Genetic And Environmental Associations With Breast Cancer Subtypes

Much work has gone into identifying genetic and environmental risk factors for breast cancer. Based on the recognition that breast cancer is more than one disease, it is possible that different risk factors may contribute to the development of different types of breast cancer.

One of the clearest examples of this phenomenon is the predisposition for basal-like breast cancers among carriers of BRCA1 genetic mutations. Patients with BRCA1 mutations are at high (up to 80%) lifetime risk for developing breast cancer (15). It has long been known that breast cancer arising in BRCA1 mutation carriers possess certain characteristics including ER-negativity, HER2-negativity, and certain histological characteristics (16). It has also become clear that when patients with inherited BRCA1 mutations develop breast cancer, it is virtually always basal-like (8,17-19). The reason for this segregation has not been determined, however, sporadic basal-like breast cancers also may have decreased expression of BRCAl even though somatic BRCA1 mutations are rare (12). In addition, the basal-like subtype appears to be more common among African American women, particularly premenopausal African American women (20). Indirect evidence of an increased prevalence of the basal-like subtype of breast cancer was observed in among participants in the Women's Health Initiative, which found that African American women who develop breast cancer were more likely than white women to develop high grade ER-negative cancers. In this population-based observational study, incidence of breast cancer was evaluated among 156,570 women. Although breast cancer was less common among African American women, when cancer did develop, 32% of tumors were both high grade and ER-negative compared to 10% among white women. In multivariate analysis including age, body mass index, hormonal therapy use, socioeconomic factors and ethnicity, ethnicity remained highly predictive of these tumor characteristics (21).

Carey et al. (20) evaluated the prevalence of breast cancer subtypes among participants in the Carolina Breast Cancer Study, a population-based, case-control study of women between 20 and 74 with breast cancer designed to assess differences in breast cancer based on race and age. Breast cancer subtypes were defined based on IHC surrogates. Among 496 evaluable subjects, the basal-like phenotype was present in 39% of premenopausal African American women compared to 14% of postmenopausal African American women, and 16% of non-African American women with breast cancer. This confirmed earlier findings of an increased percentage of ER- and PgR-negative tumors among African American patients with breast cancer compared to white patients (22) and extends this observation to note that only the basal-like subtype appears to differ by race and age; the other major ER-negative subtype, the HER2+/ER- subtype, did not differ.

There may also be differences in environmental risks for development of different subtypes of breast cancer. Much of the evidence at this time is indirect and based on observed differences by hormone receptor status. For example, large epidemiological studies suggest that the risk factors for ER-negative breast cancers, which are comprised primarily of basal-like and HER2-subtypes, differ from those of ER-positive, or luminal breast cancers. Investigators from the Nurses' Health Study have found that the traditional hormonal risk factors are far more useful in predicting ER-positive breast cancer than ER-negative (23) and hormone replacement therapy is associated only with increases in ER-positive breast cancer (24). Chemoprevention with the selective estrogen receptor modulator tamoxifen reduces only ER-positive breast cancer (25). Alcohol consumption appears to correlate with increased risk of development of ER-positive, but not ER-negative tumors in some studies (26). Conversely, diet quality, particularly in vegetable intake, has been associated with ER-negative breast cancer risk (27). Long-term aspirin use has been correlated with decreased risk of ER positive tumors and increased risk of ER negative tumors (28). Folate use appears to be associated with decreased risk of ER negative tumors only (29). Whether these associations reflect causality and whether they truly correlate with molecular subtype has not yet been established. Given the biologically distinct nature of the different breast cancer subtypes, future evaluation of genetic and environmental breast cancer risks will need to address breast cancer risk factor assessment within, rather than across, subtypes.

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