Abstract 963: Clinical impact of MTAP status in advanced cholangiocarcinoma: Genomic profile and response to treatment
Authors: Gaspar Cátia F. , Ngoi Natalie Y. , Tang Tin , Ross Jeffrey , Pavlick Dean , Buchold Gregory , Pant Shubham , Javle Milind , Ahnert Jordi 
Published: April 2023

Background: MTAP-loss is an emerging biomarker guiding druggable targets in cholangiocarcinoma and almost exclusively occurs in the setting of 9p21 loss, which has itself been associated with reduced IO responsiveness and poorer survival outcomes on a pan-cancer analysis. We sought to understand the clinical impact of MTAP status on treatment and survival outcomes, in a clinical cohort of molecularly characterized advanced cholangiocarcinoma patients.

Methods: We analyzed advanced cholangiocarcinoma patients treated and evaluated at MD Anderson Cancer Center, tested for MTAP. Clinical information including genomic co-alterations, demographic information, treatment history and response to treatment were retrieved from retrospective medical record review. Comprehensive genomic profiling was performed with FDA-approved assays. Statistical analysis was performed with SPSS24 using Fisher's exact test, multivariate Cox regression and Kaplan-Meyer method for survival analysis.

Results: 71 patients were identified (MTAP loss 31% (22/71); MTAP intact 69% (49/71)); 54,9% (39/71) were females. No significant difference in gender, age or ethnicity was seen between MTAP cohorts.

We found that altered CDKN2A (p&lt;0.01), CDKN2B (p&lt;0.01), and IDH1 (p=0.048) were highly correlated with MTAP loss, while STK11 (p=0.095), a prognostic indicator of IO resistance, also showed a tendency to be a surrogate marker of MTAP loss status. Tumor mutational burden (TMB) was lower in MTAP loss group (2.18 vs. 4.88, p &lt;0.01), but no difference was found in microsatellite instability (MSI) or PD-L1 status between groups.

On multivariate analysis, patients harboring CDKN2A loss were noted to have worse OS compared to those without CDKN2A intact (18.6 vs 29.9 months, 95% CI, p=0.035). No statistically significant difference in OS was observed by MTAP status (25.9 vs. 29.2 months, 95% CI, p=0.168). Other genomic alterations with significant impact on OS were CCNE1 (p&lt;0.01), FGF19 (p=0.04), and MYC (p=0.043).

Treatment with chemotherapy regimens containing Gemcitabine in the first line setting of metastatic disease showed higher disease control rate in the MTAP intact cohort (91.4%) vs. MTAP loss cohort (38.5%) (p&lt;0.01), but no statistically significant difference in response (PR/CR) (p=0.421). Few patients (14/71) received IO in this cohort; no significant difference in IO response was observed by MTAP status (p=0.152).

Conclusions: MTAP loss cholangiocarcinoma has a distinct molecular profile compared with MTAP intact including key differences in co-altered tumor suppressor genes and TMB. To our knowledge, this is the first real-world data describing the clinical and genomic differences in advanced cholangiocarcinoma by MTAP status. Further prospective data are required to validate these

findings.

Citation Format: Cátia F. Gaspar, Natalie Y. Ngoi, Tin Tang, Jeffrey Ross, Dean Pavlick, Gregory Buchold, Shubham Pant, Milind Javle, Jordi Ahnert. Clinical impact of MTAP status in advanced cholangiocarcinoma: Genomic profile and response to treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 963.