In this large, prospective study, we report a modest but statistically significant reduction in the risk of postmenopausal breast cancer with a high versus low level of physical activity. Women active ≥5 times per week displayed a 13% reduced breast cancer risk compared with inactive women. This relation persisted across tumor stage and select histologic subtypes. In particular, the inverse association appeared more pronounced for ER− breast cancers, for overweight and obese women, for those who never used MHT, and for women with a history of breast cancer in a first-degree female relative. These findings add to the current literature supporting the notion that physical activity influences the risk of this common and deleterious disease (2
Our observation that a high level of activity is specifically associated with a borderline significant reduction in ER− breast cancer risk distinguishes our study from prior investigations. The majority of previous evidence supporting an association between physical activity and postmenopausal breast cancer incidence is based primarily on ER+ tumors, which account for a substantial proportion of postmenopausal breast cancers (18
However, our results are consistent with the California Teachers Study, which found an inverse relation of physical activity to ER− breast cancer in postmenopausal women, whereas the association with ER+ tumors was null (19
). A U.S. case-control study also showed a statistically nonsignificant inverse relation between adult activity and ER− tumors compared with a suggested positive association with ER+ tumors, although the study population was primarily premenopausal (20
). Conversely, physical activity was selectively associated with reduced risk of ER+ postmenopausal breast cancer in the Iowa Women’s Health Study (21
). Furthermore, the relation of physical activity to breast cancer was not significantly modified by ER subtype in five case-control studies (22
Our results regarding joint ER/PR status correspond to a recent systematic review (5
) reporting a stronger association with ER−/PR− than ER+/PR+ tumors. In addition, our observation of a suggestive reduction in ER−/PR− cancer risk with increasing physical activity is consistent with results from the California Teachers Study (19
) and a Shanghai-based case-control study (24
). Physical activity was not associated with ER+/PR+ tumors in our study, in agreement with two other large cohort studies (19
) and two case-control studies (20
). In contrast, two studies (21
) reported an inverse association between physical activity and ER+/PR+ cancers. Associations with the less common discordant ER+/PR− and ER−/PR+ subtypes revealed no consistent pattern in our study and past studies (20
Our study suggests a potential role of physical activity in the prevention of ER− breast cancers. This is of considerable interest because women with ER− cancers tend to be younger (28
), to have tumors that are large and advanced at diagnosis (29
), and to experience reduced survival (30
). Moreover, there is currently a paucity of knowledge regarding risk factors for ER− tumors (18
The suggestion of a stronger relation with ER− than ER+ tumors also indicates that physical activity may influence breast cancer risk independently of estrogens. Potential alternative mechanisms include decreased levels of circulating insulin and insulin-like growth factors, reduction of chronic inflammation, and modulation of the immune response (8
However, because estrogen may actually mediate the development of ER− tumors through growth signals produced by adjacent ER+ cells following estrogen exposure (32
), physical activity could relate to ER-tumors through estrogenic mechanisms. It remains unresolved whether ER+ and ER− tumors represent two phases of one unified disease process or two distinct pathologic entities (33
), although heterogeneity in correlated risk factors (9
) and unique genetic profiles (34
) for each subtype support the latter hypothesis. Moreover, estrogen metabolites may influence breast cancer risk independently of the ER via DNA damage (35
In accordance with other reports (19
), we found no significant heterogeneity in the relation of physical activity to invasive versus in situ
breast cancers, although we did note only a weak association with in situ
tumors, similar to the Collaborative Breast Cancer Study (39
). In contrast, the Cancer Prevention Study II (40
) reported an inverse relation for physical activity specific to localized tumors, whereas a Polish case-control study (26
) observed a stronger relation with advanced tumors. Taken together, our results along with most, but not all, epidemiologic evidence suggest that physical activity operates at all stages of breast cancer pathogenesis.
Our observation that the association with physical activity does not vary by breast tumor histology is consistent with the only other report on this relation (26
), suggesting that physical activity reduces risk of both ductal and lobular carcinomas.
We found a suggestively more pronounced inverse association with physical activity for heavy than lean women, contrasting somewhat with a recent review (5
) showing a greater reduction in breast cancer risk with increasing physical activity among lean than heavy women.
We observed a lower breast cancer risk among active versus inactive women who had never used MHT compared with those with past or current MHT use, similar to results for active non-Hispanic White women with no recent MHT use in one previous investigation (25
). However, other studies (19
) have not observed effect modification of the physical activity-breast cancer relation by MHT use. One possible explanation is limited statistical power to examine effect modification by MHT use in those studies (19
). A differential association by MHT use indicates that physical activity affects breast cancer risk at least partially through a reduction in circulating sex hormones (7
). Conceivably, exogenous estrogens taken by postmenopausal women may render such individuals less sensitive to any physical activity effect if physical activity most effectively reduces breast cancer risk at low estrogen levels.
In our study, physical activity was particularly associated with reduced breast cancer risk in women with a positive family history of breast cancer. This is not consistent with previous observations of either no effect modification or a stronger inverse relation for women without a family history (5
). Apart from chance, one possible explanation for our finding is a greater potential for residual confounding by MHT use or other reproductive variables among women with a family history of breast cancer compared with those without a family history. If true, our finding suggests that women with hereditary risk require a lower “dose” of physical activity to alter their risk profile. This would have implications for targeting a subgroup of individuals who would most benefit from a physical activity intervention.
A major strength of our study is the large number of breast cancer cases. With nearly twice the number of incident cancers than any previous prospective study of the physical activity-breast cancer relation (3
), we had ample statistical power to investigate the association by tumor characteristics and by select breast cancer risk factors. However, it is possible that some of our subgroup results emerged by chance due to multiple comparisons. The prospective nature of our data collection helped avoid recall bias, and comprehensive data on lifestyle covariates allowed extensive control for potential confounding. Because physical activity may serve as a proxy for an overall healthy lifestyle, we adjusted for numerous potentially confounding factors.
A limitation of our study includes the physical activity assessment, which queried participants’ activity by self-report and did not measure all physical activity parameters. However, bias related to misreporting of true activity levels would likely be nondifferential and would tend to underestimate the association between physical activity and breast cancer risk. In addition, our physical activity classification predicts cardiovascular mortality (47
); this biologically plausible relation is consistent with the accumulated evidence and shows construct validity in the discriminatory ability of our five activity categories. An additional, although not necessarily critical, limitation is that the generalizability of our results may be limited because of the relatively low response proportion to our initial postal questionnaire.
Due to the very limited number of premenopausal participants in our cohort, we restricted the study population to postmenopausal women. Although this slightly reduced our cohort size, evidence of a stronger relation between physical activity and postmenopausal breast cancer (5
), divergent associations between lifestyle factors such as BMI and risk of premenopausal versus postmenopausal breast cancer (2
), and distinct incidence profiles for ER+ and ER− tumors by menopausal status (28
) warrants our approach of excluding premenopausal women.
In summary, physical activity was associated with a modest reduction in the risk of postmenopausal breast cancer, particularly ER− tumors. In addition, the physical activity-breast cancer relation was modified by family history of breast cancer and by the estrogen-related factors MHT use and BMI. Our results suggest the potential for prevention of the comparatively aggressive ER− breast cancer subtype, and observation of a more pronounced inverse association between physical activity and breast cancer risk among certain subgroups of women may have practical implications for targeting an at-risk population. Future studies with large cohorts will be imperative for replication of our subgroup findings, and experimental studies and controlled trials will be required to elucidate the potential biological mechanisms underlying the association between physical activity and breast cancer.