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A large cohort study provided strong evidence that physical activity reduces breast cancer risk in premenopausal women, researchers reported in the .

Iain Timmins, PhD, then at the Institute of Cancer Research in London, U.K., and colleagues pooled data on 547,601 women from 19 cohort studies in the . After adjusting for body mass index (BMI), the team found a 10% reduction in breast cancer risk for women in the 90th percentile of self-reported physical activity compared with those in the 10th percentile (HR 0.90, 95% CI 0.85-0.95).

"Risk of premenopausal breast cancer was reduced in those with higher levels of leisure-time physical activity, and this inverse association strengthened after adjustment for BMI," the researchers wrote. "The association was approximately linear in its dose-response relationship, with a stronger subtype-specific effect on human epidermal growth factor receptor 2–positive breast cancer."

Timmins, who is now at AstraZeneca, in the Oncology Biometrics and Statistical Innovation Group, provided additional details in the following interview.

What does this study add to previous research about physical activity and breast cancer risk in premenopausal women?

Timmins: Previous individual cohort studies and meta-analyses have been inconclusive in their findings here, owing to limited sample sizes, inconsistencies in how physical activity is measured, and insufficient data on breast cancer subtypes and other risk factors. Our work overcomes these limitations with a very large, well-characterized, and harmonized study, providing greater clarity that there is a protective association between higher physical activity levels and breast cancer risk before menopause.

Additionally, the large sample has allowed us to perform a more careful dose-response analysis, which suggested a linear relation between physical activity and breast cancer risk, consistent with other cancer types. We were also able to examine associations with physical activity across different subgroups of women, looking across strata of BMI, ethnicity, and other risk factors to understand which women may experience the greatest benefit from increased exercise.

How did you define and quantify physical activity in this study?

Timmins: We focused on leisure-time physical activity, which typically includes sports and exercise done for recreation rather than as part of one's occupation, housework, or travel. This is a useful measure as it is potentially more modifiable.

We ranked women in terms of their total volume of moderate-to-vigorous physical activity levels, which were recorded through self-reported questionnaires in the different cohort studies. This enabled us to compare breast cancer risk for women across the highest and lowest percentiles of physical activity levels.

What did you find in terms of risk reduction in underweight versus overweight and obese women, and what are the potential explanations for this?

Timmins: We found a stronger reduction in risk associated with physical activity in underweight women, and much weaker evidence of any such association in overweight and obese women. We suggest that for underweight women the combination of high activity levels with a diet of low energy intake could impact menstrual function and hormonal exposures in such a way that it reduces breast cancer risk. Previous studies have also found that those with higher BMI typically have a greater tendency to over-report their physical activity levels on self-reported questionnaires, which could also lead to us underestimating the effect of physical activity for overweight and obese women.

What are the proposed mechanisms or pathways linking physical activity with premenopausal breast cancer risk?

Timmins: There are several potential mechanisms that could explain this link, and much active research is being done in clarifying these. One pathway relates to the impact of physical activity on reducing levels of sex steroid hormones such as estrogens and androgens, which could subsequently reduce breast cancer risk. Other mechanisms could include the impact of exercise on fasting insulin levels, IGF [insulin-like growth factor]-signaling, and SHBG [sex hormone–binding globulin] levels, not to mention other factors such as the anti-inflammatory effects of physical activity.

You found a 43% risk reduction with HER2-enriched breast cancer. What are the potential explanations for this stronger association?

Timmins: It is unclear why there might be a stronger role of physical activity on biological pathways that are either specific to HER2 function or are independent of the action of other relevant exposures like estrogen. It is worth noting too that within our study there were only 200 women who had a diagnosis of HER2-enriched breast cancer, so our estimates for this association had comparatively higher levels of uncertainty than other findings we report. For this reason, we would be careful to single out this association without further validation on HER2-enriched subtypes from future studies.

Read the study here.