In the presented study patients with stage T2-T4 (N0 O N1) muscle-invasive bladder cancer were enrolled in either of two phase 2 NAC trials: (Discovery) dose-dense MVAC (NCT01031420) or (validation) gemcitabine/cisplatin (GC) (NCT01611662). The DNA from pretreatment tumor tissue was sequenced using next-generation sequencing (NGS) for coding exons of 287 genes and analyzed for base substitutions, indels, copy number variations (CNV) alterations, and rearrangements. For this study, sequencing was available for 58 patients. DNA repair genes mutations (ATM, RB1, and FANCC) were identified and correlated with the response at cystectomy. Patients were followed for a median of 56 months, and the 5-year overall survival and disease-specific survival were calculated.
The patient characteristics are shown in Table 1. The sequencing results in the discovery (dense dose MVAC) and validation (GC) are shown in Figure 1. The overall survival and disease-specific survival Kaplan-Meier curves are shown in Figure 2, demonstrating that mutations in the DNA repair genes (ATM, RB1, and FANCC) confer significant overall and disease-specific survival advantages, in the combined cohort, dense dose MVAC and GC specific cohorts. The proposed mechanism of cisplatin sensitivity in each mutated gene is elaborated in Table 2.
The authors conclude that mutations in ATM, RB1, and FANCC confer a significant survival benefit. This survival benefit is linked to an improved response to NAC at the time of radical cystectomy. These specific mutations may be useful in predicting pathologic response and long-term benefit from NAC before surgery.
RETAIN (NCT02710734) is an ongoing phase 2 trial evaluating ATM, RB1, FANCC and ERCC2 mutations as biomarkers to spare local therapy to the bladder after NAC.
Table 1 – Patient characteristics:
Figure 1 – DNA mutations predict response:
Figure 2 – Overall survival and disease-specific survival:
Table 2 – ATM, RB1 and FANCC are important for DNA repair:
Presented by: Benjamin Miron, MD, Fox Chase Cancer Center, Philadelphia, PA
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO) University of Toronto, Princess Margaret Cancer Centre, @GoldbergHanan at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA
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