SUNY Upstate University Hospital, Bethesda, MD
Gennady Bratslavsky , Joseph M Jacob , Andrea Necchi , Petros Grivas , Natalie Danziger , Ethan Sokol , Russell Madison , Shakti H. Ramkissoon , Ryon Graf , Douglas A Mata , Brennan James Decker , Jeffrey S. Ross
Background: When UCB presents or progresses to chemorefractory metastatic disease, the search for new therapy targets is paramount. Targeting PRMT5 arginine methyltransferase accumulation in tumors with MTAP (methylthioadenosine Phosphorylase) genomic loss has been proposed as a new SL based anti-tumor strategy and under consideration for development for UCB. We sought to evaluate the incidence of patients with candidate SL and correlate to treatment-guiding biomarkers currently evaluated in SOC. Methods: 2,683 cases of clinically advanced UCB underwent hybrid-capture based comprehensive genomic profiling in a standard of care setting using the F1CDx FDA-approved assay to evaluate all classes of genomic alterations (GA) among 324 genes. Tumor mutational burden (TMB) was determined on 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: 650 (24%) of UCB feature MTAP loss (MTAP-) (Table). The gene and age distributions were similar MTAP intact (MTAP+) and MTAP- UCB. The GA/tumor was higher in MTAP- UCB likely reflecting the significant GA co-deletions of CDKN2A/B at the 9p21 locus. Of potential therapeutic targets, FGFR3 and PTEN GA were more frequent in the MTAP- UCB. In contrast, biomarkers of immunotherapy (IO) response included higher frequencies of high TMB and high PD-L1 IHC staining in the MTAP+ UCB. Conclusions: When compared with MATP+ UCB, MTAP- UCB differs in genomic signatures including an increase in potential for targeted therapies but a lower potential for IO drug benefit. Thus, the genomic landscape in MTAP- UCB may play a significant role in the design of clinical trials incorporating SL strategies when targeting PRMT5 in MTAP deficient tumors.
UCB MTAP Intact | UCB MTAP Loss | Significance | |
---|---|---|---|
Number of Cases | 2,033 | 650 | |
Males/Females | 77%/23% | 72%/28% | NS |
Median age (range) years | 70 (16-95) | 71 (31-98) | NS |
GA/tumor | 7.4 | 9.9 | |
CDKN2A | 18% | 99.8% | P<.0001 |
CDKN2B | 8% | 96% | P<.0001 |
TP53 | 66% | 42% | P<.0001 |
TERT | 75% | 79% | NS |
FGFR3 | 13% | 33% | P<.0001 |
PIK3CA | 21% | 26% | NS |
ERBB2 | 18% | 14% | NS |
EGFR | 4% | 4% | NS |
PTEN | 4% | 6% | P=.04 |
TSC1 | 7% | 2% | P<.0001 |
BRCA1/2 | 2%/0% | 1%/2% | NS |
MSI High | 1% | 1% | NS |
Median TMB | 7.5 | 6.3 | |
Mean TMB | 11.2 | 8.5 | P<.0001 |
TMB>10 mut/Mb | 41% | 30% | P<.0001 |
TMB>20 mut/Mb | 15% | 7% | P<.0001 |
PD-L1 Low Positive | 20% | 24% | NS |
PD-L1 High Positive | 22% | 3% | P<.0001 |
Disclaimer
This material on this page is ©2024 American Society of Clinical Oncology, all rights reserved. Licensing available upon request. For more information, please contact licensing@asco.org
Abstract Disclosures
2023 ASCO Annual Meeting
First Author: Rebecca A Sager
2023 ASCO Genitourinary Cancers Symposium
First Author: Philippe E. Spiess
2022 ASCO Annual Meeting
First Author: Maroun Bou Zerdan
2024 ASCO Genitourinary Cancers Symposium
First Author: Rafee Talukder