ASCO 2019: Defects in DNA Repair Genes and Long-Term Survival in Cisplatin-Based Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer

Chicago, IL ( Neoadjuvant cisplatin (NAC) based chemotherapy is the standard of care for muscle-invasive bladder cancer. Pathologic complete response is achieved in 30-40% of cases treated with radical cystectomy. The survival benefit from NAC is linked to a complete response at the time of cystectomy. It is known that the mutations in ATM, RB1, and FANCC can predict response to cisplatin-based NAC.
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:
ASCO2019_Table2_ ATM-RB1-FANCC_important_DNA_repair.png

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

  1. Pilmack ER et al. Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer. Eur Urol 2015 Dec;68(6):959-67. Epub 2015 Aug 1
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