# Exploring novel genomic biomarkers for response and survival after neoadjuvant chemotherapy and radical cystectomy of muscle-invasive bladder cancer

## TL;DR

This study identifies genomic biomarkers linked to better treatment response and survival in bladder cancer patients undergoing chemotherapy and surgery.

## Contribution

The study introduces novel genomic biomarkers (E2F3/SOX4 amplifications and FGFR3/CDKN1A mutations) associated with treatment response and survival in muscle-invasive bladder cancer.

## Key findings

- Amplifications of E2F3 and SOX4 on chromosome 6p22.3 are linked to improved response and survival after neoadjuvant chemotherapy.
- FGFR3 mutations are associated with poor treatment response and shorter survival.
- CDKN1A mutations may serve as a biomarker for poor prognosis despite not affecting treatment response.

## Abstract

Neoadjuvant cisplatin-based combination chemotherapy (NAC) is standard perioperative treatment of patients with muscle-invasive urothelial bladder cancer (MIBC); however, about half of the patients experience recurrence of the disease. Biomarkers for response and survival represent an unmet medical need. We used tumor specimens from transurethral resections of the bladder to explore genomic alterations and their association with response and survival in MIBC patients treated by NAC and radical cystectomy.

A pan cancer panel with single-nucleotide polymorphism backbone-based sequencing approach with coverage of the most commonly perturbed cancer genes and low-pass whole genome sequencing was applied for genomic characterization of 110 clinical routine patients treated with NAC before radical cystectomy. Pathological response rates, recurrence-free and overall survival were assessed.

Amplifications of genes on chromosome 6p22.3, particularly of the E2F3 and SOX4 gene loci, were associated with improved response and survival to NAC. Patients harboring these alterations had a high pathological treatment response rate and all remained recurrence-free during a median follow-up of 5 years. Conversely, patients with FGFR3 mutations demonstrated impaired response and survival, whereas CDKN1A mutations appeared not related to treatment response but may serve as a biomarker for poor prognosis.

We found the panel-based sequencing approach feasible for exploring genomic alterations associated with clinical benefits of NAC and radical cystectomy. Amplifications of genes on chromosome 6p22.3 and FGFR3 and CDKN1A mutations hold promise as biomarkers associated with response and survival to NAC.

•This study adds to the knowledge on genomic biomarkers for response and survival after neoadjuvant chemotherapy in MIBC.•A pan cancer panel with SNP backbone-based sequencing approach was applied for genomic characterization.•Amplifications of E2F3/SOX4/CDKAL1 on chromosome 6p22 were associated with increased response and durable clinical benefit.•FGFR3 mutations were associated with impaired response and shorter survival.•CDKN1A mutations were not associated with response but might serve as a molecular biomarker for poor prognosis.

This study adds to the knowledge on genomic biomarkers for response and survival after neoadjuvant chemotherapy in MIBC.

A pan cancer panel with SNP backbone-based sequencing approach was applied for genomic characterization.

Amplifications of E2F3/SOX4/CDKAL1 on chromosome 6p22 were associated with increased response and durable clinical benefit.

FGFR3 mutations were associated with impaired response and shorter survival.

CDKN1A mutations were not associated with response but might serve as a molecular biomarker for poor prognosis.