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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

PurposeAnassociation between mutational burden andresponse toimmunecheckpoint 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 andRNAsequencing 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 thatmayserve as a biomarker of response toimmunecheckpoint 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 iCAMnegative 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 asFoundationOne (FoundationMedicine,Cambridge,MA) or StrandAdvantage (Strand Life Sciences, Bangalore, India). Using the FoundationOne-derived threshold, an analysis of 113melanoma tumors showed that patients with iCAM-positive disease have significantly better response to immune checkpoint therapy. iCAM-positive and iCAMnegative 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.

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalJCO Precision Oncology
Volume2017
Issue number1
DOIs
StatePublished - Jan 1 2017

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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