1946P - Bladder primary sarcomas (BSar): A genomic landscape and clinical outcomes study

Background

BSar are rare and often present at advanced stage with poor prognosis. Limited data on genomic alterations (GA) exist; we evaluated GA and outcomes in separate cohorts.

Methods

18 (0.2%) pts with Bsar were identified from 11,193 bladder cancers and underwent hybrid capture-based comprehensive genomic profiling (CGP) using DNA only (6 pts) or DNA and RNA seq (12 pts) to assess GA and other biomarkers. Predominant genetic ancestry was assessed using a SNP-based approach and classified as: African (AFR), European (EUR), Central and South American (AMR), South Asian (SAS), or East Asian (EAS). Assessments of tumor mutational burden (TMB), MSI status, genomic signature (GS), gLOH and prediction of germline status were performed. PD-L1 was determined in 2 pts by IHC (1 DAKO 22C3; 1 Ventana SP142). A separate analysis of 317 patients (pts) with stage I-III BSar using NCBD data (2004-2019) was done.

Results

18 Bsar (11 male, median age 66) were included: 12 leiomyosarcomas (LMS), 3 rhabdomyosarcomas (RMS),3 high grade undifferentiated sarcomas (HGS). 16 pts of EUR ancestry, 1 AMR, 1EAS. Mean driver GA frequency was 4.8 (1-10); mean TMB 2.9 mutations/Mb (0-9.6), all MS stable; 1 tumor was PD-L1 negative, the other had 1-49% TPS. Mean gLOH 10.4% (1.7-16.9%). APOBEC GS was noted in 1/12 (8.3%) with 11/12 (91.7%) with no dominant GS. Relevant germline mutations were predicted in RB1 (pt with prior retinoblastoma), VHL (pt with radiation-treated prostate cancer), PTEN (pt with Cowden Syndrome) and MUTYH (pt with intestinal polyposis); 1 pt with prior Wilms tumor had somatic GA only. Most frequently identified GA:TP53 (78%), ATRX (22%), RB1 (22%), PTEN (22%), CDKN2A (17%) and RICTOR, MLL2, DNMT3A, MTAP, KDM6A, TERT, HGF, NF1 (each 11%). In the BSar NCDB cohort (LMS only, overall survival was shorter in pts treated with surgery (S) and chemotherapy (CM), S and radiotherapy (RT) vs with S alone, HR 2.73 (95%CI 1.28-5.80), HR 2.24 (95%CI 1.03-4.88) respectively, after adjusting for sociodemographic and health factors. Age and tumor size had prognostic role.

Conclusions

CGP of Bsar revealed several GA relevant for clinical trial design and germline mutations requiring dedicated germline testing. Limitations: retrospective nature and confounding.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

J.S. Ross: Financial Interests, Personal, Full or part-time Employment, Medical Director: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche Holdings, Tango Therapeutics, Celsius Therapeutics. P. Grivas: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, BMS, Asieris Pharmaceuticals, Merck KGaA, Seattle Genetics, Aadi Bioscience, Pfizer, Janssen, Boston Gene, Mirati Therapeutics, Exelixis, Genentech/Roche, Gilead Sciences, CG Oncology, Dyania Health, Infinity Pharmaceuticals, QED Therapeutics, 4D Pharma PLC, ImmunityBio, Lucence Health, G1 Therapeutics, Fresenius Kabi, Guardant Health, PureTech, Regeneron Pharmaceuticals, Strata Oncology, Urogen, Silverback Therapeutics, Astellas Pharma; Financial Interests, Institutional, Invited Speaker: Pfizer, Clovis Oncology, Bavarian Nordic, Gilead Sciences, BMS, Debiopharm Group, MSD, QED Therapeutics, GSK, Mirati Therapeutics, G1 Therapeutics, Merck KGaA. D.C. Pavlick: Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche AG. R. Huang: Financial Interests, Personal, Stocks/Shares: Roche. A. Necchi: Financial Interests, Institutional, Research Grant: Merck, AstraZeneca, Ipsen, BMS, Gilead; Financial Interests, Personal, Invited Speaker: Roche, Janssen, Bayer, Astellas, AstraZeneca, Merck, Clovis Oncology; Financial Interests, Invited Speaker: Incyte, Pfizer; Non-Financial Interests, Leadership Role: Global society of Rare Genitourinary Tumors (GSRGT). P. Spiess: Non-Financial Interests, Personal, Leadership Role, Vice Chair For Bladder and Penile Cancer: NCCN. A. Kamat: Financial Interests, Personal, Advisory Board: Merck, Seagen, AstraZeneca, Janssen, CG Oncology, Astellas, Ferring; Financial Interests, Personal, Officer: International Bladder Cancer Group (IBCG); Financial Interests, Institutional, Invited Speaker: CyPRIT; Non-Financial Interests, Leadership Role: IBCG, IBCN; Non-Financial Interests, Member of Board of Directors: AUA; Non-Financial Interests, Advisory Role: EAU. All other authors have declared no conflicts of interest.