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<0.01) and TTD (5.6 vs 8.5 mo; HR=1.8, p<0.01) in the overall cohort, and shorter TTD (5.4 vs 12.5 months; HR=2.6, p<0.01) and TTNT (6.9 vs 15.6 mo; HR=3.2, p<0.01) in the CDK4/6i+ET subgroup. RB1 alterations (7%), with frequent co-occurring PIK3CA and PTEN mutations, were associated with significantly shorter TTNT (6.3 vs 10.6 mo; HR=1.9, p=0.04), TTD (4.7 vs 8.3 mo, HR= 1.8, p=0.05), and numerically shorter OS (20.9 vs 29.4 months; HR=1.2, p=0.6) in the overall cohort. ARID1A (16%) was associated with significantly shorter overall OS (20.1 vs 31.8 mo; HR=1.7, p=0.03). Among patients treated with CDK4/6i + ET with this alteration, TTNT was numerically shorter. GATA3 alterations (7%) were significantly associated with shorter TTD (4.4 vs 8.2 mo; HR=2.5, p=0.01) in the CDK4/6i + ET group. In the overall cohort, GATA3 alterations were associated with a trend toward shorter OS and TTD. Additional alterations, including ERBB2 (19%), PTEN (11%), ATM (12%), PIK3CA (55%), ERBB3 (8%), TBX3 (14%), MDM4 (9%), FGFR1 (14%), FGFR2 (6%), FGFR3 (3%), AKT1 (3%), and MYC (5%), did not demonstrate a statistically significant impact on survival outcomes in this analysis. Conclusions: These findings represent a large-scale systematic analysis linking specific genomic alterations to treatment resistance patterns in metastatic invasive lobular carcinoma, identifying NF1, RB1, GATA3, and ARID1A as potential predictors of reduced benefit from standard therapies. While requiring validation in independent cohorts, these associations suggest that patients with these alterations may benefit from consideration of alternative therapeutic approaches targeting these pathways. Implementation of routine genomic screening in clinical practice is essential to guide personalized therapeutic decisions and improve patient outcomes. Future research should focus on developing targeted approaches to overcome the resistance observed with these genomic alterations. Citation Format: P. Farrokhi, D. Stenehjem. Genomic Insights in Metastatic Invasive Lobular Carcinoma: A Real-World Study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-06-22.