medwireNews: Germline pathogenic variants (PVs) in five hereditary cancer genes, including BRCA2, are significantly associated with invasive lobular carcinoma (ILC) risk, US study findings indicate.
BRCA1 variants were not, however, linked to increased ILC risk, report Fergus Couch (Mayo Clinic, Rochester, Minnesota) and colleagues in the Journal of Clinical Oncology.
They say their data suggest that “multigene panel testing may be appropriate for women with ILC.”
The study included 2999 women with ILC, 20,323 women with infiltrating ductal carcinoma (IDC), and 32,544 unaffected female controls from a population-based cohort, along with 3796 women with ILC and 37,405 with IDC undergoing clinical multigene panel testing (clinical cohort).
Overall, the frequencies of germline PVs in 12 breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were 5.2% among the women with ILC in the population-based cohort and 6.5% among those in the clinical cohort.
The most common PVs in the population-based cohort were in the BRCA2 and CHEK2 genes, occurring at frequencies of 1.13% and 1.10%, respectively, with the remainder present in less than 1.0%. In the clinical cohort, variants in three genes had a frequency of more than 1.0%, namely BRCA2 (2.15%), CHEK2 (1.25%), and ATM (1.03%).
In case–control association testing in the population-based cohort, the researchers found that CDH1 PVs were a significant 15.74 times more common among ILC cases versus controls. This was followed by PVs in BRCA2 (odds ratio [OR]=4.94), and CHEK2 (OR=2.56), and a similar pattern was observed in the clinical cohort.
PVs in PALB2 were more common in ILC cases than controls in the population-based cohort (OR=3.47) but not in the clinical cohort, while ATM PVs were associated with ILC, at a similar OR, in the clinical but not population-based cohort.
Of note, BRCA1 PVs and the specific CHEK2 p.Ile157Thr PV, which has previously been linked to ILC, “were not associated with clinically relevant risks for ILC,” Couch et al remark.
The authors also report that the overall frequency of PVs among people with ILCs was similar to that observed in women with IDC in both the population-based (5.2 vs 5.9%) and clinical (6.5 vs 9.2%) cohorts.
This “suggests that breast cancer histology should not affect the decision to proceed with genetic testing,” they say.
Couch et al conclude that “PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not.”
They add that their results “have clinical implications for germline testing, counseling of PV carriers for ILC risk, and personalized management of ILC risk among carriers.”
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