210O Mutational signature analysis reveals patterns of genomic instability linked to resistance to endocrine therapy (ET) +/- CDK 4/6 inhibition (CDK4/6i) in estrogen receptor-positive/HER2-negative (ER+/HER2-) metastatic breast cancer (MBC)

Abstract

APOBEC mutagenesis is enriched in MBCs. The predictive role of APOBEC and other mutational processes on standard regimens in the MBC setting is largely unknown. We retrieved clinical and genomic data of 4,595 BCs that underwent targeted sequencing by an FDA-cleared panel comprising >400 genes. Mutational signatures were computed by the SigMA algorithm for samples with at least 5 single nucleotide variants and manually reviewed. BCs were classified as APOBEC+, HRD+ or APOBEC-/HRD- based on the dominant mutational process as defined by SigMA. Progression-free survival (PFS) to any line (L) of therapy was assessed using univariate and multivariate Cox models. APOBEC+ and HRD+ were found at higher proportion in MBCs than in primary tumors (24% and 24% vs 15% and 13%; p<0.001). APOBEC+ were highly represented in ER+/HER2- (19%) and HER2+ (47%) subtypes, while HRD+ in triple-negative (36%). Lobular BCs had a higher proportion of APOBEC+ than HRD+ and APOBEC-/HRD- (34% vs 10% vs 21%, p<0.001). ER+/HER2- MBCs with APOBEC displayed lower ESR1 hotspot mutations (p<0.001). Survival analyses were restricted to patients with available pre-treatment samples. In ER+/HER2- MBCs treated with 1L or 2L ET monotherapy (n=395), APOBEC+ tumors were independently associated to shorter mPFS (HR 1.6, 95%CI 1.2-2.2, p=0.001), regardless of the ET agent. APOBEC+ and HRD+ MBCs were associated with lower mPFS on 1L CDK4/6i+ET (n=419) than APOBEC-/HRD- (HR 1.5, 95%CI 1.1-2, p=0.01 and HR 1.7, 95%CI 1.2-2.5, p=0.006, respectively), regardless of ET partner. HRD+ BCs had a reduced mPFS on 2L (n=207) and 3L (n=372) of CDK4/6i+ET (HR 2.1, 95%CI 1-4.1, p=0.03 and HR 1.8, 95%CI 1.3-2.5, p=0.001, respectively). Patients with APOBEC+ and HRD+ ER+/HER2- MBCs experience shorter survival on ET +/- CDK4/6i, suggesting that the genomic instability conferred by APOBEC and HRD results in early resistance. Novel treatments tailored on these BC subgroups are needed. Additional genomic analyses to unravel mutational patterns related to APOBEC and HRD in this setting are underway.