Although the Protani meta-analysis showed a relationship between poor prognosis and obesity both in the setting of clinical trials and observational cohort studies, it is notable that only 7 of the 45 reports included in the analysis collected data in the setting of a clinical trial, and few other reports included in the analysis adequately controlled for systemic adjuvant therapy (1). Recent attention has focused on optimizing adjuvant therapy for obese cancer patients, as concerns regarding toxicity have led many oncologists to cap or otherwise adjust chemotherapy doses in obese patients. Studies have shown that these a priori dose reductions in obese patients lead to inferior outcomes (11, 12). For example, in Cancer and Leukemia Group B 8541 (12), a randomized trial of adjuvant anthracycline-based chemotherapy in women with node-positive breast cancer, obese women who received less than 95% of expected weight-based doses of chemotherapy for their first cycle of therapy had an increased risk of cancer recurrence as compared to obese women who received full weight-based chemotherapy (adjusted risk ratio [ARR] 0.73, 95% confidence interval [CI] 0.53-1.00). Obese women treated with full weight-based doses of chemotherapy had a similar risk of recurrence as compared to leaner women (ARR 1.02, 95% CI 0.83-1.26). Findings such as these prompted the American Society of Clinical Oncology to issue guidelines for the treatment of obese patients (13), which recommended full weight-based dosing of chemotherapy for all patients, regardless of body weight.

Body Weight and Breast Cancer Outcome (in Cooperative Group Trials)

Given the potential influence of treatment factors on the relationship between obesity and poor breast cancer prognosis, data from clinical trials, where treatments are uniform, doses are recorded, and outcomes are well documented, are especially relevant. A number of recent reports (Table 50-1) examine the relationship between obesity and breast cancer prognosis in the setting of modern adjuvant therapy trials. These studies continue to show a fairly consistent relationship between obesity at the time of breast cancer diagnosis and increased risk of recurrence and death in women with early-stage breast cancer treated with aromatase inhibitors (10, 14, 15) and modern anthracycline- and taxane-based chemotherapy regimens (7, 8 and 9).

The relationship between BMI at the time of breast cancer diagnosis and outcomes has been evaluated in three large adjuvant aromatase inhibitor trials. In each of these, the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial, the Breast International Group (BIG) 1-98 trial, and the Austrian Breast Cancer Study Group (ABCSG) 12 trial, obesity was associated with a significantly higher risk of breast cancer recurrence. However, in the ATAC and ABCSG 12 studies, obesity was associated with poor outcomes only in patients treated with anastrozole and not in patients treated with tamoxifen. In contrast, the BIG 1-98 trial, which randomized women to letrozole or tamoxifen, demonstrated a modest relationship between obesity and worse overall survival in the study population as a whole (OR 1.19, 95% CI 0.99-1.44), but did not see a difference in the relationship between etiology of obesity and poor outcomes in women treated with letrozole versus those treated with tamoxifen (p = .74). The difference in outcomes in obese aromatase inhibitor-treated women in these studies is not clear, but could potentially be a reflection of the relative potencies of the drugs (16). One report from the ALIQUOT study suggested that suppression of estradiol was more complete in obese women treated with letrozole as compared to anastrozole, although it is not clear whether these differences are clinically meaningful (17, 18).

Obesity at diagnosis has also been linked to a higher risk of recurrence in individuals treated in the context of recent adjuvant chemotherapy trials. Three recent trials—the Eastern Cooperative Oncology Group (ECOG) 1199 trial, the ADEBAR study, and CALGB 9741—have all evaluated the relationship between BMI at diagnosis and outcomes in women treated with adjuvant anthracyclines and taxanes. In all three studies, individuals who were obese at the time of breast cancer diagnosis had an increased risk of breast cancer recurrence and/or mortality as compared to leaner women. In E1199, this finding was seen only in women with hormone-receptor-positive tumors, whereas in CALGB 9741, obesity was a poor prognostic factor in both estrogen-receptor-positive and estrogen-receptor-negative tumors. These reports provide provocative information regarding
the potential role of obesity in altering breast cancer outcomes even in patients receiving contemporary anticancer adjuvant treatment.

The association between obesity and poor prognosis in earlystage breast cancer is especially worrisome given the weight gain seen in many women following diagnosis where, even with anthracycline-based adjuvant regimens, weight gain of 2 to 6 kg is commonly reported (19). A number of older studies suggest that weight gain after breast cancer diagnosis is associated with poor prognosis, but recent reports have been less consistent. A report from the Nurses’ Health Study found that nonsmoking women with early-stage breast cancer who gained 2.0 kg/m² or more (median weight gain of 17 pounds) had higher risk of breast cancer recurrence, breast cancer death, and allcause mortality than did women who did not gain weight (20). Other recent reports, including an analysis of the Life After Cancer Epidemiology Study Cohort (21), have not shown a relationship between weight gain and breast cancer prognosis.

Despite the consistent evidence that obesity at the time of breast cancer diagnosis is a poor prognostic factor, there are no data from randomized trials demonstrating that purposeful weight loss after diagnosis will lead to improvements in prognosis. Many experts have speculated that the difference in findings of two large-scale dietary intervention trials (6, 22) (see description below in dietary section), one of which induced weight loss and the other of which did not, provides evidence that weight change after diagnosis will lower the risk of cancer recurrence and related mortality, but large-scale trials are needed to test this hypothesis.

A number of smaller-scale trials have been performed in breast cancer populations demonstrating the feasibility and benefits of weight-loss interventions (23). The largest weight-loss study in breast cancer survivors to date, the Lifestyle Intervention Study for Adjuvant Treatment of Early Breast Cancer (LISA) trial, randomized 338 postmenopausal women with hormone-receptor-positive breast cancer to an educational control group or to a 2-year, telephone-based weight-loss intervention focused on calorie restriction, a lowfat diet, and increased physical activity. Intervention participants lost approximately 4.5 kg more than the control group at 6, 12, 18, and 24 months and reported a significant improvement in physical functioning scores as compared to control participants (5). A number of other weight-loss studies, including the ENERGY, SUCCESS-C, DIANA-5, and CHOICE trials, will provide additional information regarding the efficacy and benefits of weight-loss interventions in breast cancer survivors.