Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast.

PURPOSE

To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast.

MATERIALS AND METHODS

The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes (, , , , , , , , , , , and ) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC).

RESULTS

The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, and PVs were associated with high risks of ILC (odds ratio [OR] > 4) and , , and PVs were associated with moderate (OR = 2-4) risks. PVs and p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, PVs were > 10-fold enriched, whereas PVs in were substantially reduced in ILC.

CONCLUSION

The study establishes that PVs in , , , , and are associated with an increased risk of ILC, whereas PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but should be specifically discussed because of low prevalence and gastric cancer risk.