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 us...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-08-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-022-03563-9 |
| _version_ | 1828434610877366272 |
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| author | Robert S. Seitz Michael E. Hurwitz Tyler J. Nielsen Daniel B. Bailey Matthew G. Varga Brian Z. Ring Carrie F. Metts Brock L. Schweitzer Kimberly McGregor Douglas T. Ross |
| author_facet | Robert S. Seitz Michael E. Hurwitz Tyler J. Nielsen Daniel B. Bailey Matthew G. Varga Brian Z. Ring Carrie F. Metts Brock L. Schweitzer Kimberly McGregor Douglas T. Ross |
| author_sort | Robert S. Seitz |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T18:52:29Z |
| format | Article |
| id | doaj.art-559b3f8416ed47f4ba8dbc1a517b7989 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-12-10T18:52:29Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-559b3f8416ed47f4ba8dbc1a517b79892022-12-22T01:37:16ZengBMCJournal of Translational Medicine1479-58762022-08-0120111110.1186/s12967-022-03563-9Translation of the 27-gene immuno-oncology test (IO score) to predict outcomes in immune checkpoint inhibitor treated metastatic urothelial cancer patientsRobert S. Seitz0Michael E. Hurwitz1Tyler J. Nielsen2Daniel B. Bailey3Matthew G. Varga4Brian Z. Ring5Carrie F. Metts6Brock L. Schweitzer7Kimberly McGregor8Douglas T. Ross9Oncocyte, Inc.Yale Cancer Center/Smilow Cancer HospitalOncocyte, Inc.Oncocyte, Inc.Oncocyte, Inc.Oncocyte, Inc.Oncocyte, Inc.Oncocyte, Inc.Oncocyte, Inc.Oncocyte, Inc.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.https://doi.org/10.1186/s12967-022-03563-9Immuno-oncologyImmunotherapyBiomarkerTumor immune microenvironmentBladder cancerMetastatic urothelial cancer |
| spellingShingle | Robert S. Seitz Michael E. Hurwitz Tyler J. Nielsen Daniel B. Bailey Matthew G. Varga Brian Z. Ring Carrie F. Metts Brock L. Schweitzer Kimberly McGregor Douglas T. Ross Translation of the 27-gene immuno-oncology test (IO score) to predict outcomes in immune checkpoint inhibitor treated metastatic urothelial cancer patients Journal of Translational Medicine Immuno-oncology Immunotherapy Biomarker Tumor immune microenvironment Bladder cancer Metastatic urothelial cancer |
| title | Translation of the 27-gene immuno-oncology test (IO score) to predict outcomes in immune checkpoint inhibitor treated metastatic urothelial cancer patients |
| title_full | Translation of the 27-gene immuno-oncology test (IO score) to predict outcomes in immune checkpoint inhibitor treated metastatic urothelial cancer patients |
| title_fullStr | Translation of the 27-gene immuno-oncology test (IO score) to predict outcomes in immune checkpoint inhibitor treated metastatic urothelial cancer patients |
| title_full_unstemmed | Translation of the 27-gene immuno-oncology test (IO score) to predict outcomes in immune checkpoint inhibitor treated metastatic urothelial cancer patients |
| title_short | Translation of the 27-gene immuno-oncology test (IO score) to predict outcomes in immune checkpoint inhibitor treated metastatic urothelial cancer patients |
| title_sort | translation of the 27 gene immuno oncology test io score to predict outcomes in immune checkpoint inhibitor treated metastatic urothelial cancer patients |
| topic | Immuno-oncology Immunotherapy Biomarker Tumor immune microenvironment Bladder cancer Metastatic urothelial cancer |
| url | https://doi.org/10.1186/s12967-022-03563-9 |
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