Genomic Biomarkers for Response to Chemotherapy in Bladder Cancer Patients - Expert Commentary

The recommended treatment for patients with muscle-invasive bladder cancer (MIBC) is neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy. However, many patients do not respond to NAC, and extensive research is therefore being undertaken to identify biomarkers that predict response to treatment.

Some genomic biomarkers correlate with response to NAC, such as mutations in ERCC2 or ERBB2. Gil-Jimenez et al. performed a retrospective study on genomic biomarkers in MIBC patients in a large multi-center cohort.

The cohort included 165 patients with MIBC who received at least two cycles of NAC followed by radical cystectomy. Among these, 42% showed a response to treatment (defined as ypT0/Tis/Ta/T1N0), while 31% showed a complete response after surgery (defined as ypT0N0). The only factor significantly different between the response groups was tumor stage at baseline, which was higher in the non-responder group. Upon sequencing samples, authors reported that 13% of responders had a deleterious mutation in ERCC2, compared to only 2% of non-responders. Similarly, 13% of responders and 5% of non-responders exhibited a gain-of-function mutation in ERBB2. In addition, 39% of responders and 26% of non-responders had at least one genetic alteration in ATM, RB1, or FANCC. After correcting for multiple hypothesis testing, ERCC2 mutations were significantly enriched in the responder group. However, alterations in ERCC2, ERBB2, or any ATM, RB1, or FANCC were not correlated with a complete pathological response after correction.

The median follow-up period for patients was 7.2 years. The 5-year overall survival rates for patients with or without mutations in ERCC2 were 75% and 52%, respectively. Similarly, the 5-year relapse-free survival rates were 65% and 49%, respectively. However, the authors did not find a statistically significant difference in either overall survival or relapse-free survival rates between these two groups. This may have been due to low statistical power because of the low frequency of ERCC2 mutations in the study cohort. Further analysis revealed seven copy number alterations in ATM, RB1, or FANCC across all patients. Moreover, 42% of responders had at least one alteration in these genes compared to 31% of non-responders. Moreover, in an exploratory analysis of frequent mutations in MIBC, only FGFR3 mutations were correlated with response to NAC.

The findings from this study consolidate the validity of ERCC2 as a biomarker that is differentially altered in MIBC patients who respond to NAC treatment. However, there are various limitations related to the study design. First, because the study was performed across multiple centers, patient samples were sequenced using different platforms and technologies. This can lead to small but potentially significant differences in the resulting sequencing data. In addition, somatic variants were filtered using data from population databases because researchers did not have access to germline genomic data. Finally, although the study cohort was relatively large, the frequency of mutations in the target biomarkers was low. Further studies will therefore be needed to understand the association between ERCC2 and complete response or survival rates.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine

References:

  1. Gil-Jimenez A, van Dorp J, Contreras-Sanz A, et al. Assessment of Predictive Genomic Biomarkers for Response to Cisplatin-based Neoadjuvant Chemotherapy in Bladder Cancer [published online ahead of print, 2022 Aug 11]. Eur Urol. 2022;S0302-2838(22)02538-6. doi:10.1016/j.eururo.2022.07.023
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