Abstract 134P
Background
The association of BRCA inactivation and PARP inhibitor efficacy by SL is well-established. Recently, the PRMT5 arginine methyltransferase dependence in cells with MTAP (Methylthioadenosine Phosphorylase) GA has been proposed as a new SL based anti-tumor strategy.
Methods
113,211 clinically advanced malignancies were submitted for comprehensive genomic profiling (CGP) using a hybrid capture based assay (F1CDx). Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined as described. PD-L1 expression in tumor cells (Dako 22C3) was measured by IHC.
Results
10,580 (9.3%) sequenced cases featured MTAP genomic alterations with 97.5% deletions (loss) and 2.5% short variant (SV) mutations and rearrangements. Tumor types with most frequent MTAP loss were NSCLC (27.3% of total cases/13.4% in tumor type), pancreatic ductal adenocarcinoma (PDC) (11.3%/20.5%), carcinoma of unknown primary (CUP) (8.0%/15.1%), GBM (7.4%/41.6%), urothelial bladder carcinoma (UBC) (5.5%/24.4%) and hepatic cholangiocarcinoma (2.9%/15.1%). 47% of patients were female, and median age was 66 years. Median TMB was 3.8 mut/Mb with 17.2% > 10 mut/Mb and 5.5% ≥ 20 mut/Mb. Only 0.6% of cases were MSI high. PD-L1 expression was identified in 45.4% of cases (low [1-49%] expression in 26.7%, high expression in 18.7%). After frequent co-deletion of CDKN2A (98.1%) and CDKN2B (93.3%) at the 9p21 locus, additional co-altered genes involved cell cycle regulatory genes, TP53 (53.4%), CCND1 (7.4%) and MDM2 (4.0%). Notable mTOR pathway GA included PIK3CA (11.8%) and PTEN (10.1%). KRAS was altered in 28.5% (3.9% G12C GA). Other currently un-targetable GA included SMAD4 (9.0%), ARID1A (8.8%), SMARCA4 (4.7%) and TERT (19.9%). Potentially targetable GA included EGFR at 12.0% (7.3% SV GA), ERBB2 at 6.4% (4.8% amplifications) and BRAF at 6.1% (5.1% SV).
Conclusions
MTAP GA are frequent in human cancers, concentrated in select tumor types and feature moderately high TMB and high PD-L1 expression. Isolated MTAP deletion without CDKN2A/B co-deletion was extremely rare. Co-altered genes indicate potential for targeted therapies in some patients. The potential of MTAP loss in the development of novel SL based therapies warrants further study.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Foundation Medicine Inc.
Funding
Foundation Medicine Inc.
Disclosure
E.S. Sokol: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc.. R. Madison: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc.. D.C. Pavlick: Full/Part-time employment: Foundation Medicine Inc.. N.A. Danziger: Full/Part-time employment: Foundation Medicine Inc.. A.B. Schrock: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc.. J.S. Ross: Research grant/Funding (self), Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc.; Advisory/Consultancy: Celsius Therapeutics.