Challenges in Design and Interpretation of Observational Research on Health Behaviors and Cancer Survival
Authors: Rachel Ballard-Barbash
Journal: JAMA (2009)

AS OF 2006, AN ESTIMATED 11 400 000 ADULTS AND children were living with cancer in the United States, and that number is estimated to increase to nearly 17 000 000 by 2020. This increase in the number of persons living with cancer as a chronic condition has also stimulated interest in understanding whether health habits such as diet, physical activity, or weight control may result in beneficial effects on cancer survival. In this issue of JAMA, the report by Shu et al examines whether soy food intake is associated with overall mortality and breast cancer–specific disease-free mortality in a population-based cohort of 5042 breast cancer patients participating in the Shanghai Breast Cancer Survival Study. The authors report that soy food consumption was significantly associated with decreased risk of death and breast cancer recurrence, with adjusted 4-year mortality rates of 10.3% and 7.4% and 4-year recurrence rates of 11.2% and 8.0%, respectively, for women in the lowest and highest quartiles of soy protein intake. This well-designed study has a number of strengths, including detailed data on treatment, clinical characteristics, recurrence, vital status, and lifestyle habits, including diet. Only 1 prior study examining the association between soy food intake and breast cancer survival has been reported. Within a northern California–based cohort of 1954 breast cancer patients with diagnoses from 1997 through 2000, Guha et al found an inverse association between postdiagnosis soy isoflavone intake and breast cancer recurrence. However, unlike the current study, the inverse association was not observed among women not taking tamoxifen. Prior observational and intervention studies have examined the influence of soy foods and soy isoflavones on breast cancer risk as well as on the purported biological mechanisms, including effects of soy on endogenous estrogens, mammographic breast density and estrogen-independent mechanisms such as inhibition of tyrosine protein kinase, but results have been inconsistent. The limited research on the association of soy food intake with overall mortality and breast cancer–specific mortality limits the ability to make clinical recommendations but provides an opportunity to highlight the challenges in this field of research. Many of these challenges were well addressed in the study by Shu et al and include methodological issues relevant to examining associations with soy foods, overall issues of observational studies of cancer mortality, and the ability to make inferences to US populations of breast cancer survivors from studies of breast cancer survivors in China. One reason that results have been inconsistent from previous observational studies of soy food intake and cancer risk in US-based cohorts is that soy food intake in the United States is quite low. In contrast, the average daily Chinese soy intake represents 10% or more of daily protein intake. In the report by Shu et al, the average isoflavone intake in their study population was 47 mg/d, compared with 1 to 6 mg/d in the United States. Furthermore, the range of soy intake across the Chinese population is large enough to yield an exposure variable with sufficient heterogeneity across the quartiles of intake. In addition to the overall greater consumption of soy foods in China compared with the United States, the types of soy foods consumed in China may provide greater exposure to isoflavones. For example, Asian populations tend to consume traditional, whole soy foods such as cooked soybeans, edamame, tofu, miso, and soy milk. In contrast, soy supplements, meat analogs made with soy, and various processed foods with isoflavones are consumed in the United States, but these foods may have lower levels of isoflavones. Clinicians should be aware of these dietary differences in the quantity and quality of soy foods when advising patients. Shu et al have designed and presented their analysis to address a number of methodological issues that are critical to observational studies of health behaviors and cancer mortality among cancer patients that are distinct from stud-