Abstract
Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy is the recommended treatment, with the highest level of evidence, for patients with muscle-invasive bladder cancer (MIBC). However, only a minority of patients receive this treatment, mainly due to patient comorbidities, the relatively small survival benefit, and the lack of predictive biomarkers to select those patients most likely to benefit from this multimodal approach. In addition, adjuvant chemotherapy has been recommended for patients with high-risk MIBC, although randomized trials have not provided conclusive evidence on the impact of this approach. At present, however, this situation is changing, largely due to our improved knowledge of the molecular biology of bladder cancer, which has enabled us to identify new prognostic and predictive biomarkers that can be used to select the most appropriate treatment for each patient. Moreover, new active treatments, especially immunotherapy, have shown promising results in the neoadjuvant setting. In addition, the gene expression profile of bladder tumors can be used to classify them into different subtypes, which correlate with specific clinical-pathological characteristics and with treatment response or resistance. Therefore, the main objective for the near future is to introduce these translational breakthroughs into routine clinical practice in order to personalize treatment for each patient.
Highlights
This discouraging scenario has changed in recent years, mainly due to two advances
single-strand breaks (SSBs) can be repaired by base excision repair, mismatch repair, or nucleotide excision repair (NER), while double-strand breaks (DSBs) can be repaired by non-homologous end joining or homologous recombination (HR)
High levels of ERCC1 indicate a gain of NER pathway function, leading to greater repair of the DNA damage caused by cisplatin and decreased efficacy of the drug [11]
Summary
Cisplatin-based chemotherapy remains the standard treatment for BC both for advanced disease and for the perioperative or conservative treatment of localized BC [2]. These data suggest that ERCC2 may well be a predictive biomarker of response to cisplatin-based chemotherapy In this line, a recent study by the Memorial Sloan Kettering Cancer Center (MSKCC) compared the genomic profile of primary vs secondary MIBC patients treated with NAC. 13% of patients with BC were found to harbor germline variants, 75% of which were located in DDR genes, mainly in BRCA2, mutS homolog 2 (MSH2), BRCA1, checkpoint kinase 2 (CHEK2), ERCC excision repair 3 (ERCC3), nibrin (NBN), and RAD50 double strand break repair protein (RAD50) [19] In this line, a study by our group in 57 MIBC patients treated with NAC, increased BRCA1 mRNA expression negatively correlated with pathological response and survival [20]. The study of these alterations will pave the way for the discovery of new prognostic and predictive biomarkers as well as the incorporation of new biological therapies, such as PARP inhibitors, which have been shown to be effective in ovarian and breast cancer patients harboring mutations in HR genes [23]
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