Translation of the 27-gene immuno-oncology test (IO score) to predict outcomes in immune checkpoint inhibitor treated metastatic urothelial cancer patients

Abstract

Background The IO Score is a 27-gene immuno-oncology (IO) classifier that has previously predicted benefit to immune checkpoint inhibitor (ICI) therapy in triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC). It generates both a continuous score and a binary result using a defined threshold that is conserved between breast and lung. Herein, we aimed to evaluate the IO Score’s binary threshold in ICI-naïve TCGA bladder cancer patients (TCGA-BLCA) and assess its clinical utility in metastatic urothelial cancer (mUC) using the IMvigor210 clinical trial treated with the ICI, atezolizumab. Methods We identified a list of tumor immune microenvironment (TIME) related genes expressed across the TCGA breast, lung squamous and lung adenocarcinoma cohorts (TCGA-BRCA, TCGA-LUSQ, and TCGA-LUAD, 939 genes total) and then examined the expression of these 939 genes in TCGA-BLCA, to identify patients as having high inflammatory gene expression. Using this as a test of classification, we assessed the previously established threshold of IO Score. We then evaluated the IO Score with this threshold in the IMvigor210 cohort for its association with overall survival (OS). Results In TCGA-BLCA, IO Score positive patients had a strong concordance with high inflammatory gene expression (p < 0.0001). Given this concordance, we applied the IO Score to the ICI treated IMvigor210 patients. IO Score positive patients (40%) had a significant Cox proportional hazard ratio (HR) of 0.59 (95% CI 0.45–0.78 p < 0.001) for OS and improved median OS (15.6 versus 7.5 months) compared to IO Score negative patients. The IO Score remained significant in bivariate models combined with all other clinical factors and biomarkers, including PD-L1 protein expression and tumor mutational burden. Conclusion The IMvigor210 results demonstrate the potential for the IO Score as a clinically useful biomarker in mUC. As this is the third tumor type assessed using the same algorithm and threshold, the IO Score may be a promising candidate as a tissue agnostic marker of ICI clinical benefit. The concordance between IO Score and inflammatory gene expression suggests that the classifier is capturing common features of the TIME across cancer types.

The 27-gene IO score is associated with efficacy of PD-1/L1 inhibitors independent of FGFR expression in a real-world metastatic urothelial carcinoma cohort

“…Further, genes associated with extracellular exosomes, implicated in cancer progression and metastasis, align with the concept of cross-talk within the microenvironment as tumor-produced exosomes have been shown to modulate the immune response which may contribute to immune evasion [38,39]. These functional categories support our clinical findings which suggest the IO score is a classifier that captures the interplay within the TIME and may be independent of the tumor of origin as observed in previous studies [15][16][17][18][19].…”

“…Using data from a real-world UNC-108 cohort, the results confirmed the findings of the IMvigor210 study that the IO score is associated with the efficacy of ICI therapy in mUC [18]. Furthermore, this was accomplished using the same binary classification threshold used in all previous studies, and this study will discuss the potential of an evidence-based likelihood of response assessment to inform therapeutic sequencing in the treatment of advanced mUC [15][16][17][18][19][20][21].…”

“…The IO score classifies cases as positive or negative based on their correlation to established gene expression centroids for immunomodulatory, mesenchymal, and mesenchymal stem-like subtypes [23]. The classification threshold was previously established in breast and lung cancers and validated as a classifier for mUC using TCGA and IMvigor210 datasets [15][16][17][18][19]. To assess data for the UNC-108 cohort, RNA expression analysis was used to determine the IO score of patients with available data downloaded from GSE176307 using the requisite 27-genes as previously described (ITM2A gene missing, Cohen's κ = 0.99 from TCGA-BLCA (RRID:SCR_003193; Project: Bladder Urothelial Carcinoma, Table S1).…”

“…The 27-gene immuno-oncology classifier (IO score) quantifies gene expression to classify the TIME and uses an algorithm that combines results into a continuous score with a pre-specified binary IO positive (IO +) or IO negative (IO− ) classification to predict response to immune therapy [15]. The IO score classification has demonstrated an association with ICI efficacy in multiple tumor types including non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), and urothelial carcinoma (UC) [15][16][17][18][19][20][21]. Using data from a real-world UNC-108 cohort, the results confirmed the findings of the IMvigor210 study that the IO score is associated with the efficacy of ICI therapy in mUC [18].…”

“…The IO score classification has demonstrated an association with ICI efficacy in multiple tumor types including non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), and urothelial carcinoma (UC) [15][16][17][18][19][20][21]. Using data from a real-world UNC-108 cohort, the results confirmed the findings of the IMvigor210 study that the IO score is associated with the efficacy of ICI therapy in mUC [18]. Furthermore, this was accomplished using the same binary classification threshold used in all previous studies, and this study will discuss the potential of an evidence-based likelihood of response assessment to inform therapeutic sequencing in the treatment of advanced mUC [15][16][17][18][19][20][21].…”