Introduction:
Detection of genomic alterations and the presence of molecular residual disease (MRD) through the assessment of peripheral blood circulating tumor DNA (ctDNA) has important clinical relevance in muscle-invasive (MIBC) and advanced bladder cancer patients. Similarly, analysis of tumor DNA within patient urine specimens (utDNA) presents an intriguing option to optimize clinical care and investigate tumor biology in NMIBC patients. We investigated the utility of utDNA to characterize the genomic landscape and monitor MRD status in longitudinally collected urine samples from NMIBC patients treated with durvalumab containing regimens in the previously reported HCRN GU16-243: ADAPT-BLADDER Trial (Hahn N et al, Eur Urol 2023).
Methods:
Baseline peripheral blood mononuclear cell and longitudinal urine samples at baseline, 3-month, 6-month, tumor recurrence (if observed), and 24-month (if available) time points were collected from BCG-unresponsive NMIBC patients treated with durvalumab monotherapy (D), durvalumab plus BCG (D + BCG), or durvalumab plus external beam radiation therapy (D + EBRT) in the HCRN 16-243: ADAPT-BLADDER Trial. utDNA mutations, copy number aberrations, tumor mutational burden (TMB), and MRD status were assessed by the PredicineWES+ and PredicineBEACON MRD assays respectively. Mutational, copy number aberrations, and TMB data were summarized in graphical form. Associations between post-treatment utDNA MRD status and clinical outcomes were assessed by generalized estimating equation (GEE) regression testing.
Results:
Sixty-six utDNA samples from 26 patients were collected. Sixty-five (98.5%) samples were sufficient for analysis (Baseline n=25; 3-month n=19; 6-month n=16; recurrence n=1; 24-month n=4). Baseline utDNA was detectable in all (100%) patients with a median of 75 genomic alterations per sample, a median TMB of 1.4 muts/Mb (IQR 0.6 – 3.5), and a median tumor fraction (TF) of 21.0% (IQR 9.9 – 37.0). Frequent alterations in TERT, TP53, KMT2D, ARID1A, ATM, RB1, ERBB2, KDM6A, CDKN2A, and MDM2 were detected. Following treatment, MRD remained detectable in 36 (90%) samples (3-month – 17/19 (90%); 6-month – 15/16 (94%); recurrence – 1/1 (100%); 24-month – 3/4 (75%)) with 4 samples (10%) demonstrating undetectable MRD. In a multivariate GEE analysis, TF declined from baseline to cycle 4 (p=0.057), and to cycle 8 (p=0.039). TF was significantly lower in patients with RFS durations greater than 12 months, p < 0.001. Collection of utDNA specimens in additional treatment cohorts is ongoing.
Conclusion:
Detection and monitoring of utDNA MRD proved feasible in this initial investigation in BCG-unresponsive NMIBC patients treated with durvalumab containing regimens. Post-treatment utDNA MRD was detected in most samples. Post-treatment reduction of utDNA tumor fraction was associated with durable clinical benefit. Validation of the utility of utDNA MRD status as a novel biomarker of response in NMIBC patients is ongoing in larger randomized prospective trials.
Funding: Predicine, AstraZeneca, NCI P30CA006973, NCI R01CA235681
Image(s) (click to enlarge):
URINE TUMOR DNA ANALYSIS IN BCG-UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC) PATIENTS TREATED WITH DURVALUMAB CONTAINING REGIMENS IN THE HCRN GU16-243: ADAPT-BLADDER TRIAL
Category
Bladder Cancer > Non-Muscle Invasive Bladder Cancer
Description
Poster #132
Presented By: Noah M. Hahn
Authors:
Noah M. Hahn
Marianna Zahurak
Michael A. O'Donnell
Jason A. Efstathiou
Max R. Kates
Trinity J. Bivalacqua
Phuoc T. Tran
Daniel Y. Song
Alex S. Baras
Andres Matoso
Bridget McGuire
Gabriela Colocho
Burles A. Johnson III
Tanya Taylor
Debbie G. Schwartz
David J. McConkey
Tracy L. Rose
Marc Bjurlin
Emerson A. Lim
Christopher B. Anderson
Israel Deutsch
Gordon Guo
Timothy A. Masterson
Nabil Adra
Hristos Z. Kaimakliotis
Shidong Jia
Pan Du
Alexander Kulkin
Lu Tan
Frank Zhang
Myles Walsh
Daniel M. Geynisman
Mark A. Hallman
Eric M. Horwitz
David YT Chen
Alexander Kutikov