Molecular characterization of muscle-invasive bladder cancer (MIBC) has focused on chemotherapy treatment-naïve patients. To inform and guide adjuvant therapy and treatment at recurrence, we evaluated genomic alterations in patients with residual disease after neoadjuvant chemotherapy (NAC). We hypothesized that patients with chemotherapy-resistant disease would have fewer DNA damage repair (DDR) gene alterations and lower tumor mutational burden. Further, we suspected that alterations in targetable mutations could be identified in this cohort of patients with chemotherapy-resistant disease.
We identified patients with residual disease (≥pT2 or node positive) at radical cystectomy after four cycles of neoadjuvant gemcitabine and cisplatin. We then identified a cohort of patients who underwent targeted exome analysis using the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) platform. Non-paired samples were categorized as pre-NAC (transurethral resection specimens) or post-NAC (radical cystectomy, synchronous lymph node metastases, or metachronous metastases). To explore alterations influenced by NAC, we compared post-NAC samples with chemotherapy-naïve MIBC from MSK-IMPACT and from TCGA. Non-paired analysis was performed on individual samples. Targetable alterations were identified and compared between groups. Fraction of the genome altered (FGA) and tumor mutation burden (TMB) was compared between the MSK-IMPACT cohorts.
From 196 patients with residual disease after NAC, we identified 78 samples from 64 patients with MSK-IMPACT. Median (range) age was 65 (49,77) years, 73% (47/64) were male, 97% (62/64) had ≥pT2, and 44% (28/64) had positive nodes. FGFR3 was altered in 45% of metachronous metastases but <13% of radical cystectomy and transurethral resection samples (Figure 1). Post-NAC samples had lower FGA compared with pre-NAC, although not statistically significant. There were fewer ERCC2 alterations in the MSK-IMPACT chemotherapy-exposed cohort than in the MSK-IMPACT chemotherapy-naïve and TCGA cohorts, consistent with chemotherapy sensitivity of ERCC2alterations (2% vs. 20% vs. 10%, p=0.02; Figure 2). We also found that FGFR3 was altered in nearly 20% of chemotherapy-exposed samples, consistent with data suggesting its role in chemotherapy-resistance. Finally, FGA in MSK-IMPACT chemotherapy-exposed patients was lower than chemotherapy-naïve patients (median 5.4% vs. 17.4%, p<0.05) while TMB was similar (median 11.2 vs. 10.9, p=0.5).
Patients with chemotherapy-resistant disease at the time of radical cystectomy have fewer alterations in DDR genes, likely secondary to treatment selection for DDR wildtype clones. Further, these patients have lower fraction of the genome altered although tumor mutation burden is similar. Consequently, the identification of targetable alterations to be used as adjuvant therapy or at the time of recurrence is paramount.
GENOMIC CHARACTERIZATION OF RESIDUAL DISEASE AT RADICAL CYSTECTOMY FOLLOWING NEOADJUVANT CHEMOTHERAPY IN PATIENTS WITH MUSCLE-INVASIVE BLADDER CANCER
Category
Bladder Cancer > Muscle Invasive Bladder Cancer
Description
Presented By: Andrew T. Lenis
Authors: Andrew T. Lenis
Peter A. Reisz
Hong Truong
Emily Bochner
Timothy N. Clinton
Min Yuen Teo
Timothy F. Donahue
Eugene K. Cha
Alvin C. Goh
Sherri M. Donat
Harry W. Herr
Nikolaus Schultz
Michael F. Berger
Hikmat Al-Ahmadie
Dean F. Bajorin
Jonathan E. Rosenberg
Guido Dalbagni
David Solit
Bernard Bochner
Gopakumar V. Iyer
Eugene J. Pietzak