Commissioned on behalf of No Surrender Breast Cancer Foundation (NSBCF)
: : : :
Cancer Watch Digest
[V 5.0 - Updated: 1 July 2017]
Curcuminoids + D3 + EGCG + Melatonin + Selenium +
Isoflavones + RYR + OFA [see below]
CoQ10-RNP (riboflavin (Vitamin B2) + niacin + pyridoxine
+ Boswellic Acids/AKBA + DHA + Selenium + Resveratrol*
High risk (IBC, TNBC, MBC)
*Re resveratrol, see caution below.
(new) Vitamin D Influences pCR
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
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
[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
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
Expanded discussion and new evidence on the
benefits of curcumin. Includes a Buyer's Guide to choosing the optimal curcumin formulation.
of ≥10 mg (soy-derived)
was associated with significant reduced risk of recurrence [Nechutta,
Am J Clin Nutr 2012].
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)
use is associated with decreased breast cancer mortality in women
with localized or metastatic tumors [Murtola, ASCO 2013].
Nature's Plus Herbal Actives Red Yeast Rice Extended Release -- 600
mg - 120 Mini Tablets.
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)
fatty acids supplementation
favorably modulates breast tissue biomarkers including proliferation
[Fabian, ASCO 2013].
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.
Vitamin B2 and niacin (B3) are often found in these amounts in
multivitamins, and so supplementation may not be necessary.
for endocrine disease, and especially during tamoxifen therapy.
benefit in other forms of breast cancer requires further data.
- 100 mg CoQ10 + riboflavin (Vitamin B2) 10 mg + niacin (30 mg)
+ 100 mg pyridoxine (B6)
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.
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
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]
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
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.
curcumin towards to end of a large meal, preferably in three
divided doses. When using a
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;
• lipid-modulating [Panahi 2014 a];
• thrombosuppressive (anti-clot);
• hepatoprotective (against liver toxicity);
• 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.
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
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
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.
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.
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.
Why does curcumin contain anticancer properties? ResearchGate 2013 Dec 28.
Edge-CAM Regimen V. 4.1. Breast Cancer Watch Digest. Special Issue. July 2016
Kaniklidis C. CNS Metastasis from Breast Cancer – New Promise: A Review [2015 revision; pending publication]. Available on
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
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
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:
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
standardized to > 97% polyphenols, with approx 45% or higher of
the active ECGC component, as in
NSI Green Tea Extract.
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
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.
No standardization issue with melatonin.
delivers 5 mg per capsule.
/ 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.
(which is the
Vitamin D2 (which is the ergocalciferol form). No
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
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.
for (1) patients with active malignancies, and/or (2) those at
elevated risk of malignancy, recurrence or metastasis, a target
at least 66
ng/ml would be of greater potential benefit.
The Special Needs of African-American
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
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
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
(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:
Target 25OHD (aka, 25(OH)D Vitamin D3 Level
Optimal Bone Health
> 42 ng/ml
> 52 ng/ml
> 66 ng/ml
> 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.
(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.
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
Note on Optimal Dosing / Scheduling and
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
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).
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.
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
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).
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, 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.
Yang Liu and colleagues
Peking University demonstrated the activity of parthenolide
against cancer stem cells, an activity that curcumin also
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
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
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 has been found to induce
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).
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
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.
of selenium used in the study (methylseleninic acid, aka MSA) is
not readily commercially available, a non-inferor form is
(MeMSC) [best source Swanson Vitamins];
dosing is optimized at 200 mcg (micrograms) daily - single
capsule - taken with a meal.
Anyone with TNBC who is on or anticipating genotoxic
(DNA-damaging) oncotherapy, such as:
platinum agents (cisplatin or carboplatin)
cyclophosphamide (Cytoxan) (as in AC, TAC and CMF regimens)
PARP inhibitor therapy
may benefit from such selenium complex supplementation.
Agent, Commentary, and Standardization
Dosing / Schedule / Product Suggestion
[CNS: recommendations in red; otherwise the same]
Boswellic Acids / AKBA
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).
- Optimal Application:
breast cancers with elevated risk of brain
(2) HER2+ disease,
and hence may be of prophylactic benefit in
on boswellic acids, OR
on AKBA content
Standard Dosing on Boswellic Acid (BA):
Except for active brain carcinoma or metastases,
dosing should deliver no less than approximately
500 - 600 mg boswellic acid daily.
- 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.
- AKBA-Optimized Dosing:
There is a second approach emerging to boswellia
standardization: some studies are standardizing
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).
- 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.
- Standard Formulation:
Source Naturals Boswellia Extract, delivering 262 mg of boswellic acids per tablet.
- AKBA Formulation:
product is one such AKBA-standardized product,
delivering 22.5mg AKBA per capsule.
Evidence suggests that piperine itself has
antitumor activity of its own.
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
standardized to at least 90%, preferably
95+%, curcuminoids content
should be bioavailability-enhanced with
Phospholipids enhance the bioavailability / absorption
and therapeutic efficacy of curcumin, using
a commercial curcumin-phospholipid
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)
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].
For Piperine-based Curcuminoids
at least 1500 - 2000 mg/daily
6000+ mg/daily in
(1) rapidly progressing metastatic
(2) advanced multi-metastatic disease
(more than one site of metastatic
(3) CNS disease: brain and/or
leptomeningeal (spinal) metastasis
dose at 2000 mg/daily if combined with the
two other curcuminoid forms (phospholipids,
- 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)
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
- Advanced BC:
Our preference for greater optimality:
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
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.
Doctor's Best represents one affordable and
widely discounted provider:
Doctor's Best Curcumin C3 Complex With BioPerine
which allows for a steady-state optimal
curcuminoid blood level over time.
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.
proliferation of TNBC cells (MDA-MB-231),
minimizing metastatic potential via
decreasing proliferation, increasing apoptosis,
and reducing invasive potential (Blankaert et
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
- at 1.8 grams/daily, starting 7 -10
days prior to chemotherapy, continuing
concurrently with chemotherapy.
EFAs Super EPA Fish Oil
consult Consumerlab.com for high-quality
- 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
Standardized to > 97% polyphenols, with
approx 45% or higher of the active ECGC
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
- 500 - 1000 mg / daily
- ~1200 mg in
advanced metastatic disease (IBC, TNBC, HER2+)
- 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.
- If sensitive to
the modest caffeine content full daily dose
should be completed before 5PM, or use an
alternative caffeine-free formulation.
- 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.
- One affordable formulation is
Green Tea Extract
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.
Multiple human clinical RCT establish the
benefit of melatonin across all types, and at
- 20 mg / daily
- two hours before
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
strongly anti-inflammatory agent, the primary
biologically active agent in Feverfew.
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.]
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.
Liu and colleagues
in Peking University demonstrated the activity of
parthenolide against cancer stem cells, an
activity that curcumin also shares.
standardized to 0.5 to 0.7% parthenolide
content (derived from Feverfew Extract)
at least 81 (baby) to 325mg (adult) aspirin
coadministration with salicylates
enhances parthenolide activity
- 6+ mg/daily
- 18+ mg/daily in
(1) rapidly progressing metastatic disease
(2) advanced multi-metastatic disease (more
than one site of metastatic migration), or
(3) CNS disease: brain and/or leptomeningeal
- High Potency:
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
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.
Anyone with TNBC who is on or anticipating
genotoxic (DNA-damaging) oncotherapy, such as:
platinum agents (cisplatin or carboplatin)
cyclophosphamide (Cytoxan) (as in AC, TAC
and CMF regimens)
PARP inhibitor therapy
may benefit from such selenium complex
- 200 mcg (micrograms) daily - single
capsule - taken with a meal.
Best form: L-Se-methylselenocysteine (MeMSC)
[best source Swanson Vitamins].
Dosing is optimized at 200 mcg (micrograms)
daily - single capsule - taken with a meal.
- 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
- 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
- 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).
- 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.
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.).
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
(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.).
- 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"
- Target a level
for 25(OH)D of at least 66 ng/ml
- Each 1000 IUs of
Vitamin D elevates serum 25(OH)D levels
approximately 10 ng/ml above base
Retesting is prudent: three consecutive monthly
readings are advised to assure optimal 25(OH)D
Two low-allergen formulations:
A Brief Note on CAM Synergies:
Inclusion of an agent in the
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
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
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
vorinostat (Zolinza), suggesting synergy with the natural HDAC/DNMT
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
+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,
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 . . .
New Updated Version of Lifestyle
Risk Reduction Interventions (see below)
Practical Principles of Some Lifestyle-Oriented Breast Cancer Risk
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+
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
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
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
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.
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).
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.
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 Womenï¿½s Hospital and her
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
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
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
(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
which includes a broad spectrum of modalities: avoidance of
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
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
(alcohol, pesticides, etc., including
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
components), avoidance of
(now an established carcinogen; see above), among many other adverse
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
State of the Evidence: What Is the
Connection Between the Environment and Breast Cancer?
report (as PDF) from
Breast Cancer Fund
/BCF (note that this is the
new sixth edition, 2010).
Methodology for this
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
Copyright © 2017. Constantine
Kaniklidis. All rights reserved. Reproduction in whole or in
part without permission is prohibited.