ASCO GU 2019: Alterations in DNA Damage Repair Genes and Outcomes to Systemic Therapy in Immune-oncology versus Tyrosine Kinase Inhibitor Treated Metastatic Clear Cell Renal Cell Carcinoma Patients
The DDR is a network of cellular signaling events that are mediated in response to DNA damage and regulated by multiple genes. Defects in DDR genes are associated with genomic instability and predict an improved outcome to IO agents. The presence of deleterious DDR gene alterations is associated with improved clinical outcomes to IO agents in patients with mccRCC. The significance of standard IO and TKI treatments in mccRCC is unknown.
Dr. Ged then summarized the methodology of this study. Genomic data and treatment outcomes were retrospectively collected for two large cohorts of mccRCC: patients treated with pure IO therapy (cohort 1), and patients receiving first-line TKI (cohort 2). Tumor and germline DNA was subject to targeted panel testing across >400 genes of interest, including 34 DDR machinery genes. Presence of truncating mutations, deletions and functionally validated missense mutations identified the individual patient as ‘DDR altered’ (DDRa). Tumor mutational burden (TMB) was inferred for all patients. Non-parametric tests were applied to determine the association between DDR status, TMB and treatment outcomes.
Dr. Ged then highlighted the results of this study. 225 patients (pts) were included (cohort 1=107, cohort 2=118), 37 (16%) were DDRa. Most commonly altered genes were ATM (n=8, 4%) and CHEK2 (n=8, 4%). DDR germline alterations were seen in 12 patients (5%). Median TMB was 4.1 per megabase (range: 0-21.7), and higher TMB (≥ median) was associated with being DDRa (Fisher’s exact, p=0.03). DDRa status correlated significantly with longer overall survival (OS) in the IO cohort (HR 0.29, logrank p=0.04) but not in the TKI cohort (HR 0.74, logrank p=0.44). Deleterious DDR gene alterations were not associated with improved PFS in either cohort. No interaction between objective response and DDR status in either cohort was found.
Dr. Ged then concluded his talk with a summary that 17% of patients with mccRCC had deleterious DDR alterations, and those were associated with longer OS in patients treated with IO but not in those treated with VEGF-TKI. Limitations of this study include the small number of patients studied and differences in the clinical settings between the two cohorts. These hypotheses generating findings warrant validation independently and could provide a rationale for future therapeutic studies.
Presented by: Yasser Ged, MBBS, MRCPl Columbia University
Written by: Abhishek Srivastava, MD, Society of Urologic Oncology Fellow, Fox Chase Cancer Center, Fox Chase Cancer Center, Philadelphia, PA at the Annual ASCO GU meeting 2019, San Francisco, CA, Twitter: @shekabhishek at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA