Germline Multigene Panel Testing in Women With Invasive Lobular Cancer

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Importance: Invasive lobular carcinoma (ILC) represents the second most common histologic subtype of breast cancer (BC), yet its genomic landscape and clinical implications remain less well defined compared with invasive ductal carcinoma. Understanding genetic predisposition in ILC may improve risk assessment and guide tailored clinical management. Objectives: To investigate the prevalence and clinical outcomes of germline pathogenic or likely pathogenic variants (PVs) in BC predisposition genes among women with ILC and to assess the prognostic utility of polygenic risk scores (PRSs) in this population. Design, Setting, and Participants: This prospective, longitudinal cohort study was conducted at the European Institute of Oncology, Milan, Italy, from May 16, 2022, to January 31, 2025. Women diagnosed with primary ILC were enrolled and underwent multigene panel testing of 113 genes using next-generation sequencing. Follow-up data were collected until January 31, 2023. Statistical analysis was performed in January 2026. Main Outcomes and Measures: The primary outcome was BC-free survival, defined as the time from surgery to ipsilateral recurrence, contralateral disease, distant metastasis, or BC-related death. Secondary outcomes included overall survival and PRS distribution across genetic subgroups. Results: A total of 414 White women (mean [SD] age, 53.7 [9.7] years; 211 [51.0%] with postmenopausal status) with ILC were tested. No significant associations were found between germline variant subgroups and patients' characteristics. PVs were identified in 46 patients (11.1%), with 20 (4.8%) carrying variants in moderate- to high-risk BC genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, FANCM, PALB2, RAD51C, RAD51D, STK11, TP53, and PTEN). The group of women carrying PVs in moderate- to high-risk BC genes had significantly reduced 5-year BC-free survival compared with the rest of cohort (62.2% [95% CI, 32.3%-82.0%] vs 92.1% [95% CI, 87.6%-95.0%]; hazard ratio, 3.91; 95% CI, 1.99-7.67; P < .001). PRS analysis did not reveal statistically significant differences in relapse risk across quartiles of PRS, and no association was found between PRSs and germline variant status. Conclusions and Relevance: This cohort study of women with primary ILC identified a clinically relevant subset of patients carrying moderate- to high-risk germline PVs who exhibited an increased risk of early relapse. Although PRSs did not show prognostic value in this setting, multigene panel testing findings may refine genetic counseling and inform surveillance and therapeutic strategies in lobular breast tumors.

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