One of the goals of precision oncology is to predict the response to chemotherapy. Molecular predictors can be used to predict response to neoadjuvant chemotherapy (NAC). There are 3 known different pathways, including molecular subtypes, COXEN model, and DNA damage repair genes. Basal tumors are the most sensitive to NAC, while there is no big difference in response to NAC in luminal tumors (Figure 2). The ERCC2 mutations also confer a better response to chemotherapy. Mutations in DNA damage repair genes predict survival after NAC.
These specifically include mutations in ATM/RB1/FANCC, which confer better overall survival (OS) after chemotherapy. In a more practical perspective, after these markers will be validated in prospective clinical trials, we will be able to prioritize marker positive patients for NAC, and proceed to immediate cystectomy in marker negative patients. The SWOG s1314 “COXEN” clinical trial is a biomarker validation and biomarker discovery study. This trial will only include T2-T4 N0M0 cisplatin eligible patients, and randomize them to either Gem-Cis or MVAC NAC. Afterwards these patients will undergo cystectomy. The pathologic specimen will undergo molecular analysis, including gene expression, sequencing, microRNA and SNP. The final goal will be to analyze the ability of the COXEN model to predict Pt0 or <=Pt1in the final cystectomy specimen. The next future trial will divide patients according to their DNA damage repair gene status, and RNA subtypes, to either NAC + cystectomy, or to an arm, where if they are marker positive, they will undergo NAC and then cystectomy, and if they are marker negative, they will undergo only cystectomy.
The biggest limitation of precision oncology is tumor heterogeneity with different sub-clones, manifesting different molecular findings, not responding in a similar way to all treatments. Dr. Black concluded his talk by stating that our understanding of the biology of bladder cancer has increased dramatically in the last 5 years. Biomarkers to predict response to NAC are almost a reality, and targeted therapy in bladder cancer will be the next step.
Figure 1: The precision oncology workflow
Figure 2: Response of basal and luminal tumors to neoadjuvant chemotherapy:
Presented by: Peter Black, Vancouver, Canada
References:
1. Esrig et al. NEJM 1994
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, twitter: @GoldbergHanan at the 2018 European Association of Urology Meeting EAU18, 16-20 March, 2018 Copenhagen, Denmark