Untapped Benefits of Physical Activity and Weight Loss in Breast Cancer Prevention

Last week we commented on the data from the Nurses’ Health Study II showing that bike riding could reduce weight gain in premenopausal women. This is just one of many strategies available to women to increase exercise or physical activity, control their weight, and reduce their risk of breast cancer. Why do we focus on physical activity and weigh control for breast cancer prevention? The answer lies in the desire we hear from women to avoid breast cancer, to not opt for the drug strategy and to remain healthy. Below I summarize the evidence that weight loss and increases in activity could have as big a benefit in risk reduction as drug strategies for prevention. While the evidence is not yet in from a randomized controlled trial, the overall weight of evidence points to both short and long term benefits in quality of life , diabetes risk, and changes circulating hormone levels, which we refer to as intermediate markers for breast cancer.
Breast Cancer Today – a Solution
The majority of postmenopausal breast cancer is estrogen receptor positive, driven by endogenous or exogenous hormones and arise in a population of US women who are increasingly in positive energy balance as expressed by sedentary lifestyle and overweight or obesity, a trend that has increased in national data over the past 20 years. At least 70 percent of US women over 50 are sedentary and fail to meet national guidelines for activity and among obese women only 20 percent meet recommendations; over 62 percent are overweight or obese1. Prevalence rates are even higher among African American women. While white women 40 to 59 have a prevalence of obesity of 35.7 percent; African America women have a prevalence of 51.7 percent and this excess persists in women 60 and older 1. Previous studies by McTiernan show that the combination of weight loss and increase in exercise is necessary to achieve the greatest reduction in estradiol 2.
Energy balance and endogenous hormones. Among postmenopausal women, physical activity may lower breast cancer risk by reducing fat stores, which convert androstenedione to estrone 3-4. Physical activity may also increase levels of sex hormone-binding globulin, which would reduce bioavailable estrogens5.  Increasing activity associated with weight loss has produced the greatest reduction in estradiol 2. Increased physical activity also reduces insulin resistance and hyperinsulinemia 6, which may also be related to breast cancer 7. The relation of physical activity to breast cancer risk has been addressed in over 100 case-control and cohort studies 8. The most compelling evidence for long term physical activity and breast cancer risk comes from studies among premenopausal women. Bernstein noted that higher levels of physical activity related to later onset of regular menses 9 and subsequently we showed that sustained higher activity levels through premenopausal years produced similar results 10. Risk was reduced by approximately 40% among those who were consistently most active. These levels of activity may not be sufficient to modify hormone levels in premenopausal women 11, but are sufficient to impact insulin metabolism 12 and risk of type II diabetes 13 in women. Polymorphisms in the IGF pathway are related to mammographic density 14 a strong risk factor for breast cancer 15. The insulin receptor is, however, a significant major predictor of reduced disease free survival in women with node negative breast cancer 16, and supports the potential importance of the IGF pathway and insulin in breast cancer 17-18.
Obesity. Postmenopausal adiposity is an established risk for breast cancer 19-20. Components of energy balance indicate that highest energy intake, highest BMI and lowest energy expenditure may combine to more than double risk of breast cancer 21. Studies of insulin resistance in the face of energy balance suggest that C-peptide and IGF-1 are related to levels of leisure time physical activity and may mediate in part the relation between adiposity and breast cancer risk 22.
Sex steroid hormones, aromatase, and risk of breast cancer.  Endogenous steroid hormones play a key role in the etiology of breast cancer.  Reproductive factors such as parity and age at menopause influence breast cancer risk6.  In addition, selective estrogen receptor modulators (SERMs) decrease breast cancer risk in both premenopausal and postmenopausal women 23 but have substantial side effects. The association of circulating estrogen and androgen levels with risk is well established among postmenopausal women 24-25. Combined data from nine prospective studies show that circulating levels of estradiol, free estradiol, and testosterone levels are independently related to increased risk for beast cancer. Comparing the highest to lowest quintile of estradiol showed a relative risk of 2.58 (1.76-3.78; p trend<0.001) 24 comparable in magnitude to the initial reports of cholesterol and heart disease from Framingham in the 1960s 26. Similar evidence is beginning to accumulate among premenopausal women 27.
Among postmenopausal women, adiposity is the major predictor of estrogen levels, as the adipocyte (fat cell) is the primary locus for expression of aromatase 28-29. Estrogen biosynthesis is encoded by a single gene – aromatase, inhibition of which blocks estrogen production, and among women with breast cancer such inhibition has a dramatic treatment effect 30. Variants in cyp19 (aromatase cytcochrome P450) are related to circulating hormone levels but have not yet been shown to relate to breast cancer incidence 31. Maximizing changes in diet and energy balance as modifiers of this relation could produce large reductions in hormone levels and hence cancer risk.
In summary, maximizing weight loss and increasing activity will most likely produce the greatest reductions in estradiol and insulin levels leading to the greatest reductions in breast cancer risk. Strategies that combine an increase in exercise (energy expenditure) and dietary changes to limit excess energy (caloric) intake, can maximize and sustain changes in energy balance and weight loss then the reduction in breast cancer risk may be greater.
Who could gain most from a prevention strategy?
Postmenopausal women who are overweight or obese are an ideal starting point, though all women can gain in the long run from adopting these strategies. The Diabetes Prevention Trial which had targets of seven percent weight loss (10 pounds for a woman who weighs 150 pounds) and 150 met hours of activity per week, showed that lifestyle changes could be sustained and also reduce risk of disease. Changes at two years were a decrease in weight (six percent weight loss) and a significant increase in hours of physical activity. These changes resulted in a significant reduction in new cases of diabetes.
If we take the risk reduction we observed among postmenopausal women who lost weight and kept it off after menopause in the Nurses’ Health Study32, we might expect a 15 percent reduction in breast cancer based on the weight change. However, with an increase in physical activity having an independent effect on breast cancer risk from that of weight change, the total reduction in risk of breast cancer might be substantially greater. If the combination of walking and weight loss are sustained and add further support for improved energy balance and sustained weight loss, then a target of 20 or so pounds lost, and kept off after menopause, becomes achievable. Such sustained weight loss should produce a risk reduction as high as 50 percent or more based on data from the Nurses’ Health Study among postmenopausal women who had never used postmenopausal hormone therapy.  Clearly heavier women who can sustain weight loss of greater magnitude stand to gain even greater reduction in breast cancer risk while those who are less overweight will also achieve reduction but to a lesser extend. The benefits for diabetes risk, heart disease, and bone strength to avoid osteoporosis all add to the benefits of lower breast and colon cancer risks.
How big could the benefit be?
In the USA, based on 2010 population projections, there are 35.5 million women ages 50 to 69 and an expected 114,300 cases of invasive breast cancer in this age range. As the US population structure continues to age the number of cases will continue to rise. Benefits are also likely to be substantial for the 22 million women ages 70 – 84 in 2010. If 50 percent of invasive breast cancer cases are prevented through an overall population increase in physical activity and weight loss after menopause, at least 57,000 cases of breast cancer among women 50 to 69 years of age could be avoided each year. 
Simple lifestyle changes to increase activity and reduce excess energy intake to achieve and sustain weight loss could then be equal to the potential benefit of drug therapy without all the adverse effects, and with the added benefits of diabetes prevention, reduction in cardiovascular disease, and potentially other chronic disease risks.
We welcome feedback on strategies you may have used to help sustain increases in physical activity and to achieve weight control.


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