External validation of the molecular subtype classifier by immunohistochemistry for muscle-invasive bladder cancer patients within the trimodal therapy cohort
Charles Hesswani1, Chelsea L. Jackson2, Gautier Marcq1, Celine Hardy2, Ronald Kool1, Jose Joao Mansure1, Fadi Brimo3, David Berman2, Wassim Kassouf1.
1Department of Urology, McGill University, Montreal, QC, Canada; 2Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada; 3Department of Pathology, McGill University, Montreal, QC, Canada
Introduction: Bladder-sparing approaches for muscle-invasive bladder cancer (MIBC), such as trimodal therapy (TMT), are increasingly offered to select candidates. Oncological outcomes may be affected by distinct molecular subtypes based on gene expression profiling. Tumors of the basal subtype were previously shown to carry a poorer overall survival (OS) compared to tumors of the luminal subtype.
Methods: Tumoral, benign, and transition zone tissue from transurethral resection of bladder tumors of 104 patients were sampled on five tissue microarray blocks. We measured KRT5, GATA3, and P16 biomarkers expression on tumoral slides. Hierarchical clustering was used to classify patients based on the three-antibody IHC algorithm biomarker expression profile. Subtypes were evaluated for association with complete response (CR), recurrence-free survival (RFS), and OS.
Results: The median age was 75.0 years (interquartile range 65–80) and 22.6% were females. Median OS was 43 months (95% confidence interval [CI] 19–77) and median followup was 55 months (95% CI 39–75). On univariate analysis, Eastern Cooperative Oncology Group (ECOG), and CR rate were predictors of significant difference in RFS (p<0.05). For OS, age, ECOG, clinical stage, and CR were found to significantly impact OS (p<0.05). Of 104 patients, IHC-based subtype classification was feasible in 93. Patients were successfully classified into basal (23.7%), luminal genomically unstable (14.0%), luminal urothelial like (31.2%), and negative/unclassified (31.2%). On survival analysis, no significant differences were observed between the molecular subtypes when comparing basal vs. luminal vs. negatives or basal vs. luminal (p>0.05). However, on Cox regression analysis at 10 months, the basal subtype showed a poorer survival compared to the other subtypes combined (hazard ratio [HR] 0.376, 95% CI 0.161–0.882, p=0.0245).
Conclusions: Although the classifier was not predictive of CR or survival for MIBC patients post-TMT, tumors of the basal subtype may carry a poorer prognosis early after treatment. Subtype identification using the IHC-based three-antibody classification is feasible in most patients.
