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

INTRODUCTION

Homozygous deletion of upregulates 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 loss. loss patients were younger ( = 0.002) and were more frequently ER- (30% vs. 50%; < 0.0001), triple negative (TNBC) (47% vs. 27%; < 0.0001) and less frequently HER2+ (2% vs. 8%; = 0.0001) than intact MBC. Lobular histology and mutations were more frequent in intact (14%) than loss MBC ( < 0.0001). (100%) and (97%) loss (9p21 co-deletion) were significantly associated with loss ( < 0.0001). Likely associated with the increased TNBC cases, BRCA1 mutation was also more frequent in loss MBC (10% vs. 4%; < 0.0001). As for immune checkpoint inhibitors biomarkers, higher TMB >20 mut/Mb levels in the intact MBC ( < 0.0001) and higher PD-L1 low expression (1-49% TPS) in the loss ( = 0.002) were observed.

CONCLUSIONS

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 -ve cancers to benefit from the high-MTA environment of -deficient cancers.