Contralateral Breast Cancer Risk Among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2

J Clin Oncol. 2023 Mar 20;41(9):1703-1713. doi: 10.1200/JCO.22.01239. Epub 2023 Jan 9.

Abstract

Purpose: To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2.

Methods: The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status.

Results: Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2.

Conclusion: Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / genetics
  • BRCA1 Protein / genetics
  • BRCA2 Protein / genetics
  • Black or African American / genetics
  • Black or African American / statistics & numerical data
  • Breast Neoplasms* / epidemiology
  • Breast Neoplasms* / ethnology
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / surgery
  • Checkpoint Kinase 2 / genetics
  • Fanconi Anemia Complementation Group N Protein / genetics
  • Female
  • Genes, BRCA2
  • Genetic Predisposition to Disease* / genetics
  • Germ-Line Mutation
  • Heterozygote
  • Humans
  • White / genetics
  • White / statistics & numerical data

Substances

  • Ataxia Telangiectasia Mutated Proteins
  • ATM protein, human
  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • Checkpoint Kinase 2
  • CHEK2 protein, human
  • Fanconi Anemia Complementation Group N Protein
  • PALB2 protein, human