Evan M Fernandez1,2, Kenneth Eng1,2, Shaham Beg1,3, Himisha Beltran1,4,5, Bishoy M Faltas1,4,5, Juan Miguel Mosquera1,3, David M Nanus4, David J Pisapia3, Rema A Rao3, Brian D Robinson1,3,6, Mark A Rubin1,7, Olivier Elemento1,2, Andrea Sboner1,2,3, Manish A Shah4, Wei Song1,3. 1. Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medical College, New York, New York. 2. Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY. 3. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY. 4. Department of Hematology and Medical Oncology, Weill Cornell Medical College, New York, NY. 5. Department of Medicine, Weill Cornell Medical College, New York, NY. 6. Department of Urology, Weill Cornell Medical College, New York, NY. 7. Department for BioMedical Research, University of Bern, Bern, Switzerland.
Abstract
PURPOSE: To understand the clinical context of tumor mutational burden (TMB) when comparing a pan-cancer threshold and a cancer-specific threshold. MATERIALS AND METHODS: Using whole exome sequencing (WES) data from primary tumors in The Cancer Genome Atlas (TCGA) (n=3,534) and advanced/metastatic tumors from Weill Cornell Medicine (WCM Advanced) (n=696), TMB status was determined using a pan-cancer and cancer-specific threshold. Survival curves, number of samples classified as TMB high, and predicted neoantigens were used to evaluate the differences between thresholds. RESULTS: The distribution of TMB varied dramatically between cancer types. A cancer-specific threshold was able to adjust for the different TMB distributions, while the pan-cancer threshold was often too stringent. The dynamic nature of the cancer-specific threshold resulted in more tumors being classified as TMB high compared to the static pan-cancer threshold. Additionally, no significant difference in survival outcomes was found with the cancer-specific threshold compared to the pan-cancer one. Further, the cancer-specific threshold maintains higher predicted neoantigen load for the TMB high samples compared to the TMB low samples, even when the threshold is lower than the pan-cancer threshold. CONCLUSION: TMB is relative to the context of cancer type, metastatic state, and disease stage. Compared to a pan-cancer threshold, a cancer-specific threshold classifies more patients as TMB high while maintaining clinical outcomes that were not significantly different. Furthermore, the cancer-specific threshold identifies patients with a high number of predicted neoantigens. Due to the potential impact in cancer patient care, TMB status should be determined in a cancer-specific manner.
PURPOSE: To understand the clinical context of tumor mutational burden (TMB) when comparing a pan-cancer threshold and a cancer-specific threshold. MATERIALS AND METHODS: Using whole exome sequencing (WES) data from primary tumors in The Cancer Genome Atlas (TCGA) (n=3,534) and advanced/metastatic tumors from Weill Cornell Medicine (WCM Advanced) (n=696), TMB status was determined using a pan-cancer and cancer-specific threshold. Survival curves, number of samples classified as TMB high, and predicted neoantigens were used to evaluate the differences between thresholds. RESULTS: The distribution of TMB varied dramatically between cancer types. A cancer-specific threshold was able to adjust for the different TMB distributions, while the pan-cancer threshold was often too stringent. The dynamic nature of the cancer-specific threshold resulted in more tumors being classified as TMB high compared to the static pan-cancer threshold. Additionally, no significant difference in survival outcomes was found with the cancer-specific threshold compared to the pan-cancer one. Further, the cancer-specific threshold maintains higher predicted neoantigen load for the TMB high samples compared to the TMB low samples, even when the threshold is lower than the pan-cancer threshold. CONCLUSION: TMB is relative to the context of cancer type, metastatic state, and disease stage. Compared to a pan-cancer threshold, a cancer-specific threshold classifies more patients as TMB high while maintaining clinical outcomes that were not significantly different. Furthermore, the cancer-specific threshold identifies patients with a high number of predicted neoantigens. Due to the potential impact in cancer patient care, TMB status should be determined in a cancer-specific manner.
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