While it is well-established that physical activity is associated with a decreased risk of breast cancer, most studies have been conducted in populations at an average underlying breast cancer risk. In this issue of Cancer Research, Kehm and colleagues present compelling evidence that adulthood physical activity is beneficial across the risk spectrum, including among women with BRCA1 and BRCA2 mutations. These findings are significant because women who are at a higher baseline risk are not engaging in sufficient physical activity to meet current guidelines but may be more motivated to do so knowing that they, like women in the general population, may benefit.

See related article by Kehm et al., p. 116

Studies over the past two decades have established that moderate to vigorous recreational physical activity during adulthood decreases the risk of breast cancer (1), the most commonly diagnosed cancer among women in the United States and worldwide. Although associations have been consistent for breast cancer overall, studying the relationship among subgroups of women is important for both informing relevant biological mechanisms and tailoring public health messaging. Women who are at higher underlying risk may be particularly interested in modifiable lifestyle factors that are effective for breast cancer prevention. Having a family history of breast cancer puts a woman at twice the risk of breast cancer compared with a woman without a family history and this risk increases with the number of relatives diagnosed and if the diagnoses were at younger ages (2), aspects that are not captured by a binary “yes”/“no” classification of family history. In our earlier study of women who all had a family history of breast cancer, physical activity was inversely associated with postmenopausal breast cancer risk and the risk did not vary by the extent of familial risk as classified by a score that incorporated information on family structure (3). Women with a mutation in the BRCA1 or BRCA2 gene are at an especially higher baseline risk, but these groups haven't previously been considered separately. Kehm and colleagues add valuable new information to what is currently known by examining both adolescent and adulthood recreational physical activity in a population of women who encompass a wide range of familial risk and across BRCA1 and BRCA2 mutation status (4).

The Department of Health and Human Services' Physical Activity Guidelines for Americans recommend that adults engage in at least 150 minutes of moderate or 75 minutes of vigorous physical activity per week (5). A study of women with a family history of breast cancer reported that a majority (74.4%) did not meet recommended levels of physical activity, despite their higher baseline risk (6). Furthermore, women with a higher familial risk of breast cancer, even those with an extensive family history undergoing BRCA1/2 testing, did not report doing more physical activity than women with lower or no familial risk (7, 8). It is plausible that such women believe there is not much they can do in terms of lifestyle to counteract their familial risk. The findings by Kehm and colleagues, that physical activity during adulthood is associated with reduced risk of breast cancer in a cohort enriched with women who have a family history of breast cancer and that the association was not modified by BRCA1/2 carrier status or extent of lifetime familial risk (4), are therefore critically important and should encourage women at a high risk of breast cancer to increase their levels of physical activity.

Kehm and colleagues suggest that a physical activity intervention could have a greater reduction in the absolute number of breast cancer cases when tailored to women at high familial or genetic risk. However, we would advocate that their results also support public health messaging emphasizing that all women could benefit from greater amounts of physical activity to reduce their risk.

A valuable consideration by Kehm and colleagues was the analysis assessing the joint impact of adolescent and baseline adulthood physical activity, which demonstrated that adulthood physical activity was inversely associated with breast cancer risk irrespective of physical activity in adolescence (4). This is good news for the legions of women who may not have been physically active in childhood. Even so, we would like to underscore that establishing good exercise habits early in life is still beneficial because those who are more physically active as adolescents are more likely to be physically active as adults (9). This is demonstrated by the numbers in each category of Fig. 1 in the article by Kehm and colleagues where 67% were classified as active at both adolescence and adulthood compared to only 13% who were classified as active in adulthood but not during adolescence (4).

Kehm and colleagues age-adjusted the levels of physical activity by estimating residuals from regressing log-transformed metabolic equivalents (MET) per week on age at baseline. This is an interesting methodologic approach to address how relative amounts and reported intensity of physical activity vary by age. However, their models already included age as the time scale and adjusted for birth cohort. Thus, it would have been helpful to also show whether results were similar using an hours/week metric or the original METs because the refinement of using the age-adjusted residuals comes at the expense of interpretability and results cannot be compared with current physical activity recommendations. For example, with the use of age-adjusted measures of physical activity, Table 1 in the article by Kehm and colleagues shows that the number of METs or hours per week needed to be classified as active versus inactive (quintiles 2–5 vs. quintile 1) in their analysis varies by age. In practice, physical activity guidelines for adults recommend the same amount of physical activity per week irrespective of age. The use of meaningful cutpoints and interpretable physical activity measures are vital for translation of research findings to inform public health recommendations.

According to Table 1 (4), for every age at baseline above 18, the number of hours needed to be classified as active was below current Physical Activity Guidelines for Americans guidelines. For example, the average age at baseline in this study population was between 40 and 50 years old and required 1.0–1.4 hours of moderate activity per week to be considered active, about half the 2.5 hours (150 minutes) per week currently recommended. Given that their classification of active shows a reduction in breast cancer risk, this is reassuring that even modest amounts of physical activity may provide benefits for reduction in risk. However, it is also possible the magnitude of effect could be even stronger at or above guideline recommended levels. The literature would greatly benefit from breast cancer studies examining associations for categories of moderate or vigorous recreational physical activity in adulthood as defined by current physical activity guidelines. Being able to quantify that reduction in risk across levels of familial and genetic risk would be particularly useful for public health messaging and to put the levels of physical activity that are recommended broadly to Americans for a variety of health outcomes into the context of breast cancer risk.

No study has previously examined associations stratified by BRCA1 and BRCA2 status separately. Kehm and colleagues had the unique ability to do so given the large number of women who were tested and known to have a BRCA mutation in the Prospective Family Study Cohort. Consistent with the results by lifetime family risk, those with BRCA1 and BRCA2 mutations had a reduced risk associated with adult physical activity. For adolescent physical activity, the authors included an analysis where they combined the prospective cohort from their main analyses with retrospective cases from the 5 years prior to baseline to account for the possibility that BRCA1 or BRCA2 diagnoses occurred earlier and those unaffected at baseline were less susceptible. The use of the combined cohort was justifiable to increase power and to allow for examination of a younger group of women and, given the focus on adolescent physical activity, the exposure-outcome temporality was not of concern. Despite this, the findings for adolescent physical activity across BRCA mutation status were less clear than those for adulthood physical activity. Although only the result for noncarriers from the combined cohort showed a statistically significant decreased risk and associations were not evident for mutation carriers, there was considerable overlap in the confidence intervals across mutation status and between the prospective and combined cohorts.

Furthermore, adolescent (age 12–17) physical activity was not associated with breast cancer risk overall in this population enriched with women with a family history of breast cancer. This is in contrast with results from our work in the Sister Study that found physical activity during ages 5–19 was associated with a decreased risk of breast cancer, although the association was slightly attenuated when restricted to physical activity during ages 13–19 (10). Given this and the need for more clarity on the associations among BRCA mutation carriers, more studies of adolescent physical activity among large numbers of women at higher familial or genetic risk are needed to better understand the role of timing and subgroup-specific effects of early life activity.

Kehm and colleagues make an important contribution to the current literature with their findings that adulthood physical activity remains beneficial across a large distribution of underlying familial risks and among BRCA1 and BRCA2 carriers. Only this and one other study (3) went beyond a binary classification of physical activity to examine the impact in relation to the extent of familial risk. In future research, we urge the additional use of interpretable cutpoints of physical activity that can be directly translated into clear public health messages and compared with existing guidelines regarding the amount of physical activity that is needed to achieve maximum health benefits.

No potential conflicts of interest were disclosed.

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