In a study reported in the Journal of Clinical Oncology, Yadav et al estimated the risk of contralateral breast cancer among patients with invasive breast cancer and germline pathogenic variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2.
Study Details
The study population consisted of 15,104 prospectively followed individuals within the CARRIERS (Cancer Risk Estimates Related to Susceptibility) study treated with ipsilateral surgery for invasive breast cancer. Risk of contralateral breast cancer for pathogenic variant carriers vs noncarriers for each susceptibility gene was estimated in multivariate analysis accounting for death as a competing risk and adjusting for patient and tumor characteristics.
Key Findings
Median follow-up was 11 years. The frequency of germline pathogenic variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 in total was 4.4% in the overall population and and 3.7% and 7.4% in estrogen receptor (ER)-positive and ER-negative patient subsets.
Compared with noncarriers, BRCA1 (hazard ratio [HR] = 2.7, 95% confidence interval [CI] = 2.0–3.8, P < .001), BRCA2 (HR = 3.0, 95% CI = 2.1–4.3, P < .001), and CHEK2 (HR = 1.9, 95% CI = 1.1–3.3, P = .03) pathogenic variant carriers had a significantly increased risk for contralateral breast cancer. Risk was not significantly increased among all PALB2 carriers (HR = 1.3, 95% CI = 0.6–2.6, P = .50), but was increased among those with ER-negative breast cancer (HR = 2.9, 95% CI = 1.4–6.4, P =.006). ATM carriers did not have significantly increased risk (HR = 1.2, 95% CI = 0.6–2.6, P = .56).
Black pathogenic variant carriers had elevated risks of contralateral breast cancer similar to those among non-Hispanic White pathogenic variant carriers.
The estimated 10-year cumulative incidence of contralateral breast cancer in patients without pathogenic variants in the five genes was 4.3%. Among ATM, BRCA1, BRCA2, CHEK2, and PALB2 pathogenic variant carriers, the 10-year cumulative incidence of contralateral breast cancer was 4.0%, 23.1%, 16.9%, 7.9%, and 7.9%, respectively, and 19% among PALB2 carriers with ER-negative breast cancer.
Among premenopausal patients, estimated 10-year cumulative incidence of contralateral breast cancer was 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 pathogenic variant carriers, and 35% for PALB2 carriers with ER-negative breast cancer. Among postmenopausal patients, the rates were 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2 carriers.
The investigators concluded, “[Patients] diagnosed with breast cancer and known to carry germline pathogenic variants in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of contralateral breast cancer and may benefit from enhanced surveillance and risk reduction strategies.”
Fergus J. Couch, PhD, of the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the National Institutes of Health, National Cancer Institute, and Paul Calabresi Program in Clinical/Translational Research at Mayo Clinic. For full disclosures of the study authors, visit ascopubs.org.
