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Chlebowski, Rowan

0000-0002-4212-6184

Mayo Clinic

The Lundquist Institute, Torrance, California.

Citations 1

Breast Cancer Risk Modification in Women with Pathogenic Variants in BRCA1 , BRCA2 , ATM , C
Kurian, Allison W. , Hughes, Elisha , Bernhisel, Ryan , Hu, Eudora , Polley, Eric C. , Yadav, Siddhartha , Caswell‐Jin, Jennifer L. , John, Esther M. , Shadyab, Aladdin H. , Chlebowski, Rowan T. , Hu, Chunling , Caswell-Jin, Jennifer L , John, Esther M , Shadyab, Aladdin H , Chlebowski, Rowan , Nassir, Rami , Kraft, Peter , Stefanick, Marcia L , Couch, Fergus J. , Yadav, Siddhartha , Polley, Eric C , Kurian, Allison W , Hu, Chunling , Nassir, Rami , Kraft, Peter , Couch, Fergus J.

Cancer Research Communications | April 29, 2025 | Volume: 5 | Issue: 5 | Pages: 783-791

10.1158/2767-9764.crc-24-0592 Get It

Abstract There are limited prospective data on whether established risk factors modify breast cancer risk in women with pathogenic variants (PV) in BRCA1/2 and virtually no risk modification data for ATM, CHEK2, or PALB2. We conducted a nested case–control study in the Women’s Health Initiative (WHI), randomly selecting women with and without breast cancer for DNA sequencing. We evaluated breast cancer odds associated with obesity, family cancer history, smoking, alcohol, parity, breastfeeding, oophorectomy, tubal ligation, neighborhood socioeconomic status, and menopausal hormone therapy (MHT) with estrogen and progestin or estrogen only in PV carriers and noncarriers. In exploratory analyses, we grouped genes by established predisposition for estrogen receptor (ER)-positive (ATM and CHEK2) or ER-negative (BRCA1 and PALB2) disease. Multivariable models with interaction terms were used to assess differential risk modification by PVs. Among 12,957 WHI participants, 287 carried PVs. Breastfeeding was modestly associated with reduced risk for PALB2 [OR = 0.08; 95% confidence interval (CI), 0.00–0.92; P value = 0.042]. With one-sided 95% CI, power was sufficient to exclude OR ≥2.0 with obesity for ATM and BRCA2; smoking and alcohol for CHEK2; no breastfeeding for ATM; no oophorectomy for BRCA2 and CHEK2; no tubal ligation for CHEK2; and neighborhood socioeconomic status for all genes. Estrogen + progestin MHT was modestly associated with increased risk for ER-positive PVs (OR = 7.31; 95% CI, 1.14–64.20; P = 0.036). PVs did not modify risk (interaction P ≥ 0.05). BRCA1/2, ATM, CHEK2, and PALB2 PV carriers do not have breast cancer OR ≥2.0 with many established risk factors. However, MHT warrants additional study in PV carriers. Significance: There is limited information on whether established risk factors increase breast cancer risk from PVs. In the WHI, PV carriers had no substantial (≥2-fold) increase with most risk factors, except potentially MHT in ATM or CHEK2 carriers. The results may inform counseling and research on MHT.