Beyond microsatellite testing: assessment of tumor mutational burden identifies subsets of colorectal cancer who may respond to immune checkpoint inhibition

Journal of Gastrointestinal Oncology
David FabrizioSamuel J Klempner

Abstract

The clinical application of PD1/PD-L1 targeting checkpoint inhibitors in colorectal cancer (CRC) has largely focused on a subset of microsatellite instable (MSI-high) patients. However, the proposed genotype that sensitizes these patients to immunotherapy is not captured by MSI status alone. Estimation of tumor mutational burden (TMB) from comprehensive genomic profiling is validated against whole exome sequencing and linked to checkpoint response in metastatic melanoma, urothelial bladder cancer and non-small cell lung carcinoma. We sought to explore the subset of microsatellite stable (MSS) CRC patients with high TMB, and identify the specific genomic signatures associated with this phenotype. Furthermore, we explore the ability to quantify TMB as a potential predictive biomarker of PD1/PD-L1 therapy in CRC. Formalin-fixed, paraffin embedded tissue sections from 6,004 cases of CRC were sequenced with a CLIA-approved CGP assay. MSI and TMB statuses were computationally determined using validated methods. The cutoff for TMB-high was defined according to the lower bound value that satisfied the 90% probability interval based on the TMB distribution across all MSI-High patients. MSS tumors were observed in 5,702 of 6,004 (95.0%) ...Continue Reading

Citations

Jan 19, 2019·Journal of Personalized Medicine·David J Hermel, Darren Sigal
Feb 5, 2019·Molecular Oncology·Nicole M ReillyAlberto Bardelli
May 1, 2019·Annals of Oncology : Official Journal of the European Society for Medical Oncology·A B SchrockM Fakih
May 14, 2019·Expert Review of Molecular Diagnostics·Ke MaYuyang Zhang
Jul 11, 2019·Nature Reviews. Clinical Oncology·Anita SveenRagnhild A Lothe
Jun 9, 2019·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Tao WangJinru Shia
Sep 22, 2019·International Journal of Molecular Sciences·Bilikis Aderonke AbolarinwaYen-Hua Huang
Jun 21, 2019·Journal of Experimental & Clinical Cancer Research : CR·Stephan KrugerMichael von Bergwelt-Baildon
Aug 21, 2019·Journal of Experimental & Clinical Cancer Research : CR·Apostolos ZaravinosGeorgios D Ayiomamitis
Nov 7, 2018·Cold Spring Harbor Perspectives in Medicine·Elaine R Mardis
Sep 15, 2020·JCO Precision Oncology·Michael BitzerNisar P Malek
Aug 28, 2020·Journal for Immunotherapy of Cancer·Siddharth ShethJean-Charles Soria
Aug 14, 2019·Cancer Cell International·Francesca GaluppiniRaffaele Baffa
Aug 27, 2019·Frontiers in Immunology·François Ghiringhelli, Jean-David Fumet
Dec 6, 2019·Journal of Biomedical Science·Grace WakabayashiYun Yen
Jan 19, 2020·Expert Opinion on Biological Therapy·Dahna CoupezJaafar Bennouna
Nov 4, 2020·Expert Review of Gastroenterology & Hepatology·Mike NguyenEva Segelov
Nov 4, 2020·Cancer Discovery·Dan ShaFrank A Sinicrope
Nov 7, 2020·Journal of Pathology and Translational Medicine·Binnari KimKyoung-Mee Kim
Jan 13, 2021·Journal of the National Cancer Institute·Mithunah KrishnamoorthySaman Maleki Vareki
Feb 13, 2021·Cancers·Caroline ConwayKellie Dean
Nov 3, 2020·Current Colorectal Cancer Reports·Sophiya KarkiAnup Kasi
Jan 13, 2021·International Journal of Molecular Sciences·Andrea Katharina LindnerRenate Pichler
Feb 19, 2021·Journal of Translational Medicine·Leah MoralesTomas Kirchhoff
Nov 18, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·John H StricklerMustafa Khasraw
Feb 27, 2021·Frontiers in Oncology·Jiahao HuangWeizhong Tang
Nov 14, 2020·Expert Review of Anticancer Therapy·Marc T Roth, Satya Das
Dec 12, 2020·Translational Research : the Journal of Laboratory and Clinical Medicine·Ebunoluwa E OtegbeyeMatthew A Ciorba
Mar 30, 2021·Frontiers in Oncology·Zhu ZengZhengyin Liao

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