Abstract
BackgroundBreast cancer comprises several molecular subtypes with different prognoses and possibly different etiology. Reproductive and hormonal factors are associated with breast cancer overall, and with luminal subtypes, but the associations with other subtypes are unclear. We used data from a national screening program to conduct a large nested case-control study.MethodsWe conducted a nested case-control study on participants in the Norwegian Breast Cancer Screening Program in 2006 − 2014. There was information on estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) for 4748 cases of breast cancer. Breast cancer subtypes were defined as luminal A-like (ER+ PR+ HER2-), luminal B-like (ER+ PR- HER2- or ER+ PR+/PR-HER2+), HER2-positive (ER- PR- HER2+) and triple-negative (ER- PR- HER2-). Conditional logistic regression was used to estimate odds ratios (ORs) of breast cancer associated with age at first birth, number of pregnancies, oral contraceptive use, intrauterine devices and menopausal hormone therapy. Analyses were adjusted for age, body mass index, education, age at menarche, number of pregnancies and menopausal status.ResultsNumber of pregnancies was inversely associated with relative risk of luminal-like breast cancers (p-trend ≤0.02), and although not statistically significant, with HER2-positive (OR = 0.60, 95% CI 0.31–1.19) and triple-negative cancer (OR = 0.70, 95% CI 0.41–1.21). Women who had ≥4 pregnancies were at >40% lower risk of luminal-like and HER2-positive cancers than women who had never been pregnant. However, there was a larger discrepancy between tumor subtypes with menopausal hormone use. Women who used estrogen and progesterone therapy (EPT) had almost threefold increased risk of luminal A-like cancer (OR = 2.92, 95% CI 2.36–3.62) compared to never-users, but were not at elevated risk of HER2-positive (OR = 0.88, 95% CI 0.33–2.30) or triple-negative (OR = 0.92, 95% CI 0.43 − 1.98) subtypes.ConclusionsReproductive factors were to some extent associated with all subtypes; the strongest trends were with luminal-like subtypes. Hormone therapy use was strongly associated with risk of luminal-like breast cancer, and less so with risk of HER2-positive or triple-negative cancer. There are clearly some, but possibly limited, etiologic differences between subtypes, with the greatest contrast between luminal A-like and triple-negative subtypes.Trial registrationNot applicable.
Highlights
Breast cancer comprises several molecular subtypes with different prognoses and possibly different etiology
body mass index (BMI), age at first birth, education, age at menopause, duration of use of oral contraceptives and intrauterine devices, and menopausal hormone therapy use were positively associated with overall breast cancer risk whereas age at menarche, number of pregnancies and postmenopausal status were associated with a decreased risk (Table 1)
The odds ratios (ORs) associated with the oldest age at first birth (>30 years) were elevated, but not significantly so, for human epidermal growth factor receptor 2 (HER2)-positive (OR = 1.67, 95% confidence interval (CI) 0.89–3.12) and triple-negative (OR = 1.47, 95% CI 0.88–2.47) subtypes (p-trend = 0.49 and 0.16, respectively)
Summary
Breast cancer comprises several molecular subtypes with different prognoses and possibly different etiology. Reproductive and hormonal factors are associated with breast cancer overall, and with luminal subtypes, but the associations with other subtypes are unclear. There is substantial evidence for a role of female hormones in the etiology of breast cancer. Breast cancer consists of several molecular subtypes that have very different prognoses [17,18,19,20,21,22,23]. It is less clear whether these various subtypes have different etiologies. There have been two main challenges in previous literature: the various definitions used to define breast cancer subtypes, and the lack of power to examine the effect on all subtypes
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