Abstract PS1-10-18: Genomic analysis of ER+/HER2- metastatic invasive lobular carcinoma (ILC) and clinical outcomes comparison with metastatic invasive carcinoma of no special type (NST)

Abstract Background: ILC is the second most common histologic subtype of breast cancer (BC) comprising about 15% of invasive BCs. Despite differences in clinical behavior compared to NST, patients (pts) with these histologies are treated the same. Genomic analyses may provide insights into treatment strategies for this subset of BCs. The genomic landscape of early-stage ILC has been previously described. In this analysis we describe the genomic alterations of pts with metastatic ILC and clinical outcomes in the metastatic setting compared to pts with NST histology. Methods: Pts with metastatic, ER+/HER2- BC seen at least once at Dana-Farber Cancer Institute between 7/1/2001 and 8/2/2022 who had targeted tumor only DNA sequencing (OncoPanel) of ≥1 archival tissue sample collected within 3 months (mo) of diagnosis of distant recurrence/de novo metastatic disease were included. Clinical annotation for these pts was available and median time to next treatment (mTTNT) for pts receiving endocrine therapy (ET) + CDK4/6 inhibitor as first-line treatment and median overall survival (mOS) were compared between ILC and NST cohorts. Genes with oncogenic single nucleotide variants (SNV) and copy number variants (CNV) occurring at a frequency above 0.03 were tested via Fisher enrichment, with a Benjamini-Hochberg correction, for differences across clinicopathological characteristics. Kaplan-Meier analysis and Cox proportional hazards models were used to assess significant predictors of survival across and within ILC and NST cohorts. Results: 533 pts met criteria for inclusion in the final analytic cohort (ILC n=125; NST n=408, mixed histology excluded). In the ILC cohort, at the time of initial diagnosis 8.0% of pts had stage I disease, 22.4% stage II, 27.2% stage III, and 40.8% de novo metastatic disease. The median disease-free interval was 5.4 years (yr) (range 1.0-30.9). Genomic analyses of ILC samples revealed 16 genes mutated and 2 genes with high amplifications (amp) or deep deletions in ≥3% of ILC tumors. The most commonly altered genes with SNVs or INDELS were CDH1 (76%), PIK3CA (58%), TP53 (14%), ESR1 (10%), PTEN (6%), NF1 (6%), MAP3K1 (6%), ERBB2 (6%), and AKT1 (5%). The genes with most frequent CNVs were CCND1 amp (16%) and FGFR1 amp (7%). Comparing pts with early (0-5 yr, n=36) vs. late (5+ yr, n=38) recurrence showed CDH1 and ERBB2 SNVs were associated with early recurrence (odds ratio (OR)=0.18, p=0.0037, q=0.0394 and OR=0, p=0.0046, q=0.0394 respectively). Pts with liver metastases (mets) at the time of metastatic diagnosis (n=26) were more likely to have ERBB2 alteration (OR=14.1, p=0.001, q=0.0171). Comparing prevalence of gene alterations between ILC and NST, alteration in CDH1, PIK3CA, ERBB2, and MEN1 was more common in ILC while GATA3, TP53, FGFR1, ZNF217, CDKN2A, and IGF1R was more common in NST. mTTNT was not significantly different in pts who received ET + CDK4/6 inhibitor in the first line setting comparing ILC (9.5 mo [95% confidence interval (CI): 6.8-21.0]) to NST (10.2 mo [95% CI: 9.0-14.1]) (p=0.78) and mOS did not significantly differ between ILC (43.4 mo [95% CI: 38.3-not reached (NR)]) and NST (57.2 mo [95% CI: 41.8-78.8]) in this subset (p=0.74). There was no significant difference in mOS comparing all pts with ILC [4.2 yr (95% CI: 3.5-5.3)] to NST [4.3 yr (95% CI: 3.9-5.3)] (p=0.54). The presence of liver mets at diagnosis was associated with significantly shorter mOS in both ILC and NST (p<0.001) but there was no difference in mOS comparing pts with liver mets with ILC vs. NST (31.3 mo (95% CI 14.36-NR) vs 35.0 mo (95% CI: 28.5-41.4), [p=0.22]). Conclusion: Metastatic ILC has a unique genomic landscape which provides avenues for development of treatments designed specifically for this population. Pts with metastatic ILC had similar clinical outcomes to those with NST. Citation Format: K. Fanucci, S. Challa, Y. Li, G. Nader-Marta, A. Martin, M. Hughes, B. E. Johnson, L. Sholl, D. Dillon, B. Carroll, S. M. Tolaney, A. Cherniack, N. U. Lin, R. Jeselsohn. Genomic analysis of ER+/HER2- metastatic invasive lobular carcinoma (ILC) and clinical outcomes comparison with metastatic invasive carcinoma of no special type (NST) [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 PS1-10-18.