BY JENNIFER A. LIGIBEL, MD, ROWAN T. CHLEBOWSKI, MD, PHD, AND PAMELA JEAN GOODWIN, MD, MSC
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The Effect of Lifestyle Factors on Breast
Cancer Prognosis
By Jennifer A. Ligibel, MD, Rowan T. Chlebowski, MD, PhD, and
Pamela Jean Goodwin, MD, MSc
Overview: A growing body of evidence suggests that there women consuming a higher fat diet. This article reviews the
is a relationship between lifestyle factors, such as diet, currently available data examining the relationship between
exercise, and obesity, and breast cancer prognosis. Most the components of energy balance (diet, exercise, and
convincingly, the recently reported Women’s Intervention obesity) and breast cancer outcomes. Based on these data,
Nutrition Study has demonstrated that women participating the authors recommend that physicians caring for patients
in a low-fat dietary intervention after breast cancer diagno- with early-stage breast cancer counsel their patients re-
sis had a lower risk of breast cancer recurrence than did garding weight loss, dietary intakes, and physical activity.
D URING THE last 25 years, a number of observa-
tional studies have suggested a connection between
lifestyle factors, such as diet, exercise, and obesity, and
(95% CI, 1.38-1.76) for women who are obese compared
with women who are not obese. A recent update3 demon-
strated that 36 of 51 studies published before August 2004
breast cancer prognosis. Although these studies have been (representing 73.1% of women studied) identified a signif-
confounded by difficulties in measuring the exposures of icant adverse effect of weight or obesity at breast cancer
interest and by commingling of the various components of diagnosis. The magnitude of the effect of obesity was
energy balance (i.e., women who are obese are also more modest, with most hazard ratios in the range of 1.5 to 2.5.
likely to have higher fat intake and lower levels of phys- A curvilinear association of body size with breast cancer
ical activity), there is a substantial body of evidence outcome has been reported in two studies,4,5 with an
suggesting that increased weight, inactivity, and high fat additional small increase in risk in women who are
intake may be associated with a higher risk of breast underweight. One investigator6 calculated the attribut-
cancer recurrence and/or death in women with early-stage able risk of death in breast cancer because of BMI more
breast cancer. than 27 kg/m2 to be 50%, suggesting that the contribution
Most recently, a randomized trial has demonstrated of obesity to breast cancer outcome is of considerable
that women participating in a low-fat dietary intervention clinical relevance.
had a lower risk of cancer recurrence than women who Adverse prognostic effects of obesity have been identi-
maintained a higher fat diet.1 This represents the first fied in both premenopausal and postmenopausal women,
direct evidence that a lifestyle modification can influence in both hormone-receptor–positive and hormone-receptor–
breast cancer prognosis, and suggests that lifestyle negative breast cancer, and in the presence or absence of
changes could be an important part of breast cancer care systemic adjuvant therapy. Nonetheless, two recent stud-
in the future. This article outlines the currently available ies have failed to identify adverse prognostic effects of
data regarding the relationship between lifestyle factors obesity in women receiving either tamoxifen7 or
and breast cancer outcomes, as well as provides some anthracycline-based adjuvant chemotherapy.8 No study
practical advice for women with early-stage breast cancer. has examined the prognostic effect of obesity in women
receiving aromatase inhibitors. Thus, there is an urgent
OBESITY need for studies of prognostic effects of obesity in women
receiving these adjuvant therapies. The adverse prognos-
More than 50 studies have examined the prognostic tic effect of obesity appears greatest in tumors with
effects of body size in locoregional breast cancer. The favorable prognostic factors (small tumor size, uninvolved
majority of these studies calculated a measure of obesity, axillary lymph nodes, positive hormone receptors); how-
usually body mass index (BMI; weight/height2) to analyze ever, adverse effects are also seen in tumors with unfa-
prognostic effects. Most studies identified a significant vorable prognostic characteristics. Furthermore, obesity
adverse prognostic effect of weight or obesity. A meta- has been associated with more advanced stage, larger
analysis of studies published before 19902 identified a tumor size, and greater axillary nodal involvement, sug-
hazard ratio of distant recurrence of 1.91 (95% confidence gesting that even small adverse effects of obesity in
interval [CI], 1.52-2.40) and a hazard ratio of death of 1.60 patients with these tumor characteristics may have large
clinical effects.
A related problem is that of weight gain after breast
cancer diagnosis. This phenomenon has been examined in
From the Harvard Medical School, Dana-Farber Cancer Institute, and Brigham and
Women’s Hospital, Boston, MA; David Geffen School of Medicine at University of more than 35 studies. Weight gain of 1 to 3 kg during the
California, Los Angeles (UCLA); Division of Medical Oncology and Hematology, year after diagnosis is common. Weight gain has been
Harbor-UCLA Medical Center, Los Angeles, CA; and Mount Sinai Hospital, Toronto,
ON.
associated with young age, premenopausal status or onset
Authors’ disclosures of potential conflicts of interest are found at the end of this article. of menopause during chemotherapy, receipt of adjuvant
Address reprint requests to Pamela J. Goodwin, MD, MSc, 600 University Ave, Ste chemotherapy, addition of some hormone interventions to
1284, Toronto, M5G 1X5, Canada; e-mail: pgoodwin@mtsinai.on.ca.
© 2006 by American Society of Clinical Oncology. adjuvant chemotherapy (medroxyprogesterone acetate,
1092-9118/06/16-20. leuprolide, ovarian ablation, and prednisone), as well as
16LIFESTYLE AND BREAST CANCER PROGNOSIS 17
lower BMI at diagnosis. There is growing evidence that a result of any cause. Benefits of increased activity were
postdiagnosis weight gain reflects a pattern of sarcopenic similar in women who were lean or overweight, with a
obesity,9 with an increase in fat mass coupled with a suggestion that women who were obese especially bene-
decrease in lean body mass. This observation is consistent fited from higher activity levels.
with research suggesting that weight gain may reflect
reduced physical activity and/or reduced resting energy DIET
expenditure, leading to a positive energy balance. Weight A total of 14 studies have examined relationships be-
gain of more than 5 kg has been associated with poor tween breast cancer recurrence and/or survival and di-
breast cancer outcome in several studies.10-12 One group11 etary intakes in women diagnosed with breast cancer.19,20
identified a 15% to 20% difference in outcome at 7 to 10 Seven of the 14 studies that examined dietary fat intake
years after diagnosis, with women weighing more than demonstrated a significant association with breast cancer
average having the worst outcome. outcomes, indicating a lower risk of breast cancer recur-
rence in patients with lower fat intake. However, many of
EXERCISE these trials did not adjust for BMI or total caloric intake,
Many studies during the last 20 years have suggested making it difficult to separate the effect of the various
that exercise may reduce breast cancer risk, but until components of energy balance. The reports relating vege-
recently, few studies have examined the effect of exercise table intake or related nutrients to breast cancer out-
after breast cancer diagnosis. The Health, Eating, Activ- comes also provide a mixed picture.20 Eight studies have
ity, and Lifestyle study demonstrated that activity levels examined the effect of vegetable intake on breast cancer
decreased significantly in a cohort of 800 patients with prognosis, and three found a significant association be-
breast cancer in the year after cancer diagnosis13 and that tween increased intake of vegetables and decreased risk of
only 50% of patients had resumed prediagnosis levels of death in breast cancer cohorts.
activity by 3 years postdiagnosis.14 This decrease in activ- The strongest evidence relating fat intake to breast
ity levels was most pronounced in patients who were cancer outcome arises from a randomized trial, prelimi-
overweight. nary results of which were reported at the 41st Annual
A number of small interventional trials have examined Meeting of the American Society of Clinical Oncology in
the feasibility of exercise in patients with breast cancer 2005. The Women’s Intervention Nutrition Study (WINS)
undergoing adjuvant chemotherapy and/or radiation, or in randomly assigned 2,437 women within 1 year of a breast
patients who had completed breast cancer therapy.15-17 cancer diagnosis to a usual care control group or a dietary
The majority of these trials compared some form of car- intervention group. The dietary intervention was com-
diovascular exercise, most commonly walking, with usual prised of intensive dietary counseling, with a target goal of
care controls. The duration of the exercise interventions lowering fat intake to 15% of caloric intake. After a
ranged from 6 weeks to 1 year, and most trials included median of 60 months, dietary fat intake was significantly
fewer than 100 patients. The endpoints of these trials lower in the intervention group (p ⬍ 0.001). Participants
included improvements in quality of life, increased fitness, in the intervention group also achieved significant weight
weight loss or weight maintenance, improvements in loss, corresponding to a significantly lower mean body
immune system parameters, and changes in biomarkers weight in intervention participants compared with con-
such as estrogen and insulin. The exercise interventions trols (p ⫽ 0.005). The hazard ratio for breast cancer
were generally well tolerated and did not result in in- recurrence in the intervention group compared with con-
creased fatigue or injury in patients undergoing adjuvant trols was 0.76 (95% CI, 0.60-0.98; p ⫽ 0.034 for adjusted
therapy. Although results were not consistent across tri- Cox model analysis),1 suggesting benefit for the dietary
als, exercise was shown to result in improvements in change.
functional capacity and quality of life, to help prevent A second randomized trial evaluating the impact of
weight gain during adjuvant treatment, and to decrease dietary intake on breast cancer prognosis has also been
nausea and fatigue. Few studies demonstrated changes in completed. The Women’s Health, Eating and Living study
immune parameters or levels of biomarkers. has randomly assigned 3,109 premenopausal and post-
To date, only one study has examined the effect of menopausal patients with breast cancer to a control arm
postdiagnosis exercise on breast cancer prognosis. The or a dietary intervention emphasizing vegetable and fruit
Nurses’ Health Study investigators examined the rela- intake. Target goals of the intervention include daily
tionship between levels of leisure activity at least 2 years intake of 16 ounces of vegetable juice and 30 grams of
after breast cancer diagnosis and the risk of breast cancer dietary fiber, as well as limiting fat intake to 15% to 20%
recurrence and/or death.18 They stratified women by ac- of total calories.21 Importantly, this dietary approach has
tivity level and demonstrated that women who exercised not been associated with weight loss.22 Information re-
for 9 to 14.9 metabolic equivalent tasks-hours per week garding the effect of the intervention on breast cancer
(equivalent to walking at a moderate pace for 3 to 5 hours prognosis is expected shortly.
per week) had a 50% decrease in their risk of breast cancer
BASIC MECHANISMS
death (relative risk, 0.50; 95% CI, 0.31-0.82) compared
with the women who exercised less than 3 metabolic A number of mechanisms have been proposed as expla-
equivalent tasks-hours per week. Similar reductions were nations for adverse prognostic effects of lifestyle factors in
seen in the risk of breast cancer recurrence and death as breast cancer. It has been suggested that overweight18 LIGIBEL, CHLEBOWSKI, AND GOODWIN
women may present with a more advanced stage of breast PRACTICAL ADVICE
cancer, leading to poorer outcomes. Although it is true At the completion of adjuvant therapy, many women
that women who are obese present with more unfavorable with breast cancer ask their physicians, “What else can I
tumor characteristics, adverse prognostic effects of obesity do to decrease my risk of cancer recurrence?” Tradition-
are independent of these factors in many studies. A second ally, oncologists have been focused on compliance with
explanation is that chemotherapy doses may be reduced in hormone therapy, and the importance of regular follow-up
women who are obese23; however, adverse prognostic visits and mammograms. Counseling on weight loss, diet,
effects of obesity are seen in women who did not receive and exercise have largely been left to primary care physi-
chemotherapy, or after adjustment for chemotherapy, cians, despite the fact that many breast cancer treatments
suggesting that this is not a central mechanism. result in weight gain and inactivity. With the body of
Other postulated mechanisms include alterations in evidence demonstrating that excess weight increases the
hormone levels,24-26 notably estradiol and sex-hormone risk of breast cancer recurrence, and the emerging data
binding globulin. Obesity is associated with higher circu- that diet and exercise may also influence this risk, it is
lating levels of free estrogen in postmenopausal women, time for medical oncologists to provide lifestyle guidance
because of increased peripheral aromatization of andro- for patients with breast cancer.
stenedione to estriol and estradiol, coupled with reduced Studies have demonstrated a clear increase in risk of
circulating levels of sex-hormone binding globulin. How- breast cancer recurrence and death in patients who are
ever, there are no empiric data supporting this mecha- overweight or obese at the time of breast cancer diagno-
nism in obese postmenopausal patients with breast sis.24 Poor prognosis has also been associated with weight
cancer, and it is unlikely to play a central role in premeno- gain in excess of 5 kg in the year after cancer diagnosis.35
pausal women. Complicating this problem, many women will gain weight
Additional research has focused on the role of insulin during adjuvant treatment for breast cancer, especially
and other members of the insulin/insulin-like growth those who are treated with chemotherapy. Studies have
factor (IGF) family of growth factors in mediating prog- attributed this weight gain primarily to a decrease in
nostic effects of obesity, diet, and physical activity.5,25 activity.9 Declines in resting energy expenditure have
Insulin resistance syndrome, which is associated with been inconsistently reported.36 Small trials have demon-
physical inactivity, dietary excess, and being overweight, strated that exercise interventions, with or without di-
involves relative resistance of insulin receptors in skeletal etary components, can help patients prevent weight gain
muscle and other tissues to the metabolic effects of insu- during adjuvant therapy.16 Other trials have examined
lin, leading to compensatory hyperinsulinemia to main- dietary interventions in breast cancer survivors, and have
tain glucose homeostasis.27 Because insulin and IGF-I demonstrated that low-fat diets and nutritional counsel-
receptors are overexpressed in breast cancer cells,28 these ing can lead to weight loss in this patient population.1,37
cells are not insulin resistant and the hyperinsulinemia is However, robust evidence that weight loss improves prog-
nosis is largely lacking at this time.
postulated to lead to activation of these tyrosine kinase
Weight maintenance for women with a BMI less than
receptors, resulting in downstream mitogenic signaling
25, and moderate weight loss for overweight and obese
and enhanced cell growth.29 In a prospective cohort study,
women, is a reasonable goal for patients with breast
Goodwin et al30 have demonstrated that insulin is highly
cancer. Studies in the diabetic population have demon-
correlated with obesity in women with locoregional breast
strated that weight loss of 5% to 10% of body weight is
cancer, and is associated with increased risk of distant
feasible and can improve a number of health outcomes in
recurrence and of death; the effects on death are indepen-
overweight individuals.38,39 Reduction in caloric intake is
dent of BMI. Similar effects were not seen for IGF-I,
essential for weight loss, whereas exercise has been dem-
IGF-II, insulin-like growth factor-binding proteins 1 and onstrated to be a key component of maintaining weight in
3, or for estradiol; however, free levels of IGF-I and a target range. Studies have demonstrated that both
estradiol were not investigated. The observation that the exercise and dietary change are safe and effective for
adverse effects of hyperinsulinemia were greatest in patients with breast cancer during adjuvant therapy and
hormone-receptor–negative breast cancer in this cohort is afterward.17 The Nurses’ Health Study has also suggested
consistent with recent evidence that progesterone receptor that individuals who engage in moderate exercise after
negativity reflects activation of mitogenic signaling path- breast cancer diagnosis have a lower risk of cancer recur-
ways by growth factors other than estrogen. rence and death than sedentary women, even if they are
Finally, leptin has been suggested as a potential medi- overweight or obese.18 Finally, the WINS study demon-
ator of the adverse prognostic effect of obesity. Leptin, a strated that patients with breast cancer who limited their
neuroendocrine hormone that is a product of the obesity fat intake to less than 20% of dietary calories and lost a
gene,31 is a biomarker of obesity.32 Rose et al33 summarize modest amount of weight, and had a lower risk of recur-
evidence that it stimulates tumor cell growth, migration, rence than women who maintained a diet higher in fat.1
and invasion, and that it enhances angiogenesis and Specific recommendations for an individual patient
aromatase activity. However, Goodwin et al34 were unable could involve a variety of lifestyle modifications (Table 1).
to find an independent adverse effect of leptin in locore- Ongoing trials will examine further the impact of specific
gional breast cancer. Nonetheless, this observation, as dietary components (notably fruits and vegetables) on
well as those outlined, requires replication. cancer recurrence, as well as the relationship betweenLIFESTYLE AND BREAST CANCER PROGNOSIS 19
Table 1. Recommended Lifestyle Modifications for Patients with Breast Cancer
Lifestyle Factor Recommendation Evidence
Diet Avoid high-fat diets Randomized controlled study: WINS demonstrated significantly better
relapse-free survival in women who lowered fat intake to
approximately 20% of calories (HR, 0.76; 95% CI, 0.60-0.98)
Exercise At least 150 min/wk of moderate to vigorous intensity Observational study: Nurses’ Health Study demonstrated reduced risk
activity of breast cancer recurrence/death in women who participated in
moderate exercise for 3–5 h/wk (RR, 0.50; 95% CI, 0.31-0.82)
Weight Weight maintenance for women with BMI ⬍ 25, Observational data demonstrating increased risk of breast cancer
modest weight loss for women with BMI ⬎ 25 recurrence and death in women who are overweight at the time of
diagnosis or who gain weight after diagnosis
Abbreviations: WINS, Women’s Intervention Nutrition Study; HR, hazard ratio; h, hour; wk, week; RR, relative risk; CI, confidence interval; BMI, body mass index.
exercise and breast cancer prognosis. With this additional outcome. The recent release of the WINS data suggests
information, physicians in the future should be able to that lifestyle modifications can alter breast cancer prog-
provide diet and exercise prescriptions for their patients nosis. A number of ongoing studies will provide additional
as they do for drug treatments at present. guidance regarding the role of diet, exercise, and weight
In conclusion, a growing body of evidence supports the loss in reducing the risk of breast cancer recurrence and
relationship between lifestyle factors and breast cancer death.
Authors’ Disclosures of Potential Conflicts of Interest
Employment or
Leadership
Positions Consultant or Stock Research Expert Other
Author (Commercial Firms) Advisory Role Ownership Honoraria Funding Testimony Remuneration
Rowan T. Chlebowski AstraZeneca; Amgen
Lilly Oncology;
Merck kGaA;
Novartis
Oncology;
Organon; Pfizer
Oncology
Pamela J. Goodwin*
Jennifer A. Ligibel*
*No significant financial relationships to disclose.
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