ASCO GU 2018: Defining the DNA Damage Repair Genomic Landscape of Urothelial Carcinoma of the Bladder

San Francisco, CA ( Impaired DNA damage repair (DDR) genes is associated with response to platinum-based chemotherapy. Several genomically directed trials have been proposed using DDR alteration status for enrollment. In this study, the authors characterized the deleterious DDR alteration (DDRa) landscape of bladder urethral carcinoma (UCB) across various clinical states.

Targeted exon capture and sequencing of at least 341 cancer-associated genes was performed prospectively on 451 UCB specimens (MSK-IMPACT assay). The authors assessed sequencing data for deleterious alterations in 34 genes representing canonical DDR pathways. Deleterious alterations included truncating mutations, homozygous deletions, and functionally validated missense mutations.

Table 1 demonstrates that in non muscle invasive bladder cancer (NMIBC), deleterious DDRa were enriched in high-grade disease ([39/136, 28.7%] vs. low-grade [2/28, 7.1%]; p=0.02). The frequency of deleterious DDRa in chemo-naïve MIBC was enriched relative to unmatched post-neoadjuvant chemotherapy (NAC) residual MIBC ([33/112, 29.5%] vs. [8/55, 14.5%]; p=0.01). Patients with metastatic disease had similar rates of deleterious DDRa to MIBC ([31/116, 26.7%] vs. [33/112, 29.5%]). The percentage of patients having any type of DDR alteration was similar across states. The proportion of patients with a deleterious DDRa relative to any DDRa was 41/77 (53.2%) in NMIBC, 33/65 (50.8%) in chemo-naïve MIBC, 8/27(29.6%) in post-NAC residual MIBC, and 31/68 (45.6%) in metastatic disease.

In summary, DDRa are found across the UCB disease spectrum. ERCC2 and ATM are the most common DDRa although alterations were seen in most other DDR genes. Many alterations are of unknown significance and further characterization is needed to develop genomically directed treatment.

Table 1:
DefiningDNAdamagerepair 1

Presented by: Shawn Dason, Memorial Sloan Kettering Cancer Center, New York, USA

Co Authors: Victor McPherson, Min Yuen Teo, Sumit Isharwal, François Audenet, Aditya Bagrodia, Eugene K. Cha, Michael F. Berger, Ahmet Zehir, Nikolaus Schultz, Dean F. Bajorin, Jonathan E. Rosenberg, Hikmat Al-Ahmadie, Bernard H. Bochner, Eugene J. Pietzak, David B. Solit, Gopa Iyer; Memorial Sloan Kettering Cancer Center, New York, NY; Memorial Sloan Kettering Cancer Center, New York, NY, US; Icahn School of Medicine at Mount Sinai, New York, NY, France; UT Southwestern Medical Center, Dallas, TX

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA