Was Hippocrates right?Developing a diet to decrease the risk and recurrence of breast cancer.

Do we need a breast cancer diet?

  let’s look at the numbers:

* 232,670 new cases of invasive breast cancer diagnosed; * breast cancer is the most common type of cancer among women but only the second leading cause of death from cancer among women; * 1 of every 8 women (12.5%) will get breast cancer during their lifetime; * there are an estimated 3.1 million breast cancer survivors in the US today.

All statistics estimated for the US in the year 2014, provided by NIH/American Cancer Society

Age-specific Probabilities of Developing Invasive Female Breast Cancer* The probability of developing breast cancer is: If current age is: in 10 years or, 1 in: 20 0.6% 1,732 30 0.44% 228 40 1.45% 69 50 2.31% 43 60 3.49% 29 70 3.84% 26 Lifetime risk 12.29% 8 *Among those free of cancer at beginning of age interval. Based on cases diagnosed 2008-2010. Percentages and ”1 in” numbers may not be numerically equivalent due to rounding. Probability derived using NCI DevCan Software, Version 6.7.0. American Cancer Society, Surveillance And Health Services Research, 2013. 

Now for the disturbing news…

only 5 to 10% of breast cancers are the result of genetic defects such as BRCA gene or another mutations;

85% of women with breast cancer do not have a family history of this disease;

Incidence of breast cancer in the US is among the highest in the world: in 2008: 76/100,000 vs 21 cases/100,000 in China vs 22.9/100,000 in India current incidence of breast cancer: 124/100,00 what accounts for this disparity?

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That

consider:1. Westernized countries (Europe, US, Australia) all have a significantly

greater rate of breast cancer than less developed countries, or Asia however, 2. as these developing countries adopt a Westernized lifestyle and diet, their incidence rate for breast cancer increases; and 3. when Japanese/Asian women move to the US, they develop breast cancer at the same rate as American women, within 1-2 generations.

perhaps, diet, lifestyle and environment play a role in the development of breast cancer.

Risk Factors Associated with the Development of Breast CancerAge : 1 in 8 <45 and 1 in3 >55Gender – defined by estrogen production Childbirth >30 years of with 1st child; multiple children; Not breastfeeding (breastfeeding 1-1/2 to 2 years) Genetics family: risk doubles 1st degree relative, triples with 2 personal: mutations BRCA; hx of cancer increases risk of recurrence 3-4 times )

Risk Factors Associated with Breast Cancer Which May be Modified by Diet Estrogen Obesity

SBGH Aromatase IGF Vitamin D alcohol angiogenesis epigenetic changes

Before considering the therapeutic aspects of any possible diet it’s important to know what type of diet or pattern of intake you want to create… enter Hippocrates:

“let food be your medicine… and medicine be your food” Hippocrates, 440-377 BC

Was Hippocrates a dietitian? -described as the “Father of Western medicine”-separated the practices of religion from medicine-considered illness the result of poor diet and lifestyle factors-practiced lifestyle modification “walking is the best medicine”-offered therapeutic diets and used herbs and other botanical products to ameliorate illness Hippocrates is an excellent example of a clinician who recommended whole food diets to his patients.  

Whole foods diets are not simplistic, as the previous slide suggests.

Whole food diets incorporate all the science extant to provide anoptimum therapeutic combination of: calories, protein, fat and carbohydrate vitamins, minerals and trace minerals anti-oxidants phytonutrients, bioactive substances translated into the form of foods.

Whole food diets do not include: multivitamins, vitamin or mineral or trace mineral supplements extracts or artificially constructed “functional foods”

Why a whole foods diet? Because we don’t know enough… *too large a dose can be toxic (Goldilocks) *we often don’t know the right dose *we don’t know what activates it *we don’t know if or how its extraction will change or modify it *about how it works in synergy with other foods It’s simpler and likely more effective, to eat whole foods containing multiple nutrients within a meal.

Is there a down side to recommending a whole foods diet?

Yes. A whole food diet is most likely to be useful as a preventative agent. In the case where large quantities of a foodor spics are indicated to attain a therapeutic level, it may not be practical to ingest and accommodation would have to be made.

Caveats as regards any diet for breast cancer at this time:

1. Age: women for whom this diet is appropriate will generally be postmenopausal. Decreasing estrogen levels in women who maintain reproductive capacity may be feasible only within limited parameters.

2.This diet may not be appropriate for women who do not have ER+ form of breast cancer. Greater than 70% of breast cancers diagnosed are ER+.

 

What associations* have been made between diet and breast cancer? #1. High Fiber *risk of breast cancer decreases 7% for each 10 grams of fiber ingested (meta analysis 16,824 cases with 72,195 participants);

*high fiber decreases serum estrogen levels as fiber may bind to estrogen in the colon, increasing its fecal excretion ;

*increased soluble fiber may decrease insulin levels, and reduce rate of obesity and overweight - both established risk factors for breast cancer in postmenopausal women. *association vs. causation

FLAX: a Cautionary Tale

Flax contains fiber and lignans, a bioactive plant component which, when acted upon by gut bacteria, can mimic the effects of estrogen. Flaxseeds contain 3 forms of phytoestrogen: lignans, isoflavines and coumestan – the latter is an anti-coagulant.

Flax has been shown to alter estrogen metabolism (in human studies)by modestly inhibiting the aromatase enzyme from producing estrogen in fat tissue – the major source of estrogen production in postmen- opausal women.

*Women using 10-30 grams of flax QD over 1 month, displayed altered estrogen metabolism, changing the proportion of 2:16 forms of estrogen.

*Flax has been associated with decreased serum estrogen. (fiber) *Human diets with 30-35 g flax QD inhibited the growth of ER+ and ER- breast cancer cells and reduced metastasis of ER- breast tumors.

* Flax may have a greater impact on obese women who usually have increased circulating levels of estrogen and decreased SGBH.

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Why recommending flax for general use may not be prudent:

1. not for patients using anti-coagulants: Coumadin, Wayfarin, aspirin and many herbs; 2. not for patients with low bone density or who are not being regularly monitored or scheduled to receive treatment; 3. not at this time for patients using Aromatase Inhibitors (Tamoxifen, ). May enhance Tamoxifen – clinical trials under way. 4. if using flax give 1 hour before or after other medications (fiber).

Recommendations for Fiber & Flax:

1. Daily intake of 30-35 grams of fiber, primarily soluble; 2. Flax (ground) 1-4 tablespoons daily only if patient not taking anti coagulant medications, only if patient not on aromatase inhibitors only if patient not taking herbs: ginsing, ginkoba,

Associations between Diet and Breast Cancer: #2. SOY *Soybeans are legumes, members of pea family, contain genistein. daidzein and glylitein - isoflavines (types of lignans), weak forms of plant estrogen (phytoestrogens);

*protective effects are primarily from consuming soy in childhood early adulthood or 12 months after a diagnosis of breast cancer;

*soy powder isolates contain high levels of genistein can increase IGF (Insulin-Like Growth Factor) which may promote tumor growth.

Associations between Diet and Breast Cancer continued: SOY *a significant, inverse association for soy protein intake (>13 g daily) and longer survival s/p breast cancer diagnosis noted in AICR’s “Continuous Update Project” using 85 global studies; *soy foods may decrease blood levels of estrogen by prompting the liver to release SHBG* which mops up free estrogen and brings it to the liver for processing and excretion;

*SHBG= Sex hormone binding globulin.

Associations between Diet and Breast Cancer SOY Controversy and Recommendations *initial studies on soy and breast cancer suggested isoflavines in soy (phytoestrogens) elevated estrogen levels, true only in rats;*eating soy does not lead to higher estrogen levels in humans;*eating soy in childhood is protective of breast cancer, studies show a 58% lower risk of breast cancer among those eating ~13 g QD;*soy does not increase breast cancer survivors risk of recurrence or death – may be most protective among users of Tamoxifen *Evidence indicates longer survival eating soy foods”(AICR)

Recommendation for Soy:

1. girls and adolescent girls should have ~13 grams soy daily to decrease risk of breast cancer in the future;2. breast cancer survivors 2 standard servings whole soy foods edename, roasted soy beans, Veggie Burgers made with soy, tofu, miso paste, tempeh or soymilk;3. avoid soy protein isolates (powder) or other soy supplements.

Associations between Diet and Breast Cancer #3.Low Fat* “a high fat diet stimulates increased estrogen production” a ubiquitous suggestion without definitive mechanism of action;* WINS Study* of 2500 breast cancer survivors, relapse free survival time increased 24% among postmenopausal women on a very low fat diet and decreased the risk of recurrence for ER- tumors 42%;* AICR meta analysis of 85 studies including 164,416 breast cancer survivors: evidence indicates longer survival for women eating a low fat diet. *WINS = Women’s Intervention Nutrition Study; randomized control 4690 survivors.

Associations between Diet and Breast Cancer continued: low fat intake*recent Harvard observational study* of 89,000 women found that 1.5 servings of red meat QD, by premenopausal women 24-43 increased their risk of breast cancer 22%; *each additional serving daily, increased risk by 13% ;

*Conclusion: higher red meat intake during early adulthood may be a risk factor for breast cancer.

*Nurses Study II published BMJ June 2014.

June 2014.

Association of fat intake and Breast Cancer: Yet another reason to let go of the mayo … *A low fat diet decreases production of prostaglandins mediators of inflammation; *inflammation promotes cellular reproduction and inhibits cancer cell death increasing risk of cancer development; *COX enzymes cause the signs and symptoms of inflammation;

*regular dosage with a COX inhibitor such as Celexa or aspirin, is associated with a lower incidence of cancer – NIH studies ongoing.

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Calories from fat

Recommendation: Low Fat intake 1. 20%. of total calories from fat 2. 10% from saturated fat limit or avoid red meats or full fat dairy if cooking red meats avoid grilling (marinade if grilling) stew or cook at lower heat; 3. focus on healthy fats: olive oil, omega 3 fatty acid fish, nuts and seeds, avacado

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Associations between Diet and Breast Cancer #4 Sulforaphane * sulforaphane is a phytochemical found in cruciferous vegetables, liberated by the enzyme myrosinase or by gut bacteria. It is one of 3 cancer fighting agents in broccoli, kale, cabbage…

* the phytochemicals diindolmethane and indole 3 carbinol have been found to inhibit both testosterone and estrogen levels; *in numerous studies, sulforaphane has been linked to the inhibition of breast cancer cell proliferation and the induction of apatosis.

Associations between Diet and Breast Cancer,continued: Sulforaphane

* Sulforaphane suppresses both cancer cell growth and the growth of new tumor blood vessels (angiogenesis) by interrupting the cancer cells ability to recruit new blood vessels from surrounding tissue; * Sulforaphane has been shown to inhibit breast cancer stem cells in vitro and in vivo by downregulating Wyn/B-catenin pathway which regulates stem cell self renewal (eliminating the opportunity for metastasis).

To 2cubic millimeters

Angiogenesis simplified:

1. normal cells can grow blood vessels to repair damaged tissue, wounds; 2. dormant tumor cells <2 cubic mm are not vascularized, they get O2 and nutrients from adjacent cells;3. nutrients and O2 can’t travel/diffuse beyond 2 cubic mm.

4. as tumor grows, it becomes hypoxic & signals surrounding cells b y expressing growth factors, such as VEGF*; (VEGF is the primary angiogenic growth factor on all human tumors)

*VEGF= vascular, endothelial growth factor

To 2cubic millimeters

Angiogenesis simplified, 2:

5. if successful the cell has turned on the “angiogenic switch”;6. endothelial cells from the blood vessels of adjoining cells break through the sheath (basal lamina) that holds them, migrate to the source of he signal; 7. once there they multiply & form tubules (beginning of capillaries);

6. VEGF is the primary angiogenic growth factor on all human tumors

Anti-Angiogenesis * 1971 by Judah Folkman proposed a strategy to prevent dormant micro-tumors from progressing to invasive cancer; * multiple bioactive substances have been found in foods which inhibit/interrupt the ability of micro-tumors to develop a blood supply, grow into invasive cancers and metastasize.

* sulforophane is the anti-angiogenic substance most closely associated with breast cancer.

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Recommendation for Sulforaphane:*at this time there is no specific recommendation for sulforaphane researchers at the University of Michigan recommend against the use of sulforophane supplements.

*I recommend cruciferous vegetables, ½ to 1 cup, QD or 3-4 times week based on epidemiologic evidence: steam do not boil; *choose: broccoli sprouts , Brussels sprouts, turnips, kale, broccoli cauliflower and horseradish in mg of sulphorophane from most to least.

Associations between Diet and Breast Cancer #5 choose carbohydrate foods with a low glycemic index (to mitigate against elevated insulin and IGF, diabetes and obesity)

of all the risk factors associated with breast cancer and cancer in general, the strongest link between cancer and diet is obesity.

Attain/Maintain a healthy weight is the #1 focus of all cancer prevention recommendations because the evidence is the most unequivocal:

Obesity and Breast Cancer

*obese women with ER+ breast cancer have a 30% higher risk of recurrence and a 50% high risk of death tha n women of normal weight.(2012)

*many survivors lose muscle mass during treatment resulting in decreased metabolic rate and more weight gain (dx, neuropathy, asthenia/fatigue) when LBM decreases so does metabolic rate

(1) adipose tissue is metabolically active, it secretes aromatase in postmenopausal women, creating estrogen;

Obesity and Breast Cancer

(2) SHBG- sex hormone binding globulin : secreted by liver, mops up free estrogen in effort to regulate estrogen levels, inverse to to obesity;

(3) leptin: produced by white adipose tissue, mediates food intake, energy expenditure through action of hypothalamus;

can increase cytokines (IL-6, TNF-a) using macrophages, thereby stimulating cancer cells.

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What is the association of cancer, obesity and diabetes?

*epidemiologic studies suggest an association between increased levels of insulin, increased levels of IGF and cancer;

*insulin is secreted by the pancreas in response to carbohydrate ingestion; IGF is secreted by liver along with insulin; ALWAYS

the association of cancer , obesity and diabetes,continued…

*for many overweight and obese individuals poor eating habits and the lack of physical activity, sedentary lifestyle, results in insulin resistance characterized by high insulin levels and elevated IGF.

*insulin and IGF are both mitotic hormones, causing rapid cell multiplication and a decreased cellular response to apatosis; (we grow by increasing the number of our cells not their size)

the association of cancer , obesity and diabetes,continued… *choosing to limit carbohydrate intake should directly decrease the serum insulin as well as IGF directly for patients without altered carbohydrate metabolism;*patients with insulin resistance, pre-diabetes or frank diabetes will likely require a more stringent reduction of carbohydrate, increased physical activity to overcome insulin resistance and pharmacologic assistance-likely metformin. Exogenous insulin is likewise associated with increased risk of cancer, as are insulin analogs.

Recommendations:1. patients should be instructed in the principles of

the glycemic index and glycemic load;2. appropriate food choices would include a glycemic

index of 50-553. patients with altered carbohydrate metabolism should be strongly urged to increase physical activity: pedometers, dancing, exercise tapes, seated exercise. Scripts for PT evaluations should be sought.4. Encourage MD to max metformin, etc before insulin added

Diet to Decrease Risk of Breast Cancer Occurance and Recurrance: Summary1. high fiber 30-35 grams QD2. low fat 20% kcal from fat, 10% saturated fat3. soy ~13 grams QD in childhood/adolescence for

girls 2 servings soy foods QD4. sulforaphane ½ to 1 cup cruciferous vegetables QD to 3-4 days per week (no specific recommendation)5. low glycemic index carbohydrate choices (50-55) No supplements, extracts or powders to be used.

Be on the Lookout!The following concepts are cutting edge and relate to breast cancer, but don’t have enough science behind them yet to recommend:1. foods that are themselves aromatase inhibitors: white button mushrooms, pomegranate, grape seed oil, blueberries *could interact with Aromasin/Tamoxifin, no dosage2. epigenetics:

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