Background: Neoadjuvant chemotherapy has shown a modest benefit in muscle-invasive bladder cancer patients; however, the subset of patients most likely to benefit has not been identified. BRCA1 plays a central role in DNA repair pathways and low BRCA1 expression has been associated with sensitivity to cisplatin and longer survival in lung and ovarian cancer patients. Patients and methods:We assessed BRCA1 messenger RNA expression levels in paraffin-embedded pre-treatment tumor samples obtained by transurethral resection from 57 patients with locally advanced bladder cancer subsequently treated with neoadjuvant cisplatin-based chemotherapy. BRCA1 levels were divided into terciles and correlated with pathological response and survival.Results: A significant pathological response (pT0-1) was attained in 66% (24 of 39) of patients with low/intermediate BRCA1 levels compared with 22% (4 of 18) of patients with high BRCA1 levels (P = 0.01). Median survival was 168 months in patients with low/intermediate levels and 34 months in patients with high BRCA1 levels (P = 0.002). In the multivariate analysis for survival, only BRCA1 expression levels and lymphovascular invasion emerged as independent prognostic factors.Conclusions: Our data suggest that BRCA1 expression may predict the efficacy of cisplatin-based neoadjuvant chemotherapy and may help to customize therapy in bladder cancer patients.

Background: Platinum-based neoadjuvant chemotherapy (NAC) increases the survival of patients with organ-confined urothelial bladder cancer (UBC). In retrospective studies, patients with basal/squamous (BASQ)-like tumors present with more advanced disease and have worse prognosis. Transcriptomics-defined tumor subtypes are associated with response to NAC. Aim: To investigate whether immunohistochemical (IHC) subtyping predicts NAC response. Methods: Patients with muscle-invasive UBC having received platinum-based NAC were identified. Tissue microarrays were used to type tumors for KRT5/6, KRT14, GATA3, and FOXA1. Outcomes: progression-free survival and disease-specific survival; univariable and multivariate Cox regression models were applied. Results: We found a very high concordance between mRNA and protein expression. Using IHC-based hierarchical clustering, we classified 126 tumors in three subgroups: BASQ-like (FOXA1/GATA3 low; KRT5/6/14 high), Luminal-like (FOXA1/GATA3 high; KRT5/6/14 low), and mixed-cluster (FOXA1/GATA3 high; KRT5/6 high; KRT14 low). Applying multivariable analyses, patients with BASQ-like tumors were more likely to achieve a pathological response to NAC (OR 3.96; p = 0.017). The clinical benefit appeared reflected in the lack of significant survival differences between patients with BASQ-like and luminal tumors. Conclusions: Patients with BASQ-like tumors—identified through simple and robust IHC—have a higher likelihood of undergoing a pathological complete response to NAC. Prospective validation is required.

Platinum-based neoadjuvant chemotherapy (NAC) increases the survival of patients with organ-confined urothelial bladder cancer (UBC). Because not all patients benefit from treatment, NAC has not been widely applied in the clinical setting. There is strong evidence, based on retrospective studies, that patients with Basal/Squamous (BASQ)-like tumours present with more advanced disease and have worse prognosis; global transcriptomics can identify tumour subtypes associated with response to NAC. We aimed to investigate whether tumour immunohistochemical (IHC) subtyping predicts NAC response. Patients with muscle-invasive UBC having received platinum-based NAC were identified in two hospitals in Spain. Tissue microarrays were constructed; RNA and DNA were extracted from full sections. Nanostring analysis and immunohistochemistry to identify BASQ-like tumours and mutational analysis of UBC oncogenes. We used hierarchical clustering to classify 126 tumours and adjusted logistic regression to assess association with treatment response. Outcomes were progression-free survival and disease-specific survival; univariable and multivariate Cox regression models were applied. We found very high concordance between mRNA and protein for the 4 markers analyzed. We identified three main subgroups: BASQ-like (FOXA1/GATA3 low; KRT5/6/14 high), Luminal-like (FOXA1/GATA3 high; KRT5/6/14 low), and mixed-cluster (FOXA1/GATA3 high; KRT5/6 high; KRT14 low). Patients with BASQ-like tumours were more likely to achieve a pathological response to NAC, displaying a disease-specific survival similar to that of the remaining patients. In conclusion, patients with BASQ-like tumours - identified through simple and robust immunohistochemistry - have a higher likelihood of undergoing a pathological complete response to NAC. Prospective validation in independent series is required.Novelty and impactNeoadjuvant chemotherapy is an important component of the management of patietns with muscle-invasive bladder cancer but improved stratification is necessary. This retrospective study shows that patients with BASQ-like tumors can be identified using immunohistochemistry on paraffin-embedded tissue and are 4-fold more likely to achieve a pathological complete response to platinum-based NAC. The disease-specific survival of patients with BASQ-like tumours treated with NAC was not different from that of other tumour subtypes.

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