Two large breast cancer case-control studies of women from the United States, Europe, and Asia identified eight genes that had significant associations with breast cancer risk — BRCA1, BRCA2, PALB2, ARD1, RAD51C, RAD51D, ATM, and CHEK2.
Both studies were published in the New England Journal of Medicine. The first, by Fergus J. Couch, PhD, of the Mayo Clinic in Rochester, Minnesota, and colleagues, looked at a panel of 28 cancer-predisposition genes in approximately 64,000 women from the United States (32,247 with breast cancer).
The team analyzed germline pathogenic variants using data from women in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium and found pathogenic variants in 12 established breast cancer predisposition genes in 5.03% of women with breast cancer compared with 1.63% of controls.
High breast cancer risk was linked with BRCA1 and BRCA2 variants (odds ratio [OR] 7.62 and 5.23, respectively), and moderate risk was linked with PALB2 variants (OR 3.83).
Variants in BARD1, RAD51C, and RAD51D were associated with moderate risk for estrogen receptor (ER)-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with increased risk for ER-positive breast cancer. (The study did not include enough women with variants in PTEN or TP53 to assess associations with breast cancer.)
The second study, by Douglas Easton, PhD, of the University of Cambridge in the United Kingdom, and colleagues from the Breast Cancer Association Consortium, looked at 34 genes in approximately 113,000 women (60,466 with breast cancer) from 25 countries in Europe and Asia who participated in consortium studies.
Protein-truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 were associated with significant risk for breast cancer (P<0.0001), with ORs ranging from 2.10 for ATM to 10.57 for BRCA1. More modest associations were found for BARD1 (OR 2.09), RAD51C (OR 1.93), RAD51D (OR 1.80), PTEN (OR 2.25), NF1 (OR 1.76), TP53 (OR 3.06), and MSH6 (OR 1.96).
Similar to the findings in the study by Couch and colleagues, variants in ATM and CHEK2 were associated with increased risk for ER-positive disease. In contrast, variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D had higher ORs for ER-negative disease.
Writing in an accompanying editorial about both studies, Steven A. Narod, MD, of Women’s College Research Institute in Toronto, said the results help establish which genes confer a predisposition to breast cancer, although there is still a question about what best to do with the information.
For example, he noted, among women with breast cancer in the studies, the majority of the mutations were BRCA1, BRCA2, and PALB2, whereas among controls the majority of mutations were CHEK2 and ATM.
“What this means to clinicians, now that we are expanding the use of gene-panel testing to include unaffected women with moderate risk of breast cancer in the family history, is that our time will increasingly be spent counseling women with CHEK2 and ATM mutations,” Narod wrote. “This may be surprising, given that most of the pretest discussion is currently focused on the implications of finding BRCA1 or BRCA2 mutation, and ATM and CHEK2 are clumped in with ‘other genes.'”
He questioned how well equipped clinicians are to advise patients who are found to have a variant in CHEK2 and ATM. The value of testing for BRCA1 and BRCA2, Narod noted, is derived from the possibility of preventing ovarian cancer, but the risk-benefit relationship of testing for genes that do not confer a predisposition to ovarian cancer “is more nuanced.”
Management strategies for women found to have CHEK2 or ATM variants will consistent of screening alone, Narod continued. “The National Comprehensive Cancer Network recommends screening with magnetic resonance imaging starting at 40 years of age for carriers of variants in these genes, but such intensified surveillance in these women has not yet proven to reduce mortality.”
Both groups of researchers said they anticipated that the results would help guide reporting of results generated by multigene-panel testing, counseling of women who are undergoing this testing, and inform cancer screening strategies.
Easton and colleagues added that “incorporation of pedigree data and combined analyses with other studies may improve the precision of these estimates.”
Couch reported financial relationships with AstraZeneca and Qiagen Sciences; co-authors also disclosed relationships with various companies.
Easton reported no conflicts of interest; other members of the Breast Cancer Association Consortium disclosed relationships with various companies.
Narod had no disclosures.