In this population-based study of breast cancer in women under 45 years of age, the risk conferred by OC use varied significantly between TNBC and non-TNBC. OC use ≥1 year was associated with a 2.7-fold increased risk of TNBC. The risk of TNBC was further heightened in relation to longer OC duration and fewer years since last use. Among women ≤40 years the strength of the OC use association with TNBC was further magnified. Similar relationships were not observed in relation to non-TNBC, providing support for an etiologic distinction.
The relationship between OC use and breast cancer risk has been the subject of extensive research (17
). Unlike well-established risk factors such as family history, early menarche, nulliparity, and lack of breastfeeding (24
), the relationship between OC use and breast cancer risk has remained less clear. A large pooled analysis (28
) and recent meta-analysis (29
) have both reported an increased risk of breast cancer (approximately 20-30%) in relation to OC use among premenopausal women. Previous studies have also shown risk in relation to OC use to be concentrated among younger premenopausal women (30
). These findings are compatible with the present study and consistent with our prior reports on OC use effects in the two study populations from which our study population was drawn (17
The mechanism through which OC use impacts breast cancer risk in young women is unknown. Studies of estrogen's role in promoting the growth and vascularization of cancer cells have focused largely on the transcriptional effects of estrogen binding to its receptor in ER-positive mammary and ovarian cancer cells. However, a recent publication has proposed a second mechanism whereby estrogen promotes the growth of ER-negative and ER-positive cancer by systematically enhancing angiogenesis and stromal cell recruitment (32
Interest in the clinical and pathologic characterization of TNBC has grown tremendously in recent years, related in part to its poor prognosis and higher frequency in younger and African-American women. Although basal-like/TNBC tends to have a poor prognosis compared to other subtypes, it is unclear whether this is due to inherent aggressiveness or resistance to systemic therapy. Trastuzumab (Herceptin) and tamoxifen effectively target HER2+ (33
) and ER+ (35
) breast cancer, respectively, but targeted therapies for basal-like/TNBC patients are lacking. Carey et al. reported that TNBC (and less common HER2+/ER-) patients had worse survival than luminal subtypes (5
), despite higher chemosensitivity to conventional anthracycline-based therapy.
Few studies to date have focused on etiologic risk factors for basal-like/TNBC, and none have focused on young women. Millikan et al. (36
) examined common breast cancer risk factors across ‘intrinsic’ breast cancer subtypes in the population-based Carolina Breast Cancer Study of women ages 20-74. Among women of all ages, they observed an increased risk of basal-like breast cancer in relation to increasing number of live births and younger age at first full-term pregnancy. In a case-only comparison of basal-like versus luminal A breast cancer subtypes among women of all ages in relation to OC use, no differences were observed. Yang et al. (37
) evaluated established breast cancer etiologic factors by subtype within the Polish Breast Cancer Study. Among premenopausal women, increasing BMI (per 5 units) was associated with a borderline-significant increased risk of basal-like breast cancer (OR 1.2, 95% CI 0.9-1.6) and a reduced risk of luminal A breast cancer (OR .7, 95% CI 0.6-0.9; Pheterogeneity
.003). OC use was rare in this population (>60% of participants were postmenopausal) and not significantly associated with breast cancer risk overall or within subtypes.
Hormone receptor and HER2 defined breast cancers have been the subject of a more extensive literature. ER-negative breast cancer is known to be more frequent among young women (38
), African American women (39
), and BRCA1 carriers (40
). ER-positive breast cancer is associated with improved response to hormonal therapy, longer disease-free intervals, and improved survival (41
). Previous studies of etiologic heterogeneity among hormone receptor defined breast cancer have reported risk factor differences with mixed results. In a systematic literature review, Althuis et al. (42
) reported that delayed childbearing, nulliparity, and early menarche were commonly associated with an increased risk among ER-positive breast cancer only. Several studies that have examined elevated BMI in premenopausal women by hormone receptor status have discerned an increased risk of ER-/PR- breast cancer but not ER+/PR+ breast cancer (43
), while others have not (38
). The relationship between OC use and risk of ER-defined breast cancer is somewhat ambiguous. Several studies have reported an increased risk of ER-negative breast cancer in young women associated with ever using OCs (38
), and long duration of use (43
), but with varying levels of magnitude and statistical significance.
Evidence that breast cancer risk factors operate through HER2 is inconsistent. Within the Carolina Breast Cancer Study, Huang et al. (48
) found that most recognized breast cancer risk factors did not vary by HER2 status; neither high BMI nor OC use were associated with a significantly increased risk of HER+ or HER2- breast cancer in premenopausal women. In contrast, Sherman et al. (49
) found that high BMI was associated with low HER2 levels in premenopausal women (Ptrend
.01) within the Polish Breast Cancer Study. Some studies of premenopausal women have found an increased risk of HER2-positive breast cancer in relation to early OC use (50
), while others have found no association between OC use and either HER2 subtype (48
The results of this study should be considered in light of several limitations. Our study population contained few non-Caucasians, and given that TNBC is more than twice as common among African Americans, similar research is needed in a racially heterogeneous population to evaluate the generalizability of our results. Our ability to evaluate age-specific effects was constrained by the small number of TNBC cases ages 41-45. It is worth noting that the diagnosis years in this study pre-date the incorporation of HER2 and routine ER/PR clinical testing, thus requiring direct testing of samples, which was limited by the availability of tumor specimens. We obtained specimens for 1019 of the 1286 women in our study (79.2%). To the extent that the availability of tumor specimens was related to features that are also related to TNBC, our results may be biased. As with all studies of TNBC, there is also potential for misclassification of TNBC due to false negative or false positive IHC results. In particular, our study used IHC to assess HER2 expression levels, the accepted standard for HER2 assessment at the time assays were completed. Since then, fluorescence in situ hybridization (FISH) has become the standard for discrimination of HER2 intermediate IHC scores. Because a portion of the 2+ (intermediate positive) tumors would not show amplification by FISH analysis, we may have misclassified some true HER2-negative cases as HER2 positive. In addition a small number of tumors that exhibit only 1+ (low positive) immunostaining could be falsely low by IHC. For the analyses presented in this study we used the standard clinical definition of HER2-negative, which included negative and low positive staining. We also repeated all analyses with a purer HER2-negative definition by excluding low positives from the TNBC group; results were of similar magnitude, but with wider confidence intervals (data not shown).
Our study has the strength of being population-based and is the largest of its kind to evaluate breast cancer subtypes and etiologic differences in young women. In contrast to the few other studies that have examined risk factors by tumor subtype, OC use was common in our study population and extensive detail on OC usage patterns was collected, allowing us to assess OC use associations in a thorough manner. By excluding non-OC users from trend tests, we were able to discern differences in OC use above and beyond ever use, thereby providing additional support for dose-response relationships (53
). The centralized, blinded nature of tumor specimen testing removed the potential for inter-reviewer bias.
The strong association between OC use and the risk of TNBC observed in this study and the relative scarcity of such studies to date, emphasize the need for future research. Given that we have yet to understand whether the poor prognosis associated with TNBC is a reflection of fewer treatment options, or is intrinsic to the biology of the disease, the results of etiologic studies such as the present one may ultimately play an important role in elucidating the etiologic pathways of TNBC, and in facilitating the development of strategies for prevention, treatment, and management of TNBC.