1710P Genomic landscape (GL) with potential of methylthioadenosine phosphorylase (MTAP) loss in clinically advanced breast cancer (CABC)

Abstract

Homozygous deletion of MTAP causes intracellular arginine accumulation enabling anti-tumor effects of MTA2/PRMT5 inhibitors via a synthetic lethality mechanism. 7,301 cases of MBC underwent hybrid-capture based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and MSI status was determined on 114 loci. Tumor cell PD-L1 expression was determined by IHC (Dako 22C3). 208 (2.84%) of CABC featured MTAP loss. MTAP loss patients were younger (p=.002) and were more frequently ER- (30% v 50%; p<.0001), triple negative (TNBC) (47% v 27%; p<.0001) and less frequently HER2+ (2% v 8%; p=.0001) than MTAP intact MBC. Lobular histology and CDH1 mutations were more frequent in MTAP intact (14%) than MTAP loss MBC (p<.0001). CDKN2A (100%) and CDKN2B (97%) loss (9p21 co-deletion) were significantly associated with MTAP loss (p<.0001). Likely associated with the increased TNBC cases, BRCA1 mutation was also more frequent in MTAP loss MBC (10% v 4%; p<.0001). There was no clear pattern for predictive Immuno-Oncology (IO) drug biomarkers with higher TMB > 20 mut/Mb levels found in the MTAP intact MBC (p<.0001) and higher PD-L1 low expression (1-49%% TPS) in the MTAP loss MTAP (p=.002) CABC cases.Table: 1710PCases with MTAP intactCases with MTAP lossNumber7093208Mean age*57.854.5ER+/PR+ Status by IHC**70.0%/ 49.0%50.00%/29.90%HER2+ Amplification by CGP*7.80%1.92%TNBC Status*27.00%47.28%TP53*51.7061.30CDKN2A**3.10100.00CDKN2B**1.3096.70CDH1*14.300.90PTEN*13.1021.70PIK3CA**36.823.60BRCA1**3.709.90ERBB2 amplification*7.801.92ERBB2 sequence mutation*11.206.60EGFR *2.605.20MSI HighFrequency0.03%0.05%cases tested7077205TMB > 10%/>20%7.84%/7.40%5.32%/0.96%PD-L1 Positive IC expression (Dako 22C3)Low (1-49%)*11.45%42.90%High (> 50%)2.86%0.00%*Significant (P<0.05), **(P<0.0001). Open table in a new tab *Significant (P<0.05), **(P<0.0001). MTAP loss is associated with ER-, HER2- and TNBC status, features a distinctive GL with potential to impact both targeted and immunotherapies and enables emerging clinical trials testing MTA2 and PRMT5 inhibitors for patients with CABC.