Genomic landscape of metastatic breast cancer (MBC) patients with methylthioadenosine phosphorylase (MTAP) loss
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Maroun Bou Zerdan1, Prashanth Ashok Kumar2, Elio Haroun3, Nimisha Srivastava2, Jeffrey Ross4,5 and Abirami Sivapiragasam2
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
|Abirami Sivapiragasam,||email:||[email protected]|
Keywords: breast cancer; metastatic; MTAP loss
Received: January 16, 2023 Accepted: February 13, 2023 Published: March 11, 2023
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 < 0.0001), triple negative (TNBC) (47% vs. 27%; p < 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 < 0.0001). CDKN2A (100%) and CDKN2B (97%) loss (9p21 co-deletion) were significantly associated with MTAP loss (p < 0.0001). Likely associated with the increased TNBC cases, BRCA1 mutation was also more frequent in MTAP loss MBC (10% vs. 4%; p < 0.0001). As for immune checkpoint inhibitors biomarkers, higher TMB >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.
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