MIBC Comprehensive Genomic Profiling in Patients Treated With Neoadjuvant Therapy Prior to Radical Cystectomy

Andrea Necchi, MD, and colleagues sought to identify tumor biomarkers associated with pathological complete response (CR) to neoadjuvant pembrolizumab or cisplatin-based chemotherapy prior to radical cystectomy in patients with clinical T2-4N0M0 muscle invasive bladder cancer (MIBC).

Results of their comprehensive genomic profiling were presented at the 2024 American Urological Association Annual Meeting.

While identifying tumor biomarkers is a primary goal of ongoing clinical research in MIBC, evaluating the evolving spectrum of genomic alterations in matched pre-post therapy samples may inform novel therapeutic sequencing.

Dr. Necchi and colleagues retrospectively evaluated the clinical and genomic findings of patients with clinical T2-4N0M0 MIBC who received neoadjuvant pembrolizumab in the PURE-01 study (n=129), or cisplatin-based neoadjuvant chemotherapy (n=27), before radical cystectomy from 2017 to 2022. They identified genomic alterations in 324 cancer-associated genes and genomic signatures, including tumor mutational burden (TMB), which was categorized as low (<10 mutations), high (10-19 mutations), or very high (≥20 mutations).

Germline status of genomic alterations was predicted using a validated somatic-germline computational method, and genomic signatures were analyzed via the principal Kyoto Encyclopedia of Genes and Genomes pathways distribution according to the pathological response.

The primary objective of the study was to  compare differences between ypT0N0 responders and nonresponders—ypT≥2 or ypN1-3.

The median number of genomic alterations per tumor of CR was 28.8 versus 17.3 for patients receiving neoadjuvant pembrolizumab and those receiving cisplatin-based neoadjuvant chemotherapy, respectively.

For patients receiving neoadjuvant pembrolizumab, higher median genomic alterations per tumor and higher mean TMB were the only genomic alteration associated with CR (P<.001), whereas no differences were found at a single gene or gene pathway level. For patients receiving cisplatin-based neoadjuvant chemotherapy, no genomic alteration nor genomic signature was found to be significantly associated with CR.

While the median TMB of CR patients was similar between the treatment cohorts (16.4 vs 19.6 mutations, respectively), the median TMB of nonresponders was lower in the PURE-01 cohort (9.3 vs 18.6 mutations, respectively), researchers noted.

“In our study, no genomic biomarkers linked to neoadjuvant chemotherapy activity emerged at the comprehensive genomic profiling,” they concluded, adding that “TMB values could help predict the lack of benefit from neoadjuvant pembrolizumab use.”

Further confirmation of the reliability of the 10-mutation cutoff could help exclude the predicted nonresponders from future neoadjuvant pembrolizumab trials.