A substantial body of observational epidemiological evidence suggests that 1) a physically active lifestyle among both pre- and postmenopausal women can lower breast cancer risk and improve prognosis among survivors and that 2) achieving and maintaining normal body weight by postmenopausal women can also lower risk and improve prognosis. The question remains, however, whether these consistently observed protective associations are causal—which would imply a practical public health strategy for reducing breast cancer incidence and death rates—or merely reflect confounding by other lifestyle or biological factors. This question can be optimally answered with a randomized trial. Although other trials have evaluated physical activity and weight control (eg, DPP and Look AHEAD) from the standpoint of primary prevention of other chronic diseases, no trials have addressed this issue for breast cancer risk or survival.
Several large clinical trials (48
) have demonstrated that it is feasible to recruit asymptomatic high-risk women and cancer survivors to behavioral intervention trials. Moreover, several large trials (10
) have demonstrated success in implementing and fostering adherence to physical activity and/or weight control interventions. These trials also suggest that no specific intervention differences are needed between a primary prevention trial and a survival trial (). Both proposed types of trial offer an opportunity to evaluate several biomarkers that potentially mediate the relationships between physical activity, body weight, and breast cancer. Examples of such markers include hormones (particularly estrogen), insulin, and insulin-like growth factors; oxidative stress and DNA repair; target tissue markers; metabolisms; detoxification factors; noninflammatory aspects of immune function; inflammation; and growth factors.
Comparison of primary prevention and survivorship trial characteristics*
The public health impact of either trial could be great, particularly given the current paucity of modifiable breast cancer risk factors and the increasing number of women older than 50 years. Definitive evidence from a primary prevention trial would be relevant to a larger population—all asymptomatic women older than 45 years of age. Definitive evidence from a survivorship trial, however, would be directly referable to a smaller population of all women diagnosed with breast cancer, although it could be argued that such trial findings provide valuable insights about late-stage breast cancer events in general. In terms of intervention adoption, no evidence exists to suggest differences across asymptomatic and diagnosed women, and this area might be an important one for follow-up investigation.
Several considerations, however, may weigh in favor of a survivorship over prevention trial, at least as a first step in a challenging fiscal environment. First, the endpoints for a survivorship trial, such as disease-free interval, breast cancer recurrence, and second primary breast cancer, occur more frequently and sooner than invasive breast cancer among asymptomatic women in a primary prevention trial. This difference has implications for sample size, trial duration, and ultimately cost. The estimates of sample size requirements for primary prevention vs survivorship trial indicate very large differences of four- to sixfold in the numbers needed for these two trials. For example, if a 5-year follow-up is planned, a relatively conservative assumption of a reduction in risk of 20%, and a power of 85%–90%, sample size requirements for a primary prevention trial are in the range of 26 000–36 000. In contrast, sample size requirements for a survivorship trial are in the range of 4500–5000. Although the number of participants required is larger for a trial limited to 3 years of follow-up, the very large difference in sample size requirements for the two types of trials is unchanged.
Second, it may be easier to identify women who have breast cancer through registries and medical records than to identify asymptomatic women at high risk for the disease. Hence, recruitment to a survivorship trial is likely to be more efficient and less costly than recruitment for a primary prevention trial.
Third, the eligibility rates for a prevention trial may be lower than those for the survival trial. For example, the requirement that women in a primary prevention trial are postmenopausal may exclude some women at the lower end of the eligible age range of 45–75 years. Moreover, given the prevalence of HT, it is expected that the exclusion of women having used SERMs would considerably reduce eligibility rates among women recruited to a prevention trial. For either type of trial, additional evidence may be required to inform specific components of trial recruitment, such as audience-specific recruitment strategies, recruitment among racial and ethnic minorities, or timing of trial enrollment among newly diagnosed breast cancer patients.
Fourth, early termination of the trial (before a definitive breast cancer result) because of an observed reduction in the incidence or mortality from conditions other than breast cancer is a more likely scenario for a primary prevention than a survival trial because the time to diagnosis of cardiovascular disease, diabetes, or stroke endpoints is shorter among women with breast cancer than that for cancer among women without breast cancer.
In conclusion, given the magnitude of the public health problem and the amount of accumulated evidence in support for this next level of scientific evidence, it is now appropriate to explore in detail the feasibility and timing of a large randomized trial to assess the effects of physical activity and weight control on breast cancer risk and/or prognosis—and the trade-offs in moving toward the prevention vs the survival trial.