Distinct Reproductive Risk Profiles for Intrinsic-Like Breast Cancer Subtypes: Pooled Analysis of Population-Based Studies
Authors: Jung Audrey Y , Ahearn Thomas U , Behrens Sabine , Middha Pooja , Bolla Manjeet K , Wang Qin , Arndt Volker , Aronson Kristan J , Augustinsson Annelie , Beane Freeman Laura E , Becher Heiko , Brenner Hermann , Canzian Federico , Carey Lisa A ,   CTS Consortium, Czene Kamila , Eliassen A Heather , Eriksson Mikael , Evans D Gareth , Figueroa Jonine D , Fritschi Lin , Gabrielson Marike , Giles Graham G , Guénel Pascal , Hadjisavvas Andreas , Haiman Christopher A , Håkansson Niclas , Hall Per , Hamann Ute , Hoppe Reiner , Hopper John L , Howell Anthony , Hunter David J , Hüsing Anika , Kaaks Rudolf , Kosma Veli-Matti , Koutros Stella , Kraft Peter , Lacey James V , Le Marchand Loic , Lissowska Jolanta , Loizidou Maria A , Mannermaa Arto , Maurer Tabea , Murphy Rachel A , Olshan Andrew F , Olsson Håkan , Patel Alpa V , Perou Charles M , Rennert Gad , Shibli Rana , Shu Xiao-Ou , Southey Melissa C , Stone Jennifer , Tamimi Rulla M , Teras Lauren R , Troester Melissa A , Truong Thérèse , Vachon Celine M , Wang Sophia S , Wolk Alicja , Wu Anna H , Yang Xiaohong R , Zheng Wei , Dunning Alison M , Pharoah Paul D P , Easton Douglas F , Milne Roger L , Chatterjee Nilanjan , Schmidt Marjanka K , García-Closas Montserrat , Chang-Claude Jenny 
Published: June 2022

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 &lt; .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity &lt; .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.