The results from this analysis are consistent with prior studies in suggesting that reproductive factors play a different role in relation to risk of triple-negative breast cancer vs ER+ breast cancer (13
). Specifically, we found that nulliparity was associated with a 39% lower risk of triple-negative breast cancer but a 35% higher risk of ER+ disease in postmenopausal women. Among parous women, we found that having multiple children was associated with greater risk of triple-negative breast cancer but with lesser risk of ER+ breast cancer. Although associations with other risk factors were comparable across subtypes, differences in associations with parity are consistent with existing literature and with hypothesized etiologic distinctions between ER+ and triple-negative tumors.
In the largest comparative study of triple-negative and other breast cancer subtypes to date, which included 335 triple-negative patients, Ma et al. (27
) reported a decreased risk of ER+ breast cancer (odds ratio = 0.55) among women who had at least four pregnancies compared with nulligravid women but found no association with risk of triple-negative breast cancer (odds ratio = 1.00). Smaller studies that included 78–187 triple-negative patients have also reported no association between parity or age at first birth and triple-negative breast cancer risk (16
), although others have found an increased risk of triple-negative disease in multiparous women (13
In contrast to prior studies, we found no association between breastfeeding and risk of triple-negative breast cancer. Five previous studies, conducted in diverse settings, have noted a statistically significantly lower risk of triple-negative breast cancer in parous women who have ever breastfed a child (15
), or who breastfed for a cumulative duration of at least 4 (13
), 6 (25
), or 12 months (26
< .05). Most of these studies have included premenopausal and postmenopausal women, without stratification by menopausal status. Although the one study conducted only in postmenopausal women (25
) indicated a 50% lower risk of triple-negative breast cancer in parous women who breastfed for at least 6 months compared with parous women who never breastfed, another study (27
) that stratified analyses by attained age indicated that breastfeeding was more strongly associated with triple-negative breast cancer among women aged 35–44 years than among women aged 45–64 years. This latter finding is consistent with other studies that did not stratify by tumor marker expression (31
) because it suggests that associations between breastfeeding and breast cancer risk are most pronounced in premenopausal women. Thus, it is possible that we observed no association between breastfeeding and risk of triple-negative or ER+ breast cancers because of the older age and postmenopausal status of the study population.
The age range of this study population may also explain why we found no association between use of oral contraceptives and risk of triple-negative breast cancer, as was previously suggested (16
). Dolle et al. reported a 4.7-fold increased risk of triple-negative breast cancer in women who were younger than 40 years and used oral contraceptives for 6 years or more. In the same age group, they reported a 6.4-fold increased risk of triple-negative breast cancer among women who initiated use of oral contraceptives before age 18 compared with those who had never used them; however, use of oral contraceptives was not associated with risk in the upper age range of that study population (41–45 years) (16
). Recently, Ma et al. (27
) reported an increased risk of triple-negative breast cancer associated with use of oral contraceptives but only among women aged 45–64 years who first used oral contraceptives before age 18. Our study included women aged 50–79 years and included no women with triple-negative cancers who had used oral contraceptives before age 18. Thus, although our findings suggest no association between use of oral contraceptives and triple-negative breast cancer, inferences based on these results should be restricted to postmenopausal women who initiated use of oral contraceptives at a relatively older age.
As in previous reports (7
), we found race and/or ethnicity to be a major factor associated with triple-negative breast cancer: the triple-negative subtype accounted for 22% of breast cancers in African American women compared with 9% in women of other races and/or ethnicities. This difference is consistent with another analysis within the WHI cohort (33
), which reported that African American women with breast cancer are more likely to have poorly differentiated hormone receptor-negative disease than non-Hispanic white women. That analysis found that differences in breast cancer incidence rates between African American and non-Hispanic white women were not fully explained by differences in the distribution of established breast cancer risk factors. Based on the present analysis, one possibility is that differences in risk factor distributions do not explain differences in incidence rates between these groups because risk factors for the triple-negative subtype (which disproportionately occurs in African American women) differ from those for ER+ disease. Although small numbers prevented us from assessing subtype-specific associations by race and/or ethnicity, we found that the prevalence of late age at first birth was lower among African Americans with breast cancer (7.5%) than among non-Hispanic whites with breast cancer (11.8%). The prevalence of nulliparity, however, was slightly higher among African Americans with breast cancer (14.7% vs 13.6% in non-Hispanic whites).
In addition to the differences between the women with ER+ and triple-negative breast cancers that were observed here, heterogeneity within each of these groups of case subjects is also plausible. Previous studies have indicated clinical and, to a lesser extent, epidemiological differences between women who have triple-negative tumors that express basal markers (ie, basal-like cancers) and those who have triple-negative tumors that do not express basal markers (ie, normal-like cancers) (3
). Differences in risk factor associations for ER+ breast cancer according to PR and/or HER2 status have been suggested (13
). Heterogeneity within ER+ and triple-negative subtypes could influence subtype-specific associations and comparisons between subtypes. However, heterogeneity within these groups of case subjects is assumed to be less pronounced than the differences between subtypes.
There are limitations to consider in interpreting these results. Approximately 40% of case subjects had unknown HER2 status and, therefore, did not contribute to either case group. Case subjects with missing HER2 data were similar to other case subjects with regard to all exposures and covariates. In sensitivity analyses, we used multiple imputation to explore the potential impact of censoring these observations at diagnosis and found almost no difference from the results presented here. Additionally, some misclassification of case groups may have resulted from the use of tumor marker data from multiple laboratories across WHI clinical centers because testing practices can vary; however, testing results were reviewed centrally to minimize differences in classification across institutions. Misclassification of exposure status is also plausible because most exposures considered here occurred many years before study enrollment or random assignment; although errors in recall are likely, the prospective design of the WHI makes differential recall by case status unlikely. Lastly, as previously mentioned, these results may not be generalizable to younger women because the WHI was restricted to postmenopausal women.
There are several important strengths to this analysis, including its large size, prospective design, and completeness of follow-up and exposure information. To date, few studies have examined risk factors for triple-negative breast cancer, and many of these have been underpowered (N = 78 to N = 335 women with triple-negative disease). This analysis thus contributes to a sparse literature and provides further support for the distinct epidemiology of triple-negative breast cancers.
It has been hypothesized that risk of ER+ breast cancer is positively associated with a woman’s cumulative lifetime exposure to endogenous ovarian hormones (34
); thus, aspects of reproductive and menstrual history could influence risk by affecting the number of ovulatory cycles a woman experiences over her lifetime. If hormonal mechanisms predominate in the relationships between reproductive factors and breast cancer risk, it is not surprising that our results suggest that nulliparity or low parity, late age at first birth, early menarche, and late menopause are associated with risk of ER+ breast cancer. Because triple-negative breast cancers are hormone receptor negative, it seems plausible that risk factors operating through hormonal mechanisms would be less important in the etiology of triple-negative than ER+ breast cancers. Nevertheless, it remains unclear why nulliparity (or low parity) would be associated with a decreased risk of triple-negative breast cancer. It is also unclear why the difference between ER+ and triple-negative subtypes would be limited to associations with parity and age at first birth and not extend to differences in associations with other aspects of reproductive history, such as duration of breastfeeding, which also influence a woman’s cumulative lifetime exposure to endogenous estrogens.
Given the poor prognosis associated with triple-negative breast cancer, it remains important to identify the factors that influence a woman’s risk of developing this subtype of disease and to further characterize if and how such factors differ from risk factors for the more predominant ER+ breast cancer subtype that has a better prognosis.