Clinical impact and temporal evolution of mutational signatures in metastatic lobular breast cancer.

1141 Background: Invasive lobular carcinoma (ILC) has distinct genomic features, including frequent CDH1 alterations, yet the mutational processes shaping metastatic ILC and their prognostic significance remain poorly defined. We evaluated mutational signatures inferred from targeted sequencing in a large single-center cohort of metastatic ILC and their association with outcomes. Methods: Patients were included if they had ILC histology on early-stage breast biopsy/surgical pathology, and/or CDH1 mutation on metastatic site biopsy and MSK-IMPACT sequencing from a metastatic site. For survival analyses, only biopsies performed within 2 months of metastatic diagnosis were included. Clinicopathologic data were abstracted from electronic medical records. Single base substitution (SBS) signatures were inferred using SigMA; cases with ≤5 SBS were excluded. Overall survival (OS) was estimated using Kaplan–Meier and compared by dominant signature using the log-rank test. Results: 654 patients were included. 467 (71%) had hormone receptor-positive (HR+)/HER2-, 56 (8.6%) had HER2+, and 65 (9.9%) had triple negative disease at metastatic diagnosis. Among 307 (47%) with ILC variant data available, 139 (45%) had classic type, 65 (21%) had pleomorphic, 45 (15%) had mixed, and 58 (19%) had other ILC variants. 385 patients (59%) had MSK-IMPACT testing on a tissue biopsy performed within 2 months of metastatic diagnosis. Among them, the most prevalent mutations included CDH1 (85%), PIK3CA (47%), TP53 (21%), TBX3 (16%), PTEN/AKT1 (14.5%), FOXA1 (12%), ERBB2 (12%), KMT2C (9.9%), CBFB (9.9%), ARID1A (9.6%), MAP3K1 (8.8%), and NF1 (7.5%). 320/385 (83%) MSK-IMPACT tests had ≥5 SBS and were analyzable for mutational signature. The dominant mutational signature was APOBEC in 44%, clock-like (aging) in 38%, Signature 3 (homologous recombination deficiency) in 12%, Signature 17 in 5.6%, and Signature 8 in 1%. Median OS in the total cohort was 4.4 years (95%CI 4.1-4.8) and differed significantly by dominant mutational signature (log-rank p =0.001). Median OS for those with APOBEC-dominant disease was 3.1 years (95%CI 2.5-3.7) and for those with clock-like (aging) signature was 4.4 years (95%CI 3.8-6.5). Among 61 patients who had paired samples analyzable for mutational signature within 2 months of metastatic diagnosis and at another timepoint following metastatic diagnosis, the prevalence of APOBEC as the dominant mutational signature increased (29/61 [48%] to 36/61 [59%]), whereas clock-like (aging) decreased (25/61 [41%] to 17/61 [28%]). Conclusions: Dominant APOBEC mutational signature at metastatic ILC diagnosis was associated with shorter OS, with differences observed between APOBEC- and aging-dominant tumors. Serial testing demonstrating increasing APOBEC dominance over time supports mutational signatures as dynamic, clinically relevant features of metastatic ILC.