as antagonism of tamoxifen activity at physiological phytoestrogen concentrations. On the other hand, rodent phytoestrogen consumption is typically associated with less aggressive breast tumor development, with decreased metastatic potential.

    In this connection, Limer and Spiers suggest a potential benefit of phytoestrogens in breast cancer chemoprevention and therapy (Limer & Spiers, Breast Cancer Res:
    Phyto-oestrogens and breast cancer chemoprevention), whereas Atkinson et al. found that a red clover isoflavone dietary supplement demonstrated no effects estradiol in postmenopausal women, or on hot flushes or other menopausal symptoms and, unlike conventional HRT, did not increase mammographic breast density. They conclude that the isoflavone supplement at the dose given was not acting as an estrogen or as an anti-estrogen (see Atkinson et al., Breast Cancer Res: Red clover-derived isoflavones and mammographic breast density: a double-blind, randomized, placebo-controlled trial).

    Furthermore, Harris et al. have found that dietary flavonoids may be able to influence the bioavailability of endogenous estrogens, and disrupt endocrine balance, by increasing the ratio of active estrogens to inactive estrogen sulfates in human tissues (see Harris et al., J Clin Endocrinol Metab:
    Phytoestrogens Are Potent Inhibitors of Estrogen Sulfation: Implications for Breast Cancer Risk and Treatment), and similarly, Linseisen et al. found that dietary intake of certain phytoestrogen components (daidzein, genistein, and matairesinol, as well as mammalian lignans reduces premenopausal breast cancer risk (Linseisen et al., Int J Cancer: Dietary phytoestrogen intake and premenopausal breast cancer risk in a German case-control study).

    In contrast, Keinan-Boker et al have in their recent research concluded that "in Western populations, a high intake of isoflavones or mammalian lignans is not significantly related to breast cancer risk" (Keinan-Boker et al, Am J Clin Nutr:
    Dietary phytoestrogens and breast cancer risk), and Yamamoto et al in a prospective cohort study in Japan found that although high miso soup and isoflavone consumption reduced the risk of breast cancer, there was no evidence for such an association for intake of soyfoods (Yamamoto et al, J Natl Cancer Inst: Soy, Isoflavones, and Breast Cancer Risk in Japan); these findings are in conflict with many others cited above, and with the recent epidemiologic study of Bosetti et al. (Cancer Epidemiol Biomarkers Prev (2005): Flavonoids and breast cancer risk in Italy) who found an inverse association between flavones and breast cancer risk, confirming the results of an earlier Greek study.

    Finally a recent assessment of Regina Ziegler, of the National Cancer Institute concluded that "at present, scientific research does not support increasing phytoestrogen intake among US women to Asian levels, nor does it suggest that the typical US phytoestrogen intake is problematic for healthy women" (Ziegler, Am J Clin Nutr:
    Phytoestrogens and breast cancer). Similarly, Kienan-Boker(Am J Clin Nutr (2004): Dietary phytoestrogens and breast cancer risk) concluded more broadly still that a high intake of isoflavones or mammalian lignans (not naturally occurring in plant foods) is not significantly related to breast cancer risk.

    Evidencewatch Commentary:
    However, one methodological problem with the Ziegler and Kienan-Boker studies is the failure to control for or segregate menopausal status: Hirose et al. (Br J Cancer (2005):
    Soybean products and reduction of breast cancer risk: a case-control study in Japan) who found a statistically inverse association between tofu or isoflavone intake and risk of breast cancer in Japanese premenopausal women, while no statistically significant association was evident with the risk among postmenopausal women. But Boyapati et al. (Breast Cancer Res Treat (2005): Soyfood intake and breast cancer survival: a followup of the Shanghai Breast Cancer Study) found that soy intake prior to cancer diagnosis was unrelated to disease-free breast cancer survival, and did not differ according to ER/PR status, tumor stage, age at diagnosis, body mass index (BMI), waist to hip ratio (WHR), or menopausal status, concluding that soyfoods do not have an adverse effect on breast cancer survival. And Wood et al. (Cancer Res (2006): Dietary soy isoflavones inhibit estrogen effects in the postmenopausal breast) found that in the presence of estrogen higher doses of dietary soy isoflavones may alter ER signaling and induce selective antagonistic effects in the breast, but not in lower-estrogen environments.

    And some early studies had suggested that components of soy phytoestrogens may be stimulatory to breast cancer, later evidence argues against this, at least not for short-term consumption: see Gallo et al. (Carcinogenesis (2006): Lack of stimulatory activity of a phytoestrogen-containing soy extract on the growth of breast cancer tumors in mice) who found that a phytoestrogens-containing soy extract could be not harmful for women with a history of or at high risk for breast cancer, at least for short treatment-periods.
    It appears that the issue is one of complex and potentially confounding factors, with the form of isoflavone used (purified vs soy products), dose (low vs high), timing, and duration of exposure of isoflavones all playing major roles in determining overall agonistic or antagonistic effects (Kumar et al., Front Biosci (2004): Isoflavones in breast cancer chemoprevention: where do we go from here?), so further more closely controlled studies are required to be dispositive.

    Breast Cancer prevention Watch Conclusions:
    To date, Evidencewatch therefore concludes that the weight of the evidence
    (1) strongly suggests
    that soyfoods do not adversely effect breast cancer survival, and
    (2) subgroup analysis suggests that increased consumption of soy isoflavones is associated with reduced risk of breast cancer, but only in premenopausal women; in postmenopausal women there was no no statistically significant association. This is in part confirmed and explained by the findings of Wood and colleagues (Cancer Res (2006): Dietary soy isoflavones inhibit estrogen effects in the postmenopausal breast) which established that in the presence of estrogen, higher doses of dietary soy isoflavones alter estrogen receptor signaling and induce selective antagonistic (beneficial) effects in the breast, but not in lower-estrogen environments, including those of natural menopause, or an oncotherapy-induced menopausal state (see also the review of Rice & Whitehead, Endocr Relat Cancer (2006): Phytoestrogens and breast cancer –promoters or protectors? who concluded that high consumption of phytoestrogens are associated with a lower incidence of breast cancer).

    Research on drug interactions in the breast cancer setting suggests that although soy isoflavone phytoestrogens are associated with reduced breast cancer risk solely for premenopausal women, there is still a caution: the soybean components daidzein and genistein, as well as other CAM agents, most notably black cohosh, St. John's Wort, teas and extracts of goldenseal, chamomile, sage, thyme, licorice and cloves, and grapefruit juice, can interfere with the bioavailability of certain oncotherapies, in particular taxanes (docetaxel (Taxotere), paclitaxel (Taxol)) or any of the Vinca alkaloids (vinorelbine (Navelbine), vinblastine (Velban), vincristine (Oncovin)), and goldenseal and St. John's Wort can in addition, like SSRI type antidepressants, interfere with tamoxifen bioavailability. Other chemotherapies are not affected significantly, nor are any aromatase inhibitors (anastrozole (Arimidex), letrozole (Femara) and exemestane (Aromasin)). For details, see our Herbal/Drug Interactions in Breast Cancer Therapy; the tamoxifen/antidepressants interaction issue is summarized separately at: Antidepressants (SSRIs) & Tamoxifen: New Warnings.

  • The Safety of Soy in Breast Cancer
    There is some provisional data to suggest that soy or isoflavones may be associated with increased breast cancer risk, for example, exposure to physiologic concentrations of genistein in vitro activates ER-a and induces normal and malignant cell proliferation in vitro and in vivo. So on this pro-risk perspective, see especially Ju et al (J Nutr (2001):
    Physiological Concentrations of Dietary Genistein Dose-Dependently Stimulate Growth of Estrogen-Dependent Human Breast Cancer (MCF-7) Tumors Implanted in Athymic Nude Mice), Allred et al (Carcinogenesis (2004): Dietary genistein results in larger MNU-induced, estrogen-dependent mammary tumors following ovariectomy of Sprague–Dawley rats; Chen & Wong (J Clin Endocrinol Metab (2004): Genistein Enhances Insulin-Like Growth Factor Signaling Pathway in Human Breast Cancer (MCF-7) Cells); Allred et al (Carcinogenesis (2004): Soy processing influences growth of estrogen-dependent breast cancer tumors) who concluded, narrowly, that for postmenopausal women with estrogen-dependent breast cancer, the consumption of foods containing soy flour is more advisable than consuming isoflavones in more purified forms (such as purified genistein, soy protein isolate, isoflavone-rich soy extracts, or isoflavone capsules, or soy that is ground, defatted and toasted); and Ju et al. (Carcinogenesis (2006): Genistein stimulates growth of human breast cancer cells in a novel, postmenopausal animal model, with low plasma estradiol concentrations).

    [new: 5/05/07] However, our systemic review suggests that methodologically problems render much of this literature - and three researchers in particular, Clinton Allred, Kimberley Allred, and Young Ju (all at University of Illinois at Urbana) have pretty much made a career of trying to prove the dangers of soy / phytoestrogens / genistein in a breast cancer setting - inconclusive, and in conflict with other studies findings of no significant increased risk, and we often end up with the "dueling studies" phenomenon: for example, we have Young Ju and colleagues (Carcinogenesis (2006): Genistein stimulates growth of human breast cancer cells in a novel, postmenopausal animal model, with low plasma estradiol concentrations)) with the pro-risk perspective, while in the same journal, same year, we have the Italian researchers of Daniella Gallo and colleagues ((Carcinogenesis (2006): Lack of stimulatory activity of a Phytoestrogen-containing soy extract on the growth of breast cancer tumors in mice) on the opposite anti-risk side. Furthermore a protective effect of genistein is also documented in some studies: Mai and colleagues at Beth Israel in Boston determined that genistein may synergistically sensitize the response of ER+ and HER2-overexpressing breast cancer cells to TAM treatment in vitro (Mai Z, Blackburn GL, Zhou JR. Genistein sensitizes inhibitory effect of tamoxifen on the growth of estrogen receptor-positive and HER2-overexpressing human breast cancer cells. Mol Carcinog. 2007 Feb 12). And Martijn Verheus and colleagues investigated the association between plasma phytoestrogen levels and breast cancer risk in a prospective nested case-control study using the Prospect cohort within the European Prospective Investigation into Cancer and Nutrition, finding that high genistein circulation levels were associated with reduced breast cancer risk, with no difference across premenopausal, perimenopausal women, and in postmenopausal women (Verheus M, van Gils CH, Keinan-Boker L, Grace PB, Bingham SA, Peeters PH. Plasma phytoestrogens and subsequent breast cancer risk. J Clin Oncol. 2007 Feb 20; 25(6):648-55).

    Now, note also that all these studies issue, necessarily, a large numbers of provisos and qualifications that essentially render generalizing to a clear and decisive conclusion one way or the other just about impossible, especially given the narrow scope of product form and formulation (which soy?) and trial design particularities, and of course these studies are often preclinical animal model-based or epidemiological, intrinsically not inspiring the high confidence of tightly controlled and designed prospective RCTs or better yet, systematic reviews of high-quality RCTs.

    And all fail to control for stage-dependent effects of specific dietary components on carcinogenesis, where there may be wide variety of results, and conclusions, contingent on whether the design or model is dealing with early, middle and late stages of tumorogenesis (what I call the tumor-stage fallacy; see Jennifer Fenton and Norman Hord's thoughtful discussion of this issue (Carcinogenesis (2006): Stage matters: choosing relevant model systems to address hypotheses in diet and cancer chemoprevention research), in addition to confounding as to equol versus non-equol producers, pre- and post-menopausal status, receptor status (ER/PR) and degree of receptor positivity of negativity, other co-dietary consumption, etc. Thus, a rare study that controlled for equol - the intestinal bacterial metabolite of daidzein, which together with genistein form the two main isoflavones in legumes - to evaluate the estrogenic potential of daidzein and equol, finding that dietary daidzein had a slight but significant stimulatory effect on tumor growth, whereas equol did not stimulate the growth of estrogen-dependent breast tumor growth nor increase the cell proliferation in tumors, and therefore that pharmacokinetic and/or metabolic factors may mute or weaken the estrogenic effects of daidzein and equol in vivo, and since most people consume complex combinations of these various components, the final overall impact on risk is indeterminate and may be an increase or a decrease indifferently, unless we can control, concurrently, for all relevant components, tumorogenesis stages, receptor and menopausal status, form of soy or isoflavone, co-dietary factors, age, and numerous other parameters.

    Therefore even if these studies were to weakly suggest an estrogenic effect, and more importantly (since such an effect may be clinically nonsignificant) a theoretical potential for increased breast cancer risk, nonetheless the estrogenic activity of soy appears to be minimal, even in the most susceptible populations, that of postmenopausal women (as first shown by DD Baird and colleagues at the National Institute of Environmental Health Sciences, J Clin Endocrinol Metab (1995): Dietary intervention study to assess estrogenicity of dietary soy among postmenopausal women [pdf], and most recently in the meta-analysis of Bruce Trock and colleagues, J Natl Cancer Inst (2006): Meta-Analysis of Soy Intake and Breast Cancer Risk).

    In addition, these studies commit another fallacy, that of failing to recognize and control for potential cross-neutralization: so for example many of the above cited pro-risk studies focus on putative proliferation-stimulative activity of genistein and more specifically on a potential interference effect on tamoxifen efficacy; but Andreas Constantinou and colleagues at University of Illinois at Chicago (Eur J Cancer (2005): The soy isoflavone daidzein improves the capacity of tamoxifen to prevent mammary tumours) in a cleverly designed study showed conclusively that the combination of daidzein with tamoxifen produces increased protection against mammary carcinogenesis, in contrast to the combination of genistein with tamoxifen which produces an opposing/ compromising effect when compared with tamoxifen alone. Given that soybeans contain both isoflavone components, net effect is unlikely to be either strongly positive or negative on tamoxifen activity.

    Furthermore, although the recent meta-analysis of Trock and colleagues (J Natl Cancer Inst (2006): Meta-Analysis of Soy Intake and Breast Cancer Risk) suggest that soy intake is associated with a modest reduction in the risk of breast cancer, this is muted by the basic limitation of most meta-analyses, that of broad and potentially statistically significant heterogeneity across the underlying studies aggregated, and in addition can be no stronger than the data type analyzed which is epidemiologic (see also the thoughtful commentary by María Elena Martínez of the Arizona Cancer Center and colleagues, J Natl Cancer Inst (2006): Soy and Breast Cancer: The Controversy Continues).

    Essentially, the Trock meta-analysis examined 18 epidemiologic studies (12 case–control and six cohort or nested case–control) published between 1978 and 2004 to determine the association of soy exposure and breast cancer risk, and found among all studies a small reduction in risk of breast cancer with high soy intake versus low intake.

    Breast Cancer Prevention Watch: Conclusions
    Upon systematic review and critical appraisal, we find on the weight of the evidence that there is weak but not sufficiently dispositive data to support a modest protective effect of the standard American soy diet on breast cancer, with best guidance suggesting that the safest soy consumption is that of foods containing soy flour, in preference to more purified forms of isoflavones such as purified genistein, soy protein isolate, isoflavone-rich soy extracts, or isoflavone capsules, or soy that is ground, defatted and toasted, and that furthermore whole soybean products by virtue of their containing both the genistein and daidzein isoflavone components are unlikely to have any net-adverse impact on tamoxifen activity.

  • Black Cohosh:
    Hormone replacement therapy is contraindicated in women with breast cancer. Extracts from the rhizomes of Cimicifuga racemosa, have gained acceptance as a natural alternative for the treatment of menopausal symptoms. In the present study we investigated the antiproliferative activity of C. racemosa extracts (isopropanolic and ethanolic) on the estrogen receptor positive MCF-7 and estrogen receptor negative MDA-MB231 breast cancer cells. These results indicate that C. racemosa extract exerts no proliferative activity, but kills the estrogen receptor positive MCF-7 as well as estrogen receptor negative MDA-MB231 cells by activation of caspases and induction of apoptosis (Hostanska et al., Breast Cancer Res Treat:
    Cimicifuga racemosa extract inhibits proliferation of estrogen receptor-positive and negative human breast carcinoma cell lines by induction of apoptosis).
    One study found that black cohosh contains constituents that inhibit the growth of human breast cancer cells, and therefore might eventually be useful in the prevention or treatment of breast cancer. (Einbond et al., Breast Cancer Res Treat:
    Growth inhibitory activity of extracts and purified components of black cohosh on human breast cancer cells).

    For complete coverage of
    (1) the use of black cohosh for menopausal vasomotor symptoms, especially hot flashes,
    (2) its safety in the breast cancer setting,
    (3) its bone osteoprotective activity, and
    (4) the issue of interaction with oncotherapeutic agents,

    see Black Cohosh Issues: Hot Flashes, Osteoprotection, Breast Cancer
    on our special Menopause page.

  • Essiac Tea
    This product, and the Essiac based Flor-Essence, created by a Canadian nurse, Renèe M. Caisse (‘Caisse’ spelled backwards is ‘Essiac’), has been in use for over 70 years both to ameliorate the adverse effects of traditional oncotherapies and as a putative cancer therapy itself. Essiac tea contains four herbals: (1) burdock root, (2) Indian rhubarb root, (2) sheapshead sorrel, and (4) slippery elm bark, while Flor-Essence adds: (5) watercress (6) blessed thistle (7) red clover and (8) kelp.

    With respect to Essiac tea, one systematic review conducted by the Task Force
    on Alternative Therapies of the Canadian Breast Cancer Research Initiative (CBCRI) concluded that although some weak evidence of its effectiveness may exist, the nature and quality of studies reporting benefit are such that the findings can only be regarded as preliminary (E. Kaegi, CMAJ (1998): Unconventional therapies for cancer: 1. Essiac [pdf]). A second more recent systematic review (Boon & Wong, Expert Opin Pharmacother (2004): Botanical medicine and cancer: a review of the safety and efficacy) concluded that additional research is needed in order to determine the efficacy of essiac, and both reviews failed to uncover any published clinical trial of essiac.

    See also National Cancer Institute, NCI Cancer Topics (2005): Essiac/Flor•Essence (PDQ®) [health professional version]; Memorial Sloan-Kettering Cancer Center (MSKCC) About Herbs (2005): ESSIAC (Burdock root (Arctium lappa), sheep sorrel (Rumex acetosella), slippery elm bark (Ulmus fulva), turkish rhubarb root (Rheum palmatum)); MD Anderson Cancer Center, CIMER (Complementary/Integrative Medicine Education Resources) Reviews of Therapies (2005): Herbal / Plant Therapies: Essiac.

    Breast Cancer Prevention Watch
    Conclusion: Essiac Tea

    Although some researchers such as Leonard et al. (J Ethnopharmacol (2006): Essiac tea: Scavenging of reactive oxygen species and effects on DNA damage) have found that Essiac tea possesses potent antioxidant and DNA-protective activity, properties that are speculated to be common to natural anticancer agents (see also Cheung et al., Oncol Rep (2005): Antioxidant and anti-inflammatory properties of ESSIAC and Flor-Essence), and at least one uncontrolled case report (Can J Urol (2005): Remission of hormone-refractory prostate cancer attributed to Essiac) has suggested a response by one 64-year-old man with hormone-refractory prostate cancer from Essiac tea, nonetheless such non-clinical considerations and isolated uncontrolled case reports are uncompelling and given this, Breast Cancer Prevention Watch concludes on the balance of the evidence that there is currently insufficient evidence to establish the efficacy and safety of Essiac tea or Flor-Essence in any aspect of cancer therapy. In addition, researcher at the University of Toronto found that essiac tea failed to demonstrate significant hypoglycemic, hepatoprotective, or immunomodulatory properties (Leonard et al., Anticancer Res (2006) An in vivo analysis of the herbal compound essiac).

    Breast Cancer Prevention Watch Warning:
    Furthermore, Breast Cancer Prevention Watch notes that Flor-Essence - which contains in addition to the four herbs of Essiac, also watercress, blessed thistle, red clover, and kelp - can actually promote mammary tumor development in the Sprague-Dawley rat model (Bennett et al. Breast Cancer Res Treat (2005): Flor-Essence herbal tonic does not inhibit mammary tumor development in Sprague Dawley rats), suggesting caution in human application, especially contraindicated in women with existing breast carcinoma. And recently findings (Kulp et al., Breast Cancer Res Treat (2006):
    Essiac((R)) and Flor-Essence((R)) herbal tonics stimulate the in vitro growth of human breast cancer cells) suggest that even the simpler compound of Essiac tea as well as Flor-Essence herbal tonic adversely increase the growth of human breast cancer cells: Essiac tea and Flor-Essence stimulated cell proliferation relative to untreated controls in both ER-positive and ER-negative cell lines (also producing a dose-dependent increase in ER dependent luciferase activity in MCF-7 cells), showing that both herbal tonics can stimulate the growth of human breast cancer cells through ER mediated as well as ER independent mechanisms of action.

  • Mistletoe (Iscador):
    Extracts of mistletoe (Viscum album L.), a semi-parasitic plant living on various trees such as oak, pine, fir, elm and apple, are marketed under several trade names, mainly in Europe (Iscador, Helixor, Eurixor, Isorel), and have been extensively studied for antitumor activity in laboratory, animal and human clinical trials.

    Postoperative complementary treatment of breast cancer patients with lectin-standardized mistletoe extract (sME) proved to be a well tolerated optimization of standard tumor-destructive therapies, mainly improving quality of life and relapse-free intervals in defined UICC stages (Schumacher et al., Anticancer Res:
    Influence of postoperative complementary treatment with lectin-standardized mistletoe extract on breast cancer patients. A controlled epidemiological multicentric retrolective cohort study).

    And in a comprehensive epidemiological study, Bock et al. (Arzneimittelforschung (2004): Efficacy and safety of long-term complementary treatment with standardized European mistletoe extract (Viscum album L.) in addition to the conventional adjuvant oncologic therapy in patients with primary non-metastasized mammary carcinoma. Results of a multi-center, comparative, epidemiological cohort study in Germany and Switzerland) confirmed the safety of a standardized mistletoe extract in patients with primary, non-metastatic breast cancer, with reduced disease and treatment-associated symptoms, and prolonged overall survival in the mistletoe extract group as compared with controls. Similarly Grossart-Maticek et al. in their review (Altern Ther Health Med (2001): Use of Iscador, an extract of European mistletoe (Viscum album), in cancer treatment: prospective nonrandomized and randomized matched-pair studies nested with a cohort study [pdf]) in their review of a mistletoe extract preparation (Iscador) found that prospective controlled nonrandomized and randomized matched-pair studies nested within a cohort study of 10,226 cancer patients treated with Iscador and derivatives suggested that survival time was longer in patients treated with Iscador.

    A recent cell study by Dutch researchers Harmsma and colleagues (Harmsma et al., Arzneimittelforschung (2006): Effects of mistletoe (Viscum album L.) extracts Iscador on cell cycle and survival of tumor cells) found that both formulations of Iscador Quercus Spezial and Iscador Malus Spezial induced apoptotic activity after early cell cycle inhibition in a dose dependent manner, with a stronger response exerted by Iscador Malus than Iscador Quercus; and the in vitro cell study of Swiss researchers Kovacs and colleagues (Arzneimittelforschung (2006):
    Cytostatic and cytocidal effects of mistletoe (Viscum album L.) quercus extract Iscador) on the Viscum album Quercus extract form confirmed mistletoe operation as first a cell proliferation inhibitory effect followed by apoptosis, with the greatest activity seen in cells having a high proliferation rate, and the French research team of Elluru and colleagues summarized the mechanisms underlying the antitumoral activity of mistletoe to involve apoptosis and angiogenesis, as well as immunomodulation.

    And in one of the few human trials, an EORTC international research team (Schöffski et al., Ann Oncol (2004): Phase I trial of intravenous aviscumine (rViscumin) in patients with solid tumors: a study of the European Organization for Research and Treatment of Cancer New Drug Development Group) designed the very first study for the i.v. administration of the recombinant protein form of mistletoe, aviscumine, an escherichia coli-derived recombinant type II ribosome-inactivating protein which is the recombinant counterpart of natural mistletoe lectin-l, in patients with advanced cancers refractory to conventional treatment, including colorectal, ovarian, renal cell and breast cancer patients. The best response obtained was stable disease in 11 patients, lasting for two to eight cycles, and on the basis of their findings they recommended 5600 ng/kg twice weekly as the optimal dose.

    Note that the preparation of mistletoe extract can be important: of two forms, lectin-rich form (Iscador Qu and a lectin-poor but viscotoxin-rich form (Iscador Pini (Weleda Company, Germany), the lectin rich form may induce eosinophilia [abnormal levels of eosinophils, a type of white blood cell], unobserved in the viscotoxin-rich form (Huber et al., J Altern Complement Med (2002): Effects of a lectin- and a viscotoxin-rich mistletoe preparation on clinical and hematologic parameters: a placebo-controlled evaluation in healthy subjects).

    Nonetheless, as pointed out by a recent extensive review conducted by NCI (National Cancer Institute, NCI Cancer Topics (2006): Mistletoe Extracts PDQ), almost all surveyed studies exhibited methodological problems and weaknesses compromising the ability to draw decisive conclusions, and as of this writing mistletoe extracts require further confirming trials to achieve a compelling level of evidence for efficacy in various human cancers. Similarly, an early systematic review (E. Kaegi, CMAJ (1998): Unconventional therapies for cancer: 3. Iscador [pdf]) concluded that although there is laboratory evidence of biological activity that may be beneficial to cancer patients, the evidence of clinical benefit from human studies remains weak and inconclusive, and the same conclusion of insufficient or methodologically compromised evidence of the efficacy of mistletoe as anticancer therapy has been drawn in other systematic reviews: Bar-Sela et al. (Harefuah (2006): Mistletoe (Viscum Album) Preparations: An Optional Drug for Cancer Patients?), Ernst et al. (Int J Cancer (2003): Mistletoe for cancer? A systematic review of randomised clinical trials), and Kienle et al. (Eur J Med Res (2003): Mistletoe in cancer - a systematic review on controlled clinical trials).

    Mistletoe is presently under several clinical trials, including one NCCAM (National Center for Complementary and Alternative Medicine)-sponsored study (NIH Clinical Trials: Mistletoe Extract and Gemcitabine for the Treatment of Solid Tumor Cancers) of mistletoe extract and gemcitabine in patients with solid tumor cancers including breast carcinoma.

    See also Memorial Sloan-Kettering Cancer Center (MSKCC) About Herbs (2005): MISTLETOE (EUROPEAN) (Viscum album, Viscum coloratum), and MD Anderson Cancer Center, CIMER (Complementary/Integrative Medicine Education Resources) Reviews of Therapies (2005): Herbal / Plant Therapies: Mistletoe.

    Breast Cancer Prevention Watch
    Conclusion: Mistletoe

    Breast Cancer Prevention Watch concludes on the balance of the evidence that there is currently insufficient evidence to establish the efficacy and safety of Essiac tea or Flor-Essence in any aspect of cancer therapy.

  • Calcium d-glucarate:
    Calcium-D-glucarate is the calcium salt of D-glucaric acid, a substance produced naturally in small amounts by mammals, including humans. Glucaric acid is also found in many fruits and vegetables with the highest concentrations to be found in oranges, apples, grapefruit, and cruciferous vegetables. Oral supplementation of calcium-D-glucarate has been shown to inhibit beta-glucuronidase, an enzyme produced by colonic microflora and involved in Phase II liver detoxification. Elevated beta-glucuronidase activity is associated with an increased risk for various cancers, particularly hormone-dependent cancers such as breast, prostate, and colon cancers. Other potential clinical applications of oral calcium-D-glucarate include regulation of estrogen metabolism and as a lipid-lowering agent. (See Altern Med Rev:
    Calcium-D-glucarate [pdf]).

  • Vitamin D + Calcium
    It has been recently found that higher intakes of vitamin D and calcium (400 IU vitamin D and 1,000 mg calcium) from food and supplements are associated with lower levels of breast density among premenopausal, but not postmenopausal, women, and given that breast density is one of the strongest breast cancer risk indicators, this suggests that increased intake of vitamin D and calcium may represent a safe inexpensive strategy for breast cancer prevention (Berube et al., Cancer Epidemiol Biomarkers Prev (2005):
    Vitamin D and Calcium Intakes from Food or Supplements and Mammographic Breast Density).

    This has also been confirmed in the prospective study of McCullough et al. (Cancer Epidemiol Biomarkers Prev (2005):
    Dairy, calcium, and vitamin D intake and postmenopausal breast cancer risk in the Cancer Prevention Study II Nutrition Cohort) who found that women with the highest intake of dietary calcium (>1,250 mg/daily) were at a lower risk of breast cancer than those reporting <=500 mg/daily; however, it is important to note that neither use of supplemental calcium nor vitamin D intake was associated with risk. Consumption starting at two or more servings of dairy products per day was likewise inversely associated with risk, compared with less than a half a servings/daily), with associations slightly stronger in women with estrogen receptor–positive tumors, supporting the hypothesis that dietary calcium and/or some other components in dairy products may modestly reduce risk of postmenopausal breast cancer.

  • Vitamin E
    Many observational studies have suggested that vitamin E from dietary sources (a-tocopherol with or without other related tocopherols and tocotrienols) may provide women with at least modest protection from breast cancer, through antiproliferative and pro-apoptotic effects: so Schwenke, J Nutr Biochem (2002): Does lack of tocopherols and tocotrienols put women at increased risk of breast cancer?) found in his review, noting however that there is no evidence that non-dietary vitamin E supplements confer any protection whatever against breast cancer (animal studies suggest that a-tocopherol supplementation alone has little effect on mammary tumors; see also Kimmick et al. (Nutr Cancer (1997): Vitamin E and breast cancer: a review).

    The exact impact of Vitamin E on breast cancer risk has not wholly been clarified, but a recent study sheds some considerable light on the matter and may help account for inconsistent fin dings to date. Charmas et al. (Nutr Cancer (2005): Novel interactions of vitamin E and estrogen in breast cancer) investigated the effect of vitamin E (alpha-tocopherol) on breast cancer cell growth, finding a dose-dependent inhibition of cell proliferation in estrogen receptor (ER)-positive cells, reducing significantly the response of breast cancer cell lines to estrogen. However, no growth inhibition was observed when cells were grown in the absence of estrogen, and indeed vitamin E altered and decreased the growth inhibition induced by tamoxifen, suggesting an effect of vitamin E on the expression of ER. Thus, vitamin E may inhibit ER-positive cell growth by altering the cellular response to estrogen, but may compromise the antitumor efficacy of tamoxifen due tamoxifen's anti-estrogen activity.

    As Vitamin E is known to be a complex group of compounds, research is investigating what compounds are most active in antiproliferative activity.
    It appears that one compound known as alpha-TEA (alpha-tocopherol ether linked acetic acid analogue) is a potent inducer of apoptosis (inducing cancer cells but not normal cells to undergo a form of programmed cell death) in a wide variety of epithelial cancer cell types, including breast, prostate, lung, colon, ovarian, cervical, and endometrial, and in combination with the COX-2 inhibitor celecoxib (Celebrex) and the chemotherapeutic agent 9-nitro-camptothecin (9NC, an analogue of Camptothecin (CPT)) decreases breast cancer animal model tumor burden and inhibits metastasis significantly better than do single-agent treatments (Kline et al., J Nutr (2004): Vitamin E and Breast Cancer), suggesting that Vitamin E's antitumor activity may require for maximal expression combination with other antitumor or cell-expressive agents.

    [new] However, Breast Cancer Prevention Watch notes that at least some recent evidence appears to suggest potential interference between Vitamin E and tamoxifen: supplemental antioxidant vitamin E (alpha-tocopherol) acts at the plasma membrane to alter the effectiveness of tamoxifen in ER-positive breast cancer cell lines, as confirmed in the cell study of Elizabeth Peralta and colleagues (Surgery (2006):
    Effect of vitamin E on tamoxifen-treated breast cancer cells) reported at the 63rd Annual Meeting of the Central Surgical Association, Louisville, Kentucky (March 9-11, 2006), who found that that supplemental vitamin E decreased the proliferation-inhibitory effect of tamoxifen on ER+ breast cancer cells and nullified the rapid rise in intracellular calcium leading to apoptosis stimulated by tamoxifen; hence, the use of such vitamin E acetate supplements would appear to be inadvisable for ER+ breast cancer patients on tamoxifen.

    Vitamin C and Vitamin E, Selenium: Summary
    Several studies have suggested an inverse association between Vitamin C and Vitamin E, as well as selenium, and breast cancer risk (i.e., higher consumption is associated with reduced risk), primarily through increasing serum levels of a lignan called enterolactone. Lignans are phytonutrients that exhibit strong antioxidant properties, and can modulate hormone levels. The human lignan enterolactone is a mammalian lignan produced by intestinal bacteria from plant components obtained in the diet. Enterolactone, and certain other lignans - especially flaxseed (see below) and the lignans found concentrated in berries - and have been associated with a reduced risk of breast cancer for both premenopausal and postmenopausal women, as well as with a reduced risk of other hormone-dependent cancers (like prostate cancer), reduced risk of acute coronary events, and possibly also reduced risk of osteoporosis.

    However, except for selenium, there are other contradictory studies with respect to supplementary Vitamins C and E, so that on the balance of the evidence, supplementation with the antioxidant vitamins C and E is not established to be associated with a beneficial reduction in breast cancer risk (in part due to possible interfering interactions with certain oncotherapies), and pending further more decisive trials, breast cancer patients should avoid such supplementation and restrict intake to quality dietary sources in fruits and vegetables. On the other hand, selenium supplementation is well-established as beneficial in hormone-dependent cancers, including breast cancer, at a level of 200 micrograms daily.

  • Green Tea:
    Although there is substantial in vitro and in vivo evidence suggestive of tea polyphenols as chemopreventive agents against various cancers, epidemiologic data is not clearly supportive of the chemoprotective role of tea in breast cancer etiology. Thus, in one pooled analysis of two prospective studies green-tea intake was not associated with a lower risk of breast cancer (see Suzuki et al., Br J Cancer:
    Green tea and the risk of breast cancer: pooled analysis of two prospective studies in Japan).

    However, Anna Wu and colleagues (Int J Cancer:
    Green tea and risk of breast cancer in Asian Americans; also Wu et al., Cancer Res: Tea Intake, COMT Genotype, and Breast Cancer in Asian-American Women) at the Department of Preventive Medicine, University of Southern California discovered a significant trend of decreasing risk with increasing amount of green tea intake in their population-based, case-control study of breast cancer among Los Angeles county Chinese, Japanese and Filipino women. Their study found that although breast cancer risk was not related to consumption of black tea, green tea drinkers showed a significantly reduced risk of breast cancer, maintained even after adjusting for age, specific Asian ethnicity, birthplace, age at menarche, parity, menopausal status, use of menopausal hormones, body size and total caloric and black tea intake, and other potentially confounding factors such as smoking, alcohol, and coffee intake, breast cancer family history, physical activity, and intake of soy and dark green vegetables. They also noted that although both green tea and soy intake had significant, independent protective effects on breast cancer risk, the benefit of green tea was primarily observed among low soy consumer subjects, while the protective effect of soy was primarily observed among nondrinkers of green tea. Therefore, at least as to In Asian-American women, there appears to be an important role for both green tea and soy intake in relation to breast cancer risk.

    And Seely et al. (Integr Cancer Ther (2005): The effects of green tea consumption on incidence of breast cancer and recurrence of breast cancer: a systematic review and meta-analysis) conducted a systematic review and meta-analyses of observational studies, concluding on the basis of the evidence that (1) to date, the epidemiological data indicates that consumption of 5 or more cups of green tea a day shows a non-statistically significant trend towards the prevention of breast cancer development, and (2) that evidence indicates that green tea consumption may possibly help prevent breast cancer recurrence in early stage (I and II) cancers, but that further studies are needed before clinical guidance can be put forth on the potential therapeutic application of green tea in breast carcinoma. In addition, Sun et al. (Carcinogenesis (2005): Green tea, black tea and breast cancer risk: a meta-analysis of epidemiological studies) examined populations in eight countries with respect to consumption of either green tea or black tea, or both, in relation to breast cancer risk, finding that for green tea, a meta-analysis of the studies shows a reduced risk of breast cancer for highest versus non/lowest intake, while in contrast for black tea, there appears to be a possible late-stage, promotional effect of black tea on breast carcinogenesis.

    Given the conflicting results and conclusions of the recent Suzuki analysis cited above on the one hand and the work of Wu and colleagues just cited, it is clear that further studies are needed to more precisely determine the relationship, if any, of green tea consumption and risk of breast cancer. Evidencewatch notes in this context that Wu's observation of the benefit of green tea primarily among low soy consumer subjects is intriguing, and may suggest that in high soy consumption populations, as found in Japanese subjects resident in Japan, the potential chemopreventive may be muted. Nonetheless, the balance of the evidence suggests at least that high green tea consumption (> 5 cups/daily) appears to exert beneficial effect on breast cancer prevention and possibly also recurrence. Another possible explanation of conflicting effects is suggested in the study of Yuan et al. (Carcinogenesis (2005): Green tea intake, ACE gene polymorphism and breast cancer risk among Chinese women in Singapore) where they hypothesized that the effect of polyphenols should be more prominent among women possessing high-activity ACE (angiotensin-converting enzyme) genotype than women with low-activity ACE genotype, given that it is known that women with low-activity genotype of the ACE gene had a reduced risk of breast cancer compared with those possessing high-activity ACE genotype; they further reasoned the inhibition of angiotensin II-induced reactive oxygen species production by green tea polyphenols may be one mechanism by which these polyphenols protect against human breast cancer, and so conducted a nested case–control study to test these hypotheses. They indeed found that no association between intake frequencies of green tea and risk of breast cancer among all women or those with low-activity ACE genotype, but among women with high-activity ACE genotype, intake frequency of green tea was associated with a statistically significant decrease in risk of breast cancer; black tea intake was unrelated to breast cancer risk irrespective of the ACE genotype. Thus, this study highlights the importance of genetically determined factors in evaluating the role of green tea intake in breast cancer development.

    Issues of Safety and Interaction
    Sherry Crow and and colleagues at the Arizona Cancer Center (Cancer Epidemiol Biomarkers Prev (2006): Effects of Repeated Green Tea Catechin Administration on Human Cytochrome P450 Activity) observed that preclinical studies suggested that green tea or green tea catechins can modulate the activities of drug-metabolizing enzymes, and they conducted a clinical study to determine the effect of repeated green tea catechin administration on human cytochrome P450 (CYP) enzyme activities, finding that Repeated green tea catechin administration (at a dose that contains 800 mg epigallocatechin gallate (EGCG) daily) is not likely to result in clinically significant interference with the disposition of drugs metabolized by CYP enzymes (CYP1A2, CYP2D6, CYP2C9, and CYP3A4).

    Synergy with Chemotherapy and Reversal of Drug Resistance
    Yuying Mei et al. (Landes Biosci (2005): Reversal of Multidrug Resistance in KB Cells with Tea Polyphenol Antioxidant) explored the reversal effects on multidrug resistance (MDR) via the antioxidant capacities of tea polyphenols, and EGCG in particular, based on the observation that drug resistance cells undergo oxidative stress, confirmed in doxorubicin (Adriamycin)-induced intracellular concentration of ROS (reactive oxygen species), and this MDR was reversed by tea polyphenols and EGCG. This was confirmed in the study by Feng Qian and colleagues at the East China University of Science and Technology (Boimed Pharmacotherap (2005): Modulation of P-glycoprotein function and reversal of multidrug resistance by (–)-epigallocatechin gallate in human cancer cells) who investigated the molecular mechanism of EGCG and its activity in the reversal of P-glycoprotein (P-gp) mediated MDR (multidrug resistance), finding that in vitro EGCG potentiated the cytotoxicity of doxorubicin to drug-resistant KB-A1 cells, and that in a KB-A1 cell xenograft model, EGCG addition enhanced the efficacy of doxorubicin, increasing the concentration of doxorubicin in resistant tumors, suggesting that EGCG modulates the function of P-gp and reverses P-gp mediated multidrug resistance in human cancer cells. And these findings themselves further confirm the earlier in vivo results of Qiang Zhang and colleagues who found that EGCG increased by 51% the concentration of doxorubicin in resistant tumors and also increased doxorubicin-induced apoptosis in those tumors, with the doxorubicin/EGCG combination being well-tolerated, and concluded therefore that EGCG chemosensitizes resistant tumor cells to doxorubicin (Zhang et al., Cancer Letters (2004): In vivo reversal of doxorubicin resistance by (?)-epigallocatechin gallate in a solid human carcinoma xenograft).

    Similar results were established in animal studies of leukemia, with doxorubicin-resistant (P388) leukemia cells by Yasuyuki Sadzuki and colleagues at the University of Shizuoka Japan, who found that green tea components (including caffeine, theanine, and EGCG) increased the doxorubicin-induced efficacy against these cells via an increase in the doxorubicin concentrations in the tumors and hence increasing the doxorubicin-induced antitumor activity (Sadzuki et al. (2000): (Efficacies of tea components on doxorubicin induced antitumor activity and reversal of multidrug resistance). These results were confirmed and extended in the research of the Mayo Clinic (Rochester, MN) team of Yean Lee and colleagues who observed that it has been previously established that CLL (chronic lymphocytic leukemia) cells synthesize and release VEGF (vascular endothelial growth factor) under normoxic and hypoxic conditions, and that CLL B cells also express VEGF membrane receptors (VEGF-R1 and VEGF-R2) which are spontaneously phosphorylated on these cells, suggesting that these cells are using VEGF as a survival factor, given that VEGF significantly increases the apoptotic resistance of CLL B cells. They therefore evaluated the impact of EGCG (epigallocatechin-3-gallate) (), a known receptor tyrosine kinase (RTK) inhibitor, on the VEGF receptor status and viability of CLL B cells, finding that EGCG significantly increased apoptosis/cell death in 8 of 10 CLL cell samples and suppressed both the Bcl-2 (B-cell leukemia/lymphoma-2), XIAP (X-linked inhibitor of apoptosis protein), and Mcl-1 (myeloid cell leukemia-1) proteins in the CLL cells, as well as VEGF-R1 and VEGF-R2 phosphorylation (incomplete suppression); they concluded from these findings that VEGF signaling regulates CLL cell survival signals and that interruption by EGCG of this autocrine pathway results in caspase activation and subsequent leukemic cell death (Lee at al., Blood (2004): VEGF receptor phosphorylation status and apoptosis is modulated by a green tea component, epigallocatechin-3-gallate (EGCG), in B-cell chronic lymphocytic leukemia).

    And more recently TD Shanafelt and colleagues at the Mayo Clinic (Rochester, MN) confirmed the ability of EGCG to induce apoptotic cell death in the leukemic B-cells in patients with CLL (chronic lymphocytic leukemia (CLL)). Indeed, the researchers document several patients with low grade B-cell malignancies seen in clinical practice at the clinic with steady clinical, laboratory, and/or radiographic evidence of progression who on their own initiative, began EGCG consumption and subsequently developed objective clinical response (Shanafelt et al., Leukemia Res (2006): Clinical effects of oral green tea extracts in four patients with low grade B-cell malignancies).

    Tae heung Kang and Chinese and Korean colleagues and researchers at Johns Hopkins found that a multimodality treatment regimen using DNA vaccination in combination with EGCG was effective in inhibiting large tumor growth, inducing tumor cellular apoptosis in a dose-dependent manner and enhanced tumor-specific T-cell immune response and enhanced antitumor effects, resulting in a higher cure rate than either immunotherapy or EGCG alone, as well as providing long-term antitumor protection in cured mice (Kang et al. Cancer Res (2007): Epigallocatechin-3-Gallate Enhances CD8+ T Cell–Mediated Antitumor Immunity Induced by DNA Vaccination).

    Mechanisms of EGCG Antitumor and Chemopreventive Activity
    EGCG is known to act at numerous points regulating cancer cell growth, survival, and metastasis, including effects at the DNA, RNA, and protein levels (Ann Beltz et al., Anticancer Agents Med Chem (2006): Mechanisms of cancer prevention by green and black tea polyphenols). Thus EGCG exerted caspase activation and altered Bcl-2 family member expression to induce cell cycle arrest or apoptosis; inhibited telomerase activity; reduction of nitric oxide production by means of the suppression of inducible nitric oxide synthase via blocking nuclear translocation of the transcription factor nuclear factor-kB; metastasis inhibition via effects on urokinase and matrix metalloproteinases; reduction of angiogenesis, in part by decreasing VEGF (vascular endothelial growth factor) production and receptor phosphorylation; reduction of dihydrofolate reductase activity affecting nucleic acid and protein synthesis; antagonism of aryl hydrocarbon receptor by directly binding the receptor's molecular chaperone, HSP-90 (heat shock protein 90). See also Zigang Dong at the University of Minnesota, BioFactors (2000): Effects of food factors on signal transduction pathways); and Nihal Ahmed and colleagues at the Case Western Reserve University (Arch Biochem Biophys (2000): Green Tea Polyphenol Epigallocatechin-3-Gallate Differentially Modulates Nuclear Factor ?B in Cancer Cells versus Normal Cells), who suggests that EGCG-induced cell cycle deregulation and apoptosis of cancer cells may be mediated through NF-kB inhibition.

    In the breast cancer specific context, it has been shown that EGCG is an inhibitor of VEGF induction and breast cancer angiogenesis (Maryam Artippour, J Nutr (2002): Green Tea Inhibits Vascular Endothelial Growth Factor (VEGF) Induction in Human Breast Cancer Cells, who concluded that inhibition of VEGF transcriptionappears to be one of the molecular mechanism(s) involved in the antiangiogenic effects of green tea, which may contribute to its potential use for breast cancer treatment and/or prevention). And Young-Joon Surh and colleagues at the Seoul National University, Mutat Res (2001): Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kB activation) found that curcumin, EGCG and resveratrol suppress activation of NF-kB.

    Hye-Kyung Na and Young-Joon Surh at Seoul National University found that EGCG blocked each stage of carcinogenesis by modulating signal transduction pathways involved in cell proliferation, transformation, inflammation, apoptosis, metastasis and invasion (Na & Surh, Mol Nutr Food Res (2006: Intracellular signaling network as a prime chemopreventive target of (-)-epigallocatechin gallate), including via transcription factors such as NF-kappa B (NF-kB). And EGCG inhibits the expression of VEGF (vascular endothelial growth factor) by breast, colon, and head and neck squamous cell carcinoma (HNSCC) carcinoma cells (Joshua Lambert and Chung Yang, J Nutr (2003): Mechanisms of Cancer Prevention by Tea Constituents).

    The benefits of green tea polyphenols, especially EGCG, appears to be part and parcel of the entire class of polyphenols, that includes the flavonoids, a large and diverse family of compounds synthesized by plants, with flavonoid subclasses of

    - anthocyanidins
    in berries and grapes with active components cyanidin, delphinidin, malvidin, pelargonidin peonidin, and petunidin,

    - flavanols
    in tea with catechin, epicatechin, epigallocatechin, epicatechin gallate, epigallocatechin-3-gallate (EGCG) and theaflavins, thearubigins, proanthocyanidins being the principle components of this flavanols subclass,

    - flavanones
    in citrus fruits with principle hesperetin, aringenin and eriodictyol components,

    - flavonols
    in onions that include principle components of quercetin, kaempferol, myricetin, and isorhamnetin,

    - flavone
    s in herbs and peppers with apigenin and luteolin as principle components, and

    - isoflavones
    in soy, especially the daidzein and genistein components (see Roderick Dashwood, J Nutr (2007): Frontiers in Polyphenols and Cancer Prevention).

    One question that arises is whether concurrent administration of two (or more) polyphenols, that is, dual polyphenols, or a polyphenol and another antitumor nutritional component, would yield synergistic activity. It would appear this is not always the case: although both sulforaphane, an isothiocyanate from broccoli, and the green tea component EGCG are highly across a number of cancers, no synergistic effects were seen when both agents were combined - on the contrary, one agent counteracted the beneficial effects of the other, yielding no significant aggregate chemopreventive action (Myzak et al., FASEB (2006): Sulforaphane inhibits HDAC activity in vivo and suppresses tumorogenesis in Apcmin mice). What we don't know is if this applies across the board to combinations of polyphenols and other nutritional agents operating over similar underlying pathways, or is an agent-with-agent specific interaction that must be explored for each potential synergy, or lack thereof, questions the new field of epigenetics is beginning to explore.

  • Curcumin
    Curcumin is the most active component of the Curcuma longa (turmeric) plant, and within curcumin, curcuminoids are responsible for the yellow color of turmeric and curry powder, and exhibits a broad range of biological effects ranging from antioxidant and anti-inflammatory / COX-2 inhibitory, to inhibition of angiogenesis (likely due to down regulation of proangiogenic genes such as VEGF and angiopoitin and a decrease in migration and invasion of endothelial cells), and antitumoral activity; at the molecular level, the active curcuminoids components exhibit multiple pathways of anticancer activity (Aggarwal et al: Curcumin Derived from Tumeric (Curcuma longa): A Spice for All Seasons [pdf], In: Preuss H, ed. Phytopharmaceuticals in Cancer Chemoprevention (CRC Press, 2005) including:

    • Exhibits tumorogenesis

    • Antiproliferative activity against Cancer Cells

    • Down-Regulates Activity of EGFR and Expression of HER2/neu

    • Down-Regulates Activation of Nuclear Factor kappa-b (NF-kappa-b)
      (factors implicated in chemoresistance and induced chemosensitivity)

    • Down-Regulates the Activation of STAT3 Pathway

    • Activates Peroxisome Proliferator-Activated Receptor-gamma

    • Down-Regulates the Activation of Activator Protein-1 (AP-1)
      and C-Jun Terminal Kinase (JNK)

    • Suppresses the Induction of Adhesion Molecules

    • Down-Regulates Cyclooxygenase-2 (COX-2) Expression

    • Inhibits Angiogenesis

    • Suppresses the Expression of MMP9 and
      Inducible Nitric Oxide Synthase (INOS)

    • Down-Regulates Cyclin D1 Expression

    • Exhibits Chemopreventive Activity

    • Inhibits Tumor Growth and Metastasis in Animals

    • Inhibits Androgen Receptors and AR-Related Cofactors

    • Induces apoptosis via the p53 pathway

    • mTOR (mammalian target of rapamycin) inhibitor (as recently found by Beevers et al., Carcinogenesis (2006): Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells)

  • In addition, curcumin can make susceptible to apoptosis cell lines that are resistant to certain apoptotic inducers and radiation (Singh & Khar, Anticancer Agents Med Chem (2006): Biological Effects of Curcumin and Its Role in Cancer Chemoprevention and Therapy) who conclude their review observing that "Curcumin . . . has emerged as one of the most powerful chemopreventive and anticancer agents"). And the recent study of the Spanish research team of Montagut et al (Endocr Relat Cancer (2006): Activation of nuclear factor- B is linked to resistance to neoadjuvant chemotherapy in breast cancer patients) suggests that curcumin's well-established activity as a NF-kappa-B inhibitor can be used to prevent or overcome chemoresistance in breast cancer.

    Preclinical findings also suggest that curcumin play play a critical role in the treatment and potential chemoprevention of organ/visceral breast cancer metastases. In this connection, note the findings of Aggarwal and his team at the Cytokine Research Laboratory of M.D. Anderson Cancer Center (Clin Cancer Res (2005): Curcumin Suppresses the Paclitaxel-Induced Nuclear Factor-B Pathway in Breast Cancer Cells and Inhibits Lung Metastasis of Human Breast Cancer in Nude Mice who hypothesized that because curcumin suppresses nuclear factor-kappa-B (NF-kappa-B) activation, and since most chemotherapeutic agents activate NF-kappa-B that mediates cell survival, proliferation, invasion, and metastasis, curcumin would potentiate the effect of chemotherapy in advanced breast cancer and inhibit lung metastasis, and their preclinical findings validated that hypothesis, showing that dietary administration of curcumin significantly decreased the incidence of breast cancer metastasis to the lung and suppressed the expression of NF-kappa-B, COX-2, and MMP-9 (matrix metalloproteinase-9), indicating that curcumin has a strong therapeutic potential in preventing breast cancer metastasis, probably through suppression of NF-kappa-B and NF-kappa-B–regulated gene products. For the lay reader, note that this study is discussed in the ACS News story: A Cancer Treatment in the Spice Cabinet? Researchers See Promise in Turmeric.

    It is highly interesting to note that our research suggests that this ability of curcumin to inhibit lung metastasis may also be shared by oral silibin (the active component of Silymarin / Milk Thistle), already in human use as a hepatoprotective drug, via the same mechanism of suppression of NF-kappa-B (see the study of Singh et al. at the University of Colorado: Clin Cancer Res (2004): Oral Silibinin Inhibits Lung Tumor Growth in Athymic Nude Mice and Forms a Novel Chemocombination with Doxorubicin Targeting Nuclear Factor B–Mediated Inducible Chemoresistance) who found that silibinin inhibits in vivo lung tumor growth and reduces systemic toxicity of doxorubicin with an enhanced therapeutic efficacy most likely via an inhibition of doxorubicin-induced chemoresistance involving NF-kappa-B signaling, concluding that silibinin is a potential agent for lung tumor growth inhibition, alone and in combination chemotherapy with antineoplastic agents including anthracycline drugs, and also exhibits preventive effects against doxorubicin-caused systemic toxicity. An more intriguing is the potential for silibin and related natural NF-kappa-B suppressors such as green tea polyphenols to form a multifocal angiostatic regimen (see Block, Integr Cancer Ther (2005): Multifocal Angiostatic Therapy: An Update).

    And other related research suggests that NF-B and its associated genes may also be relevant therapeutic targets in osteolytic tumor burden (Gordon et al., Cancer Res (2005): Nuclear Factor-B–Dependent Mechanisms in Breast Cancer Cells Regulate Tumor Burden and Osteolysis in Bone) thus suggesting that curcumin may have anti-metastatic activity in bone as well as lung breast cancer metastases.

    Besides inhibiting the activation of NFkappaB, it also inhibits the expression of HER-2 (Wu et al., Acta Pharmacol Sin (2006): Down-regulation of p210bcr/abl by curcumin involves disrupting molecular chaperone functions of Hsp90); see also Kim et al (Oncology Rep (2002): The role of HER-2 oncoprotein in drug-sensitivity in breast cancer [pdf]) who notes that curcumin reduces the tyrosine kinase activity of HER-2, which corresponds to the growth inhibition of HER-2 overexpressing breast cancer cell lines. Similarly, Hong et al., Clin Cancer Res (1999): Curcumin Inhibits Tyrosine Kinase Activity of p185neu and Also Depletes p185neu) have observed that curcumin also has anti-tyrosine kinase activity and has been shown to inhibit ligand-induced activation of the EGFR (epidermal growth factor receptor) tyrosine phosphorylation, leaving the protein level unaffected, and that curcumin was at that time the only natural compound known to inhibit tyrosine kinase activity and also to deplete the tyrosine kinase protein itself (see also Atalay et al., Ann Oncol (2003): Novel therapeutic strategies targeting the epidermal growth factor receptor (EGFR) family and its downstream effectors in breast cancer; and Dorai & Aggarwal, Cancer Let (2004): Role of chemopreventive agents in cancer therapy [pdf]).

    In conclusion, we agree with the summary observation of Aggarwal et al. (Curcumin Derived from Tumeric (Curcuma longa): A Spice for All Seasons [pdf], In: Preuss H, ed. Phytopharmaceuticals in Cancer Chemoprevention (CRC Press, 2005) that it is clear that curcumin exhibits activities against cancer, cardiovascular, diseases, and diabetes and that epidemiological evidence is further supportive, given that in countries like India with exceptional high consumption of dietary curcuminoids in the form of the Turmeric spice, the incidence of breast cancer is one eighth of that in the US, and interesting ovarian cancer rate in India is one fourth that of the US, while the incidence of lung cancer is one sixteenth of that of the US, and brain cancer one third of the US incidence level (and melanoma is 1/260th the level of that in the US).

    These observations on the efficacy and safety of curcumin have been similarly confirmed in the literature review of approx. 1500 papers on curcumin by Stig Bengmark of the Institute of Hepatology at the London Medical School (S Bengmark, JPEN J Parenter Enteral Nutr (2006): Curcumin, An Atoxic Antioxidant and Natural NFB, Cyclooxygenase-2, Lipooxygenase, and Inducible Nitric Oxide Synthase Inhibitor: A Shield Against Acute and Chronic Diseases ) who found that curcumin " . . . has been shown to be non-toxic, to have antioxidant activity, and to inhibit such mediators of inflammation as NF-kappaB, cyclooxygenase-2 (COX-2), lipooxygenase (LOX), and inducible nitric oxide synthase (iNOS)" and therefore that "there is ample evidence to support its clinical use, both as a prevention and a treatment".

    Safety of Curcumin: Issues of Drug Interference
    Researchers at the Lineberger Comprehensive Cancer Center at the University of North Carolina (Sivagurunathan et al, Cancer Res (2002): Dietary Curcumin Inhibits Chemotherapy-induced Apoptosis in Models of Human Breast Cancer) used an in vivo model of human breast cancer, finding that dietary supplementation with curcumin significantly inhibited cyclophosphamide-induced tumor regression, via a decrease in the activation of apoptosis by cyclophosphamide, as well as decreased JNK activation, supporting the hypothesis that dietary curcumin consummation and supplementation can inhibit chemotherapy-induced apoptosis through inhibition of ROS generation and blockade of JNK function.

    Breast Cancer Prevention Watch has reviewed these claims and has determined them to be against the overwhelming balance of the evidence, and the study on which these claims are purportedly founded exhibits severe methodological flaws that render the drawn conclusions wholly illicit: curcumin has distinct and sometimes contrary behavior that is acutely dose-related and it would appear that the level used in the study (10 µM) is insufficient to (1) produce superoxide radicals and (2) induce apoptosis especially as reactive oxygen species (ROS) appears to be necessary for curcumin’s apoptotic effect, setting in at levels of 50 µM and above, a fact further evidenced recently by the Polish team of Sikora et al. (Mol Cancer Ther (2006): Curcumin induces caspase-3-dependent apoptotic pathway but inhibits DNA fragmentation factor 40/caspase-activated DNase endonuclease in human Jurkat cells) who observed that curcumin's ability to induce cell death in many cancer cells depends on the cell type and curcumin concentration, and that in Jurkat cells, 50 µmol/L curcumin was required to severely lower cell survival.

    Furthermore, curcumin has been shown to augment the cytotoxic effects of chemotherapeutic drugs, including tamoxifen (Nolvadex) , doxorubicin (Adriamycin, Doxil), cisplatin (Platinol), camptothecin (CPT) , daunorubicin (Cerubidine, Daunomycin), vincristine (Oncovin), and melphalan (Alkeran)(see TM Mitchell's critique of the study in Cancer Res (2003): Correspondence re: Somasundaram et al., Dietary Curcumin Inhibits Chemotherapy-induced Apoptosis in Models of Human Breast Cancer), in direct contradiction of the Lineberger teams findings.

    In addition, the bioavailability issue is wholly ignored by the researchers: in humans after a dose of 2 g curcumin serum levels were either subtherapeutic being either wholly undetectable, or extremely low, but concomitant administration of piperine, an inhibitor of hepatic and intestinal glucuronidation, at 20 mg/kg produced much higher concentrations within 15 min to 1 hour later, with an increase in bioavailability of 2000%, demonstrating that piperine enhances the serum concentration, degree of absorption, and bioavailability of curcumin in humans (and with no adverse effects) (Shoba et al., Planta Med (1998): Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers). And even more unaccountably the Lineberger team used a maximum time limit of just 15 hours, despite the fact that curcumin’s cytotoxic effects typically do not occur for at least 48 hours (Hanif et al., J Lab Clin Med (1997): Curcumin, a natural plant phenolic food additive, inhibits cell proliferation and induces cell cycle changes in colon adenocarcinoma cell lines by a prostaglandin-independent pathway), with maximal growth inhibition at 72 hours (Goel et al., Cancer lett (2001): Specific inhibition of cyclooxygenase-2 (COX-2) expression by dietary curcumin in HT-29 human colon cancer cells). Therefore, for these reasons and the weight of the evidence, that we conclude that there is no compelling evidence curcumin exhibits any interference with established anticancer agents, with the further weight of the fact that to date, there are no animal or human data to corroborate the finding of Sivagurunathan and the Lineberger team.

    Safety of Curcumin: Safety in Human Clinical Trials
    Numerous human clinical trials have further attested to the safety of curcumin. Christopher Lao at the University of Michigan (UM)/Ann Arbor) headed a research team from UM, UCSD, and NCI/NIH who conducted a systematic dose escalation study (Lao et al., BMC Complement Altern Med (2006): Dose escalation of a curcuminoid formulation) of the pharmacology and safety / toxicology of standardized curcumin (from Sabinsa corporation) in humans to determine the MTD (maximum tolerated dose) and safety of a single dose of standardized curcumin extract, concluding that the safety and tolerance of curcumin in high oral dose appears to be excellent, with no significant toxicity in a dose step-through from 500, 1,000, 2,000, 4,000, 6,000 up to 8,000 mg., with no limiting maximum tolerated dose. Similarly, researchers at the National Taiwan University College of Medicine (Cheng et al., Anticancer Res (2001): Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions) reported no treatment-related toxicity of curcumin in doses up to 8,000 mg/day for 3 months, in a high-risk population of subjects with urinary bladder cancer, arsenic Bowen's disease of the skin, uterine CIN (cervical intraepithelial neoplasm) (CIN), oral leucoplakia, and intestinal metaplasia of the stomach. In another dose-escalation study to determine the pharmacology and safety of curcumin in humans, Ricky Sharma at the University of Leicester and coresearchers (Sharma et al., Clin Cancer Res (2001): Pharmacodynamic and Pharmacokinetic Study of Oral Curcuma Extract in Patients with Colorectal Cancer) studied Sabinsa-standardized curcumin doses between 0.45 and 3.6 g daily for up to 4 months in advanced refractory colorectal cancer patients, finding that curcumin was well tolerated at all dose levels, with only manageable mild diarrhea in some subjects, and with no dose-limiting toxicity observed. And Nita Chainani-Wu at UCSF conducted a systematic review (J Altern Complement Med (2003): Safety and Anti-Inflammatory Activity of Curcumin: A Component of Tumeric (Curcuma longa)) of the literature on the safety of curcumin, noting that in addition to the the seminal studies cited here, five other human trials using curcumin in a dose range of 1125 to 2500 mg per day have also concluded it's high safety, observing that just as of 2003, curcumin has been demonstrated to be safe in six human trials.

    And recently Hanai and colleagues at the Hamamatsu University School of Medicine (Clin Gastroenterol Hepatol (2006): Curcumin Maintenance Therapy for Ulcerative Colitis: Randomized, Multicenter, Double-Blind, Placebo-Controlled Trial) evaluated 2 grams of curcumin daily for 6 months as maintenance therapy in patients with quiescent ulcerative colitis, finding clinical significant efficacy with no significant toxicity. And confirmatory, Ishita Chattopadhyay of the Indian Institute of Chemical Biology and coresearchers at the Central Drug Research Institute (Curr Sci (2004): Turmeric and curcumin: Biological actions and medicinal applications [pdf]) conducted another review of curcumin's safety and efficacy, concluding that "safety evaluation studies indicate that both
    turmeric and curcumin are well tolerated at a very high dose without any toxic effects

    All these findings are in agreement with the conclusions on human toxicology of curcumin by IPCS (International Programme on Chemical Safety) and WHO, prepared by Dr. D Benford with the United Kingdom Food Standards Agency in behalf of JECFA - Joint Expert Committee on Food Additives (Benford, IPCS / JECFA Monograph 1084: Curcumin - WHO Food Additives Series 52 (2004)).

  • Grape Seed Extract (GSE)
    Researchers at the University of Colorado Health Sciences Center (Sharma et al., Breast Cancer Res Treat (2004): Synergistic Anticancer Effects of Grape Seed Extract and Conventional Cytotoxic Agent Doxorubicin Against Human Breast Carcinoma Cells) examined the antitumor and chemotherapy-synergistic activity of grape seed extract (GSE) with the anthracycline doxorubicin (Adriamycin) in estrogen receptor-positive human breast carcinoma cells, confirming a synergistic efficacy of GSE and doxorubucin for breast cancer treatment, and this was independent of estrogen receptor status of the cancer cell. More recently, a team of researchers at the University of Alabama at Birmingham (Mantena et al., Carcinogenesis (2006): Grape seed proanthocyanidins induce apoptosis and inhibit metastasis of highly metastatic breast carcinoma cells) investigated the effects of grape seed proanthocyanidins (GSPs) on a highly metastatic mouse mammary carcinoma cell line, finding that GSPs exhibit chemotherapeutic efficacy against breast cancer including inhibition of metastasis, with particularly prominent inhibition of metastasis of tumor cells to the lungs benefiting overall survival.

    And researchers at the Beckman Research Institute / City of Hope Comprehensive Cancer Center (Kijima et al, Cancer Res (2006): Grape Seed Extract Is an Aromatase Inhibitor and a Suppressor of Aromatase Expression) sought to confirm previous findings that the high levels of procyanidin dimers contained in grape seed extract (GSE) are potent inhibitors of the aromatase enzyme that converts androgen to estrogen; the new study found that GSE inhibited aromatase activity in a dose-dependent manner and reduced androgen-dependent tumor growth in an aromatase-transfected MCF-7 breast cancer xenograft model, which the researchers concluding that "We believe that these results are exciting in that they show GSE to be potentially useful in the prevention/treatment of hormone-dependent breast cancer through the inhibition of aromatase activity as well as its expression". Optimal consumption levels need for antitumor activity await the results of a dose-finding study (ClinicalTrials (2006): IH636 Grape Seed Extract in Preventing Breast Cancer in Postmenopausal Women at Risk of Developing Breast Cancer).

  • Lignans and Flax:
    Flaxseed, also known as linseed, is a concentrated source of omega-3 fatty acids and phytoestrogenic lignans. Recent studies (in vitro, animal, and epidemiological) suggest that dietary lignans may be chemopreventive by virtue of anti-estrogenic, anti-angiogenic, pro- apoptotic, and anti-oxidant mechanisms (see Webb & McCullough (2005): Nutr Cancer (2005):
    Dietary Lignans: Potential Role in Cancer Prevention, who found the most support for a role of lignans in cancer for premenopausal breast cancer; see also Godnough, Nutrition Bytes (2005): Antitumorigenic Effects of Flaxseed and Its Lignan, Secoisolariciresinol Diglycoside (SDG).

    Although MD Anderson Cancer Center, CIMER (Complementary/Integrative Medicine Education Resources) Reviews of Therapies (2005): Herbal / Plant Therapies: Flaxseed & Flaxseed Oil (Linum usitatissimum) cautiously concluded that there is not sufficient human evidence to make a recommendation concerning flaxseed consumption and breast cancer risk reduction, another systematic review - Memorial Sloan-Kettering Cancer Center (MSKCC) About Herbs (2005): FLAXSEED ( Linum usitatissimum. Family: Linacae) - concluded that flaxseed has been shown to have chemoprotective effects and that mice studies have shown that flaxseed inhibits the growth and metastasis of human breast cancer, prostate cancer, and melanoma, and that furthermore flaxseed was also as effective as hormone replacement therapy in improving mild menopausal vasomotor symptoms.

    McCann et al., Int J Cancer (2004):
    Dietary lignan intakes and risk of pre- and postmenopausal breast cancer found that premenopausal women in the highest quartile of dietary lignan intake had reduced breast cancer risk, but no association was observed between lignan intakes and postmenopausal breast cancer, concluding that dietary lignans may be important in the etiology of breast cancer, particularly among premenopausal women).

    More recently, the RCT study of Thompson et al. (Clin Cancer Res (2005):
    Dietary Flaxseed Alters Tumor Biological Markers in Postmenopausal Breast Cancer) examined the effects of dietary flaxseed (daily intake of 25g flaxseed-containing muffin) on tumor biological markers and urinary lignan excretion in postmenopausal newly diagnosed breast cancer patients, finding reductions in two biological markers (Ki-67 labeling index and c-erbB2 expression) used to measure cancer cell growth, and an increase in apoptosis, suggesting that dietary flaxseed has the potential to reduce tumor growth in patients with breast cancer; the researchers suggest that the anti-proliferative action of flax was comparable to results for tamoxifen and aromatase inhibitors in other studies. And the review of Hanf & Gonder (Eur J Obstet Gynecol Reprod Biol (2005): Nutrition and primary prevention of breast cancer: foods, nutrients and breast cancer risk) observed that lignans from traditionally made sourdough rye bread, linseed/flaxseed and berries are local sources of potentially cancer-protective phytoestrogens. We note that the bioavailability of the antitumor component of flaxseed, the enterolignans, was 28% greater with ground flaxseed compared to whole flaxseed, and furthermore crushed or milled flaxseed was 43% more bioavailable compared with ground flaxseed, so it is clear that crushing and milling of flaxseed substantially improves the bioavailability of the antitumor enterolignans (J Nutr (2005): The Relative Bioavailability of Enterolignans in Humans Is Enhanced by Milling and Crushing of Flaxseed). And population-based studies have tended to confirm: so in their case-control study among women who resided in Nassau and Suffolk counties on Long Island, Brian Fink and colleagues found that intake of flavonols, flavones, flavan-3-ols, and lignans was associated with reduced risk of incident postmenopausal breast cancer among this sample population (Fink BN, Steck SE, Wolff MS, et al. Dietary Flavonoid Intake and Breast Cancer Risk among Women on Long Island. Am J Epidemiol. 2007;165(5):514-523).

    And the prospective study of Marina Touillaud and her colleagues at the National Institute of Health and Medical Research in France examined the associations between the risk of postmenopausal invasive breast cancer and dietary intakes of the four plant lignans pinoresinol, lariciresinol, secoisolariciresinol, and matairesinol) and estimated exposure to the two enterolignans, enterodiol and enterolactone, in 58,049 postmenopausal French women for a median follow-up, 7.7 years, finding that both high dietary intake of plant lignans and high exposure to enterolignans were associated with reduced risks of ER- and PR-positive postmenopausal breast cancer (Touillaud MS, Thiébaut AC, Fournier A, Niravong M, Boutron-Ruault MC, Clavel-Chapelon F. Dietary lignan intake and postmenopausal breast cancer risk by estrogen and progesterone receptor status. J Natl Cancer Inst. 2007 Mar 21; 99(6):475-86).

    Evidencewatch Commentary on Lignan Consumption and Breast Cancer
    Although these findings, especially those of the Thompson study (above) are highly promising, the quite small number of subjects studied (19 and 13 respectively in the treatment and placebo groups) as well as the very short study duration (approx. one month) caution against drawing definitive conclusions concerning long-term flaxseed consumption benefits for women with breast cancer, and it is certainly highly premature to suggest that flax/lignan consumption may be a substitute for tamoxifen and/or aromatase inhibitors.

    However, that said, given the well-known healthful benefits of flax/lignan consumption, and the potential for other positive health benefits independent of breast cancer risk, suggests that incorporation of high fiber flaxseed/lignan components into the diet appears to be without harm and may be healthful overall, especially for premenopausal women.

    And for menopausal women, there may also be a benefit: the randomized blinded crossover trial of Dr. Lorraine Turner reported at the annual breast cancer symposium sponsored by the Cancer Therapy and Research Center held in San Antonio (Turner et al., 27th Annual San Antonio Breast Cancer Symposium (2004): Does flaxseed relieve vasomotor symptoms?) found that flaxseed (40g daily consumption) significantly relieved vasomotor hot flashes in 85 postmenopausal women treated for breast cancer, with the fall in hot flushes correlating with a rise in urinary lignan markers, an important finding suggesting that lignans may potentially be deployed as an alternative for hot flash relief in women who have undergone breast cancer treatment, and possibly other postmenopausal women in general; the median number of hot flashes - from a baseline of 208 per month - was reduced by 38% during flaxseed supplementation. Furthermore, despite some previous studies appearing to suggest that isoflavones can cause hypothyroidism, the study found that flaxseed was not associated with any thyroid function abnormalities.

    The Thompson study is confirmative of the earlier work of Brooks et al. (Am J Clin Nutr (2004): Supplementation with flaxseed alters estrogen metabolism in postmenopausal women to a greater extent than does supplementation with an equal amount of soy) which found that dietary supplementation in postmenopausal women with 25 g ground flaxseed (but not with 25 g soy flour) significantly alters the metabolism of estradiol in favor of the less biologically active estrogen metabolite (2OHE1).

    Furthermore, given the fact that enterolactone is quantitatively the most important circulating lignan, Pietinen et al. (Cancer Epidemiol Biomarkers Prev (2001): Serum Enterolactone and Risk of Breast Cancer: A Case Control Study in Eastern Finland) examined the association between serum enterolactone and risk of breast cancer, finding a significant inverse association between serum enterolactone and risk of breast cancer was seen both among premenopausal and postmenopausal women, and noting that high enterolactone levels were associated with higher consumption of rye products, tea and higher intake of dietary fiber and vitamin E.

    And following up their earlier research, McCann et al. (Breast Cancer Res Treat (2006): Dietary lignan intakes and risk of breast cancer by tumor estrogen receptor status) have further established that the observed inverse association of lignans with breast cancer may be limited to ER- tumors.

  • High-fiber Diet:
    Although some studies fail to support a strong association between fiber intake and breast cancer risk (Cho et al., Cancer Epidemiol Biomarkers Prev:
    Premenopausal dietary carbohydrate, glycemic index, glycemic load, and fiber in relation to risk of breast cancer), more recently, and more definitively, found that a high-fiber, low-fat diet intervention is associated with reduced serum bioavailable estradiol concentration in women who have breast cancer, with increased fiber intake independently related to the reduction in serum estradiol concentration (see Rock et al., Clin Oncol: Effects of a High-Fiber, Low-Fat Diet Intervention on Serum Concentrations of Reproductive Steroid Hormones in Women With a History of Breast Cancer; see also Mattison et al, Br J Cancer: Intakes of plant foods, fibre and fat and risk of breast cancer - a prospective study in the Malmo Diet and Cancer cohort, where it was found that high fiber intakes was associated with a significant 40% reduction in breast cancer risk, and that the lowest risk of breast cancer was associated with the combination high fiber-low fat). Note however that intake of dietary fat per se has not been conclusively established as associated with higher breast cancer risk. Nonetheless, increased dietary fat is typically associated with increased caloric intake, in turn potentially leading to overweight and obesity, which are known risk factors for breast cancer, thus motivating in this way a low dietary fat diet. See also the work of Australian researchers Graham Giles and colleagues (Giles et al., Int J Cancer (2005): Dietary carbohydrate, fibre, glycaemic index, glycaemic load and the risk of postmenopausal breast cancer) who found that that increased intake of fiber and carbohydrate may be associated with the diagnosis of cancers of more favorable prognosis, and the earlier results of the DIANA Trial (Berrino et al., Cancer Epidemiol Biomarkers Prev (2001): Reducing Bioavailable Sex Hormones through a Comprehensive Change in Diet: the Diet and Androgens (DIANA) Randomized Trial) who found that a radical modification in diet targeted to reduce insulin resistance, and involving increased phytoestrogen intake, decreases the bioavailability of serum sex hormones in hyperandrogenic postmenopausal women; see also the review of these issues by Michele Forman (J Nutr (2007): Changes in Dietary Fat and Fiber and Serum Hormone Concentrations: Nutritional Strategies for Breast Cancer Prevention over the Life Course).

    More recently the UK Women's Cohort Study conducted by Jane Cade and her colleagues at the University of Leeds (Cade et al., Int J Epidemiol (2007): Dietary fibre and risk of breast cancer in the UK Women's Cohort Study)

  • Fat Intake:
    The literature on the relationship between fat intake, including intake of specific fats, and breast cancer risk is complex and as yet has not produced wholly definitive resolution to all the involved intricate sub-issues, although certain recent findings appear reasonable and clarifying..

    It has been suggested that a low-fat diet might influence breast cancer risk through hormonal mechanisms. One early study concluded that there is no positive association between total dietary fat intake and the risk of breast cancer (Hunter et al., N Engl J Med:
    Cohort Studies of Fat Intake and the Risk of Breast Cancer — A Pooled Analysis). However, a recent meta-analysis by Boyd et al. (Br J Cancer: Dietary fat and breast cancer risk revisited: a meta-analysis of the published literature) did find an association between higher intakes and breast cancer risk.

    A protective effect of fish consumption against breast cancer risk has been suggested in several animal studies, but the epidemiologic evidence of this remains weak. However, a recent study disputes this assumption, finding that higher intakes of fish were significantly associated with higher breast cancer incidence rates, although the association was limited to development of ER+ breast cancer (Stripp et al, J Nutr:
    Fish Intake Is Positively Associated with Breast Cancer Incidence Rate).

    Goodstine et al. (J Nutr: Dietary (n-3)/(n-6) Fatty Acid Ratio:
    Possible Relationship to Premenopausal but Not Postmenopausal Breast Cancer Risk in U.S. Women) investigated the relationship between (n-3) fatty acid intake and the (n-3)/(n-6) PUFA intake ratio and risk of breast cancer, concluding, with some appropriate cautions that overall fat intake is unrelated to breast cancer risk, but possibly that a higher (n-3)/(n-6) PUFA ratio may reduce breast cancer risk in premenopausal but not postmenopausal women.

    [new] Furthermore, intake during premenopausal years of both saturated and monounsaturated fat, especially animal fat, mainly from red meat and high-fat dairy foods, was related to modestly elevated breast cancer risk (Cho et al, J Natl Cancer Inst (2003):
    Premenopausal fat intake and risk of breast cancer). This was further extended to find that among premenopausal women (aged 26 to 46 years) higher red meat intake may be a risk factor for ER+/PR+ breast cancer, as assessed in the Nurses' Health Study II.

    Another study (Saadatian-Elahi et al., Int J Cancer: Biomarkers of dietary fatty acid intake and the risk of breast cancer: A meta-analysis) found a complex landscape of associations dependent on the type of fat involved; the major findings of this study:
    (1) a significant protective effect for total n-3 polyunsaturated fatty acids,
    (2) total monounsaturated fatty acids, oleic acid, and palmitic acid were significantly associated with increased breast cancer risk,
    (3) total saturated fatty acids were significantly associated with breast cancer risk only in postmenopausal women
    (4) alpha linolenic acid showed an inverse association bordering on statistical significance.
    However, the authors correctly and cautiously note that further more powerful studies are needed to "determine the contribution of different types of fatty acids in the etiology of breast cancer", nonetheless this and other studies suggests strongly that it is the type of fatty acids consumed that is determinative in modulating mammary carcinogenesis.

    Independent confirmation of some of these findings - the protective effect of n-3 polyunsaturated fatty acids - was made by Gago-Dominguez et al., (Br J Cancer:
    Opposing effects of dietary n-3 and n-6 fatty acids on mammary carcinogenesis: The Singapore Chinese Health Study), but only for the narrower class of marine n-3 fatty acids (n-3 fatty acids from fish/shellfish), finding that:
    (1) consumption of saturated, monounsaturated or polyunsaturated fat overall was unrelated to risk;
    (2) n-6 fatty acids were not associated with breast cancer risk;
    (3) high levels of dietary marine n-3 fatty acids were significantly associated with reduced risk. As the authors note, these appear to be the first prospective findings linking the intake of marine n-3 fatty acids to breast cancer protection. See also Larsson et al. (Am J Clin Nutr:
    Dietary long-chain n–3 fatty acids for the prevention of cancer: a review of potential mechanisms) where they observe that apparent inconsistencies re dietary fat and breast cancer risk may be due to the fact that most epidemiologic studies focused largely on the intake of n–3 PUFAs without taking into account n–6 PUFA intake, reasoning persuasively that the ratio of n–3 to n–6 PUFAs may be more important than the absolute intake of n–3 PUFAs.

    Binukumar & Matthew (World J Surg Oncol (2005):
    Dietary fat and risk of breast cancer) carried out a Pubmed search for literature on the consumption of dietary fat and risk of breast cancer published from January 1990 through December 2003, finding a positive association between increased consumption of both total fat and saturated fat and the development of breast cancer, and an inverse association in the case of oleic acid, the most abundant MUFA (monounsaturated fatty acids) and a core constituent of olive oil; they also found a moderate inverse association between consumption of n-3 fatty acids and breast cancer risk and a moderate positive association between n-6 fatty acids and breast cancer risk.

    Recently, Webb et al. (Cancer Epidemiol Biomarkers Prev:
    A Prospective Study of Diet and Benign Breast Disease) have come at this issue from a fresh direction, examining the relationship between breast cancer risk and benign breast disease (BBD), reasoning convincingly from the fact that BBD, especially atypical hyperplasia (AH), is a marker of increased breast cancer risk, and hence speculating that studying diet and BBD "may provide evidence about the effect of diet at an early stage in the process of breast carcinogenesis". They examined the relationship between the incidence of BBD and fat, fiber, antioxidant and caffeine intake, concluding that:
    (1) there was no increase in BBD risk with increasing fat intake;
    (2) increasing vegetable fat was associated with a significant reduction in the rate of proliferative BBD without atypia;
    (3) there was no significant association between any type of BBD and micronutrient intake;
    (4) high caffeine consumption was positively associated with BBD;
    (5) use of multivitamin supplements was inversely associated with risk of AH.

    And Michels et al. (Epidemiol (2005): Preschool diet and adult risk of breast cancer) found that a fatty diet during preschool age may affect a woman's risk of breast cancer later in life, finding more specifically that increased risk of breast cancer was observed among woman who had frequently consumed French fries at preschool age.

    And according to the food diary a daily intake of 35 g doubles the risk of breast cancer compared to women with daily intake of 10 g or less (CA Gonzalez, Public Health Nutr (2006): The European Prospective Investigation into Cancer and Nutrition (EPIC)).

    Finally, it appears that some of the inconsistent results in this arena of dietary fat intake and breast cancer risk may be explained and resolved in part by the customary focus on a single fatty acid, while the true association may depend on a complex of lipid interactions: thus Bougnoux et al. (Cancer Epidemiol Biomarkers Prev (2006): Diet, Cancer, and the Lipidome) have suggested that a composite indicator combining elevated monounsaturates and low omega- 6 / omega-3 fatty acid ratio is associated with breast cancer protection.

  • Dietary Fat Restriction and Breast Cancer Relapse
    Findings from Women’s Intervention Nutrition Study (WINS), a randomized phase III dietary intervention study in early-stage breast cancer, conducted by Chelbowski et al. (2005 ASCO Annual Meeting (2005): Dietary fat reduction in postmenopausal women with primary breast cancer: Phase III Women’s Intervention Nutrition Study (WINS)) suggests that dietary fat restriction favorably influences RFS (relapse-free survival): using a relatively strict dietary intervention with a goal of 15% of caloric intake (most women effected a fat intake reduction from 30% to 20% of total calories - a 33% reduction; (through cutting back on butter and other oils, eating more fruits, vegetables, fish, poultry, egg whites, and in general substituting lower-fat foods for higher-fat ones, for a total average daily fat intake of 33.3 grams). At 5 years the low-fat group sustained a 24% reduction in relapse-free survival, with approximately 20% improvement in disease-free survival, with the most benefit seen in ER-negative subgroups. This study represents a rare well-controlled randomized trial suggesting that dietary fat reduction might directly and positively influence the course of breast cancer and that more particularly postmenopausal women with early breast cancer may significantly reduce their risk of a recurrence with a reduced-fat diet.

    In a similar vein, Bahl et al. (Breast Cancer Res Treat (2005): Serum Lipids and Outcome of Early-stage Breast Cancer: Results of a Prospective Cohort Study) found a trend towards risk of breast cancer recurrence with higher total cholesterol serum levels. And data from the WINS ongoing randomized multi-center phase III dietary intervention study in early-stage breast cancer (using as subjects postmenopausal women with resected breast cancer receiving standard adjuvant therapy) suggests that dietary fat restriction - as a reduction of mean fat consumption from about 30% to 20% of the total caloric
    fat intake, representing an approximate 23-g/day reduction in
    fat intake from baseline over 5 years - might influence relapse free survival of early-stage breast cancer (Chelbowski et al., J Clin Oncol (2005), 2005 ASCO Annual Meeting Proceedings: Dietary fat reduction in postmenopausal women with primary breast cancer: Phase III Women’s Intervention Nutrition Study (WINS)); an exploratory analysis of the WINS trial suggests that patients with ER– disease had greater clinical benefit than ER+ disease following dietary fat intervention.

  • Olive Oil :
    The balance of the evidence suggests that the Mediterranean diet - with a high intake of oleic acid-rich olive oil - protects against breast cancer, and Menendez et al. (Ann Oncol (2005): Oleic acid, the main monounsaturated fatty acid of olive oil, suppresses Her-2/neu (erbB-2) expression and synergistically enhances the growth inhibitory effects of trastuzumab (HerceptinTM) in breast cancer cells with Her-2/neu oncogene amplification) found that oleic acid dramatically cuts the levels the Her-2/neu gene (high levels of of which are associated with aggressive tumors in many breast cancer patients). The same researchers also found that oleic acid boosts the effectiveness of breast cancer monoclonal antibody treatment with trastuzumab (Herceptin), which targets Her-2/neu, and that oleic acid increases the expression of a tumor suppresser protein. And Garcia-Segovia and colleagues (Public Heath Nutr (2006): Olive oil consumption and risk of breast cancer in the Canary Islands: a population-based case-control study) found that higher monounsaturated fat intake was significantly related to a lower risk of breast cancer.

    Interestingly, it appears that the monounsaturated fatty acid (MUFA,) oleic acid, of olive oil may be in particular suppressive of HER2 overexpression, specifically blocking HER2 promoter activity- in breast, ovarian and stomach cancer cell lines and hence regulating the malignant behavior of these cancer cells, as shown recently by Colomer & Menendez (Clin Transl Oncol (2006): Mediterranean diet, olive oil and cancer) who conclude that high olive oil MUFA consumption may be an effective means of influencing the outcome of Her-2/neu-overexpressing human carcinomas with poor prognosis, and that olive oil-induced transcriptional repression of HER2 oncogene may represent a novel genomic explanation for the link between the Mediterranean diet, olive oil and cancer as it seems to equally operate in various types of Her-2/neu-related carcinomas.

    The same researchers found in another study (Menendez et al., Clin Transl Oncol (2006): HER2 (erbB-2)-targeted effects of the omega-3 polyunsaturated. Fatty acid alpha-linolenic acid (ALA; 18:3n-3) in breast cancer cells: the <<fat features>> of the <<Mediterranean diet>> as an <<anti-HER2 cocktail>>)
    that anti-HER2 activity may also be inherent in the ALA (alphalinolenic acid) component which is the main omega-3 polyunsaturated fatty acid (PUFA) commonly found in the Western diet, since ALA-rich dietary flaxseed induces significant reductions in tumor growth and in HER2 (erbB-2) oncogene expression in postmenopausal patients with primary breast cancer. Thus it appears that ALA inhibits breast cancer cell growth and metastasis formation via a direct regulation of HER2. In addition, they found that omega-3 PUFA ALA suppresses overexpression of HER2 oncogene at the transcriptional level, which, in turn, interacts synergistically with anti-HER2 trastuzumab- based immunotherapy (Herceptin), findings that support other RCT results suggesting that ALA may be a potential dietary alternative or adjunct to currently used drugs in the management of HER2-positive breast carcinomas.

    The cumulative findings of these studies taken together suggest that a combination of (1) low omega-6/omega-3 PUFA ratio and (2) elevated MUFA levels, which are the two prominent fat characteristics of the Mediterranean diet, should be extremely efficient at blocking HER2 expression in breast cancer cells.

  • Carbohydrates:
    Cho et al. (Cancer Epidemiol Biomarkers Prev:
    Premenopausal dietary carbohydrate, glycemic index, glycemic load, and fiber in relation to risk of breast cancer) found that "the associations between carbohydrate intake or glycemic load and breast cancer risk among young adult women differ by body weight". Higginbotham et al. (Cancer Epidemiol Biomarkers Prev: Dietary Glycemic Load and Breast Cancer Risk in the Women’s Health Study) further examined whether high glycemic diets increase breast cancer risk in women, concluding that although they they found no evidence that a high glycemic diet increases overall breast cancer risk, "the increase in risk in premenopausal women with low levels of physical activity suggests the possibility that the effects of a high glycemic diet may be modified by lifestyle and hormonal factors".

    More recently, Tavani et al. (Ann Oncol (2005): Consumption of sweet foods and breast cancer risk in Italy) found a direct association between breast cancer risk and the consumption of sweet foods with high glycemic index and load; the negative impact on breast cancer risk was for women in the highest tertile of intake of desserts (including biscuits, brioches, cakes, puffs, ice-cream) and sugars (including sugar itself,as well as honey, jam, marmalade and chocolate), all of which increase insulin and insulin growth factors. The researcher suggest on the basis of these findings that excess risk for frequent sweet consumption may account for as much as 12% of breast cancer cases in this Italian population. This is buttressed by the recent findings of Borugian et al., (Cancer Epidemiol Biomarkers Prev (2005): Insulin, Macronutrient Intake, and Physical Activity: Are Potential Indicators of Insulin Resistance Associated with Mortality from Breast Cancer?) who found a highly significant risk associated with percentage of total calories derived from sweets (especially sucrose and fructose (Daly et al., Am J Clin Nutr (1997): Dietary carbohydrates and insulin sensitivity: a review of the evidence and clinical implications [pdf]).

    Another study (Potiscchman et al., Cancer Causes Control (2002): Increased risk of early-stage breast cancer related to consumption of sweet foods among women less than age 45 in the United States) found a modest but significant relationship between intakes of sweet items (particularly sodas and desserts) with risk of in-situ and localized breast cancer in young women, with the risk increasing linearly with percent of calories from sweets and the frequency of sweets intake, a relation consistent with the hypothesized link of high insulin exposure and risk of breast cancer (see our section on insulin and breast cancer risk, immediately below). And also consistent with an insulin-related mechanism, there was some suggestion that women who ate many times during the day were at reduced risk of disease.

  • Insulin
    Recent evidence suggests that fasting insulin level is associated with outcome in women with early breast cancer, with high fasting insulin levels (measured shortly after surgical treatment) identifying women (without known diabetes) with poor outcomes; women with insulin levels in the uppermost quartile had a two-fold increased risk of distant recurrence and a three-fold increased risk of death compared with those with levels in the lowermost quartile (Goodwin et al., J Clin Oncol (2002): Fasting Insulin and Outcome in Early-Stage Breast Cancer: Results of a Prospective Cohort Study). The precise mechanism of adverse impact is still being research it is known that IGF (insulin/insulin-like growth factor, a factor closely related to insulin) interferes with cancer therapy, adversely affecting prognosis, and as Boyd notes (Integr Cancer Ther (2003): Insulin and Cancer), insulin and IGF-1 are important growth factors, acting through the tyrosine kinase growth factor cascade in enhancing tumor cell proliferation. And as Goodwin et al. (above) note, up to 90% of breast cancer cells express IGF-I, IGF-II, insulin, and/or hybrid insulin/IGF-I receptors.

    Also see the additional supporting studies of Hirose et al. (Asian Pac J Cancer Prev (2003): Insulin, insulin-like growth factor-I and breast cancer risk in Japanese women [pdf]) who reported that insulin levels as significant predictors of postmenopausal breast cancer; Schairer (Int J Cancer (2003): Serum concentrations of IGF-I, IGFBP-3 and c-peptide and risk of hyperplasia and cancer of the breast in postmenopausal women) who found that insulin and insulin resistance may play a role in breast pathology in postmenopausal women; Lawlor et al. (Cancer Causes Control (2004): Hyperinsulinaemia and increased risk of breast cancer: findings from the British Women's Heart and Health Study) who found positive associations between insulin levels and breast cancer were found for both pre- and post-menopausal breast cancers; Muti et al. (Cancer Epidemiol Biomarkers Prev (2002): Fasting Glucose Is a Risk Factor For Breast Cancer: A Prospective Study) who found that chronic alteration of glucose metabolism (glucose, insulin, and IGF-1 pattern) is related to breast cancer development, following up on the earlier conclusion of Muti (Ann. N.Y. Acad. Sci. (2004): The Role of Endogenous Hormones in the Etiology and Prevention of Breast Cancer: The Epidemiological Evidence) that evidence indicates that among the metabolic factors, glucose metabolism, hyperinsulinemic insulin resistance, and insulin-like growth factor bioavailability may also play a role in breast cancer; Key et al. (Endogenous Hormones Breast Cancer Collaborative Group, J Natl Cancer Inst (2003): Body Mass Index, Serum Sex Hormones, and Breast Cancer Risk in Postmenopausal Women) have found that the increase in breast cancer risk with increasing BMI (body mass index) among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol; (Cho et al., cited above, (Cancer Epidemiol Biomarkers Prev:
    Premenopausal dietary carbohydrate, glycemic index, glycemic load, and fiber in relation to risk of breast cancer), who found that the associations between carbohydrate intake or glycemic load and breast cancer risk among young adult women differ by body weight, with a positive association seen among heavier women; Rinaldi et al. (Cancer Epidemiol Biomarkers Prev (2005): Insulin-Like Growth Factor-I, IGF Binding Protein-3, and Breast Cancer in Young Women: A Comparison of Risk Estimates Using Different Peptide Assays) who found an association of breast cancer risk in young women with elevated IGF-I and IGFBP-3 (insulin-like growth factor-I and its major binding protein IGF binding protein-3) and Dioro et al. (Cancer Epidemiol Biomarkers Prev (2005): Insulin-Like Growth Factor-I, IGF-Binding Protein-3, and Mammographic Breast Density) who also confirmed that IGF-I and IGFBP-3 were associated with breast density among premenopausal women, and they suggest that these growth factors may affect breast cancer risk, at least in part, through their influence on breast tissue morphology (mean breast density ) as reflected on mammogram; Voskuil et al. (Cancer Epidemiol Biomarkers Prev (2005): The Insulin-like Growth Factor System in Cancer Prevention: Potential of Dietary Intervention Strategies); Schernhammer et al. (Cancer Epidemiol Biomarkers Prev (2005): Circulating Levels of Insulin-like Growth Factors, their Binding Proteins, and Breast Cancer Risk) who found that circulating IGF-I levels seem to be modestly associated with breast cancer risk among premenopausal women, but not among postmenopausal women; Malin et al. (Cancer (2004): Evaluation of the synergistic effect of insulin resistance and insulin-like growth factors on the risk of breast carcinoma) who found that insulin resistance and IGFs may synergistically increase the risk of breast carcinoma, and Yu et al. () who found Yu et al (Cancer Epidemiol Biomarkers Prev (2004): Joint Effect of Insulin-like Growth Factors and Sex Steroids on Breast Cancer Risk) who reported a synergy on breast cancer risk for insulin-like growth factor-I (IGF-I) with hormones estrone or testosterone in both pre and postmenopausal women; Lajous et al. (Cancer Causes Control (2005): Glycemic Load, Glycemic Index, and the Risk of Breast Cancer Among Mexican Women) who found that high intake of rapidly absorbed carbohydrate appears to play an important role in the risk of breast cancer in Mexican women.

    And Borugian et al., Cancer Epidemiol Biomarkers Prev (2005): Insulin, Macronutrient Intake, and Physical Activity: Are Potential Indicators of Insulin Resistance Associated with Mortality from Breast Cancer?) have found that (1) high levels of insulin were associated with poorer survival for postmenopausal women, while (2) high dietary fat intake was associated with poorer survival for premenopausal women, (3) higher dietary protein intake was associated with better survival for all women, and (4) a highly significant risk associated with percentage of total calories derived from sweets. This is reinforced by the findings of Borugian et al. ( Am J Epidemiol (2003): Waist-to-Hip Ratio and Breast Cancer Mortality) who discovered that waist-to-hip ratio was directly related to breast cancer mortality in postmenopausal women but not in premenopausal women; waist-to-hip ratio (WHR) is a marker for insulin resistance and hyperinsulinemia, and high insulin levels have been associated with increased risk of breast cancer and poorer survival after a breast cancer diagnosis.

    And Chlebowski et al. (J Clin Oncol (2004): Insulin, Physical Activity, and Caloric Intake in Postmenopausal Women: Breast Cancer Implications) working from the Women's Health Initiative clinical trials and observational study, concluded that reduction in BMI (body mass index) achieved by increasing physical activity, reducing caloric intake, or both, should lower insulin levels, providing support for clinical trials evaluating insulin level change and breast cancer risk, given that lower BMI, higher levels of physical activity, and lower caloric intake were all independently related to lower fasting insulin levels. And a related positive finding from this study of a large population of predominantly inactive postmenopausal was that even relatively modest increases in physical activity (even as low as 28 minutes per week of brisk walking equivalent) or decreases in caloric intake could contribute to lower insulin levels.

    All these results support the hypothesis that hyperinsulinemia and related factors may predict higher breast cancer mortality in postmenopausal women. Note finally that higher insulin levels have also been proposed as a potential mediator of an increased risk of colorectal cancer (Giovannucci, Horm Metab Res (2003): Nutrition, insulin, insulin-like growth factors and cancer), among others.

    All the above findings are further validated by the finding Lipscombe et al., Breast Cancer Res Treat (2006): Diabetes mellitus and breast cancer: a retrospective population-based cohort study) that predominantly postmenopausal population of women with diabetes sustain a small but significant increase in incident breast cancer compared to non-diabetic women, supporting the association of insulin resistance with the promotion of breast cancer.

  • Vitamins, Fruits and Vegetables:
    Do et al., (J Korean Med Sci:
    Intake of Dietary Fat and Vitamin in Relation to Breast Cancer Risk in Korean Women: A Case-Control Study) found that the antioxidants beta-carotene and vitamin C were significantly associated with decreasing risk of breast cancer. Punj et al. (Int J Cancer: Effect of vitamin D analog (1alpha hydroxy D5) immunoconjugated to Her-2 antibody on breast cancer) found that "targeted delivery of D5 by immunoconjugation to cell surface receptor antibodies may be of potential therapeutic value for the treatment of Her-2 positive breast cancer". And a strong association of vitamin C, vitamin E and selenium with breast cancer has been similarly found in a population study (Singh et al., Asian Pac J Cancer Prev (2005): Association between breast cancer and vitamin C, vitamin E and selenium levels: results of a case-control study in India [pdf]).

    Furthermore, the protective effect of carotenoids has been studied. Case-control studies show an inverse association between dietary beta-carotene intake and breast cancer risk. One study found that combined high intake of total carotenoids and docosahexaenoic acid (DHA) may reduce the risk of breast cancer (see Nkondjock & Ghadirian, Am J Clin Nutr:
    Intake of specific carotenoids and essential fatty acids and breast cancer risk in Montreal, Canada). And Rock et al. (J Clin Oncol (2005): Plasma Carotenoids and Recurrence-Free Survival in Women With a History of Breast Cancer), found that given that plasma carotenoids are a biologic marker of intake of vegetables and fruit, their own observations supports previous findings linking increased vegetable and fruit intake with greater likelihood of recurrence-free survival in women who have been diagnosed with early-stage breast cancer.

    Similarly, Masala et al. (Int J Cancer (2005): Dietary and lifestyle determinants of mammographic breast density. A longitudinal study in a Mediterranean population) found a negative association between increasing consumption of vegetables, cheese and high intakes of beta-carotene, vitamin C, calcium and potassium on the one hand and high mammographic breast density, which is known to be associated with increased breast cancer risk, even after adjustment for established BC risk factors (however Evidencewatch notes that despite this finding of a potentially beneficial effect of cheese in breast cancer, we know that prospective cohort studies support the hypothesis that high intakes of dairy foods and lactose may increase the risk of ovarian cancer (see Larsson et al., Int J Cancer (2005): Milk, milk products and lactose intake and ovarian cancer risk: A meta-analysis of epidemiological studies)). And Gallus et al. (Ann Oncol (2005): Does an apple a day keep the oncologist away?) found that consumption of one apple a day or more was inversely associated with the risk of cancers of the breast, ovary, oral cavity and pharynx, esophagus, larynx, colorectum, and prostate.

    In addition, Adzersen et al. (Nutr Cancer:
    Raw and cooked vegetables, fruits, selected micronutrients, and breast cancer risk: a case-control study in Germany) found high intake of some selected vitamins and minerals which appear to possess putative DNA-stabilizing properties showed significant inverse risk associations; these were vitamin C, folate, b-carotene , zinc and copper. Note, however that a recent study by Branda et al. (Cancer (2005): Effect of vitamin B12, folate, and dietary supplements on breast carcinoma chemotherapy-induced mucositis and neutropenia) determined that the neutrophil count decrease consequent to chemotherapy was ameliorated by dietary supplementation with a multivitamin or vitamin E, but this neutrophil decrease was actually exacerbated by high serum folate levels.

    Another benefit of dietary intervention can be seen on sarcopenic obesity, the unique chemotherapy-mediated weight gain where patients lose lean body mass while they gain weight, often with a abdominal bias informally called "chemobelly": a specialized program of strength training, aerobic activity and a healthful diet with characteristics of no more than 20% fat coupled with high consumption of fruits and vegetable and calcium, was tested to determine its ability to prevent sarcopenic body composition change among Stage I/II premenopausal breast cancer patients to receive adjuvant chemotherapy. The intervention was successful, lowering body weight and % body fat and body mass, and increasing lean body mass (Demark-Wahnefried et al, Clin Exerc Physiol (2002): Preventing sarcopenic obesity among breast cancer patients who receive adjuvant chemotherapy: results of a feasibility study; see also Demark-Wahnefried et al., J Clin Oncol (2001):
    Changes in Weight, Body Composition, and Factors Influencing Energy Balance Among Premenopausal Breast Cancer Patients Receiving Adjuvant Chemotherapy).

  • Dairy
    Despite speculative reports, the available epidemiologic evidence does not support a strong association between the consumption of milk or other dairy products and breast cancer risk, although given the limitations of such studies, it is possible that measurement error attenuated any modest association of breast cancer risk with dairy products, as Moorman & Terry have noted (Am J Clin Nutr (2004): Consumption of dairy products and the risk of breast cancer: a review of the literature).

    But against this, some researchers () McCullough et al., Cancer Epidemiol Biomarkers Prev (2005) Dairy, calcium, and vitamin D intake and postmenopausal breast cancer risk in the Cancer Prevention Study II Nutrition Cohort) have sought to determine the effects and interactions of calcium, vitamin D, and dairy products (all highly correlated) with breast cancer risk in postmenopausal women, weighing in also the influence of estrogen receptor status: women with the highest intake of dietary calcium, defined as greater than 1,250 mg/daily, were at a lower risk of breast cancer than those reporting 500 mg/d, neither supplemental calcium nor vitamin D intake was associated with risk, and furthermore consumption starting at two or more servings of dairy products daily was likewise inversely associated with risk reduction, compared with less than a half a serving daily, with associations were slightly stronger in women with estrogen receptor–positive tumors, thus supporting the hypothesis that dietary calcium and/or some other components in dairy products may modestly reduce risk of postmenopausal breast cancer.

    Breast Cancer Prevention Watch Conclusions
    What We Know: Dairy and Breast Cancer Risk

    Despite some suggestive evidence, we don not find compelling at this time the evidence for a significant association of dietary dairy consumption and increased risk of breast cancer. There may be countervailing factors that effectively mute or cancel overall benefit or harm: thus, on the one hand dairy products are suspected of containing contaminants such as pesticides with carcinogenic potential, as well as growth factors such as insulin-like growth factor I (IGF1), demonstrated to promote breast carcinoma cell growth, while on the other hand calcium and vitamin D content have been hypothesized to reduce breast cancer risk. Note however that it has at various times been suggested that bGH (bovine growth hormone) sometimes given to dairy cattle to increase milk production may result in increased concentrations of IGF-I in cow milk, but Breast Cancer Prevention Watch failed to find convincing evidence to support this claim. And note that as Parodi has observed in a recent review (J Am Coll Nutr (2005): Dairy product consumption and the risk of breast cancer), the daily intake of insulin-like growth factor-1 (IGF1) and biologically active estrogens from dairy products is relatively minute in comparison to the daily endogenous secretion of these factors in women, and bGH (bovine growth hormone) appears to be biologically inactive in humans, while against these potentially negative influences, components of milk include such potentially beneficial factors as rumenic acid, vaccenic acid, branched chain fatty acids, butyric acid, cysteine-rich whey proteins, as well as calcium and vitamin D. Thus Breast Cancer Prevention Watch agrees with Parodi that evidence from more than 40 case-control studies and 12 cohort studies does not support an association between dairy product consumption and breast cancer risk.

    Breast Cancer Prevention Watch Warning:
    Dairy and Ovarian Cancer

    However Breast Cancer Prevention Watch notes that despite some findings of a potentially beneficial effect of cheese in breast cancer, we know that prospective cohort studies support the hypothesis that high intakes of dairy foods and lactose may increase the risk of ovarian cancer (see Larsson et al., Int J Cancer (2005): Milk, milk products and lactose intake and ovarian cancer risk: A meta-analysis of epidemiological studies). In addition, it appears that the milk sugar lactose is a risk factor for epithelial ovarian cancer (possibly by virtue of direct toxicity of lactose metabolites - especially the metabolite galactose - on oocytes, or by compensatory gonadotropin stimulation) but this appears limited to the serous subtype of ovarian cancer, according to findings of the Nurses' Health Study (Fairfield et al., J Int Cancer (2004): A prospective study of dietary lactose and ovarian cancer): for each 11-gram increase in lactose consumption (approximately, that found in one glass of milk), there was a 20% increase in risk of serous subtype epithelial ovarian cancers, with skim and low-fat milk being the largest contributors to dietary lactose so that women who consumed one or more servings of skim or low-fat milk daily had a 32% higher risk of any ovarian cancer and a 69% higher risk of serous ovarian cancer compared to women consuming 3 or fewer servings monthly, and controlling for fat intake did not change these findings. These findings are in essential agreement with those of the prospective population-based cohort study of the Swedish Mammography Cohort (Larsson et al., A J Clin Nutr (2004): Milk and lactose intakes and ovarian cancer risk in the Swedish Mammography Cohort) where it was concluded that high intakes of lactose and dairy products, particularly milk, are associated with an increased risk of serous ovarian cancer but not of other subtypes of ovarian cancer.

    In further support, the prospective Adventist Health Study (Kiani et al., Cancer Causes Control (2006): Dietary risk factors for ovarian cancer: the adventist health study (United States) tested the association of dietary variables with either all ovarian cancer cases or postmenopausal cases, finding the strongest hazardous risk factor associations for meat intake (for one or more times weekly versus no meat intake), and cheese intake (for intake of more than twice weekly versus less than once weekly; protective influences for reduced risk of all ovarian cancer was found with higher tomato consumption (intakes of five times/or more weekly versus none or less than once /weekly, and also with higher fruit consumption.

    But there are findings in conflict with these: Mommers et al. (B J Cancer (2006): Dairy consumption and ovarian cancer risk in the Netherlands Cohort Study on Diet and Cancer), using a self-administered questionnaire on dietary habits and other risk factors for cancer, failed to find any association between consumption of milk, yogurt, cheese or fermented dairy products, and ovarian cancer risk, and found that lactose or dairy fat intakes were not associated with specifically serous ovarian cancer risk, in contradiction of the Nurses Health Study (Fairfield et al., cited above), but that dairy fat intake was associated with risk, and so the authors suggest that it may be such dairy fat consumption that influences ovarian cancer risk through increased estrogen levels, and since this effect was absent for serous ovarian cancer, they hypothesize that dairy fat may present a risk for non-serous ovarian cancers such as the endometrioid subtype. In this study, furthermore, consumption of fermented dairy products was not associated with risk, and the authors speculate that fermented milk bacteria have potentially protective effects, providing a detoxification mechanism through the binding of heterocyclic aromatic amines (HCAs) directly to their cell walls (see also our own discussion below of HCAs and increased risk of breast cancer), in keeping with the work of Knasmuller et al. (Mutat Res (2001): Impact of bacteria in dairy products and of the intestinal microflora on the genotoxic and carcinogenic effects of heterocyclic aromatic amines).

    In their population-based case-control study in Canada, Pan et al. (Cancer Epidemiol Biomarkers Prev (2004): A Case-Control Study of Diet and the Risk of Ovarian Cancer) assessed the association of ovarian cancer with dietary factors, and like Mommers and colleagues, failed to find an association with diary products: ovarian cancer risk was positively associated with (1) higher consumption of dietary cholesterol and eggs (egg consumption was positively, but not significantly, associated with elevated risk), and (2) inversely associated with higher intake of total vegetables, cruciferous vegetables, and with at least 10 years of supplementation of vitamin E, beta-carotene, and B-complex vitamins. But here too conflicting results exists: so although Pan and colleagues observed an inverse association of vegetable consumption and ovarian cancer risk, a more recent study of Koushik et al. (Cancer Epidemiol Biomarkers Prev (2005): Fruits and Vegetables and Ovarian Cancer Risk in a Pooled Analysis of 12 Cohort Studies) concluded that fruit and vegetable consumption in adulthood has no important association with the risk of ovarian cancer. And Qin et al. (Eur J Cancer prev (2005): Milk/dairy products consumption, galactose metabolism and ovarian cancer: meta-analysis of epidemiological studies) collected epidemiological studies on the association between milk/dairy products consumption or galactose metabolism and ovarian cancer, and their meta-analysis similar failed to find any association between milk/dairy products or galactose metabolism and ovarian cancer risk.

    Breast Cancer Prevention Watch:
    What We Know:
    Dairy, Cancer and other Risks
    Across these conflicting results, one consistent pattern emerges: the hypothesis that high intakes of dairy foods and lactose may increase the risk of ovarian cancer is in general supported prospective cohort studies, but is in general not supported in case-control studies (Larsson et al, Int J Cancer (2005): Milk, milk products and lactose intake and ovarian cancer risk: A meta-analysis of epidemiological studies), and given this and the methodological compromises inherent in case control and cohort trials, although there is some suggestive data to link dairy with elevated ovarian cancer risk, we conclude that it is to date inconclusive, as is the association of dairy intake with elevated breast cancer risk. Nonetheless, explicit testing of hormonal (estrogen and progesterone) content and level (see Ganmaa & Sato, Med Hypotheses (2005): The possible role of female sex hormones in milk from pregnant cows in the development of breast, ovarian and corpus uteri cancers), as well as of environmental toxins / pesticides, in milk and dairy products has not been undertaken and reported with sufficient quality and diligence, and so we urge caution in all but casual dairy consumption.

    There may be a small potential increased risk of prostate cancer associated with high intake of dairy products and calcium (Gao et al., J Natl Cancer Inst (2005): Prospective Studies of Dairy Product and Calcium Intakes and Prostate Cancer Risk: A Meta-Analysis). And note that even calcium itself has been implicated as a potentially adverse risk factor: Tseng et al. (Dairy, calcium, and vitamin D intakes and prostate cancer risk in the National Health and Nutrition Examination Epidemiologic Follow-up Study cohort) found that dairy consumption may increase prostate cancer risk through a calcium-related pathway, given that they further found that dietary calcium (but neither Vitamin D nor phosphorus) was also strongly associated with increased prostate cancer risk, in agreement with the review of Chan et al. (J Clin Oncol (2005): Role of Diet in Prostate Cancer Development and Progression) who found that milk, dairy (and also calcium, zinc at high doses, saturated fat, grilled meats, and heterocyclic amines) may increase prostate cancer risk (tomatoes/lycopene, other carotenoids, cruciferous vegetables, vitamin E, selenium, fish/marine omega-3 fatty acids, soy, isoflavones and polyphenols were potentially protective dietary elements).

    However, the presence in high-fat dairy foods of several potentially anticarcinogenic factors, of particular note conjugated linoleic acid (CLA) can affect certain cancer risk favorably: thus, Larsson et al. (Am J Clin Nutr (2005): High-fat dairy food and conjugated linoleic acid intakes in relation to colorectal cancer incidence in the Swedish Mammography Cohort) found that that high intakes of high-fat dairy foods and CLA may reduce the risk of colorectal cancer. And the JACC (Japan Collaborative Cohort) study recently found that high intake of milk (as well as fresh fish, Chinese cabbage, and fruits) has preventive effects against urothelial cancer (Sakauchi et al., J Epidemiol (2005): Dietary Habits and Risk of Urothelial Cancer Incidence in the JACC Study).

    Outside of oncological risk, dairy exhibits some checkered influences in other disease states: higher dairy intake, especially low-fat dairy, may lower the risk of type 2 diabetes in men (Choi et al., Arch Intern Med (2005): Dairy consumption and risk of type 2 diabetes mellitus in men: a prospective study), and intakes of calcium and dairy products may be associated with lower prevalence of the metabolic syndrome in middle-aged and older women (Liu et al., Diabetes Care (2005): Dietary calcium, vitamin D, and the prevalence of metabolic syndrome in middle-aged and older U.S. women). But here too there are some conflicting results: the ATTICA study (Papakonstantinou et al., Diabetes Care (2005): Food Group Consumption and Glycemic Control in People With and Without Type 2 Diabetes) found that increased consumption of whole milk products (and red meat) is associated with insulin resistance, thus potentially leading to the development of chronic diseases, such as obesity, type 2 diabetes, and cardiovascular disease. But this is in conflict with the earlier population-based prospective CARDIA (Coronary Artery Risk Development in Young Adults) study (Pereira et al., JAMA (2002): Dairy Consumption, Obesity, and the Insulin Resistance Syndrome in Young Adults - The CARDIA Study) which found that increased dairy consumption exhibits a strong inverse association with insulin resistance syndrome (IRS) - including obesity, glucose intolerance, hypertension, and dyslipidemia - among overweight adults and may reduce risk of type 2 diabetes and cardiovascular disease.

    And note that claims of dairy being a potential weight-loss aid (for example, MB Zemel, J Am Coll Nutr (2005): The Role of Dairy Foods in Weight Management and S Schrager, J Am Board Fam Pract (2005): Dietary Calcium Intake and Obesity) are insufficiently evidence at this juncture: see the findings of M-P St-Onge, Am J Clin Nutr (2005): Dietary fats, teas, dairy, and nuts: potential functional foods for weight control?, Harvey-Berino et al., Obes Res (2005): Th Impact of Calcium and Dairy Product Consumption on Weight Loss, and Thompson et al., Obes Res (2005): Effect of Energy-Reduced Diets High in Dairy Products and Fiber on Weight Loss in Obese Adults who all failed to find that higher dairy or calcium intake enhances weight reduction beyond what is seen with calorie restriction alone (see also the commentary of JR Holman, Am Diabetes Assoc, Doc News (2005): Dairy Data Deliver Mixed Messages - Wading through milk's cloudy connection to weight loss). Indeed there may be opposing influences in dairy products on insulin due to different components: soluble milk proteins, especially whey and to a much lesser extent casein, appear to be insulinotropic (inducing high insulin responses, despite their low glycemic index), while milk carbohydrates, especially in the form of lactose, were not majorly insulinotropic in effect (Nilsson et al., Am J Clin Nutr (2004): Glycemia and insulinemia in healthy subjects after lactose-equivalent meals of milk and other food proteins: the role of plasma amino acids and incretins). And note that it may be especially important to control hypergylcemia in oncology settings, as CA Krone (Inter Cancer Ther (2005): Controlling Hyperglycemia as an Adjunct to Cancer Therapy) has observed.

    Some trials, like the SUN cohort (Alonso et al., Am J Clin Nutr (2005): Low-fat dairy consumption and reduced risk of hypertension: the Seguimiento Universidad de Navarra (SUN) cohort) have suggested that low-fat dairy consumption, but not whole-fat dairy consumption, is associated with a lower risk of incident hypertension. But again, in an all too rare RCT conducted by Reid et al. (J Clin Endocrinol Metab (2005): Effects of Calcium Supplementation on Body Weight and Blood Pressure in Normal Older Women: A Randomized Controlled Trial) found that calcium supplementation of 1 gram/daily did not produce biologically significant effects on body weight, and although there was a modest hypotensive effect, this was typically small and transient in most women.

    Even in the light of some of these favorable associations, Breast Cancer Prevention Watch continues to caution against all but casual and restricted intake of dairy products, and other sources should be exploited for the potentially beneficial components such as CLA (conjugated linoleic acid), calcium and Vitamin D.

  • Noni Juice (Morinda citrifolia)
    The various parts (roots, stems, bark, leaves, flowers and fruit) of the Morinda citrifolia, commonly known as the Noni plant, small evergreen tree found in Polynesia, have all been used in many distinct Polynesian health remedies, and use in the US and elsewhere has lately shown a sharp increase, as an aid in cancer, hypertensive disorder, and diabetes, among others. Preclinical animal studies using noni juice extracts have demonstrated some antitumor and immunomodulatory activity, and in vitro and animal studies suggest some antibacterial, antiviral, and analgesic activity (. Acta Pharmacol Sin (2002): Wang et al.,
    Morinda citrifolia (Noni): A literature review and recent advances in Noni research [pdf]).

    Although some promising preclinical findings have emerged for noni juice deployment as an antitumor agent - see the University of Illinois review by Wang & Su (Ann N Y Acad Sci. (2001): Cancer Preventive Effect of Morinda citrifolia (Noni)), as well as W McClatchey (Integr Cancer Ther (2002): From Polynesian Healers to Health Food Stores: Changing Perspectives of Morinda citrifolia (Rubiaceae)), and the research carried out at the University of Hawaii by Furusawa et al. (Phytother Res (2003): Antitumour potential of a polysaccharide-rich substance from the fruit juice of Morinda citrifolia (Noni) on sarcoma 180 ascites tumour in mice) building on the earlier original findings of Hirazumi & Furusawa (Phytother Res (2003):
    An immunomodulatory polysaccharide-rich substance from the fruit juice of Morinda citrifolia (noni) with antitumour activity); also more recently, Hormick et al. (Angiogenesis (2004): Inhibition of angiogenic initiation and disruption of newly established human vascular networks by juice from Morinda citrifolia (noni) [pdf]) - there are to date no well documented peer-reviewed clinical studies, and thus the weight of the evidence is insufficient to determine either the efficacy or the safety of noni juice and extracts in the human clinical setting, for any disease application or cancer treatment. We await the findings of a currently accruing clinical trial by Brian Issell at the Cancer Research Center of Hawaii (Clinical Trials (2005): Phase I Study of Morinda Citrifolia (Noni Fruit Extract) in Patients With Advanced Cancer) which is designed to determine, at a preliminarily stage, the efficacy of this therapy, in terms of anticancer and symptom control in patients with advanced cancer. We furthermore warn that there have been a few case reports of serious hepatotoxicity (Millonig et al, Eur J Gastroenterol Hepatol (2005): Herbal hepatotoxicity: acute hepatitis caused by a Noni preparation (Morinda citrifolia)) and Stadbauer et al., World J Gastroenterol (2005): Hepatotoxicity of NONI juice: Report of two cases), probably from the anthraquinone components of noni juice (nordamnacanthal, moridone, and rubiadin), and its high intrinsic sugar content suggest caution in a diabetic setting, while its high Vitamin K content similarly suggest against use in a setting of existing anticoagulant therapy.

  • Heterocyclic Amines (HCAs) and Cooked Meat and Fish:
    Research has shown that cooking certain meats and fish at high temperatures may create carcinogenic chemicals, such as heterocyclic amines (HCAs), not otherwise present present in uncooked meats (see the recent study of Sugimura et al, Cancer SCI:
    Heterocyclic amines: Mutagens/carcinogens produced during cooking of meat and fish [pdf], and the recent comprehensive review of Mitra et al. (J Environ Health: Breast cancer and environmental risks: where is the link?, and the earlier but still valuable NCI Cancer Facts: Heterocyclic Amines in Cooked Meats), and that consumption of these chemicals may increase the risk of several cancers, including those of the breast, colon, rectal, esophagus, among others.

    This has been more recently further confirmed by the research of Gallicchio et al. (Breast Cancer Res Treat (2006): Flame-broiled food, NAT2acetylator phenotype, and breast cancer risk among women with benign breast disease) where it was found that flame-broiled food may be a modifiable risk factor for the progression of benign breast disease (BBD) to invasive breast cancer among women with genotypes consistent with rapid acetylation.

    HCAs as carcinogenic chemicals are formed from the cooking of muscle meats (beef, pork, fowl, and fish) at high cooking temperatures, primarily through amino acids reacting with creatine; other protein sources (milk, eggs, tofu, and organ meats) appear to have very little or no HCA content both in their natural form and when cooked. NCI (National Cancer Institute) and Japanese and European researchers found that an increased risk of developing breast cancer (as well as stomach, colorectal, and pancreatic cancer) is associated with high intakes of well-done, fried, or barbecued meats.

    Several factors are involved in HCA formation besides type of food (discussed above): cooking method, cooking temperature, and cooking time, with temperature being the most influential. With respect to cooking Temperature, there was a threefold increase HCA content when the cooking temperature was increased from 200° to 250° C (392° to 482° F). Since oven roasting and baking are typically done at lower temperatures, and stewing, boiling, or poaching at still lower ones (at or below 100° C (212 F), lower and possibly negligible levels of HCAs are likely to be formed.

    Since muscle meats are cooked at very high temperatures when frying, broiling, and barbecuing, these cooking methods produce the largest amounts of HCAs. However, foods cooked for a longer time - such as well-done rather than medium) even by other methods are expected to also form somewhat more HCAs.

    One countervailing factor is microwave precooking: meats partially cooked by microwave before cooking by other methods have lower HCA levels; microwaving meat prior to cooking appears to decrease mutagens by removing the precursors, with 2 minutes of microwaving prior to cooking decreased HCA content by 90%, with further reduction if the liquid that forms during microwaving is poured off before further cooking .

    Although, as the NCI research notes, there is no good measure of how much HCAs would have to be consumed to substantially increase cancer risk, their concluding recommendations are rational under the circumstances: "concerned individuals can reduce their exposure to HCAs by varying methods of cooking meats; microwaving meats more often, especially before frying, broiling, or barbecuing; and refraining from making gravy from meat drippings".

    In addition, cross-national research teams in Singapore coordinating with USC Norris Comprehensive Cancer Center have found that even inhalation of these HCA carcinogens, and others produced during frying of meat and carried on the oily fumes, may increase the risk of lung cancer among smokers (Seow et al., Cancer Epidemiol Biomarkers Prev (2000): Fumes from Meat Cooking and Lung Cancer Risk in Chinese Women), and later studies have found that this increased increased also extends to nonsmokers who are exposed to cooking fumes from frying, stir-frying and deep-frying (Yu et al, Cancer Res (2006): Dose-Response Relationship between Cooking Fumes Exposures and Lung Cancer among Chinese Nonsmoking Women), and clearly such risk may be exacerbated in the presence of existing carcinoma, such as that of the breast with its prepensity to lung metastases. See also the report from Breast Cancer Fund and Breast Cancer Action: State of the Evidence 2006: What Is the Connection Between the Environment and Breast Cancer? [pdf].

  • NCI Dietary Open Questions:

    The latest NCI (NCI:
    Breast Cancer (PDQ)), citing primarily the study of Smith-Warner et al (JAMA: Intake of fruits and vegetables and risk of breast cancer: a pooled analysis of cohort studies) concludes re an association between fruit and vegetable consumption and reduced breast cancer risk that the association "may be weak or not easily discernible in clinical studies of limited power". However,

    Evidencewatch Commentary:
    Evidencewatch considers this judgment of NCI to be too conservative and against the present weight of the evidence. We have already presented the highly persuasive findings on dietary indole-3-carbinol (I3C) and brassica/cruciferous vegetables (see our section on I3C / Cruficerous Vegetables above). In addition, Adzersen et al. (Nutr Cancer:
    Raw and cooked vegetables, fruits, selected micronutrients, and breast cancer risk: a case-control study in Germany) found (1) that intake of raw vegetables, total vegetables, and whole-grain products, but not cooked vegetables, was inversely associated with breast cancer risk, (2) high intake of some selected vitamins and minerals which appear to possess putative DNA-stabilizing properties showed significant inverse risk associations; these were vitamin C, folate, b-carotene , zinc and copper. (Re the protective effect of vegetables on breast cancer risk, see also Riboli & Norat, Am J Clin Nutr: Epidemiologic evidence of the protective effect of fruit and vegetables on cancer risk).

    Further, the recent ORDET Cohort study (Sieri et al., Cancer Epidemiol Biomarkers Prev: Dietary Patterns and Risk of Breast Cancer in the ORDET Cohort) found that a a diet rich in raw vegetables and olive oil is protective against breast cancer. In another study, Olsen et al. (J Nutr:
    Fruits and vegetables intake differentially affects estrogen receptor negative and positive breast cancer incidence rates) speculated that given that other breast cancer risk factors for seem to vary with the estrogen receptor status of the tumor, then the perceived inconsistent results regarding a preventive effect of fruits and vegetables may be due to lack of controlling for such estrogen receptor status, and indeed their study found a preventive effect but only for estrogen receptor–negative (ER-) breast cancers. And Rock et al. (J Clin Oncol (2005): Plasma Carotenoids and Recurrence-Free Survival in Women With a History of Breast Cancer) examined the relationship between plasma carotenoid concentration, as a biomarker of vegetable and fruit intake, and risk for a new breast cancer event in a cohort of women with a history of early-stage breast cancer, finding that increased vegetable and fruit intake was associated with greater likelihood of recurrence-free survival in women who have been diagnosed with early-stage breast cancer, while Ahn et al. (Am J Epidemiol (2005): Associations between Breast Cancer Risk and the Catalase Genotype, Fruit and Vegetable Consumption, and Supplement Use) speculated that the observed weak or null associations between fruit and vegetable intake and breast cancer risk in some studies could be due to heterogeneity in endogenous antioxidant capabilities, so they evaluated potential relations between a functional polymorphism in catalase, an antioxidant enzyme, and breast cancer risk, particularly in relation to fruit and vegetable intake and supplement use, finding that vegetable and, particularly, fruit consumption but not via supplements contributed to the decreased risk associated with the catalase CC genotype, suggesting a significant beneficial role of diet, rather than supplement use, in concert with endogenous antioxidant capabilities in the reduction of breast cancer risk.

Copyright © 2013. Constantine Kaniklidis. All rights reserved.