Abstract 1205: Clinical and genomic features of advanced urothelial carcinoma with 9p21 deletion
Authors: De Souza Andre L. , Srinivasan Praveen , Soliman Luke B. , Golijanin Dragan J. , Amin Ali , Safran Howard , Mega Anthony E. , El-Deiry Wafik S. , Carneiro Benedito A. 
Published: July 2021

Abstract
Chromosome 9p21 deletion occurs in 25% of urothelial carcinomas (UC). 9p21 includes the MTAP gene that encodes methylthioadenosine phosphorylase, a critical enzyme in the alternate pathway of adenine synthesis. MTAP-deleted UC tumors are very sensitive to pemetrexed-induced blockage of purine synthesis. MTAP is commonly co-deleted with CDKN2A, an immediately adjacent gene associated with sensitivity to CDK4/6 inhibitors. We describe clinical and molecular features of a 9p21-deleted subgroup of UC to better inform targeted therapy approaches. We retrospectively analyzed 46 patients (pts) with UC treated at our institution. All tumor specimens were submitted to next-generation sequencing (NGS). Patient demographics, clinic-pathological and genomic features, and clinical outcomes were summarized with descriptive statistics. MTAP/CDKN2A co-deletion was defined as a surrogate for 9p21 deletion. Fifteen (32%) pts with 9p21-deleted UC were identified. The median age was 68 years-old (range 54-79), 80% of pts were former or active smokers. Fifty-three percent (8 of 15) of these tumors showed squamous differentiation. Other histology variants were papillary differentiation (6), micropapillary (1), and sarcomatoid (1). Sites of tumor specimens submitted to NGS included bladder (11), lymph node (1), abdominal wall (1), renal pelvis mass (1), and bone (1). All pts had metastatic disease involving bone (9), lung (8), lymph nodes (7), liver (3), abdominal wall (2), penis (2), peritoneum (1), and pararenal mass (1). Most pts (8) underwent curative surgery and later developed metastases; seven pts presented with de novo metastases. Among 9 pts with progression-free survival (PFS) data available, median PFS was 2 months (range 1-17). Median overall survival was 6 months (range 1-35). Median PD-L1 expression on tumor cells was 1% (range 1-20); 4 tumors were PD-L1 (-). All evaluable patients (14) had stable microsatellite tumors. The most common genomic alterations co-occurring with 9p21 deletion affected CDKN2B (100%), TERT (87%), KDM6A (60%), TP53 (40%), and FGFR3 (20%). The best response associated with immune checkpoint inhibitors among 7 patients with 9p21 deletion was a disease control rate of 28.5%. Our cohort with UC and 9p21 deletion had predominantly squamous cell differentiation. Thus, MTAP is always co-deleted with CDKN2A and is a potential biomarker for pemetrexed-based combinations. Molecular characterization of 9p21 deleted UC may in the future inform targeted therapeutic approaches.
Citation Format: Andre L. De Souza, Praveen Srinivasan, Luke B. Soliman, Dragan J. Golijanin, Ali Amin, Howard Safran, Anthony E. Mega, Wafik S. El-Deiry, Benedito A. Carneiro. Clinical and genomic features of advanced urothelial carcinoma with 9p21 deletion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1205.