Distinct Reproductive Risk Profiles for Intrinsic-Like Breast Cancer Subtypes: Pooled Analysis of Population-Based Studies

Abstract

Background: Reproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear.

Methods: Analyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2-like, HER2-enriched-like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided.

Results: Compared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2-like, and HER2-enriched-like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like.

Conclusions: This large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared with other subtypes, with implications for the understanding of disease etiology and risk prediction.

Figure 1.

Odds ratios (ORs) and 95% confidence intervals (CIs) for case-control analyses of associations between reproductive factors (time since last birth by number of births, age at first birth, breastfeeding duration, age at menarche, and age at menopause) and intrinsic-like subtypes. The multivariable model was also adjusted for reference age (age at diagnosis for cases, age at interview for controls) and study. The error bars in the bottom panel represent the 95% confidence intervals.

Figure 2.

Odds ratios (ORs) and 95% confidence intervals (CIs) for case-control analyses of association between number of births and luminal A-like and triple-negative tumors according to reference age in 5-year categories (age at diagnosis for cases, age at interview for controls). The multivariable model was also adjusted for study. The error bars represent the 95% confidence intervals.

Figure 3.

Odds ratios (ORs) and 95% confidence intervals (CIs) for case-control analyses of associations between reproductive factors (time since last birth by number of births, age at first full-term birth, breastfeeding duration, age at menarche, and age at menopause) and estrogen receptor subtypes and in situ tumors. The multivariable model was also adjusted for reference age (age at diagnosis for cases, age at interview for controls) and study. The error bars in the bottom panel represent the 95% confidence intervals.