Risk Factors for Estrogen Receptor Subtype-Specific Contralateral Breast Cancer in Women Under Age 55 Years.

Women with estrogen receptor negative (ER-) contralateral breast cancer (CBC) are 50% more likely to die of CBC compared to women with estrogen receptor positive (ER+) CBC. We comprehensively investigated risk factors for ER subtype-specific CBC using the Women's Environmental Cancer and Radiation Epidemiology Study, a population-based, case-control study of 1521 CBC cases under age 55 years and 2212 individually matched unilateral breast cancer controls. Information about breast cancer risk factors and ER status was obtained by interview and medical record abstraction and common genetic variants with GWAS. Multivariable rate ratios and 95% confidence intervals were estimated using conditional logistic regression models, adjusting for known and suspected risk factors. Among 2800 women where the matched case had known ER CBC status, chemotherapy, hormone therapy, and increasing number of full-term pregnancies were associated with decreased ER+ CBC risk. Drinking, smoking, first breast cancer lobular histology, first-degree breast cancer family history, a polygenic risk score (PRS) of 313 common variants, and an ER+ subtype-specific PRS were associated with increased ER+ CBC risk. More than 2 years of breastfeeding was associated with decreased ER- CBC risk. While none of the PRSs were associated with ER- CBC risk, first- and second-degree family history of breast cancer and second-degree family history of ovarian cancer were associated with increased ER- CBC risk. We identified differential risk factors for ER subtype-specific CBC which can inform individualized risk prediction models for future clinical impact. There remains an unexplained genetic component of ER- CBC.