Weight Loss Interventions and Breast Cancer Survival: The Time Is Now

In the last three decades we have made considerable progress in combating breast cancer, and during this time certain lifestyle behaviors have emerged as important modifiable risk factors that play a key role in both the prevention and treatment of this disease. Specifically, consistent observational evidence has shown that women who are obese at breast cancer diagnosis have an approximate 33% higher risk of recurrence and mortality compared with normal-weight women, and being physically active after a breast cancer diagnosis is associated with a 30% to 40% lower risk of breast cancer recurrence and mortality. A growing number of studies have also observed an association between postdiagnosis weight gain and a higher risk of recurrence and mortality, independent of body mass index at diagnosis. However, a major remaining question is whether postdiagnosis weight loss in overweight or obese breast cancer survivors negates this adverse association between obesity and poor prognosis. The article by Goodwin et al that accompanies this editorial adds to the growing body of evidence supporting the benefits of weight loss interventions in overweight breast cancer survivors. Although previous studies have evaluated the feasibility and effectiveness of weight loss interventions in breast cancer survivors, the majority of studies have been small (ie, 100 patients), recruited patients from a single institution, had short study durations, and primarily involved inperson weight loss counseling. Strengths of the Lifestyle Intervention Study in Adjuvant Treatment of Early Breast Cancer (LISA) by Goodwin et al included a multicenter recruitment approach, a large sample size, a telephone-based intervention, and a 2-year intervention duration. After enrolling overweight breast cancer survivors receiving adjuvant letrozole into a weight loss intervention versus mail-based delivery of general health information, the researchers observed a significant 5.3% weight loss at 6 months in the weight loss group compared with a 0.7% weight loss in the mail-based group. Although the weight loss observed was statistically significant and sustained (3.6% loss at 2 years in the weight loss group v 0.4% weight loss in the mail-based group), questions remain regarding the impact of this amount of weight loss on breast cancer recurrence and mortality. The original aim of LISA was to examine the impact of weight loss on disease-free survival; however, accrual was terminated after the enrollment of 338 of the 2,150 planned participants because a loss of funding, leaving these clinically important questions unanswered. LISA was coordinated by the Ontario Clinical Oncology Group (OCOG), and the 338 patients were recruited from 16 Canadian and four American centers between 2007 and 2010. The primary eligibility criteria for the study were a body mass index of 24 kg/m or higher and receiving letrozole for hormone receptor–positive breast cancer. The study was funded by a pharmaceutical company, demonstrating a unique partnership between industry and behavioral research that could serve as a model for future collaborations. However, that same partnership imposed limitations on the study, restricting eligibility to women taking a particular aromatase inhibitor (AI). Additionally, the funding for the trial was discontinued prematurely, preventing the study from achieving its primary goal and raising another unanswered question: How can important lifestyle trials with definitive mortality end points best be funded? Given that pharmaceutical companies primarily fund therapeutic trials, with little incentive to fund lifestyle interventions, and given the scarcity of funding from government agencies for large-scale, long-term trials of lifestyle interventions with disease-free survival end points, another option may be to require pharmaceutical companies to include lifestyle interventions as an active comparison arm to drug trials, especially in cases when drug options provide modest benefit, or uptake or adherence to particular medications is low. Most medications have negative adverse effects, and AIs, including letrozole, have been shown to have adverse effects that negatively influence adherence to the medication, resulting in a reduced survival benefit. Recently, exercise has been shown to decrease AI adverse effects, specifically arthralgia, and may in turn improve adherence to AIs and breast cancer recurrence and mortality rates. Future research examining the impact of lifestyle interventions and medications such as AIs, together and separately, would provide critical information on the clinical importance of lifestyle interventions with respect to diseasefree survival, quality of life, and medication adherence. While we await the funding of lifestyle interventions with the primary aim to improve mortality, breast cancer survivors need to be informed about the numerous benefits of maintaining a healthy weight and being physically active. Although improvements in early detection and treatment have increased overall survival rates, many patients are left with long-term adverse effects. Favorable changes in lifestyle habits may prevent or attenuate the negative treatmentassociated adverse effects. However, more than 65% of breast cancer survivors are overweight or obese, with a majority of normal-weight women gaining weight after diagnosis, and fewer than 30% engaging in recommended levels of physical activity. Future research efforts need to focus on developing cost-effective lifestyle interventions that are easy to implement in communities. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 21 JULY 2