Characterization of the Germline Pathogenic Mutational Landscape and Oncologic Outcomes Among 877 Patients with...

There is a paucity of literature on germline pathogenic variants (gPVs) in patients with invasive lobular carcinoma (ILC). This study characterizes the landscape and compares clinicopathologic variables and treatment outcomes between those with and without gPVs.

A prospectively maintained institutional database was used to identify all patients diagnosed with nonmetastatic ILC who had germline genetic testing. Clinicopathologic characteristics and time to recurrence, contralateral cancer, and death were compared for patients with and without gPVs. Conditional hazard ratios, computed by Cox proportional hazards models, described associations between clinicopathologic factors, including gPV status, and cancer events.

Of 4398 patients with nonmetastatic ILC seen between 1989 and 2024, 1170 patients were evaluated by genetic counselors; 877 underwent genetic testing. 10% (83/877) had gPVs, of whom 87% (72/83) had gPVs in known breast cancer predisposition genes; 13% had gPVs in preliminary evidence genes or genes not previously known to be breast cancer associated. Patients with gPVs were more likely to be younger than 40 years, be premenopausal, have high grade and triple-negative receptor status, and undergo mastectomy compared with those without gPV (p < 0.01). At median follow-up of 80 months (interquartile range, IQR 38-135 years), there was no significant difference in the time to contralateral breast cancer, distant or local-regional recurrence, and survival among patients with and without gPVs.

In this large single-institutional analysis, patients with ILC had a distinct landscape of gPVs in breast cancer and non-breast cancer predisposition genes. A significant proportion of patients with ILC have gPVs, and these findings have potentially actionable implications.