THE CUTTING EDGE
EVIDENCE BASED INFORMATION
CONSTANTINE KANIKLIDIS
DIRECTOR, MEDICAL RESEARCH
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.
Finally, 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. Finally, 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.
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).
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