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 (WXS) or using commercially available sequencing panels.
WXS and RNA-seq data of 33 solid cancer types from TCGA 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 for response to immune checkpoint blockade therapy.
We find that a robust iCAM threshold, associated with signatures of immune checkpoint activation, exists in 8 of 33 solid cancers: melanoma, lung adenocarcinoma, colon adenocarcinoma, endometrial cancer, stomach adenocarcinoma, cervical cancer, ER+HER2- breast cancer, and bladder-urothelial cancer. Tumors with mutational burden higher than the threshold (iCAM+) also had clear histologic evidence of lymphocytic infiltration. In published datasets of melanoma, lung adenocarcinoma and colon cancer, patients with iCAM+ tumors had significantly better response to immune checkpoint therapy compared to those with iCAM- tumors. ROC analysis using TCGA predictions as gold standard showed that iCAM+ tumors are accurately identifiable using clinical sequencing assays, such as FoundationOne or StrandAdvantage. Using the FoundationOne derived threshold, analysis of 113 melanoma tumors, showed that iCAM+ patients have significantly better response to immune checkpoint therapy. iCAM+ and iCAM- tumors have distinct mutation patterns and different immune microenvironments.
In 8 solid cancers, a mutational burden threshold exists that may predict response to immune checkpoint blockade. This threshold is identifiable using available clinical sequencing assays.
JCO precision oncology. 2017 Dec 07 [Epub]
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
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ., Strand Life Sciences, Bangalore, India., Foundation Medicine, Cambridge, MA., Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ., Department of Medicine, Massachusetts General Hospital, Boston, MA., Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, TN., Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL.