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Is the Whole Larger Than the Sum of the Parts? The Promise of Combining Physical Activity and Diet to Improve Cancer Outcomes

¹ Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD

Anne McTiernan²

² Fred Hutchinson Cancer Research Center, Seattle, WA

In 2003, the National Cancer Institute identified the need for research examining the integrated effects of physical activity, diet, and weight in multiple arenas to reduce the cancer burden.¹ Before that time, most research on the effect of these health and lifestyle factors had examined the effect on one factor at a time, although a number of epidemiologic studies had adjusted for the potential confounding of other factors to identify whether the effect of one factor was independent of other factors. However, given that patterns of physical activity, diet, and weight are often correlated it may be difficult to determine the isolated independent effect of these complex health behaviors within human populations.

In this issue of the Journal of Clinical Oncology, the report by Pierce et al² on the beneficial effect on breast cancer survival of the combination of a physically active lifestyle with high vegetable and fruit intake is responsive to the National Cancer Institute call for research examining the integration of physical activity, diet, and weight. The present study by Pierce et al used women enrolled onto the control arm of the ongoing Women's Healthy Eating and Living (WHEL) Study, which is a randomized controlled trial (RCT) on the effect of a plant-based diet on future breast cancer events. In contrast to the WHEL RCT, which focused on diet alone, this observational study investigates the effect on breast cancer mortality of specific aspects of a variety of health and lifestyle factors: diet (vegetables and fruit, energy intake, percent energy from fat, and fiber), physical activity, body mass index, alcohol consumption, and smoking, as well as the combined effect of low compared with high levels of vegetable and fruit consumption and physical activity. The WHEL RCT was not designed to test the effect of physical activity, but the comparison group within the trial provides an opportunity to examine the question of the combined effect of diet and physical activity on breast cancer mortality before the release of the primary WHEL trial results. Given the long delay between initiation of RCTs and final results, it is a valuable contribution to explore questions that can be addressed in observational study designs within comparison groups for RCTs. As noted by the authors, this is the first study to suggest that a lifestyle combining high levels of physical activity and vegetable-fruit intake may improve breast cancer survival. However, a number of other cohort studies suggest that combinations of healthy lifestyle behaviors may reduce cancer, coronary heart disease, or all-cause deaths.^3,4

Several methodologic issues unique to the study of the effect of health behaviors on breast cancer mortality should be considered in interpreting the results, particularly in terms of whether they can be generalized to most women with breast cancer. The first issue pertains to whether women enrolled onto the WHEL study are representative of the general population of breast cancer survivors. The WHEL study enrolled women with early-stage breast cancer, who were 18 to 70 years, were within 4 years of their diagnosis, were not scheduled to undergo or currently undergoing chemotherapy, and who had not had evidence of recurrence or new breast cancer since completion of initial therapy.⁵ Therefore, women in the WHEL study are likely healthier than the overall population of women diagnosed with breast cancer. A second issue is whether levels of vegetable-fruit intake or physical activity are comparable to those of other studies of breast cancer survivors. The median vegetable-fruit intake in women in this study was 4.9 servings/d. However, this level of intake is in the range of the mean intakes of between 4.6 and 5.1 servings/d for adult women age 31 to 50 and 51 to 70 years, respectively, in the US population from the 1996 to 2000 NHANES, a similar time period to the baseline period of this study.⁶ It is somewhat higher than reports of vegetable-fruit intake from other observational studies of breast cancer survivors. For example, in the Health, Eating and Lifestyle Study of Breast Cancer Prognosis, a cohort study of women with early-stage breast cancer, mean fruit and vegetable intake 3 years postdiagnosis was 3.7 servings/d, somewhat lower than the level reported in the WHEL study. However, it has been observed in many surveys and studies that adult women, particularly older women, report higher intakes of vegetables-fruits than the general population, and it is a well-known phenomenon that participants in trials are healthier than the population from which they are drawn. For this trial, although there was no prior screening or exclusion criteria for intake of specific foods or nutrients, there was extensive screening and exclusion for inability to complete the trial intervention and assessments, including the 24-hour recalls of diet.⁵ Therefore, the members of this trial cohort are likely more knowledgeable than most about their own dietary habits.

A second issue pertains to how best to address the possible imbalance in the exposure groups regarding prognostic factors, such as hormone receptor status and stage at diagnosis, and treatment that may have influenced mortality. In the WHEL study, among these factors, only stage and tumor grade at diagnosis were associated with mortality, and therefore were included in the final model examining the effects of physical activity and vegetable-fruit intake. However, the possible effects of completeness or dosage of adjuvant chemotherapy or extent of adherence to tamoxifen therapy was not addressed in this or other studies, in large part because current data on such information are difficult to obtain from women and are not collected systematically as part of the hospital record, which is the source of data for cancer registries. If women who are obese and sedentary are less likely to receive the full dose or schedule of chemotherapy or are less compliant with tamoxifen therapy, it may confound the association between health behaviors and mortality.

This report on the WHEL study focused on breast cancer mortality, but the WHEL trial is designed to examine the effect of a plant-based diet on disease-free survival, which will include examining the effect of diet not only on mortality but also on second breast cancer events, including recurrence. Data are currently limited on whether there are differences in the association of health behaviors with different mortality or survival end points. In the Nurse's Health Study, physical activity after diagnosis of breast cancer was associated with a reduction in risk of several outcomes, including total and breast cancer mortality, and recurrence.⁷ The relative risk estimates for physical activity were similar for both breast cancer deaths and recurrence. Interim results from the Women's Intervention Nutrition Study found that a low-fat dietary intervention improved relapse-free survival among women with early-stage breast cancer.⁸ An unexpected finding was the occurrence of a greater reduction in recurrence among women with hormone receptor–negative compared with hormone receptor–positive disease. More research is needed on whether health behaviors have differential effects on these other events. Recurrences, for example, are significant events for breast cancer survivors even if they do not lead to increased mortality. The WHEL trial will be able to examine this issue after additional follow-up.

In contrast to the Women's Intervention Nutrition Study trial, the present study found that the reduction in mortality associated with a physically active lifestyle and high vegetable-fruit intake was limited to women with hormone receptor–positive breast cancer. Increased physical activity and intake of vegetables and fruits may affect the progression of breast cancer by reducing hormones and growth factors that increase breast cancer cell proliferation. Increased physical activity and diets low in fat and high in vegetables and fruit have been shown in randomized trials to reduce circulating levels of estradiol and estrone in women without breast cancer.^9,10 A prominent role of sex hormones in the link between physical activity, intake of vegetables and fruits, and mortality in the article by Pierce et al² is supported by the greater association observed in women with estrogen receptor–positive and progesterone receptor–positive tumors. Other factors that might link these lifestyle behaviors with cancer progression include changes in testosterone, insulin, inflammatory markers, immune function, and DNA repair capacity.¹¹

There is increasing evidence that the host, in addition to the tumor, determines the likelihood and extent of cancer metastasis. The collection of data on lifestyle and basic health factors in therapeutic trials, such as body mass index, physical activity level, and dietary patterns, would allow examination of possible effect modification of treatments by lifestyle, and the role of these factors on prognosis within cohorts of patients that are well characterized with regard to tumor characteristics, treatment type and dose, and completion/compliance with treatment. Several recent reports, for example, indicate that obese breast cancer patients are receiving lower chemotherapy dose per body-surface area compared with normal-weight persons, suggesting that obese women are receiving suboptimal treatment dosing. This lower dosing could contribute, in part, to the association between increased overweight or obesity and decreased prognosis.¹² Furthermore, the increasing prevalence of obesity in the breast cancer population emphasizes the importance of including obese women in therapeutic trials, so that the dosing and effectiveness of adjuvant therapies can be established for these patients.

Although the data from the article by Pierce et al² are intriguing, there is still the potential for confounding by unknown or poorly characterized variables. In particular, increased physical activity and intake of vegetables and fruit may be markers of overall health behaviors including adherence to adjuvant treatments. A randomized controlled clinical trial testing the effects of physical activity and weight loss on breast cancer recurrence and survival would provide critical information for women about whether and how much lifestyle change can affect their prognosis. In addition, evidence from such a clinical trial would aid clinicians, professional organizations, and second-party payers in making recommendations and in providing support for lifestyle change interventions in breast cancer patients and survivors.

In summary, the data from the WHEL control cohort add to a growing body of literature that lifestyle does matter in breast cancer prognosis. Increasing physical activity to 30 to 60 minutes per day is a recommendation for the general population (US Department of Agriculture, the Department of Health and Human Services), and these data suggest that this recommendation should be extended to breast cancer patients and survivors. Similarly, increasing intake of vegetables and fruit is recommended for reducing risk for several diseases, and now seems to aid in improving breast cancer prognosis.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Rachel Ballard-Barbash, Anne McTiernan

Manuscript writing: Rachel Ballard-Barbash, Anne McTiernan

Final approval of manuscript: Rachel Ballard-Barbash, Anne McTiernan

Other: Rachel Ballard-Barbash

REFERENCES

1. National Institutes of Health: Optimizing energy balance to reduce the cancer burden. The Nation's Investment in Cancer Research: A plan and budget proposal for fiscal year 2005. Bethesda, MD, National Institutes of Health, NIH publication 03-5446, October 2003

2. Pierce JP, Stefanick ML, Flatt SW, et al: Greater survival after breast cancer in physically active women with high vegetable-fruit intake regardless of obesity. J Clin Oncol 25:2345-2351, 2007[Abstract/Free Full Text]

3. Knoops KT, de Groot LC, Kromhout D, et al: Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: The HALE project. JAMA 292:1433-1439, 2004[Abstract/Free Full Text]

4. Stampfer MK, Hu FH, Manson JE, et al: Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med 343:16-22, 2000[Abstract/Free Full Text]

5. Guenther PM, Dodd KW, Reedy J, et al: Most Americans eat much less than recommended amounts of fruits and vegetables. J Am Diet Assoc 106:1371-1379, 2006[CrossRef][Medline]

6. Pierce JP, Faerber S, Wright FA, et al: A randomized trial of the effect of a plant-based dietary pattern on additional breast cancer events and survival: The Women's Healthy Eating and Living (WHEL) Study. Control Clin Trials 23:728-756, 2002[CrossRef][Medline]

7. Holmes MD, Chen WY, Feskanich D, et al: Physical activity and survival after breast cancer diagnosis. JAMA 293:2479-2486, 2005[Abstract/Free Full Text]

8. Chlebowski RT, Blackburn GL, Thomson CA, et al: Dietary fat reduction and breast cancer outcome: Interim efficacy results from the Women's Intervention Nutrition Study. J Natl Cancer Inst 98:1767-1776, 2006[Abstract/Free Full Text]

9. McTiernan A, Tworoger S, Schwartz RS, et al: Effect of exercise on serum estrogen in postmenopausal women: A 12-month randomized controlled trial. Cancer Res 64:2923-2928, 2004[Abstract/Free Full Text]

10. Prentice RL, Caan B, Chlebowski RT, et al: Low-fat dietary pattern and risk of invasive breast cancer: The Women's Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 295:629-642, 2006[Abstract/Free Full Text]

11. International Agency for Research on Cancer. IARC Handbooks of Cancer Prevention: Vol. 6, Weight Control and Physical Activity. Lyon, France, IARC Press, 2002

12. Chlebowski RT, Aiello E, McTiernan A: Weight loss in breast cancer patient management. J Clin Oncol 20:1128-1143, 2002[Abstract/Free Full Text]

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