Abstract PS2-06-22: Genomic Insights in Metastatic Invasive Lobular Carcinoma: A Real-World Study

Abstract Background: Despite recognition that invasive lobular carcinoma (ILC) harbors distinct genomic alterations that bypass estrogen and CDK4/6 dependence, systematic outcome data linking specific alterations to therapeutic response remain limited. This represents a critical research gap, as ILC comprises 10-15% of breast cancers yet exhibits unique biological behavior and treatment resistance patterns compared to invasive ductal carcinoma. This study aimed to identify how individual genomic alterations affect clinical outcomes in patients with metastatic ILC. Methods: This observational cohort study used the Flatiron Health-Foundation Medicine clinicogenomics database to identify adults with hormone receptor-positive, HER2-negative metastatic ILC who underwent genomic profiling between 90 days before metastatic diagnosis and 90 days after initiation of first-line therapy (January 2015-September 2022). Patients enrolled in clinical trials or with less than six months of follow-up were excluded. We evaluated alterations in PIK3CA, RB1, ERBB2, ERBB3, NF1, AKT1, PTEN, FGFR1, FGFR2, FGFR3, ARID1A, TBX3, MDM4, ATM, MYC, and GATA3—assessing ERBB2 only in tumors with HER2-negative status confirmed by IHC and FISH. Overall survival (OS), time to treatment discontinuation (TTD), and time to next treatment (TTNT) were compared using Kaplan-Meier analysis and multivariable Cox proportional hazards models adjusted for age, tumor grade, menopausal status, ECOG performance status, and co-alterations. A subgroup analysis focused on patients receiving first-line CDK4/6 inhibitors plus endocrine therapy (CDK4/6i + ET). Results: A total of 256 patients were included (median age 65 years), with 141 patients (55%) receiving first-line CDK4/6i + ET. NF1 alterations (16%), often co-occurring with PIK3CA alterations, were associated with significantly worse TTNT (6.8 vs 11.8 mo; HR=2.2, p