MTAP Loss in Metastatic Breast Cancer Patients: Genomic Landscape | Oncotarget
Channel: Oncotarget
Date: 2023-03-14

Oncotarget published this research paper on March 11, 2023 in Volume 14, entitled, “Genomic landscape of metastatic breast cancer (MBC) patients with methylthioadenosine phosphorylase (MTAP) loss" by researchers from the Department of Internal Medicine, SUNY Upstate Medical University, Syracuse, NY; Department of Internal Medicine, Division of Hematology Oncology, SUNY Upstate Medical University, Syracuse, NY; SUNY Upstate Medical University, Syracuse, NY; Foundation Medicine, Inc., Morrisville, NC; Departments of Pathology and Urology, SUNY Upstate Medical University, Syracuse, NY.
#openaccess   #cancer   #breastcancer #research   #openscience   #peerreview   #journal   #publication   #researchpaper   #oncologyresearch  #cancerpatients  #oncology 

DOI - https://doi.org/10.18632/oncotarget.28376

Correspondence to - Abirami Sivapiragasam - sivapira@upstate.edu

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 less than 0.0001), triple negative (TNBC) (47% vs. 27%; p less than 0.0001) and less frequently HER2+ (2% vs. 8%; p = 0.0001) than MTAP intact MBC. Lobular histology and CDH1 mutations were more frequent in MTAP intact (14%) than MTAP loss MBC (p less than 0.0001). CDKN2A (100%) and CDKN2B (97%) loss (9p21 co-deletion) were significantly associated with MTAP loss (p less than 0.0001). Likely associated with the increased TNBC cases, BRCA1 mutation was also more frequent in MTAP loss MBC (10% vs. 4%; p less than 0.0001). As for immune checkpoint inhibitors biomarkers, higher TMB greater than 20 mut/Mb levels in the MTAP intact MBC (p less than 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.

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Keywords - breast cancer, metastatic, MTAP loss

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