Commissioned on behalf of No Surrender Breast Cancer Foundation (NSBCF)
compiled by   
constantine kaniklidis
 
  : : : :   Breast Cancer Watch Digest  
   last revision: july 2017  
Edge-CAM Regimen [V 5.0 - Updated: 1 July 2017]

Curcuminoids + D3 + EGCG + Melatonin + Selenium +

Isoflavones + RYR + OFA [see below]

All

CoQ10-RNP (riboflavin (Vitamin B2) + niacin + pyridoxine (B6))

Endocrine-responsive BC

+ Boswellic Acids/AKBA + DHA + Selenium + Resveratrol*

High risk (IBC, TNBC, MBC)


*Re resveratrol, see caution below. 

 



Important Updates:

 

(new) Vitamin D Influences pCR [7/2016]
A prospective  trial reported at  SABCS 2015 found that Vitamin D deficient patients may be at increased odds of NOT achieving a pathological complete response (pCR) from neoadjuvant chemotherapy (NAC), being at increased odds of having residual disease in the breast.
[Raman R, Link BK, Mott SL, Schroeder MC, Thomas A. Vitamin D deficiency in various breast cancer subtypes and its impact on response to neoadjuvant chemotherapy in operable breast cancer. Cancer Res 2016; 76(4 Suppl):Abstract nr P5-08-48.] 

 

(new) Suboptimal VD3 --> More Aggressive Tumors [7/2016]
Based on data from the Malmö Diet and Cancer Study, a recent nested case-control study found that Vitamin D levels below 30.8 ng/ml (77 nmol/L) was associated with a higher risk of prognostically aggressive / unfavorable tumors including ER negative tumors, PR negative tumors and highly proliferative tumors, with a high expression of the Ki67 proliferation index. 
[Shirazi L, Almquist M, Malm J, Manjer J. Serum vitamin D (25OHD3) levels and the risk of different subtypes of breast cancer: A nested case-control study. Breast 2016 Jun 18; 28:184-190]

 

(new) Melatonin --> Improves Objective Response and Overall Survival [1/2016]
Melatonin significantly improves (1) objective response (both complete and partial remission), (2) 1-year overall survival rates, and (3) dramatically decreases radiotherapy and chemotherapy-related adverse effects,  including thrombocytopenia, neurotoxicity, and fatigue.
[Wang YM, Jin BZ, AI F, et al. The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials. Cancer Chemother Pharmacol 2012; 69(5):1213-20] [Basler M, Jetter A, Fink D, Seifert B, Kullak-Ublick GA, Trojan A. Urinary excretion of melatonin and association with breast cancer: meta-analysis and review of the literature. Breast Care (Basel) 2014; 9(3):182-7] [Di Bella G, Mascia F, Gualano L, Di Bella L. Melatonin anticancer effects: review. Int J Mol Sci 2013; 14(2):2410-30]

 

(new) New Data and Discussion on Curcumin, with Optimal Formulations [6/2016]
Expanded discussion and new evidence on the benefits of curcumin. Includes a Buyer's Guide to choosing the optimal curcumin formulation.

 

Isoflavones
Consumption of ≥10 mg (soy-derived) isoflavones/daily was associated with significant reduced risk of recurrence [Nechutta, Am J Clin Nutr 2012]. 

Sources: unsweetened soymilk (e.g., Westsoy)= 30 mg isoflavone per glass.
Dosing: 60+ mg daily (2 glasses soymilk or equivalent). Current weight of the evidence supports safety of soy in breast cancer populations.

 

Statins and HD-RYR (High-dose Red Yeast Rice)
Statin use is associated with decreased breast cancer mortality in women with localized or metastatic tumors [Murtola, ASCO 2013].

Source: Nature's Plus Herbal Actives Red Yeast Rice Extended Release -- 600 mg - 120 Mini Tablets.

Dosing: Using red yeast rice (RYR) as pharmaceutical statin equivalent, high-dose consumption = 2400 mg RYR extract (4 tablets daily). 

Important: Like any statin, RYR depletes CoQ10, so supplement with at least 100 - 200 mg of CoQ10. 

 

HD-OFA (High-dose Omega-3 Fatty Acids)

High-dose omega-3 fatty acids supplementation favorably modulates breast tissue biomarkers including proliferation [Fabian, ASCO 2013]. 

Source: Barlean’s Fresh Catch Signature Fish Oil is the most concentrated source (2 to 2.5 teaspoons daily).

Dosing: At least 4 g daily of omega-3-acid with EPA. 




CoQ10-RNP

  • Primarily for endocrine disease, and especially during tamoxifen therapy.
  • Potential benefit in other forms of breast cancer requires further data.
  • No standardization issue
  • Dose: 90 - 100 mg CoQ10 + riboflavin (Vitamin B2) 10 mg + niacin (30 mg) + 100 mg pyridoxine (B6)
  • The recently published Multiethnic Cohort from Galina Lurie and colleagues has found that higher circulating levels of vitamin B6 are associated with a reduced risk of invasive breast cancer in postmenopausal women with hormone receptor-positive tumors, with a 30% reduced risk of invasive breast cancer compared with women with lower B6 levels.
  • [A Caution re CoQ10: bear in mind that although there may be some methodological questions still unresolved, still one Multi Ethnic Cohort (MRC) study (2010) found that higher CoQ10 levels in postmenopausal women may be associated with increased breast cancer risk, exerting a potentially negative role in the development, and progression, of BC. And although the later SWHS study (2011) found an inverse relationship between circulating CoQ10 and breast cancer risk, nonetheless those authors candidly and commendably acknowledge that there may be no contradiction and that the findings of the large MEC prospective trial cannot be ignored other than at peril, since it is plausible that there a may be a possible nonlinear (U-shaped) association of CoQ10 with risk, with elevated risk both at the very low and at the high ends. I would therefore caution not exceeding a median levels of 90 – 120mg/daily of CoQ10 supplementation]
  • Note: Vitamin B2 and niacin (B3) are often found in these amounts in multivitamins, and so supplementation may not be necessary.

 

Curcuminoids

  • Optimal Formulation: Standardized to deliver at least 90%+ curcuminoids (the antitumor component) content, and Sabinsa-certified (the pharmaceutical grade formulation used in the studies). One leading pharmaceutical grade product comes from the Doctor's Best brand, as the product Best Curcumin.
  • Optimal Dosing: Minimal effective dosing is 500mg / daily of curcuminoid component, but this can be escalated to up to at least 1500 to 2000 mg / daily in: (1) advanced disease and metastatic settings, or in, (2) elevated risk contexts. A new study from Mathilde Bayet-Robert at the Centre Jean Perrin has established although the MTD (maximum tolerated dose) of curcumin is 8000 mg/daily, the recommended dosing for near-optimal clinical benefit in human trial of women with advanced or metastatic breast cancer is 6000 mg/daily.
  • Take curcumin towards to end of a large meal, preferably in three divided doses. When using a piperine (Bioperine) bioavailability-enhanced curcumin formulation, be aware that the piperine ingredient may enhance (but fortunately not decrease) the efficacy of other agents consumed approximately concurrently, so if at all possible, separate co-consumption by at least one hour.
  • I consider: (1) TNBC, (2) IBC, (3) MBC, and (4) HER2+ disease as contexts of elevated risks, in which cases optimize at 6000 mg/d.
  • Evidence suggests that piperine itself has antitumor activity of its own.
  • New evidence reported (9/09) from researchers at the Winship Cancer Institute and Emory University suggests that curcumin may be genotoxic (DNA-damaging), of particular  benefit to triple negative and BRCA1 deficient patients, the first ever demonstration of the specific TNBC-potential activity of curcumin, showing curcumin-induced promotion of apoptosis and prevention of growth and migration of TNBC cells.
  • The multifaceted role of this dietary agent is mediated through its inhibition of dozens of critical molecular pathways at multiple levels [Shanmugam 2015]. Besides its anticancer preventive and therapeutic activity [Perrone 2015] [Rahmani 2014] [Kaniklidis 2013], the evidence finds for:
     
    • anticancer preventive and therapeutic activity
    • anti-inflammatory / anti-arthritic;
    • anti-infective;
    cardioprotective;
    • lipid-modulating [Panahi 2014 a];
    • thrombosuppressive (anti-clot);
    • hepatoprotective (against liver toxicity);
    • anti-ulcerative-colitis;
    antidiabetic;
    anti-obesity, and anti-metabolic syndrome [Yang 2014] [He 2015];
    • powerful antidepressant
    (the BCM-95 formulation of curcumin matching the conventional antidepressant fluoxetine (Prozac) in a randomized controlled trial [Sanmukhani 2014],and can enhance their efficacy [Yu 2015], with antidepressant benefits confirmed in meta-analysis [Al-Karawi 2015);
    • anti-anxiety [Esmaily 2015];
    • anti-lichen and anti-mucositic;
    • and pro-cognitive functioning activity
    (including potential modulation of the pathology of Alzheimer's Disease via neuroprotective and cognitive-enhancing properties [Goozee 2015]),

    among dozens of other benefits in dermatological, cardiovascular, neurological, skeletal-muscular, and endocrinological human systems, and note that these benefits are supported by human clinical evidence (selectively cited below), not just preclinical (in vitro and in vivo) data. There are now over 300 pages of publication references for curcumin in the medical literature as confirmed by the vast online Curcumin Resource Database (http://crdb.in/), totalling over 9000 studies stretching almost a century, from 1919 to 2015.

    In the Oncology-specific Context
    A curcuminoid (480 mg) and quercetin (20 mg) combination therapy (curcuminoids are the active anticancer component of curcumin) consumed over a 6 month period was found to reduce both the size and number of colorectal polyps in patients with familial adenomatous polyposis [Cruz-Correa 2006]. And cross-confirmative of these findings, a month of curcuminoid supplementation reduced the number of foci in smokers with aberrant crypt foci on colonoscopy, in a non-randomized open-label study, where 4 grams/daily but not 2 grams/daily was effective [Carroll 2011].

    And in one of our most challenging malignancies, high-dose curcumin at 8 g/d induced response in several patients with advanced pancreatic cancers [Dhillon 2008]. In confirmation, a recent Phase II trial found that the addition of curcumin (as Meriva, 2000 mg/daily) to gemcitabine (Gemzar) for the treatment of locally advanced or metastatic pancreatic cancer conferred a high (60%) disease control rate [Soldà 2015].

    Furthermore, findings from a recent randomized double-blind placebo-controlled trial [Panahi 2014 b] of curcuminoids in patients with solid tumors (including breast cancer) supported the clinical efficacy of adjuvant therapy with curcuminoids using a bioavailable phosphatidylcholine complex formulation (commercially, Meriva) in improving the QoL of patients with solid tumors. This finding was accompanied by a significant reduction in serum levels of key adverse inflammatory mediators and biomarkers (IL-6, TNF-α, MCP-1, CGRP, substance P and hs-CRP) revealing that curcuminoids suppress systemic inflammation. Thus adjuvant therapy with a bioavailable curcuminoid preparation can significantly improve both QoL and suppress systemic inflammation in patients with solid tumors under treatment with standard chemotherapy.

    In addition, a randomized, double-blind, placebo-controlled clinical trial [Ryan 2013] found that oral curcumin dosed at 6 grams daily during radiotherapy in breast cancer patients significantly reduced the severity of radiation dermatitis. And in further confirmation, a recent controlled study [Belcaro 2014] reported significant improvement in QoL and the reduction in side effects associated with chemotherapy or radiotherapy in 160 cancer patients (including breast cancer) treated for 4 months with a proprietary curcumin-phosphatidylcholine phytosome complex (commercially available as Meriva).

    In a recent single-arm, phase II trial [Mahammedi 2016], 26 patients with progressing castration-resistant prostate cancer (CRPC) and rising PSA received 6 cycles of conventional docetaxel (Taxotere) / prednisone in combination with curcumin dosed at 6,000 mg/day from day -4 to day +2 of docetaxel, with level of prostate-specific antigen (PSA) was decreased in most patients and was normalized in 36% of them, and the co-administration of curcumin with drugs showed no toxicity beyond adverse effects already related to docetaxel monotherapy.

    Collectively, these and numerous other lines of evidence strongly entail the exceptional benefits of curcumin against a wide spectrum of human diseases, including numerous challenging malignancies, delivering these benefits with uncommon tolerability and safety.

    A Consumer's Guide to Curcumin
    Sabinsa-standardized C3 Complex
    This is a standardized formulation delivering optimal amounts of the critical active component of curcumin, known as curcuminoids, where a pepper-derived compound piperine is used to enhance bioavailability. It is the most widely studied form, for which we have the greatest base of peer-reviewed studies, and the one most widely used in oncology trials, including the in-progress CUFOX trial which is combining curcumin with the standard-of-care FOLFOX (5-FU, folinic acid and oxaliplatin) chemotherapy regimen in patients with inoperable colorectal cancer [Irving 2015], with preliminary findings of enhanced efficacy in the context of colorectal liver metastasis, exerting anti-proliferative and proapoptotic (programmed death) effects on patient-derived cancer stem cells. It has also been used in completed successful randomized controlled trials in favourable cardiovascular lipid/cholesterol modulation [Panahi 2014 (a)], in an MD Anderson Phase IIb prevention study in women at increased risk for breast cancer, in depression and schizophrenia, osteoarthritis, in dyslipidemia and obesity, in oral lichen planus, and in, to date, over 34 clinical trials and dozens of other studies.

    Thus, in the cancer context, no other formulation of curcumin is more evidenced by the clinical data to date, and this form remains the first choice in oncology deployment. There are currently 12 commercial preparations identified by Sabinsa Corporation as using their C3 Complex formulation (http://www.curcuminoids.com/users.htm), although the list may not be exhaustive; of these, Doctor's Best, Physician Naturals, and Pure Prescriptions are some of the more commonly available commercial labels.

    Tip: the absorption of any Sabinsa-standardized C3 Complex preparation can be enhanced when taken with a fatty (oily) meal (such as with olive oil).

    Essential Oils-based Curcumin
    A second formulation is BCM-95 (manufactured by Arjurna Natural Extracts), which combines curcuminoids with other components of turmeric such as essential turmeric oils that have their own anticancer activity.  Life Extension Bio Curcumin is one BCM-95-based commercial product. This form of curcumin was shown to have especially powerful antidepressant activity, along with benefits in inflammatory conditions and bone/joint diseases.

    Phytosomal-based Curcumin
    A third formulation is known as a phytosomal form, meaning it achieves enhanced bioavailability by binding curcumin to phosphatidycholine (PC), in humans a source of choline which also functions as a precursor to the neurotransmitter, acetylcholine;. Several studies have demonstrated the anticancer benefit of phytosomal-based curcumin, along with anti-inflammatory and anti-osteo-arthritic activity, and benefits in prostate/urinary disease, among other applications. Phytosomal-based curcumin (also known as Curcumin Phytosome, or "Curcuminoid Phospholipid Complex" (CPC)) is marketed under the Meriva (manufacturer, Indena).

    A Note on the "Bioavailability Follies"
    Although widespread marketing has suggested that commercial brands like Meriva, Longvida, BCM-95, CurcuWin, Theracumin and others are vastly more bioavailable (with claims of up to bioavailability enhancement up to 4,490%!) than the current most widely evidenced standard-of-care piperine-enhanced Sabinsa-standardized C3 Complex, this has been disputed by Sabinsa founder and curcumin expert Dr Muhammed Majeed, who has noted that phytosomal-based curcumins like Meriva only increase the bioavailability of curcuminoid metabolites (principally curcumin glucuronide and curcumin sulfate), but not of the critical active ingredients, curcuminoids, themselves [Watson 2011], and there remains the issues of (1) precisely how well bioavailability improvements of the various commercially available bio-enhanced formulations actually relate to true clinically relevant uptake or efficacy [Metzler 2013], and (2) accounting for the "curcumin paradox", namely the phenomenon in which curcumin extracts almost invariably result in undetectable levels of free curcumin in the plasma, yet are demonstrated to produce clinically significant effects [Douglass 2015] (which may suggest the biological relevance of curcuminoid metabolites) [Vareed 2008] [Mohammadi 2013] [Metzler 2013]. Indeed, the preponderance of the evidence indicates that only small amounts of free curcumininoids enter the circulation and such “free” components are rapidly conjugated or otherwise transformed, hence the paradox of non-bio-enhanced curcumin ("Plain Old Curcumin" as it were) being demonstrably and clinically effective despite these seemingly contrary pharmacodynamics and pharmakinetics.

    Particulate-based Curcumin
    The fourth formulation, under the commercial label Longvida (verdure Sciences) uses what's called solid lipid curcumin particle technology (SLCP) based on a form of free curcumin that designed to survive the stomach environment to assure better absorption, bio-availability and efficacy, and the particulate technology involved allows the company to claim that this is the only form of curcumin that can cross the blood brain barrier (BBB). Although our own research suggests that the claim of being the only Curcumin formulation to have cross-BBB capability is arguable and requires more robust clinical trials, nonetheless it is the only form to date to demonstrate significant improvements in short-term memory after consumption [Cox 2015], but this was a small clinical trial in healthy older adults and the benefit was for up to 3 hours after consumption, leaving it unclear what more durable impact it may have. Still, these findings are sufficiently suggestive to warrant favouring the Longvida formulation if one's primary intent is benefit against age-related short-term memory loss.

    Hydrophilic Curcumin
    A fifth formulation, under the commercial CurcuWin (OmniActive Health Technologies) label, combines curcumin with a hydrophilic carrier to make it more dispersible in water, which is claimed to yield the most dramatic effect on bioavailability, however the study [Jäger 2014] was sponsored by the manufacturer, and used a relatively short sampling time frame rather than a more realistic 24 sample, so independently, we need robust human clinical studies of actual benefit before judging that such bioavailability is of any true clinical relevance.

    Technical Note - The Issue of Brain Activity: Myth and Reality
    It is often claimed that at least some forms of curcumin can cross the protective blood-brain barrier (BBB) to allow them to exert CNS (central nervous system) effects in the brain which is otherwise relatively impermeable, which most of the focus being on the Longvida formulation because of some human clinical evidence of benefit in memory function [Cox 2015], besides weaker and only provisional preclinical data. But several studies have in fact shown that native curcumin, due to its lipophilicity, can cross the blood-brain barrier, reaching brain tissue at a functional pharmacological level [Estabeyoglu 2012, [Faria 2010], [Pluta 2015].

    But a more serious error in reasoning also occurs. From this cross-BBB activity, many have deduced the potential use and benefit in the treatment of brain metastasis from various cancers, including breast cancer, and also in the treatment of brain tumors like glioblastoma (GBM). However this is in error and is based on a misunderstanding of what is required for anticancer activity in the brain: it is not enough that an agent cross the BBB; favourable activity is also dependent on other complex factors of dynamic flow (and flow gradient differentials) and resistance, as well as factors affecting barrier permeability. In fact, some of the non-oncological CNS benefits of curcumin may modulate permeability negatively [Kaniklidis 2015]. Thus, in a study of curcumin's effect on the permeability of the blood–brain barrier during brain ischemia / hypoxia [Wang 2013], it was found that curcumin improved the barrier function of the BBB under these ischemic conditions, which is good for protection against ischemic damage (stroke) but definitely not good for antimetastatic brain activity, as enhanced barrier function restores greater impermeability, limiting cranial anticancer activity. This is further confirmed in other studies that document curcumin's reversal of the permeability of the blood-brain barrier, hence protecting blood–brain barrier integrity [Estabeyoglu 2012] [Jiang 2007], which again would limit curcumin-based anticancer activity in the brain.

    The clinical lesson to take away here is that from any curcumin formulation's ability to merely cross the blood-brain barrier (BBB), it does not even in the remotest degree follow that curcumin will exert clinical significant anticancer activity within the brain, and in fact we have no data whatever of cranial anticancer / antimetastatic benefit. This does NOT mean that curcumin is of no potential benefit in the brain-metastatic context, since it must be remembered (1) that mortality is generally due to extracranial metastases (lung, liver), not cranial mets themselves, and (2) in the case of brain metastases, the blood-brain barrier (BBB) is often partially disrupted [Kaniklidis 2015]. Still, the possibility of restoration of the integrity of the barrier function strongly suggests that on its own, curcumin is unlikely to provide significant and clinical relevant anticancer activity in the brain, although it's anticancer activity in other organs and viscera (see my discussion above) may still hold some potential attraction in fighting systemic disease.

    Patient Buying Summary

    1. The preponderance of data supporting curcumin's benefits across multiple diseases and conditions still rests with the piperine-enhanced Sabinsa-standardized C3 Complex formulations, discussed and identified above.

    2. For potential benefit in short-term memory function in healthy older adults, there is limited but suggestive evidence that particulate-based curcumin (Longvida) may hold some special advantage although this still requires confirmation in larger more robust trials.

    3. For the specific oncology context, for general broad anticancer activity, no formulation has shown superiority over piperine-enhanced Sabinsa-standardized C3 Complex formulations, and that remains the best-evidenced option to date.

    4. Data shows that curcumin is relatively well-tolerated even at higher doses of six grams daily, but tolerability always shows some non-trivial individual variation, so a user who experiences any GI adverse events on Sabinsa-standardized C3 Complex formulations can do a trial of a phytosomal-based curcumin like Meriva which appears to have minimal side effects.

    5. We will review any new data that may change these clinical lessons as they may appear in the future.

    Selected References
    Al-Karawi D, Al Mamoori DA, Tayyar Y. The Role of Curcumin Administration in Patients with Major Depressive Disorder: Mini Meta-Analysis of Clinical Trials. Phytother Res 2015 Nov 27.
    Belcaro G, Hosoi M, Pellegrini L, et al. A controlled study of a lecithinized delivery system of curcumin (Meriva®) to alleviate the adverse effects of cancer treatment. Phytother Res 2014; 28(3):444-50.
    Carroll RE, Benya RV, Turgeon DK, et al. Phase IIa clinical trial of curcumin for the prevention of colorectal neoplasia. Cancer Prev Res (Phila) 2011; 4: 354–364.
    Cox KH, Pipingas A, Scholey AB. Investigation of the effects of solid lipid curcumin on cognition and mood in a healthy older population. J Psychopharmacol 2015 May; 29(5):642-51.
    Cruz-Correa M, Shoskes DA, Sanchez P, et al. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clin Gastroenterol Hepatol 2006; 4: 1035–1038.
    Dhillon N, Aggarwal BB, Newman RA, et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res 2008;14:4491–9.
    Douglass BJ, Clouatre DL Beyond Yellow Curry: Assessing Commercial Curcumin Absorption Technologies. [Review] J Am Coll Nutr 2015; 34(4):347-58.
    Esmaily H, Sahebkar A, Iranshahi M, et al. An investigation of the effects of curcumin on anxiety and depression in obese individuals: A randomized controlled trial. Chin J Integr Med 2015; 21(5):332-8.
    Estabeyoglu T, Huebbe P, Ernst IMA, Chin D, Wagner AE, Rimbach G. Curcumin-From molecule to biological function. Angew Rev Int Ed 2012; 51: 5308-5332.
    Faria A, Pestana D, Teixeira D, Azevedo J, De Freitas V, Mateus N, Calhau C. Flavonoid transport across RBE4 cells: a blood-brain barrier model. Cell Mol Biol Lett 2010; 15: 234-241.
    Goozee KG, Shah TM, Sohrabi HR, et al. Examining the potential clinical value of curcumin in the prevention and diagnosis of Alzheimer's disease. Br J Nutr 2015 Dec 14; :1-17.
    He Y, Yue Y, Zheng X, Zhang K, Chen S, Du Z. Curcumin, inflammation, and chronic diseases: how are they linked? Molecules 2015; 20(5):9183-213.
    Irving GR, Iwuji CO, Morgan B, et al. Combining curcumin (C3-complex, Sabinsa) with standard care FOLFOX chemotherapy in patients with inoperable colorectal cancer (CUFOX): study protocol for a randomised control trial. Trials 2015; 16:110.
    Jäger R, Lowery RP, Calvanese AV, Joy JM, Purpura M, Wilson JM. Comparative absorption of curcumin formulations. Nutr J 2014; 13:11.
    Jiang J, Wang W, Sun YJ, Hu M, Li F, Zhu DY. Neuroprotective effect of curcumin on focal cerebral ischemic rats by preventing blood-brain barrier damage. Eur J Pharmacol 2007; 561: 54-62.
    Kaniklidis C. Why does curcumin contain anticancer properties? ResearchGate 2013 Dec 28.
    Kaniklidis C. Edge-CAM Regimen V. 4.1. Breast Cancer Watch Digest. Special Issue. July 2016 [rev].
    Kaniklidis C. CNS Metastasis from Breast Cancer – New Promise: A Review [2015 revision; pending publication]. Available on Academia.edu.
    Mahammedi H, Planchat E, Pouget M, et al. The New Combination Docetaxel, Prednisone and Curcumin in Patients with Castration-Resistant Prostate Cancer: A Pilot Phase II Study. Oncology 2016; 90(2):69-78.
    Metzler M, Pfeiffer E, Schulz SI, Dempe JS: Curcumin uptake and metabolism. Biofactors 39:14–20, 2013.
    Mohammadi A, Sahebkar A, Iranshahi M, et al. Effects of supplementation with curcuminoids on dyslipidemia in obese patients: a randomized crossover trial. Phytother Res 2013; 27:374–379.
    Panahi Y, Khalili N, Hosseini MS, et al. Lipid-modifying effects of adjunctive therapy with curcuminoids-piperine combination in patients with metabolic syndrome: results of a randomized controlled trial. Complement Ther Med 2014; 22(5):851-7. [a]
    Panahi Y, Saadat A, Beiraghdar F, Sahebkar A. Adjuvant Therapy with Bioavailability-Boosted Curcuminoids Suppresses Systemic Inflammation and Improves Quality of Life in Patients with Solid Tumors: A Randomized Double-Blind Placebo-Controlled Trial. Phytother Res 2014 Mar 19. [b]
    Perrone D, Ardito F, Giannatempo G, et al. Biological and therapeutic activities, and anticancer properties of curcumin. Exp Ther Med 2015; 10(5):1615-1623.
    Pluta R1, Bogucka-Kocka A, Ułamek-Kozioł M, et al. Neurogenesis and neuroprotection in postischemic brain neurodegeneration with Alzheimer phenotype: is there a role for curcumin? Folia Neuropathol. 2015;53(2):89-99.
    Rahmani AH, Al Zohairy MA, Aly SM, Khan MA. Curcumin: a potential candidate in prevention of cancer via modulation of molecular pathways. Biomed Res Int 2014; 2014:761608.
    Ryan JL, Heckler CE, Ling M, et al. Curcumin for radiation dermatitis: a randomized, double-blind, placebo-controlled clinical trial of thirty breast cancer patients. Radiat Res 2013; 180(1):34-43.
    Sanmukhani J, Satodia V, Trivedi J, et al.. Efficacy and safety of curcumin in major depressive disorder: a randomized controlled trial. Phytother Res 2014; 28(4):579-85.
    Shanmugam MK, Rane G, Kanchi MM, et al. The multifaceted role of curcumin in cancer prevention and treatment. Molecules 2015; 20(2):2728-69.
    Soldà C, Bardini R, Sperti C, et al. Phase II study of Gemcitabine and Curcumin (Meriva®) as first line treatment for locally advanced or metastatic pancreatic cancer: preliminary results. Ann Oncol (2015) 26 (suppl 6): vi.
    Vareed SK, Kakarala M, Ruffin MT, at al. Pharmacokinetics of curcumin conjugate metabolites in healthy human subjects. Cancer Epidemiol Biomarkers Prev 2008; 17:1411–1417.
    Wang YF, Gu YT, Qin GH, Zhong L, Meng YN. Curcumin ameliorates the permeability of the blood-brain barrier during hypoxia by upregulating heme oxygenase-1 expression in brain microvascular endothelial cells. J Mol Neurosci 2013; 51(2):344-51.
    Watson E. Sabinsa weighs into curcumin bioavailability debate. NutraIngredients 02 May 2011. At: http://www.nutraingredients-usa.com/Research/Sabinsa-weighs-into-curcumin-bioavailability-debate.
    Yang YS, Su YF, Yang HW, Lee YH, Chou JI, Ueng KC. Lipid-lowering effects of curcumin in patients with metabolic syndrome: a randomized, double-blind, placebo-controlled trial. Phytother Res 2014; 28(12):1770-7.
    Yu JJ, Pei LB, Zhang Y, Wen Zy, Yang JL. Chronic Supplementation of Curcumin Enhances the Efficacy of Antidepressants in Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Pilot Study. J Clin Psychopharmacol 2015; 35(4):406-10.


EGCG/Green Tea Extract

  • Optimal Formulation: standardized to > 97% polyphenols, with approx 45% or higher of the active ECGC component, as in NSI Green Tea Extract
  • Optimal Dosing: 250 - 500mg / daily, so 2 capsules daily, taken with meals, would be required (delivering 450mg/daily EGCG content. If sensitive to the modest caffeine content full daily dose should be completed before 5PM, or use an alternative caffeine-free formulation.
  • Recent data has shown that EGCG functions as an DNMT inhibitor, a function it shares with parthenolide, and is synergized by co-administration with an HDAC inhibitor such as  parthenolide and/or curcumin, constituting the backbone of what's called epigenetic reprogramming (which may facilitate the conversion of breast cancer subtypes to more prognostically favorable, less aggressive ones).  EGCG potentiates the efficacy of radiotherapy in breast cancer patients, while showing strong anticancer activity (per the human clinical trial of Zhang et al., Curr Mol Med, 2012), and has been found of benefit in all BC subtypes including TNBC, and works synergistically with traditional oncotherapy agents (Suganuma et al., Cancer Sci, 2011; Li  et al., Nutrceut Cancer, 2012). Activity is synergistic with curcumin.
  • EGCG potentiates the efficacy of radiotherapy in breast cancer patients, while showing strong anticancer activity (per the human clinical trial of Zhang et al., Curr Mol Med, 2012), and has been found of benefit in all BC subtypes including TNBC, and works synergistically with traditional oncotherapy agents (Suganuma et al., Cancer Sci, 2011; Li et al., Nutrceut Cancer, 2012). Activity is synergistic with curcumin.


Melatonin

  • Optimal Formulation: No standardization issue with melatonin. Natrol Melatonin delivers 5 mg per capsule.
  • Optimal Dosing:20mg / daily (45 - 60 minutes before sleeptime). Begin with 5mg / daily, and step up an additional 5mg every 3 to 4 days to the 20mg level; note however that any amount at or above 3mg/daily, although not optimal, may still be beneficial and preferable to no melatonin consumption).
  • New research from the Institute of Biological Medicine (in Milan) has found  that melatonin added to to AI therapy in metastatic BC patients with poor clinical outcome (metastases to lung, liver, or bone) achieves an impressively high objective tumor response (complete responses (CR) 14% + partial responses (PR) 43%) of 57%, compared to the norm for AI monotherapy reported in the literature which is generally below 40%, with an  additional 29% stable disease (SD), yielding a disease control rate (DCR: CR + PR + SD) of 86% in a poor outcome metastatic disease population, suggesting the enhancement of AI therapy via melatonin.


HD-D3

  • Optimal Formulation: Vitamin D3 (which is the cholecalciferol form), not Vitamin D2 (which is the ergocalciferol form). No standardization issues.
  • Optimal Dosing:  The best way to determine the optimal level for antitumor benefit is through a simple 25(OH)D (Vitamin D3) assay or laboratory test, also known as a cholecalciferol assay / test (or the "25-Hydroxy Vitamin D" test). Aim for a target level for 25(OH)D of at least 66 ng/ml [see Update notes above] which typically will require at least 3000 - 4000 IU of Vitamin D/daily, remembering that each 1000 IUs of Vitamin D elevates serum 25(OH)D levels approximately 10 ng/ml above base.
  • Benefits of High-Optimal 25(OH)D Levels
    It is known that 52 ng/ml levels are associated with a 50% reduction in risk of breast cancer, compared to 13 ng/ml (per Cedric Garlands's 2006 APHA review). And there is now compelling human clinical data in a case study presented by John Sievenpiper and Simon Pearce with the Royal Victoria Infirmary of high-dose Vitamin D3 (HD-D3) averaging at 10,000 IU/daily that has induced complete remission of distant metastasis (bone), with implications beyond bone metastases.
  • Therefore, for (1) patients with active malignancies, and/or (2) those at elevated risk of malignancy, recurrence or metastasis, a target level of at least 66 ng/ml would be of greater potential benefit.
  • The Special Needs of African-American Women:
    In addition, adequate testing and supplementation are even more imperative for postmenopausal African-American women who, as the NHANES III study has demonstrated, have lower serum 25(OH)D concentrations at all ages than do whites, and the research of John Aloia at Winthrop University Hospital has established that this population is relatively resistant to low-dose supplementation, finding that supplementation with 800 - 1000 IU vitamin D per day for 3 years effected absolutely no raising of 25(OH)D or PTH concentrations , in contrast to other racial/ethnic populations.
  • But note that there is considerable interpersonal variation, so retesting is prudent: three consecutive monthly readings are  advised to assure optimal 25(OH)D levels (amounts of 10,000 IUs/daily and even above have been found unproblematic).
  • HD-D3 for AI-Induced Disability
    It's been recently  established that Vitamin D deficiency and insufficiency may be a, if not the, major contributor to musculoskeletal symptoms and bone loss observed in women taking aromatase inhibitors (AIs): Carol Fabian at the University of Kansas, along with Qamar Khan and their colleagues, showed that supplementation with VHD-D3 (very high dose Vitamin D3) in the form of injectable 50,000 IU weekly can reduce musculoskeletal symptoms and fatigue in women with suboptimal vitamin D levels.  At baseline, 63% of women exhibited vitamin D deficiency (<20 ng/ml) or insufficiency (20–31 ng/ml).  25(OH)D levels >40 ng/ml were achieved in all women put on 12 weeks of 50,000 IU D3 supplementation with no adverse effects, and after 16 weeks of AI therapy (letrozole (Femara)), more women with median 25(OH)D levels >66 ng/ml reported no disability from joint pain than did women with any levels  below, by an order of 52% versus 19%, respectively.  Thus, very high levels of 25(OH)D, >= 66 ng/ml, are needed to significantly reduce disability and fatigue from AI-induced arthralgias/myalgias and associated fatigue. 
    In addition, Aruna Krishnan and David Feldman's team at Stanford have just reported that the combination of calcitriol, the active form of vitamin D3, and an AI yields: (1) AI augmentation by acting as a SAM, selective aromatase modulator, increasing aromatase expression in bone - but decreasing it elsewhere - helping to reduce the estrogen deprivation induced AI side effects on bone; (2) suppression of both estrogen synthesis and biological activity in a tissue-selective manner, causing enhanced cancer cell inhibition in both BC cells and in the surrounding breast adipose tissue; and (3) an indirect anti-aromatase effect due to COX-2 suppression.  Thus the powerful anti-aromatase activity of Vitamin D3 can enhance the anti-proliferative effect of AI therapy, while  ameliorating the AI-induced adverse effects on the bone.
  • Vitamin D3 for TNBC: New evidence suggests that the triple-negative breast cancer (TNBC) phenotype has the lowest average vitamin D level and the highest percentage of patients that are vitamin D deficient, strongly suggesting that low vitamin D levels are characteristic of the triple-negative phenotype. In a case series presented by Christa Rainvillle and colleagues,  patients with the more aggressive triple-negative phenotype had a mean serum vitamin D level of 20 ng/ml compared to a mean of 36 ng/ml for normal volunteers.  This may help to account for the fact African American women have the highest breast cancer specific mortality rates, the lowest serum levels of 25(OH)D, and the highest incidence of aggressive triple-negative or basal-like tumors (39%), as Lisa Carey and colleagues found in their Carolina Breast Cancer Study of race, breast cancer subtypes, and survival, and the Rainville findings further support that lack of vitamin D transport into cells may contribute to aggressive phenotypic expression (especially of TNBC, but possibly also, evidence suggests, of aggressive HER2+ and IBC disease). Therefore, my strong guidance for TNBC patients is to assure consistent (3 consecutive monthly readings) optimal (66+ ng/ml) Vitamin D3 levels, with periodic retesting (every 6 months).

  • Clinical Lessons re High Dose Vitamin D3:

 

 

Benefit Objective

Target 25OHD (aka, 25(OH)D Vitamin D3 Level

Optimal  Bone Health

> 42 ng/ml

Anticancer Activity

> 52 ng/ml

AI-Disability Relief

> 66 ng/ml

Optimal All-around

> 66 ng/ml

 


Boswellic Acids [For special populations]

  • Boswellic acids, derived from Boswellia serrata (Frankincense), are powerful LOX inhibitors, where the LOX-5 pathway has been implicated in the inflammatory component of many cancers including breast cancer, and especially of brain cancer or brain metastasis.
  • Optimal Formulation: (1) Source Naturals Boswellia Extract, delivering 262 mg of boswellic acids per tablet, and (2) NSI Boswellia Extract, delivering 200 mg of boswellic acids per tablet.
  • Optimal Dosing: Certain breast cancer classes have an elevated risk for development of metastases to the brain (CNS metastasis), and this includes (1) TNBC (and probably basal and BRCA1 mutated) and (2) HER2+ disease, and therefore it may be of prophylactic benefit for these populations to supplement with boswellic acids. Except for active brain carcinoma or metastases, dosing should deliver no less than approximately 500 - 600 mg boswellic acid daily.
  • Note on Optimal Dosing / Scheduling and Components
    Many clinical trials have used the Sabinsa Boswellin product (under different labels), which yields approx. 150 to 162mg per dose, with the  schedule typically being 3X to 4X daily, for a daily dosing of 450 - 486mg of boswellic acid content (not the extract itself) at the 3X schedule, and 600mg - 648mg daily at the 4X schedule.  Therefore, following a Sabinsa-based schedule,  the range would be from a low of 450mg daily to a high of 648mg daily, the general rough rule being to consume no less than 500 - 600mg daily as an average. 
  • So for example the Nature's Herb Boswellin delivers 150mg standardized boswellic acids per tablet, while Now Foods Boswellin delivers 162mg per capsule.  The Source Naturals Boswellia Extract product is one of the higher potency formulations, delivering 262mg per tablet.  And note that some European studies are using up to 1000mg of boswellia extract for active disease, which would typically deliver 650 mg (at 65%) to 950mg daily of boswellic acid content.
  • There is a second approach emerging to boswellia standardization: some studies are standardizing on the AKBA component of boswellic acids, known from recent research to be the critical apoptotic, anti-angiogenic and anti-proliferative component, with dosing in the range of 45 - 100mg AKBA content daily.  The NSI 5-Loxin product is one such AKBA-standardized product, delivering 22.5mg per capsule, hence dosing would between 2 and 4 capsules daily (45mg to 90mg, respectively).
  • The AKBA approach, as opposed to the overall boswellic acids (BA) approach, is more targeted, seeking to assure that of all the many boswellic acids, the critical AKBA boswellic acid component is delivered precisely, so although we don't have data to resolve the efficacy comparison of the AKBA and BA approaches, the AKBA approach appears to be of higher assured quality delivery of antitumor activity. 
  • Important Note on Concurrent Food Intake:
    Pharmacokinetic studies have revealed poor bioavailability for the most critical component of boswellic acids, AKBA, which may compromise efficacy.  Therefore optimal administration is dosing with a high-fat meal  which dramatically maximizes bioavailability and hence delivered efficacy; the high fat can be intrinsic to the meal, or realized just by adding at least 1 - 2 tablespoons or higher of olive oil.

 

Resveratrol [For special populations]

  • Even though, as I noted, the potential benefit of resveratrol are not quite as mature as those on curcuminoids, EGCG and melatonin, I consider supplementation sufficiently motivated in these cases: TNBC, IBC, MBC, or HER2+, observing the caution below.
  • Optimal Formulation: One of these pharmaceutical grade formulations:
    (1) Now Foods Natural  Resveratrol  Mega Potency
    (2) Enzymatic Therapy Resveratrol Forte
    (3) NSI Resveratrol Grape Seed & Red  Wine Extract
  • Optimal Dosing:  Until now, the best extrapolation of the optimal anticancer dose of resveratrol has been approximately 100 mg resveratrol content / daily. But new evidence just published from Edwina Scott and colleagues at the University of Leicester based on several human clinical pilot studies now clarify that optimal anticancer therapeutic activity in humans requires 1 gram (1000 mg) daily. In contrast, the intake of resveratrol from red wine after moderate consumption, which is 250 mL (one medium glass) in a 70 kg (154 lbs) person would be 1.25mg/day, which is just 1/800th of the optimal dose (remembering of course that the overwhelming weight of the evidence shows that no amount of alcohol is safe, so only supplementation is viable).
  • Caution:
    An in press preclinical study of resveratrol from Masuyuki Fukui and colleagues at the University of Kansas found that that resveratrol strongly diminished the susceptibility of certain breast cancer cells, including triple negative (MDA-MB-231 cells)" to paclitaxel-induced cell death in culture, and also in vivo in mice (not observed in non-TNBC MCF-7 cells), and although this has not been demonstrated in the human clinical setting, it suggests caution in co-administration of resveratrol and paclitaxel (Taxol) (and possibly by extrapolation with other taxanes, although these were not studied).

 

 

Parthenolide

 

  • Parthenolide, a strongly anti-inflammatory agent, is the primary biologically active agent in Feverfew commonly used for migraine and arthritis, and  the  focus of considerable investigation as a natural oncotherapeutic and cytotoxic agent in several malignancies including breast cancer.
  • In endocrine/hormonal disease, Rebecca Riggins and colleagues at Georgetown demonstrated that parthenolide restored fulvestrant (Faslodex)-mediated suppression of cell growth, yielding 4-fold synergistic cell growth reduction and apoptosis enhancement (and this may not be restricted just to fulvestrant, but to other endocrine agents).
  • In hormone-negative disease, including and especially TNBC, my  own research in epigenetic reprogramming has uncovered parthenolide to be a natural HDAC inhibitor as well as a DNMT inhibitor, properties similar the investigational epigenetic agent vorinostat (Zolinza), so it too may like vorinostat have potential to change or modulate a challenging breast cancer subtype, TNBC, into a prognostically more favorable phenotype.
  • Finally, Yang Liu and colleagues in Peking University demonstrated the activity of parthenolide against cancer stem cells, an activity that curcumin also shares. 
  • Dosing and Optimal Formulation

    The inclusion of parthenolide into the Edge-CAM regimen is marked provisional solely because we as yet lack decisive dose-finding studies, but extrapolating from the existing preclinical and in vivo data, the target dosing would be hazarded on that basis to be approximately 6 mg of parthenolide content daily.  Source Naturals Feverfew Extract delivers 200 mg of feverfew extract per tablet, standardized at 0.5% parthenolide content, so that yields 1mg/tablet, with optimal schedule being two capsules 3X daily with meals, supplemented with at least 81 (baby) to 325mg (adult) aspirin daily as coadministration with salicylates enhances activity.

  • HD-Parthenolide:  High-dose parthenolide in special circumstances - higher anti-inflammatory potency for example in the treatment of peritumoral (cerebral) edema in CNS disease to  reduce reliance on steroid medication - is feasible and safe: studies have shown that parthenolide is essentially non-toxic, so dosing  at levels of 2X  to 3X  the target 6mg/daily  are  plausible to determine if greater relief and benefit are attainable. A high-potency formulation is typically needed. One of the most concentrated in Solaray Migra Gard standardized at 0.7% parthenolide content in 350mg Feverfew capsules, yielding 2.45mg of parthenolide per capsule (in contrast to the Source Naturals product delivering 1mg per tablet).

 

DHA (Docosahexaenoic Acid)

 

  • DHA is a lipid of marine origin, and is one of the two principal components of omega-3 fatty acids (OFAs), with preliminary studies showing both chemosensitization and radiosensitization activities, the enhancement of sensitivity appearing to apply preferentially to aggressive tumor cells.
  • Phillippe Bougnoux and colleagues reported results of a phase II clinical trial in which DHA was added during a 7 - 10 day loading period before anthracycline-based chemotherapy (FEC) and then continued for the 5 months of chemotherapy, in a population of metastatic BC patients with compromised prognosis (68% had liver metastases in addition to other metastatic sites) with rapidly progressing visceral metastases (17 liver, 9 lung patients), along with 15 patients with bone metastasis, 5 with skin metastasis, and one with brain metastasis. The ORR (overall response rate) was 44% with one complete response (CR) and 10 partial responses (PR), and given that there were 11 stable disease SD cases, the clinical benefit rate (CBR) was 88%, with median overall survival (OS) significantly greater in the sub-population of patients with the highest plasma DHA.
  • This clinical trial therefore confirms previous positive findings, and demonstrates that DHA + chemotherapy may improve the outcome of metastatic BC patients, with DHA chemosensitizing tumors.
  • Vincent Blankaert and colleagues at IUT de Laval have found that DHA (docosahexaenoic acid) slows the proliferation of triple negative breast cancer cells (MDA-MB-231) and minimizes their metastatic potential, via decreasing proliferation, increasing apoptosis, and reducing the invasive potential of triple negative tumor cells.
  • Dose: at 1.8 grams/d.
  • Consult Consumerlab.com for high-quality approved products.
  • Important: It was thought until recently that Vitamin E might abolish the DHA-induced sensitization (chemo- and radio-) of tumor cells, but Ailan Xiong and colleagues at the University of Texas have recently (2012) shown that positive anticancer activity of DHA-induced apoptosis in TNBC cells is only inhibited by the alpha tocopherol, while the gamma tocopherol form actually cooperates with and enhances the beneficial effect of DHA-induced apoptosis in TNBC cells. Therefore, TNBC users of DHA can gain even more anti-TNBC activity by supplementing with both DHA and the gamma (not alpha) tocopherol form of Vitamin E, and the alpha from should be avoided in TNBC patients.

 

Selenium

 

Selenium has been found to induce p53 redox modification which has the  potential for at least partial restoration of p53 function to mutant p53.  This is important for TNBC tumors because the vast majority of TNBCs express a mutant p53, and such failure of p53 signaling is associated with chemoresistance of tumors to therapy, especially to DNA-damaging oncotherapy (see below). 

  • Therefore therapies directed toward restoring p53 function / signaling to the highly accumulated mutant p53 seen in most TNBC tumors can yield substantial benefit by improving the outcome of these oncotherapy for TNBC tumors in which p53 is prevalently mutated. 
  • A Tulane University study reported at SABCS 2009 demonstrated that selenium greatly increase the growth-inhibitory potency of genotoxic (DNA-damaging) chemotherapy (doxorubicin) in TNBC cell lines expressing mutant p53 and this represents a safe and highly effective approach for increasing the efficacy of genotoxic oncotherapies in the treatment of TNBC. 
  • The form of selenium used in the study (methylseleninic acid, aka MSA) is not readily commercially available, a non-inferor form is L-Se-methylselenocysteine (MeMSC) [best source Swanson Vitamins]; dosing is optimized at 200 mcg (micrograms) daily - single capsule - taken with a meal. 
  • Guidance
    Anyone with TNBC who is on or anticipating genotoxic (DNA-damaging) oncotherapy, such as:
    • anthracyclines
    • platinum agents  (cisplatin or carboplatin) 
    • cyclophosphamide (Cytoxan)  (as in AC, TAC and CMF regimens)
    • radiation therapy 
    • PARP inhibitor therapy

 

may benefit from such selenium complex supplementation.

  




Edge-CAM

 

Agent, Commentary, and Standardization

Dosing / Schedule / Product Suggestion

 

[CNS: recommendations in red; otherwise the same]

    Boswellic Acids / AKBA

Derived from Boswellia serrata (Frankincense), these are powerful LOX inhibitors, the LOX-5 pathway being implicated in the inflammatory component of many cancers including breast cancer, and especially of brain tumors or metastasis. Known to cross the blood-brain barrier (BBB).

  1. Optimal Application: breast cancers with elevated risk of brain metastases:
    (1) TNBC
    (2) HER2+ disease,
    and hence may be of prophylactic benefit in these classes.
  2. Standardization:
    • on boswellic acids, OR
    • on AKBA content

       

     

    Standard Dosing on Boswellic Acid (BA):

  1. Except for active brain carcinoma or metastases, dosing should deliver no less than approximately 500 - 600 mg boswellic acid daily.
  2. The Source Naturals Boswellia Extract product is one of the higher potency formulations, delivering 262mg boswellic acids per tablet.  And note that some European studies are using up to 1000mg of boswellia extract for active disease, which would typically deliver 650 mg (at 65%) to 950mg daily of boswellic acid content. 
    Dose at: 4 capsules (Source Naturals Boswellia Extract) daily.
  3. AKBA-Optimized Dosing:
    There is a second approach emerging to boswellia standardization: some studies are standardizing on the
    AKBA component of boswellic acids, known from recent research to be the critical apoptotic, anti-angiogenic and anti-proliferative component, with dosing in the range of 45 - 100mg AKBA content daily
    Dose at: 4 capsules (NSI 5-Loxin) daily, escalated higher in cases of severe cerebral edema (safety is unproblematic).
  4. The AKBA approach, as opposed to the overall boswellic acids (BA) approach, is more targeted, seeking to assure that of all the many boswellic acids, the critical AKBA boswellic acid component is delivered precisely, so although we don't have data to resolve the efficacy comparison of the AKBA and BA approaches, the AKBA approach appears to be of higher assured quality delivery of antitumor activity. 
  5. Important Note on Concurrent Food Intake
    Pharmacokinetic studies have revealed poor bioavailability for the most critical component of boswellic acids, AKBA, which may compromise efficacy.  Therefore optimal administration is dosing with a high-fat meal  which dramatically maximizes bioavailability and hence delivered efficacy; the high fat can be intrinsic to the meal, or realized just by adding at least 1 - 2 tablespoons or higher of olive oil.
     
  6. Standard Formulation:
    Source Naturals Boswellia Extract, delivering 262 mg of boswellic acids per tablet.
  7. AKBA Formulation:
    The
    NSI 5-Loxin product is one such AKBA-standardized product, delivering 22.5mg AKBA per capsule.

    Curcuminoids

    Piperine-based

    Phospholipid-based

    Liposomal/phytosome

  1. Evidence suggests that piperine itself has antitumor activity of its own.
  2. New evidence from researchers at the Winship Cancer Institute and Emory University suggests that curcumin may be genotoxic (DNA-damaging), of particular  benefit to TNBC and BRCA1 deficient patients, the first ever demonstration of the specific TNBC-potential activity of curcumin, showing curcumin-induced promotion of apoptosis and prevention of growth and migration of TNBC specific cells.
     
  3. Standardization:

    Piperine-based

    • standardized to at least 90%, preferably 95+%, curcuminoids content
    • should be bioavailability-enhanced with piperine (Bioperine)
    • Sabinsa-certified


    Phospholipid-based

    • Phospholipids enhance the bioavailability / absorption and therapeutic efficacy of curcumin, using  a commercial curcumin-phospholipid complex formula BCM-95 CG (Biocurcumax): compared to a curcumin-piperine formula (Sabinsa-certified comparable), the relative bioavailability of curcumin-phospholipid complex was  6.3-fold as high
    • Phospholipid-based curcuminoids standardized to be a BCM-95 compliant curcumin-phospholipid complex (CPC) formulation with 95% curcuminoid content from a 400 mg extract using a curcumin-phospholipid complex (CPC)  


    Liposomal/Phytosome-based

    A liposomal/phytosome curcuminoid preparation, commercially Meriva, that  has enhanced bioavailability (6X AUC) but more critically higher penetrance, and has been found to have  high penetration and accumulation in the liver with AUC and CMAX up to 20 fold above standard curcuminoids [Marczylo and colleagues at University  of Leicester]. 

     


     

  1. For Piperine-based Curcuminoids
    • at least 1500 - 2000 mg/daily
    • 6000+ mg/daily in
      • (1) rapidly progressing metastatic disease or
      • (2) advanced multi-metastatic disease (more than one site of metastatic migration), or
      • (3) CNS disease: brain and/or leptomeningeal (spinal) metastasis
    • dose at 2000 mg/daily if combined with the two other curcuminoid forms (phospholipids, and liposomal/phytosome)
  2. For Phospholipid-based Curcuminoids
    • A BCM-95 compliant curcumin-phospholipid complex (CPC) formulation with 95% curcuminoid content with a 400 mg extract  yields 380 mg curcuminoid content. Dose at either (1) 6000 mg/daily (5 capsules, each three times daily, with meals), or (2) 2000 mg/daily if combined with the two other curcuminoid forms (piperine, and liposomal/phytosome)
  3.  For Liposomal/Phytosome Curcuminoids
    • Dose Meriva-SR at either 6000 mg/daily if used as monotherapy, or (2) 2000 mg daily, when mixed with the two other curcuminoid forms (piperine-based and phospholipid-based).
  4. Advanced BC: Mixed-base Curcuminoids
    • Our preference for greater optimality:
      Combine  these three forms of curcuminoid formulations, as there may be a difference and lack of overlap in targeting various viscera and organs, splitting the 6000 mg/daily target for advanced disease roughly equally into 2000 mg/daily of each formulation. 
    • Consume with meals to avoid unlikely GI irritation (if necessary, add an anti-secretory agent). For convenience to minimize number of pills to be swallowed, capsules can be emptied and consumed in / with a flavored blender drink.
       
  5. Piperine-based
    • Doctor's Best represents one affordable and widely discounted provider:

    Doctor's Best Curcumin C3 Complex With BioPerine
     

  6. Phospholipid-based
  7. Liposomal/phytosome-based 
    • sustained-release Meriva-SR which allows for a steady-state optimal curcuminoid blood level over time.

     

    DHA

  1. Docosahexaenoic acid (DHA), a marine  omega-3 fatty acid, with preliminary studies showing both chemosensitization and radiosensitization activities, the enhancement of sensitivity appearing to apply preferentially to aggressive tumor cells.
  2. Slows proliferation of TNBC cells (MDA-MB-231),  minimizing metastatic potential via decreasing proliferation, increasing apoptosis, and reducing invasive potential (Blankaert et al.).
  3. Results of a phase II clinical trial in which DHA was added during a 7 - 10 day loading period before anthracycline-based chemotherapy (FEC) and continued for the 5 months of chemotherapy, in MBC patients with compromised prognosis with rapidly progressing visceral metastases (along with 15 patients with bone metastasis, 5 with skin metastasis, and one with brain metastasis) have been reported (Bougnoux et al.). The ORR (overall response rate) was 44% with one complete response (CR) and 10 partial responses (PR), with 11 stable disease (SD) cases, the clinical benefit rate (CBR) was 88%, with median overall survival (OS) significantly greater in the sub-population of patients with the highest plasma DHA, confirming previous positive findings that DHA + chemotherapy may improve the outcome of metastatic BC patients, with DHA also chemosensitizing tumors.
  4. Standardization: None
  1. at 1.8 grams/daily, starting 7 -10 days prior to chemotherapy, continuing concurrently with chemotherapy.
     
  2. EFAs Super EPA Fish Oil
  3. or consult Consumerlab.com for high-quality approved products.

    EGCG

  1. Recent data has shown that EGCG functions as an DNMT inhibitor, very much like parthenolide, and is synergized by co-administration with an HDAC inhibitor such as  parthenolide and/or curcumin, these two classes of inhibition constituting the backbone of what's called epigenetic reprogramming (which may facilitate the conversion of breast cancer subtypes to more prognostically favorable or less aggressive ones). 
  2. Standardization:
    • Standardized to > 97% polyphenols, with approx 45% or higher of the active ECGC component
    • Several pharmacokinetic studies in humans have clarified the range of safety to extend to at least 1200 mg EGCG content daily, entailing another capsules (total of 5 daily).

     

  1. 500 - 1000 mg / daily
  2. ~1200 mg in advanced metastatic disease (IBC, TNBC, HER2+)
  3. Since the NSI Green Tea Extract  formulation contains 50% EGCG per 500 mg capsule, translating to 250 mg EGCG per caps, then 4 (1000 mg EGCG) or 5 (1250 mg EGCG) caps daily would meet the target level for advanced disease.
  4. If sensitive to the modest caffeine content full daily dose should be completed before 5PM, or use an alternative caffeine-free formulation.
  5. Based on the pharmacokinetic findings for the  EGCG dosing should be in a fasting state (at least one hour before (preferably two), and at least two hours after,  a meal (the data  from Chow and colleagues has found a > 5 fold higher average maximum plasma concentration of EGCG compared to the fed condition, allowing for a very  large leveraging of availability and hence activity.

     

  6. One affordable formulation is  Green Tea Extract

    Melatonin

  1. New research from the Institute of Biological Medicine in Milan) has found  that melatonin added to to AI therapy in MBC patients with poor clinical outcome (metastases to lung, liver, or bone) achieves an impressively high objective tumor response (complete responses (CR) 14% + partial responses (PR) 43%) of 57%, compared to the norm for AI monotherapy reported in the literature which is generally below 40%, with an  additional 29% stable disease (SD), yielding a disease control rate (DCR: CR + PR + SD) of 86% in a poor outcome metastatic disease population, suggesting the enhancement of AI therapy via melatonin.
  2. Multiple human clinical RCT establish the benefit of melatonin across all types, and at all stages.
  3. Standardization: none
  1. 20 mg / daily
  2. two hours before bedtime

     

  3. Melatonin - Two Stage Release 1 mg, from Now Foods.  The two-stage delivery yields about a 3-to-1 ratio of potency, with their 1 mg formulation being equivalent to 3 mg of standard melatonin the equivalent of 20 mg melatonin can be obtained by just 7 mg of the 2-stage delivery (2S-D) form 

     

    Parthenolide

  1. A strongly anti-inflammatory agent, the primary biologically active agent in Feverfew.
  2. In endocrine/hormonal disease, parthenolide restored fulvestrant (Faslodex)-mediated suppression of cell growth, yielding 4-fold synergistic cell growth reduction and apoptosis enhancement (and this may not be restricted just to fulvestrant, but to other endocrine agents) [Riggins et al.]
  3. In hormone-negative disease, including and especially TNBC, research in epigenetic reprogramming has uncovered parthenolide as a natural HDAC inhibitor as well as a DNMT inhibitor, properties similar the investigational epigenetic agent vorinostat (Zolinza), so it too may like vorinostat have potential to change or modulate a challenging breast cancer subtype, TNBC, into a prognostically more favorable phenotype.
  4. Yang Liu and colleagues in Peking University demonstrated the activity of parthenolide against cancer stem cells, an activity that curcumin also shares. 
  5. Standardization:
    • standardized to 0.5 to 0.7% parthenolide content (derived from Feverfew Extract)
    • at least 81 (baby) to 325mg (adult) aspirin daily:  coadministration with salicylates enhances parthenolide activity
  1. 6+ mg/daily
  2. 18+ mg/daily in
    • (1) rapidly progressing metastatic disease or
    • (2) advanced multi-metastatic disease (more than one site of metastatic migration), or
    • (3) CNS disease: brain and/or leptomeningeal (spinal) metastasis
       
  3. High Potency:
    Solaray
    MigraGard (0.7%)

    Selenium

  1. Found to at least partial restore favorable p53 function to mutant p53 which includes most TNBC tumors, helping to overcome chemoresistance of tumors to therapy, especially to DNA-damaging oncotherapy.
  2. Tulane University study reported at SABCS 2009 demonstrated that selenium greatly increase the growth-inhibitory potency of genotoxic (DNA-damaging) chemotherapy (doxorubicin) in TNBC cell lines expressing mutant p53 and this represents a safe and highly effective approach for increasing the efficacy of genotoxic oncotherapies in the treatment of TNBC.
  3. Guidance
    Anyone with TNBC who is on or anticipating genotoxic (DNA-damaging) oncotherapy, such as:
     
    • anthracyclines
    • platinum agents  (cisplatin or carboplatin) 
    • cyclophosphamide (Cytoxan)  (as in AC, TAC and CMF regimens)
    • radiation therapy 
    • PARP inhibitor therapy

     

    may benefit from such selenium complex supplementation.

  4. Standardization: none
  1. 200 mcg (micrograms) daily - single capsule - taken with a meal. 

     

  2. Best form: L-Se-methylselenocysteine (MeMSC) [best source Swanson Vitamins].

  3. Dosing is optimized at 200 mcg (micrograms) daily - single capsule - taken with a meal. 

    Vitamin D3

  1. TNBC phenotype has the lowest average vitamin D level and the highest percentage of patients that are vitamin D deficient, suggesting that low vitamin D levels are characteristic of the triple-negative phenotype.
  2. Patients with the more aggressive triple-negative phenotype had a mean serum vitamin D level of 20 ng/ml compared to a mean of 36 ng/ml for normal (rainville et al.).
  3. These findings further support that lack of vitamin D transport into cells may contribute to aggressive phenotypic expression (especially of TNBC, but possibly also, evidence suggests, of aggressive HER2+ and IBC disease).
  4. The combination of calcitriol, the active form of vitamin D3, and an AI yields: (1) AI augmentation by acting as a SAM, selective aromatase modulator, increasing aromatase expression in bone - but decreasing it elsewhere - helping to reduce the estrogen deprivation induced AI side effects on bone; (2) suppression of both estrogen synthesis and biological activity in a tissue-selective manner, causing enhanced cancer cell inhibition in both BC cells and in the surrounding breast adipose tissue; and (3) an indirect anti-aromatase effect due to COX-2 suppression (Krishnan et al.).  Thus the powerful anti-aromatase activity of Vitamin D3 can enhance the anti-proliferative effect of AI therapy, while ameliorating the AI-induced adverse effects on the bone.
  5. It is known that 52 ng/ml levels are associated with a 50% reduction in risk of breast cancer, compared to 13 ng/ml (Garland review). And there is now compelling human clinical data: high-dose Vitamin D3 (HD-D3) averaging at 10,000 IU/daily has induced complete remission of distant metastasis (bone), with implications beyond bone metastases (case study of Sievenpiper et al.).
  6. It's been recently  established that Vitamin D deficiency and insufficiency may be a, if not the, major contributor to musculoskeletal symptoms and bone loss observed in women taking aromatase inhibitors (AIs): VHD-D3 (very high dose Vitamin D3) in the form of injectable 50,000 IU weekly can reduce musculoskeletal symptoms and fatigue in women with suboptimal vitamin D levels.  At baseline, 63% of women exhibited vitamin D deficiency (<20 ng/ml) or insufficiency (20–31 ng/ml).  25(OH)D levels > 40 ng/ml were achieved in all women put on 12 weeks of 50,000 IU D3 supplementation with no adverse effects, and after 16 weeks of AI therapy (letrozole (Femara)), more women with median 25(OH)D levels >66 ng/ml reported no disability from joint pain than did women with any levels  below, by an order of 52% versus 19%, respectively.  Thus, very high levels of 25(OH)D, >= 66 ng/ml, are needed to significantly reduce disability and fatigue from AI-induced arthralgias/myalgias and associated fatigue (fabian et al.). 
  7. Standardization: none
  1. Determine the optimal level for antitumor benefit and AI-induced adverse musculoskeletal relief via the simple 25(OH)D (Vitamin D3) assay, also known as the "25-Hydroxy Vitamin D" test) /span>
  2. Target a level for 25(OH)D of at least 66 ng/ml
  3. Each 1000 IUs of Vitamin D elevates serum 25(OH)D levels approximately 10 ng/ml above base
  4. Retesting is prudent: three consecutive monthly readings are  advised to assure optimal 25(OH)D levels

     

  5. Tip:  Two low-allergen formulations:

 


 

A Brief Note on CAM Synergies:

Inclusion of an agent in the Edge-CAM regimen follows ten broad inclusion/eligibility requirements (and many exacting  methodological and strength-of-evidence sub-requirements). Briefly, the components of the Edge-CAM regimen are (1)  selected through a process of evidence-based review and critical appraisal (2) to exhibit multiple cross-confirmatory data of (3) efficacy, (4)  safety and (5) absence of clinically significant adverse pharmacokinetic interactions as to their anticancer activity in both (6)  chemopreventive and therapeutic contexts, and (7) at the in vivo level or higher (human clinical trials), and (8) must affect positively multiple molecular pathways (suggested and enumerated elsewhere) known to be active in carcinogenesis, tumorigenesis, malignant transformation and metastatic development and migration, and related malignant processes, and (9) with minimal potential for MDR (multi-drug resistance), or evidence of anti-MDR, activity, and finally (10) with non-interfering complimentary, additive or synergistic activity in concurrent administration with each other.  Although therefore individual agent activity is required, the sum can manifest  synergies of activity suggesting the core coherence of the regimen as a whole. 

 

One example, of many: Rhonda Rosengren's team in New Zealand showed that the combination of EGCG + curcumin suppressed tumor growth in a mouse model of human breast carcinoma, finding the combination EGCG + curcumin to be synergistically cytotoxic toward MDA-MB-231 (triple negative) human breast cancer cells in vitro, while also decreasing ER+ tumor growth in vivo, and this correlated with a significant decrease in levels of VEGFR-1 (an angiogenic factor) in the tumors, and with tumor growth in the EGCG + curcumin group being inhibited by 49% compared to a tumor-suppressing rate of 31% in an EGCG only treated group.

 

Another example: curcumin is known to markedly sensitize tumor cells to the growth inhibition and apoptosis from the HDAC inhibitor vorinostat (Zolinza), suggesting synergy with the natural HDAC/DNMT inhibitor parthenolide and furthermore, given the ability of the HDAC inhibitor vorinostat to prevent the brain metastasis (micro and macro) of triple-negative breast cancer (Diane Palmieri et al.) via induction of DNA double-strand breaks, this suggests the potential of parthenolide +curcumin to inhibit brain metastatic colonization. We know that many tumors evade antitumor activities along one molecular pathway via activating one, typically several, other "escape" pathways (aka, cross-signaling), so  that the degree of effective antitumor activity is dependent on multi-pathway targeting, and on any molecular pathways synergies  that can be leveraged via  concurrency. So in Edge-CAM, there  are  synergies, and broad-spectrum activities, everywhere.  The whole is greater  . . .  

 

IMPORTANT: New Updated Version of  Lifestyle Risk Reduction Interventions (see below)

 


 


Practical Principles of Some Lifestyle-Oriented Breast Cancer Risk Reduction


 

 

Dietary Restriction

Interventions to control the degree of adiposity (amount of body fat) via promotion of both exercise and caloric restriction) are likely to have a greater impact on breast cancer incidence and recurrence than just a reduction in fat intake.  In addition, there appears to be enhanced risk of second breast cancers associated with obesity, as found by James Digham at the University of Chicago Cancer Research Center and colleagues.

 

The benefits of dual-reduction of adiposity, that is by both physical activity / exercise AND caloric restriction, are likely to be greater than either single intervention alone (via at least the reduction of circulating levels of estradiol and estrone, as shown by both the research of Anne McTieran with the Fred Hutchinson Cancer Research Center, as well as the WHI-DM trial). 

 

The benefits of dietary restriction is favored by younger age, premenopausal status, and double or triple negative receptor status, although some significant / non-trivial benefits remain for women outside these categories, especially when using the more favored mode of dual-reduction of adiposity (physical activity + caloric restriction). And note that the positive results of the Moving Forward weight loss intervention for African American breast cancer survivors (as per Melinda Stolley and colleagues at the University of  Illinois) suggest that lifestyle interventions may help to reduce the disparities in breast cancer mortality rates.  Indeed, given recent evidence that TNBC patients have the lowest levels of Vitamin D3, this may help account for the disparity in the apparent in prognosis of African American women with triple negative disease, strongly motivating for those women both a rigorous program of physical exercise and dietary / caloric restriction, and a vigilant commitment to assuring optimal Vitamin D3 levels (at 66+ ng/ml). 

 

The benefits of dietary restriction are further favored by particular reduction in saturated fats, and by increase in MUFA - mono-unsaturated (especially the oleic acid component derived from olive oil, and also by some extent canola oil - and to a lesser extent, PUFA (polyunsaturated) fatty acids, especially marine origin high in omega-3 EPA / DHA components.

 


A Better Way to Diet: Intermittent Energy Restriction (IER)

 

Michelle Harvie at CRUK University in Manchester showed that intermittent energy restriction (IER) is a potential strategy for promoting periods of energy restriction on a long-term basis, with preclinical and human data suggesting that IER may have cancer preventative effects beyond that of chronic energy restriction (CER) and weight loss. Current and emerging data strongly therefore suggest that IER may be a potential strategy for the primary prevention of various cancers. Also in this connection, a recent study conducted by Michael Pollak at General Jewish Hospital in Montreal demonstrated that intermittent energy restriction (IER) at 650 kcal on any 2 days a week and 1800 kcal on remaining 5 days, may be superior to CER at 1500 kcal/daily, with greater insulin serum level reduction with IER, and with greater patient compliance than with CER. Both diets are considered approximately isocaloric (within an accepted margin of 200 calories weekly).

 

To translate to real life, if one also reduced the constant 5-day caloric intake down from 1800 kcal to 1500 or below, that would provide both improved insulin (gylcemic) control and modest weight loss; you can also adjust the 2-day kcal level to above 650 kcal if that is too Spartan for some, as long as the 5-day kcal is reduced in step. So in all, intermittent energy restriction (IER) can positively modulate insulin, assist in weight control, and enhance compliance with dieting. And there is independent evidence from the Cancer Prevention Laboratory at Colorado State suggesting that dietary energy restriction modulates favorably the mTOR intracellular energy sensing pathway in both mammary and liver malignancies, a primitive molecular developmental pathway that is the focal point of translational research into breast cancer curative objectives.

 


Insulin Control

 

The combined evidence of epidemiological data supports a modest association between insulin dysfunction in type 2 diabetes and risk of breast cancer, more consistently among postmenopausal than among premenopausal women (confirmed in the recent comprehensive meta-analysis of 26 epidemiological studies conducted by Fei Xue and Karin Michels at Harvard's Brigham and Women's Hospital, and also independently by Patrizia Pasanisi and her colleagues team at the National Tumor Institute in Milan), buttressing independent evidence for a fundamental role of underlying insulin pathways on the carcinogenesis, tumorigenesis, and possibly also metastatic development and recurrence of breast carcinoma. Therefore, strict limitation of sweets and carbohydrates is imperative, within a prudent overall diet such as the Mediterranean Diet, along with strict glycemic control (see below).  In addition, Pamela Goodwin and colleagues at the University of Toronto found that high insulin levels in women with locoregional breast cancer reflect the presence of insulin resistance and are associated with other components of the IRS. 

 

This is in keeping also with the recent findings about metformin (Glucophage), an insulin control agent widely used in diabetes.  The report by Sao Jiralerspong and Anna Gonzalez-Angulo at MD Anderson (is association also with the male breast cancer expert Sharon Giordano and TNBC expert Cornelia Liedtke) revealed a three-fold greater complete pathologic response in diabetic patients with breast tumors ingesting metformin undergoing neoadjuvant chemotherapy compared with diabetic patients not ingesting metformin, and in the general non-diabetic breast cancer population, metformin has been shown to inhibit the growth of cancer cells, including breast cancer, in vitro and of tumors in vivo, via  activation of the AMP-activated protein kinase (AMPK)., leading to decreased serum glucose and a secondary lowering of serum levels of growth promoting insulin/insulin-like growth factors (IGFs), while also metformin inhibiting activation of the MAP kinase, Akt, and mTOR signaling pathways.  And Bolin Liu and colleagues at the University of Colorado demonstrated the unique effects of metformin on cell proliferation and signaling pathways in triple negative breast cancer cells, finding that triple negative cells appear to be more sensitive to metformin than non-TNBC cells in proliferation assays, with metformin-induced inhibition of cell cycle progression, decreases in cyclins D1 and E, and the induction of apoptosis via both intrinsic and extrinsic pathways, this pro-apoptosis activation of apoptosis being unique to TNBC cells, as it was not seen in their previous  non-TN cell study, again via metformin-induced inhibitory effect on pro-growth signaling through the EGFR, MAPK and Akt pathways (and note that metformin has also recently been found of benefit in HER2-positive disease).

 

Collectively these findings suggest the importance of insulin / glycemic control requiring a low/no-sugar / low glycemic / caloric-restricted diet rich in fiber content (as from vegetable fibers, flax, and high-viscosity fiber supplements like glucomannan) and with other component reflective of the Mediterranean Diet, and of several components of the Edge-CAM regimen (especially curcumin, EGCG and resveratrol which all favorably affect IGF pathways and insulin resistance).

 


Glycemic Control

 

As the glycemic markers (gylcemic index and gylcemic load, GI and GL, respectively), they can be viewed as essentially biomarkers of underlying activity of the molecular IGF (insulin growth factor) pathway, and of the insulin demand of the diet, and we know from very recent findings (especially Sabina Sieri's with the National Cancer Institute in Milan) - in agreement with a stratified analysis of 946 breast cancer cases in the Women's Health Study - that high dietary glycemic marker levels, especially GL (glycemic load) but also high dietary glycemic index (GI), are significantly associated with a greater risk of breast cancer, especially in, but not wholly restricted to, premenopausal women, and this strongly signals that the consumption of large quantities of high-GI (glycemic index) foods is linked to the development of breast cancer. This is also in agreement with the ORDET Study cohort findings that breast cancer risk increases significantly with increasing serum concentrations of IGF-1 (insulin-like growth factor 1) and glucose in premenopausal women (possibly via alteration of cell cycle kinetics or apoptosis inhibition, although there may also be adverse contributions via a gonadotropic effect given that insulin stimulates ovarian androgen synthesis, or via metabolic effects on the liver given that insulin inhibits the synthesis of sex hormone binding globulin and IGF-1 binding proteins 1 and 2, thereby increasing the bioavailability of both sex hormones and IGF-1, powerfully stimulative of breast cancer pathogenesis, as well as of several other cancers).

 

Increased dietary amounts of fiber-rich low-glycemic index natural foods, and avoidance or radical consumption reduction of sweets and sugars, especially, but not only, fructose, improves blood glucose control, reduces the number of hypoglycemic events, and can be an aid in lowering IGF-mediated elevated breast cancer risk, and moreover, with comparable benefits for colorectal and thyroid cancer (as demonstrated in the recent findings of Giorgia Randi). The most authoritative source of GI and GL food values is The Glycemic Index, maintained by the University of Sydney.

 


Physical Activity/Exercise (PE)

It's also important to remember that, in this connection of the positive value of physical activity, just 5 or more weekly hours of vigorous recreational activity as compared to no recreational activity results in ~40% risk reduction (as shown by the French research team of Bertrand Tehard and colleagues), and the greatest risk reduction ~ 50% - occurs in women who perform the equivalent of walking 3 to 5 hours per week at an average pace (with little evidence of a correlation between any increased benefit from greater energy expenditure above this level, as shown by the findings of Michelle Holmes at Brigham and Women�s Hospital and her colleagues).

 

What we now know therefore based on the cumulative evidence is that high-PE (physical exercise), defined as greater than or equal to 5 weekly hours of vigorous PE (>= 5 wk hrs) reduces risk of breast cancer by approximately 40%, and that in addition women with hormone-responsive breast cancer who engaged in 9 or more MET-hours/ week of activity sustain an even higher 50% risk reduction of breast cancer death, compared with women who engage in less than 9 MET-hours/week. Here the concept of a MET (metabolic equivalent task) hour is understood by the fact that walking one hour at 3 miles/hr expends 3 MET-hrs. And one can obtain an even higher 60% reduction in the risk of death from breast cancer by engaging in 24 or more MET-hours/week, which would be equivalent to walking at least 8 hours per week (about 1 and one-quarter hours, or 75 minutes daily) of walking at 3 miles per hour. If high-PE were further coupled with both caloric restriction, adherence to Modified Cretan-Mediterranean (MCM) Diet of high-fiber/lignan, low saturated fat, low-glycemic consumption + high fruit and vegetable intake, and vigorous resistance training, especially if sufficient to establish and maintain consistent normal weight control and significant reduction of abdominal sarcopenic obesity (aka, "chemobelly"), then the combination lifestyle-nutritional regimen of:

 

Caloric Restriction + MCM Diet adherence + Resistance Training + high-PE (high MET hours aerobic physical exercise)

 

should significantly heighten these gains further.  And note that the two potential mechanisms by which physical activity could affect breast cancer survival are not only the estrogen pathway but also the insulin pathway.

 

Reinforcing this, Tricia Peters and colleagues at NCI conducted a large prospective study, the NIH-AARP Diet and Health Study, finding that physical activity was associated with reduced postmenopausal breast cancer risk, particular to ER-negative tumors, the later finding also supported by the results of the California Teachers Study.

 

These results, along with heterogeneity in the physical activity-breast cancer relation for subgroups of menopausal hormone therapy use and adiposity, indicate that physical activity likely influences breast cancer risk via both estrogenic and estrogen-independent mechanisms.  This study is unique in (1) suggesting a potential role of physical activity in the prevention of ER-negative breast cancers, in turn suggesting the potential for prevention of the comparatively aggressive ER− breast cancer subtype, and (2) that physical activity does not vary by breast tumor histology, reducing risk of both ductal and lobular carcinomas. And a just published study from Xiaoli Chen and colleagues at Vanderbilt has shown that women with a higher exercise level (>= 8.3 MET h/wk) were less likely to have depression than non-exercisers (as were women with higher tea consumption.

 

Finally, collectively reinforcing these findings, we have the just published (JCO, May 2012) RCT of a Caloric Restriction + (Physical) Exercise intervention, CREX for short, from Anne McTiernan and colleagues at the  Fred Hutchinson Cancer Research Center which showed an estradiol reduction of 20.3% and a free estradiol reduction of 26%, with a 15.6% decrease in free testosterone, along with significant reductions in insulin, C-reactive protein CRP), and leptin, and favorably increased adiponectin.  And as the investigators correctly observed, based on best evdience to date, the decrease in mean estradiol alone could represent a ≥ 50% reduction in breast cancer risk, solely from the caloric restriction / weight loss part of the intervention.  And we know from the just published (JCO, July 2012) NEW (Nutrition and Exercise for Women) trial results that patients randomly assigned to exercise alone experienced smaller but significant changes in estrogen, testosterone, and leptin levels, and the combination of these trial suggests that modest weight loss is able to effect the same change in biomarkers as more significant weight loss, if - and only if - the modest weight loss was combined with exercise (and given the pathogenic role of insulin molecular pathways in TNBC, these findings are not constrained to only endocrine positive BC).   

 

To flesh out an example in real life, high-PE (physical exercise), defined as greater than or equal to 5 weekly hours of vigorous PE (>= 5 wk hrs) reduces risk of breast cancer by approximately 40%, and that in addition women with hormone-responsive breast cancer who engaged in 9 or more MET-hours/ week of activity sustain an even higher 50% risk reduction of breast cancer death, compared with women who engage in less than 9 MET-hours/week. Here the concept of a MET (metabolic equivalent task) hour is understood by the fact that walking one hour at 3 miles/hr expends 3 MET-hrs. And one can obtain an even higher 60% reduction in the risk of death from breast cancer by engaging in 24 or more MET-hours/week, which would be equivalent to walking at least 8 hours per week (about 1 and one-quarter hours, or 75 minutes daily) of walking at 3 miles per hour.

 

In breast cancer, overwhelming evidence accumulated by numerous researchers, including Wendy Demark-Wahnefried at Duke, among many others has demonstrated the particularly adverse consequences on breast cancer risk and recurrence of the unique pattern of abdominal and upper leg adiposity called sarcopenic obesity (aka, "chemobelly" in popular jargon, and technically meaning gain of adipose tissue at the expense of lean body mass), and is actually now known to be a side effect of both chemotherapy and endocrine (hormonal) therapy. We know further that remediation to lower risk requires an emphasis on resistance (strength) training (over aerobic training) with an abdominal focus (such as leg raises with attached ankle weights).

 


How to Think About Environmental Tumorigenic Exposure Reduction

 

The final component of a program for reduction breast cancer risk and recurrence is avoidance of pro-tumorigenic factors, which includes a broad spectrum of modalities: avoidance of HCAs (heterocyclic amines) produced by high-heat cooking of animal and fish proteins (meats, poultry and fish when grilled, fried, barbecued or otherwise subjected to high heat, including oil-based wok cooking), avoidance of environmental smoke (including all second hand smoke, and third-hand smoke (for example, from being in the proximity of the clothes of a smoker although the smoker is not actively smoking at the time), avoidance of other ingested carcinogens (alcohol, pesticides, etc., including dietary estrogen-promoters (such as grapefruit and grapefruit juice: as I have documented, just one quarter of one medium grapefruit per day increases the risk of breast cancer by an alarming 30%, primarily via the highly antioxidant estrogenic furanocoumarin components), avoidance of light-at-night (now an established carcinogen; see above), among many other adverse exposures.

 

There are many excellent resources on this issue: the BCERF program at Cornell University is foremost, and in addition everyone should obtain and read the latest edition of the authoritative State of the Evidence: What Is the Connection Between the Environment and Breast Cancer?  report (as PDF) from the Breast Cancer Fund /BCF (note that this is the new sixth edition, 2010).

 




Methodology for this Review

A search of the PUBMED, Cochrane Library / Cochrane Register of Controlled Trials, MEDLINE, EMBASE, AMED (Allied and Complimentary Medicine Database), CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO, ISI Web of Science (WoS), BIOSIS, LILACS (Latin American and Caribbean Health Sciences Literature), ASSIA (Applied Social Sciences Index and Abstracts), and SCEH (NHS Evidence Specialist Collection for Ethnicity and Health) was conducted without language or date restrictions, and updated again current as of date of publication, with systematic reviews and meta-analyses extracted separately. Search was expanded in parallel to include just-in-time (JIT) medical feed sources as returned from Terkko (provided by the National Library of Health Sciences - Terkko at the University of Helsinki). Unpublished studies were located via contextual search, and relevant dissertations were located via NTLTD (Networked Digital Library of Theses and Dissertations) and OpenThesis. Sources in languages foreign to this reviewer were translated by language translation software.


Copyright © 2017. Constantine Kaniklidis. All rights reserved. Reproduction in whole or in part without permission is prohibited.