Genomic landscape of metastatic breast cancer (MBC) patients with methylthioadenosine phosphorylase (MTAP) loss

// Maroun Bou Zerdan 1 , Prashanth Ashok Kumar 2 , Elio Haroun 3 , Nimisha Srivastava 2 , Jeffrey Ross 4 , 5 and Abirami Sivapiragasam 2 1 Department of Internal Medicine, SUNY Upstate Medical University, Syracuse, NY 13210, USA 2 Department of Internal Medicine, Division of Hematology Oncology, SUNY Upstate Medical University, Syracuse, NY 13210, USA 3 SUNY Upstate Medical University, Syracuse, NY 13210, USA 4 Foundation Medicine, Inc., Morrisville, NC 27560, USA 5 Departments of Pathology and Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA Correspondence to: Abirami Sivapiragasam, email: sivapira@upstate.edu Keywords: breast cancer; metastatic; MTAP loss Received: January 16, 2023     Accepted: February 13, 2023     Published: March 11, 2023 Copyright: © 2023 Bou Zerdan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Introduction: Homozygous deletion of MTAP upregulates de novo synthesis of purine (DNSP) and increases the proliferation of neoplastic cells. This increases the sensitivity of breast cancer cells to DNSP inhibitors such as methotrexate, L-alanosine and pemetrexed. Materials and Methods: 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 microsatellite instability (MSI) was determined on 114 loci. Tumor cell PD-L1 expression was determined by IHC (Dako 22C3). Results: 208 (2.84%) of MBC featured MTAP loss. MTAP loss patients were younger ( p = 0.002) and were more frequently ER− (30% vs. 50%; p 20 mut/Mb levels in the MTAP intact MBC ( p < 0.0001) and higher PD-L1 low expression (1–49% TPS) in the MTAP loss MTAP ( p = 0.002) were observed. Conclusions: MTAP loss in MBC has distinct clinical features with genomic alterations (GA) affecting both targeted and immunotherapies. Further efforts are necessary to identify alternative means of targeting PRMT5 and MTA2 in MTAP -ve cancers to benefit from the high-MTA environment of MTAP -deficient cancers.