Abstract
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.
Highlights
Cisplatin-based neoadjuvant chemotherapy (NAC) is the recommended treatment for locally advanced muscle-invasive bladder cancer (MIBC), with the highest level of evidence [1]
A fraction of patients was not analyzed; the main reason for patient exclusion was that the tumor tissue was unavailable (n = 76) because one of the hospitals was a referral center for other hospitals in its catchment area and the transurethral resection of the bladder tumor (TURBT) was performed elsewhere
To analyze the association with the response to NAC, we focused on the consensus markers of the BASQ-like cluster
Summary
Cisplatin-based neoadjuvant chemotherapy (NAC) is the recommended treatment for locally advanced muscle-invasive bladder cancer (MIBC), with the highest level of evidence [1]. Meta-analyses have shown that the benefit of NAC is limited to a subset of patients, with an overall improvement of 5–6.5% in 5-year survival compared to cystectomy alone [2,3]. A recent meta-analysis shows a significant overall survival (OS) benefit associated with cisplatin-based NAC (hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.79–0.96) [4]. The inability to select patients who can benefit has limited the use of NAC: treatment can lead to unnecessary toxicity in patients who fail to respond, and it delays a potentially curative cystectomy, with a negative survival impact [6,7]. Platinum-based neoadjuvant chemotherapy (NAC) increases the survival of patients with organ-confined urothelial bladder cancer (UBC). Outcomes: progression-free survival and disease-specific survival; univariable and multivariate Cox regression models were applied
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