Four pathogenic variants (PVs) in women diagnosed with breast cancer increased the risk of developing cancer in both breasts, according to researchers.
Their study of more than 15,000 women who had undergone ipsilateral surgery for invasive breast cancer showed that carriers of germline PVs in BRCA1, BRCA2, and CHEK2 had a roughly two- to threefold higher risk of contralateral breast cancer (CBC):
- BRCA1: HR 2.7 (95% CI 2.0-3.8)
- BRCA2: HR 3.0 (95% CI 2.1-4.3)
- CHEK2: HR 1.9 (95% CI 1.1-3.3)
Moreover, while PALB2 PV carriers did not have an increased risk of CBC overall, those with estrogen receptor (ER)-negative breast cancer had a nearly threefold increased risk (HR 2.9, 95% CI 1.4-6.4), reported Fergus Couch, PhD, of the Mayo Clinic in Rochester, Minnesota, and colleagues in the Journal of Clinical Oncology.
Germline ATM PV carriers, meanwhile, did not have a significantly elevated risk.
Among PV carriers of these four genes, premenopausal women had a higher risk compared with postmenopausal women, the group noted. In women 65 and over, however, the CBC risk in PV carriers appeared similar to noncarriers.
Couch and his colleagues also reported that African American PV carriers and non-Hispanic white PV carriers of these four genes had comparable risks of CBC.
“Many women will undergo bilateral mastectomy to reduce the possibility of a second breast cancer,” Couch said in a release. “Now we have data to work from when making the decision to remove the second breast, pursue aggressive surveillance or take preventive medication.”
Their analysis included 15,104 women from the the Cancer Risk Estimates Related to Susceptibility Genes (CARRIERS) consortium, which included 10 prospective studies with information on CBC after an initial breast cancer diagnosis.
Women had undergone ipsilateral surgery for initial invasive breast cancer and had at least 1 year of follow-up after their initial breast cancer diagnosis. Patients’ median age at diagnosis was 62 years, and the median follow-up was 11 years. Approximately 66% were non-Hispanic white, while 15% were African American.
Estimated risks for CBC in PV carriers of the five genes adjusted for age of diagnosis, race/ethnicity, menopausal status, histology, and ER status of the first breast cancer, along with the use of endocrine therapy.
Frequency of germline PVs in ATM, BRCA1, BRCA2, CHEK2, or PALB2 was 4.4% for the overall study and 3.7% and 7.4% for the ER-positive and ER-negative subsets, respectively.
The authors also evaluated CBC risks among 14,237 women with breast cancer from the general population. While these women were slightly older and more likely postmenopausal than those in the overall CARRIERS study population, the estimated CBC risks for PV carriers in the general population were similar.
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, 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.
Couch reported relationships with Ambry Genetics/Konica Minolta, U.S. Oncology Network, Natera, AstraZeneca, Qiagen, and Grail.
Other co-authors reported relationships with industry.
Journal of Clinical Oncology
Source Reference: Yadav S, et al “Contralateral breast cancer risk among carriers of germline pathogenic variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2″ J Clin Oncol 2023; DOI:10.1200/JCO.22.01239.