Genomic characteristics, clinical profiling, and outcomes of advanced pancreatic ductal adenocarcinoma (PDAC) with <i>MTAP</i> -deletion ( <i>MTAP</i> -del): Analyses from a multimodal real-world dataset.

Abstract

682 Background: Homozygous MTAP -del is found in 10–15% of all cancers. Patients (pts) with tumors harboring MTAP -del have a worse prognosis vs those with MTAP –wild-type (WT) tumors, highlighting the need for more effective treatment options. Targeted therapies that exploit synthetic lethality with MTAP -del, such as PRMT5 inhibitors, are currently in clinical development. Here, we report MTAP -del prevalence, association with other genetic alterations, clinical characteristics, and outcomes of pts with PDAC from the TEMPUS multimodal real-world dataset. Methods: Deidentified records of pts aged ≥ 18 y with stage III–IV PDAC at the time of biopsy collection who received ≥ 1 fluoropyrimidine-based or gemcitabine-based chemotherapy between 2006 and 2021 were retrieved from the TEMPUS database and retrospectively analyzed. Pts must have had tissue assessed using the TEMPUS xT assay with samples having ≥ 40% tumor purity. Pts in the treatment-naive group had a biopsy collected between the primary diagnosis of PDAC and first treatment; pts in the treatment-exposed group had a biopsy performed between treatment initiation and death/censorship. OS was indexed at first treatment for the treatment-naive group. OS was not assessed in the treatment-exposed group because of delayed entry bias. Results: In the TEMPUS PDAC cohort (n = 295), the prevalence of homozygous MTAP -del was 24% (35/144) in treatment-naive and 22% (34/151) in treatment-exposed samples. All samples with homozygous MTAP -del also had homozygous CDKN2A deletion. Of those with homozygous MTAP -del, 80% (n = 28) of treatment-naive and all (n = 34) treatment-exposed samples also had KRAS mutation. With a median follow-up of 14.7 mo (range, 0.4–71.6 mo), pts in the treatment-naive group with MTAP -del tumors had a numerically shorter OS vs those with MTAP -WT tumors (median [95% CI], 7.4 mo [2.7–21.2] vs 12.7 mo [10.4–21.1]). Transcriptome (RNA-seq)–based gene set enrichment analysis showed that MTAP -del was associated with downregulation of inflammation-related pathways . A numerically higher proportion of samples with MTAP -del vs MTAP -WT had a basal-like subtype (43% vs 25%). No significant differences in tumor mutational burden and CLDN18.2 expression were observed between MTAP -del and MTAP -WT tumors. Additional analyses of clinicopathological factors and outcomes by MTAP and CKDN2A alteration status will be presented. Conclusions: This real-world data analysis demonstrated that pts with homozygous MTAP -del represent a significant subset of PDAC with poorer survival outcomes. Additionally, the study provides valuable biological insights into the MTAP -del segment and further supports the development of novel therapies or combinations for pts with MTAP -del PDAC.