Abstract P2-23-09: Ultra-high Tumor Mutation Burden in Metastatic/Clinically Advanced Breast Cancer (MBC)

Abstract Background: High (HTMB) tumor mutation burden (TMB) defined as ≥10 mutations/megabase (Mb) identifies breast cancer patients who could benefit from pembrolizumab. The higher the TMB the greater the likelihood of benefit. The goal of this analysis was to determine the frequency and genomic landscape of MBC with ultra-high TMB (UHTMB) defined as a TMB > 20 mutations/Mb. Design 2,049 MBC patients (pts) underwent hybrid capture based comprehensive genomic profiling for genomic alterations (GA) in at least 324 genes including determination of TMB to guide therapy decisions using the FoundationOne®CDx assay. ER, PR and HER2 expression were abstracted from submitted pathology reports. Results: 165 of 2049 MBC (8.1%) had HTMB > 10 mutations/Mb, among these 45 (2.2% of all cases) had UHTMB. When compared with the 2,004 non-UHTMB MBC pts with TMB < 20 mutations/Mb, the 45 UHTMB pts were older (mean 64.6 yrs vs 58.2 yrs; p<.0001), more often had lobular histology (40.00% vs 14.5%; p<.0001) and ER+ disease (86.6% vs 70.0%), had higher average driver GA/tumor (9.84 vs 5.7; p<.0001), and less often had TNBC (13.3% vs 27.0%; p=.041) compared to non-UHTMB high cancers. There were no significant differences in ancestry. Mutation signature analysis revealed that APOBEC was predominant in UHTMB samples (82.5%) with a minor portion with an MMR signature (10%), however, MSI-H status was significantly higher in UHTMB high cases (11.6% vs 0.40%; p<.0001). GA more frequently identified in UHTMB cases included CDH1 (45.50% vs 14.32%; p<.0001), PIK3CA (81.80% vs 37.86%; p<.0001), CDKN2A (11.40% vs 3.19%; p=.017), ARID1A (25.00% vs 5.01%; p<.0001) and NF1 (20.50% vs 5.94%; p=.0014). PD-L1 (CD274) gene amplification (2.3% vs 1.3%) or protein expression by the Ventana SP142 assay (57.14% vs 51.10%) were not significantly different. Conclusions: UHTMB MBC is a rare but clinically important subset in breast cancer that could have high response rates to single agent pembrolizumab. This phenotype is driven by APOBEC mutagenesis, more often seen in ER+ lobular cancers, and have higher frequencies of MSI-high status and mutations in CDH1 and PIK3CA. Citation Format: Kristina Fanucci, maryam lustberg, Neal Fischbach, Maureen Pelletier, Abirami Sivapiragasam, Prashanth Ashok Kumar, Mansi Kallem, Natalie A. Danziger, Ethan Sokol, Smruthy Sivakumar, Dean Pavlick, Jeffrey S. Ross, Lajos Pusztai. Ultra-high Tumor Mutation Burden in Metastatic/Clinically Advanced Breast Cancer (MBC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-23-09.