Identifying a Clinically Applicable Mutational Burden Threshold as a Potential Biomarker of Response to Immune Checkpoint Therapy in Solid Tumors

Anshuman Panda; Anil Betigeri; Kalyanasundaram Subramanian; Jeffrey S Ross; Dean C Pavlick; Siraj Ali; Paul Markowski; Ann Silk; Howard L Kaufman; Edmund Lattime; Janice M Mehnert; Ryan Sullivan; Christine M Lovly; Jeffrey Sosman; Douglas B Johnson; Gyan Bhanot; Shridar Ganesan

doi:10.1200/PO.17.00146

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Identifying a Clinically Applicable Mutational Burden Threshold as a Potential Biomarker of Response to Immune Checkpoint Therapy in Solid Tumors

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Identifying a Clinically Applicable Mutational Burden Threshold as a Potential Biomarker of Response to Immune Checkpoint Therapy in Solid Tumors

Anshuman Panda, Anil Betigeri, Kalyanasundaram Subramanian, Jeffrey S Ross, Dean C Pavlick, Siraj Ali, Paul Markowski, Ann Silk, Howard L Kaufman, Edmund Lattime, …

JCO precision oncology, Vol.2017(1), pp.1-13

11/2017

DOI: https://doi.org/10.1200/PO.17.00146

PMCID: PMC6016848

PMID: 29951597

Abstract

Purpose An association between mutational burden and response to immune checkpoint therapy has been documented in several cancer types. The potential for such a mutational burden threshold to predict response to immune checkpoint therapy was evaluated in several clinical datasets, where mutational burden was measured either by whole-exome sequencing or by using commercially available sequencing panels. Methods Whole-exome sequencing and RNA sequencing data of 33 solid cancer types from The Cancer Genome Atlas were analyzed to determine whether a robust immune checkpoint–activating mutation (iCAM) burden threshold associated with evidence of immune checkpoint activation exists in these cancers that may serve as a biomarker of response to immune checkpoint blockade therapy. Results We found that a robust iCAM threshold, associated with signatures of immune checkpoint activation, exists in eight of 33 solid cancers: melanoma, lung adenocarcinoma, colon adenocarcinoma, endometrial cancer, stomach adenocarcinoma, cervical cancer, estrogen receptor–positive/human epidermal growth factor receptor 2–negative breast cancer, and bladder-urothelial cancer. Tumors with a mutational burden higher than the threshold (iCAM positive) also had clear histologic evidence of lymphocytic infiltration. In published datasets of melanoma, lung adenocarcinoma, and colon cancer, patients with iCAM-positive tumors had significantly better response to immune checkpoint therapy compared with those with iCAM-negative tumors. Receiver operating characteristic analysis using The Cancer Genome Atlas predictions as the gold standard showed that iCAM-positive tumors are accurately identifiable using clinical sequencing assays, such as FoundationOne (Foundation Medicine, Cambridge, MA) or StrandAdvantage (Strand Life Sciences, Bangalore, India). Using the FoundationOne-derived threshold, an analysis of 113 melanoma tumors showed that patients with iCAM-positive disease have significantly better response to immune checkpoint therapy. iCAM-positive and iCAM-negative tumors have distinct mutation patterns and different immune microenvironments. Conclusion In eight solid cancers, a mutational burden threshold exists that may predict response to immune checkpoint blockade. This threshold is identifiable using available clinical sequencing assays.

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Title: Identifying a Clinically Applicable Mutational Burden Threshold as a Potential Biomarker of Response to Immune Checkpoint Therapy in Solid Tumors
Creators: Anshuman Panda - Anshuman Panda, Ann Silk, Howard L. Kaufman, Edmund Lattime, Janice M. Mehnert, Gyan Bhanot, and Shridar Ganesan, Rutgers Cancer Institute of New Jersey; Paul Markowski, Ann Silk, Howard L. Kaufman, Janice M. Mehnert, and Shridar Ganesan, Rutgers Robert Wood Johnson Medical School, New Brunswick; Anshuman Panda and Gyan Bhanot, Rutgers University, Piscataway, NJ; Anil Betigeri and Kalyanasundaram Subramanian, Strand Life Sciences, Bangalore, India; Jeffrey S. Ross, Dean C. Pavlick, and Siraj Ali
Anil Betigeri - Anshuman Panda, Ann Silk, Howard L. Kaufman, Edmund Lattime, Janice M. Mehnert, Gyan Bhanot, and Shridar Ganesan, Rutgers Cancer Institute of New Jersey; Paul Markowski, Ann Silk, Howard L. Kaufman, Janice M. Mehnert, and Shridar Ganesan, Rutgers Robert Wood Johnson Medical School, New Brunswick; Anshuman Panda and Gyan Bhanot, Rutgers University, Piscataway, NJ; Anil Betigeri and Kalyanasundaram Subramanian, Strand Life Sciences, Bangalore, India; Jeffrey S. Ross, Dean C. Pavlick, and Siraj Ali
Kalyanasundaram Subramanian - Anshuman Panda, Ann Silk, Howard L. Kaufman, Edmund Lattime, Janice M. Mehnert, Gyan Bhanot, and Shridar Ganesan, Rutgers Cancer Institute of New Jersey; Paul Markowski, Ann Silk, Howard L. Kaufman, Janice M. Mehnert, and Shridar Ganesan, Rutgers Robert Wood Johnson Medical School, New Brunswick; Anshuman Panda and Gyan Bhanot, Rutgers University, Piscataway, NJ; Anil Betigeri and Kalyanasundaram Subramanian, Strand Life Sciences, Bangalore, India; Jeffrey S. Ross, Dean C. Pavlick, and Siraj Ali
Jeffrey S Ross - Anshuman Panda, Ann Silk, Howard L. Kaufman, Edmund Lattime, Janice M. Mehnert, Gyan Bhanot, and Shridar Ganesan, Rutgers Cancer Institute of New Jersey; Paul Markowski, Ann Silk, Howard L. Kaufman, Janice M. Mehnert, and Shridar Ganesan, Rutgers Robert Wood Johnson Medical School, New Brunswick; Anshuman Panda and Gyan Bhanot, Rutgers University, Piscataway, NJ; Anil Betigeri and Kalyanasundaram Subramanian, Strand Life Sciences, Bangalore, India; Jeffrey S. Ross, Dean C. Pavlick, and Siraj Ali
Dean C Pavlick - Anshuman Panda, Ann Silk, Howard L. Kaufman, Edmund Lattime, Janice M. Mehnert, Gyan Bhanot, and Shridar Ganesan, Rutgers Cancer Institute of New Jersey; Paul Markowski, Ann Silk, Howard L. Kaufman, Janice M. Mehnert, and Shridar Ganesan, Rutgers Robert Wood Johnson Medical School, New Brunswick; Anshuman Panda and Gyan Bhanot, Rutgers University, Piscataway, NJ; Anil Betigeri and Kalyanasundaram Subramanian, Strand Life Sciences, Bangalore, India; Jeffrey S. Ross, Dean C. Pavlick, and Siraj Ali
Siraj Ali - Anshuman Panda, Ann Silk, Howard L. Kaufman, Edmund Lattime, Janice M. Mehnert, Gyan Bhanot, and Shridar Ganesan, Rutgers Cancer Institute of New Jersey; Paul Markowski, Ann Silk, Howard L. Kaufman, Janice M. Mehnert, and Shridar Ganesan, Rutgers Robert Wood Johnson Medical School, New Brunswick; Anshuman Panda and Gyan Bhanot, Rutgers University, Piscataway, NJ; Anil Betigeri and Kalyanasundaram Subramanian, Strand Life Sciences, Bangalore, India; Jeffrey S. Ross, Dean C. Pavlick, and Siraj Ali
Paul Markowski - Anshuman Panda, Ann Silk, Howard L. Kaufman, Edmund Lattime, Janice M. Mehnert, Gyan Bhanot, and Shridar Ganesan, Rutgers Cancer Institute of New Jersey; Paul Markowski, Ann Silk, Howard L. Kaufman, Janice M. Mehnert, and Shridar Ganesan, Rutgers Robert Wood Johnson Medical School, New Brunswick; Anshuman Panda and Gyan Bhanot, Rutgers University, Piscataway, NJ; Anil Betigeri and Kalyanasundaram Subramanian, Strand Life Sciences, Bangalore, India; Jeffrey S. Ross, Dean C. Pavlick, and Siraj Ali
Ann Silk - Anshuman Panda, Ann Silk, Howard L. Kaufman, Edmund Lattime, Janice M. Mehnert, Gyan Bhanot, and Shridar Ganesan, Rutgers Cancer Institute of New Jersey; Paul Markowski, Ann Silk, Howard L. Kaufman, Janice M. Mehnert, and Shridar Ganesan, Rutgers Robert Wood Johnson Medical School, New Brunswick; Anshuman Panda and Gyan Bhanot, Rutgers University, Piscataway, NJ; Anil Betigeri and Kalyanasundaram Subramanian, Strand Life Sciences, Bangalore, India; Jeffrey S. Ross, Dean C. Pavlick, and Siraj Ali
Howard L Kaufman - Anshuman Panda, Ann Silk, Howard L. Kaufman, Edmund Lattime, Janice M. Mehnert, Gyan Bhanot, and Shridar Ganesan, Rutgers Cancer Institute of New Jersey; Paul Markowski, Ann Silk, Howard L. Kaufman, Janice M. Mehnert, and Shridar Ganesan, Rutgers Robert Wood Johnson Medical School, New Brunswick; Anshuman Panda and Gyan Bhanot, Rutgers University, Piscataway, NJ; Anil Betigeri and Kalyanasundaram Subramanian, Strand Life Sciences, Bangalore, India; Jeffrey S. Ross, Dean C. Pavlick, and Siraj Ali
Edmund Lattime - Anshuman Panda, Ann Silk, Howard L. Kaufman, Edmund Lattime, Janice M. Mehnert, Gyan Bhanot, and Shridar Ganesan, Rutgers Cancer Institute of New Jersey; Paul Markowski, Ann Silk, Howard L. Kaufman, Janice M. Mehnert, and Shridar Ganesan, Rutgers Robert Wood Johnson Medical School, New Brunswick; Anshuman Panda and Gyan Bhanot, Rutgers University, Piscataway, NJ; Anil Betigeri and Kalyanasundaram Subramanian, Strand Life Sciences, Bangalore, India; Jeffrey S. Ross, Dean C. Pavlick, and Siraj Ali
Janice M Mehnert - Anshuman Panda, Ann Silk, Howard L. Kaufman, Edmund Lattime, Janice M. Mehnert, Gyan Bhanot, and Shridar Ganesan, Rutgers Cancer Institute of New Jersey; Paul Markowski, Ann Silk, Howard L. Kaufman, Janice M. Mehnert, and Shridar Ganesan, Rutgers Robert Wood Johnson Medical School, New Brunswick; Anshuman Panda and Gyan Bhanot, Rutgers University, Piscataway, NJ; Anil Betigeri and Kalyanasundaram Subramanian, Strand Life Sciences, Bangalore, India; Jeffrey S. Ross, Dean C. Pavlick, and Siraj Ali
Ryan Sullivan - Anshuman Panda, Ann Silk, Howard L. Kaufman, Edmund Lattime, Janice M. Mehnert, Gyan Bhanot, and Shridar Ganesan, Rutgers Cancer Institute of New Jersey; Paul Markowski, Ann Silk, Howard L. Kaufman, Janice M. Mehnert, and Shridar Ganesan, Rutgers Robert Wood Johnson Medical School, New Brunswick; Anshuman Panda and Gyan Bhanot, Rutgers University, Piscataway, NJ; Anil Betigeri and Kalyanasundaram Subramanian, Strand Life Sciences, Bangalore, India; Jeffrey S. Ross, Dean C. Pavlick, and Siraj Ali
Christine M Lovly - Anshuman Panda, Ann Silk, Howard L. Kaufman, Edmund Lattime, Janice M. Mehnert, Gyan Bhanot, and Shridar Ganesan, Rutgers Cancer Institute of New Jersey; Paul Markowski, Ann Silk, Howard L. Kaufman, Janice M. Mehnert, and Shridar Ganesan, Rutgers Robert Wood Johnson Medical School, New Brunswick; Anshuman Panda and Gyan Bhanot, Rutgers University, Piscataway, NJ; Anil Betigeri and Kalyanasundaram Subramanian, Strand Life Sciences, Bangalore, India; Jeffrey S. Ross, Dean C. Pavlick, and Siraj Ali
Jeffrey Sosman - Anshuman Panda, Ann Silk, Howard L. Kaufman, Edmund Lattime, Janice M. Mehnert, Gyan Bhanot, and Shridar Ganesan, Rutgers Cancer Institute of New Jersey; Paul Markowski, Ann Silk, Howard L. Kaufman, Janice M. Mehnert, and Shridar Ganesan, Rutgers Robert Wood Johnson Medical School, New Brunswick; Anshuman Panda and Gyan Bhanot, Rutgers University, Piscataway, NJ; Anil Betigeri and Kalyanasundaram Subramanian, Strand Life Sciences, Bangalore, India; Jeffrey S. Ross, Dean C. Pavlick, and Siraj Ali
Douglas B Johnson - Anshuman Panda, Ann Silk, Howard L. Kaufman, Edmund Lattime, Janice M. Mehnert, Gyan Bhanot, and Shridar Ganesan, Rutgers Cancer Institute of New Jersey; Paul Markowski, Ann Silk, Howard L. Kaufman, Janice M. Mehnert, and Shridar Ganesan, Rutgers Robert Wood Johnson Medical School, New Brunswick; Anshuman Panda and Gyan Bhanot, Rutgers University, Piscataway, NJ; Anil Betigeri and Kalyanasundaram Subramanian, Strand Life Sciences, Bangalore, India; Jeffrey S. Ross, Dean C. Pavlick, and Siraj Ali
Gyan Bhanot - Anshuman Panda, Ann Silk, Howard L. Kaufman, Edmund Lattime, Janice M. Mehnert, Gyan Bhanot, and Shridar Ganesan, Rutgers Cancer Institute of New Jersey; Paul Markowski, Ann Silk, Howard L. Kaufman, Janice M. Mehnert, and Shridar Ganesan, Rutgers Robert Wood Johnson Medical School, New Brunswick; Anshuman Panda and Gyan Bhanot, Rutgers University, Piscataway, NJ; Anil Betigeri and Kalyanasundaram Subramanian, Strand Life Sciences, Bangalore, India; Jeffrey S. Ross, Dean C. Pavlick, and Siraj Ali
Shridar Ganesan - Anshuman Panda, Ann Silk, Howard L. Kaufman, Edmund Lattime, Janice M. Mehnert, Gyan Bhanot, and Shridar Ganesan, Rutgers Cancer Institute of New Jersey; Paul Markowski, Ann Silk, Howard L. Kaufman, Janice M. Mehnert, and Shridar Ganesan, Rutgers Robert Wood Johnson Medical School, New Brunswick; Anshuman Panda and Gyan Bhanot, Rutgers University, Piscataway, NJ; Anil Betigeri and Kalyanasundaram Subramanian, Strand Life Sciences, Bangalore, India; Jeffrey S. Ross, Dean C. Pavlick, and Siraj Ali
Publication Details: JCO precision oncology, Vol.2017(1), pp.1-13
Date published: 11/2017
Academic Unit: Molecular Oncology; Education and Training; Molecular Biology and Biochemistry (SAS)
Language: English
Resource Type: Journal article
Identifiers: 991031664343204646