AI Insight
This genomic study analyzed whole-exome sequencing data from 23 BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC) tumors to identify molecular features associated with response to intravesical gemcitabine/docetaxel (Gem/Doce) chemotherapy. Responders (recurrence-free survival >12 months) showed lower tumor mutational burden and harbored clonal BAP1 and subclonal BRCA2 mutations, suggesting that DNA repair pathway defects may sensitize tumors to this regimen. In contrast, non-responders displayed higher mutational burden, more frequent whole-genome doubling, and clonal FGFR3 mutations, pointing to a biologically distinct, potentially chemotherapy-resistant tumor subtype.
Why it matters
These findings could help stratify BCG-unresponsive NMIBC patients prior to treatment, potentially sparing non-responders from ineffective chemotherapy and directing them toward alternative strategies such as FGFR3-targeted therapies, ultimately preserving bladder function and improving outcomes.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Background and Objectives: Intravesical gemcitabine/docetaxel (Gem/Doce) is an effective therapy for Bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC), achieving 50% complete responses at 2 years. However, the genomic determinants underlying response and resistance to Gem/Doce remain poorly defined. Our objective was to define the mutational landscape of BCG-unresponsive NMIBC and nominate genomic features associated with response or resistance Gem/Doce. Methods: Patients with BCG-unresponsive NMIBC treated with Gem/Doce were classified as responders (recurrence-free survival [RFS] >12 months) or non-responders (RFS <12 months). Whole-exome sequencing was performed on tumors prior to Gem/Doce treatment (n=23). Single nucleotide variants were identified and annotated using a Cancer Genome Analysis pipeline. Copy number alterations were inferred with ABSOLUTE, and clonal architecture was reconstructed using PhylogicNDT. Key Findings and Limitations: Responders demonstrated significantly prolonged time to high-grade recurrence (3.5 vs 42 months, p<0.001) and cystectomy compared with non-responders (9.5 months vs not reached; p<0.001). Non-responders exhibited higher tumor mutational burden (13.66 vs 8.71; p=0.02) and more frequent whole-genome doubling (2/2 non-responders vs 0/1 responders; p=0.33). Phylogenetic analyses revealed clonal BAP1 and subclonal BRCA2 mutations in responders, whereas non-responders harbored clonal FGFR3 mutations. Limitations include small sample size and retrospective design. Conclusions and Clinical Implications: Distinct genomic features underlie differential response to Gem/Doce in BCG-unresponsive NMIBC. In responders, alterations in DNA repair pathways (e.g., BRCA2) may sensitize tumors to chemotherapy, while non-responders with FGFR3 mutations may benefit from alternative targeted strategies. These findings warrant validation in larger cohorts and support the development of biomarker-driven clinical trials.