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Clinical responses to PD-1 inhibition and their molecular characterization in six patients with mismatch repair-deficient metastatic cancer of the digestive system

PURPOSE: Immune checkpoint inhibitors have shown efficacy in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) gastrointestinal (GI) cancers. However, depth and duration of clinical response is not uniform. We assessed tumor mutation burden (TMB) as a response mark...

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Autores principales: Hirsch, Daniela, Gaiser, Timo, Merx, Kirsten, Weingaertner, Simone, Forster, Michael, Hendricks, Alexander, Woenckhaus, Matthias, Schubert, Thomas, Hofheinz, Ralf-Dieter, Gencer, Deniz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810640/
https://www.ncbi.nlm.nih.gov/pubmed/32776177
http://dx.doi.org/10.1007/s00432-020-03335-2
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author Hirsch, Daniela
Gaiser, Timo
Merx, Kirsten
Weingaertner, Simone
Forster, Michael
Hendricks, Alexander
Woenckhaus, Matthias
Schubert, Thomas
Hofheinz, Ralf-Dieter
Gencer, Deniz
author_facet Hirsch, Daniela
Gaiser, Timo
Merx, Kirsten
Weingaertner, Simone
Forster, Michael
Hendricks, Alexander
Woenckhaus, Matthias
Schubert, Thomas
Hofheinz, Ralf-Dieter
Gencer, Deniz
author_sort Hirsch, Daniela
collection PubMed
description PURPOSE: Immune checkpoint inhibitors have shown efficacy in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) gastrointestinal (GI) cancers. However, depth and duration of clinical response is not uniform. We assessed tumor mutation burden (TMB) as a response marker in patients with GI cancers treated with immune checkpoint inhibitors. METHODS: Detailed clinical and response data were collected from six patients with metastatic MSI-H/dMMR GI cancers treated with immune checkpoint inhibitors. Efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Tumors and matched normal tissue were profiled by targeted next generation sequencing (127 gene panel, size 0.8 Mb). Impact of included mutation types, germline filtering methodology and different variant allele frequency thresholds on TMB estimation was assessed. RESULTS: Objective radiographic responses were observed in all six patients, and complete response was achieved in two of the six patients. Responses were durable (minimum 25 months). TMB estimates were clearly above the two recently reported cut-offs for metastatic colorectal cancer of 12 or 37 mutations per megabase for five of six patients, respectively, while one patient had borderline TMB elevation. TMB did not show an association with extent and duration of response but was influenced by included mutation types, germline filtering method and variant allele frequency threshold. CONCLUSION: Our case series confirms the clinical benefit of immune checkpoint blockade in patients with metastatic MSI-H/dMMR GI cancers and illustrates the vulnerability of TMB as predictive marker in a subset of patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00432-020-03335-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-78106402021-01-25 Clinical responses to PD-1 inhibition and their molecular characterization in six patients with mismatch repair-deficient metastatic cancer of the digestive system Hirsch, Daniela Gaiser, Timo Merx, Kirsten Weingaertner, Simone Forster, Michael Hendricks, Alexander Woenckhaus, Matthias Schubert, Thomas Hofheinz, Ralf-Dieter Gencer, Deniz J Cancer Res Clin Oncol Original Article – Clinical Oncology PURPOSE: Immune checkpoint inhibitors have shown efficacy in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) gastrointestinal (GI) cancers. However, depth and duration of clinical response is not uniform. We assessed tumor mutation burden (TMB) as a response marker in patients with GI cancers treated with immune checkpoint inhibitors. METHODS: Detailed clinical and response data were collected from six patients with metastatic MSI-H/dMMR GI cancers treated with immune checkpoint inhibitors. Efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Tumors and matched normal tissue were profiled by targeted next generation sequencing (127 gene panel, size 0.8 Mb). Impact of included mutation types, germline filtering methodology and different variant allele frequency thresholds on TMB estimation was assessed. RESULTS: Objective radiographic responses were observed in all six patients, and complete response was achieved in two of the six patients. Responses were durable (minimum 25 months). TMB estimates were clearly above the two recently reported cut-offs for metastatic colorectal cancer of 12 or 37 mutations per megabase for five of six patients, respectively, while one patient had borderline TMB elevation. TMB did not show an association with extent and duration of response but was influenced by included mutation types, germline filtering method and variant allele frequency threshold. CONCLUSION: Our case series confirms the clinical benefit of immune checkpoint blockade in patients with metastatic MSI-H/dMMR GI cancers and illustrates the vulnerability of TMB as predictive marker in a subset of patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00432-020-03335-2) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2020-08-09 2021 /pmc/articles/PMC7810640/ /pubmed/32776177 http://dx.doi.org/10.1007/s00432-020-03335-2 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Original Article – Clinical Oncology
Hirsch, Daniela
Gaiser, Timo
Merx, Kirsten
Weingaertner, Simone
Forster, Michael
Hendricks, Alexander
Woenckhaus, Matthias
Schubert, Thomas
Hofheinz, Ralf-Dieter
Gencer, Deniz
Clinical responses to PD-1 inhibition and their molecular characterization in six patients with mismatch repair-deficient metastatic cancer of the digestive system
title Clinical responses to PD-1 inhibition and their molecular characterization in six patients with mismatch repair-deficient metastatic cancer of the digestive system
title_full Clinical responses to PD-1 inhibition and their molecular characterization in six patients with mismatch repair-deficient metastatic cancer of the digestive system
title_fullStr Clinical responses to PD-1 inhibition and their molecular characterization in six patients with mismatch repair-deficient metastatic cancer of the digestive system
title_full_unstemmed Clinical responses to PD-1 inhibition and their molecular characterization in six patients with mismatch repair-deficient metastatic cancer of the digestive system
title_short Clinical responses to PD-1 inhibition and their molecular characterization in six patients with mismatch repair-deficient metastatic cancer of the digestive system
title_sort clinical responses to pd-1 inhibition and their molecular characterization in six patients with mismatch repair-deficient metastatic cancer of the digestive system
topic Original Article – Clinical Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810640/
https://www.ncbi.nlm.nih.gov/pubmed/32776177
http://dx.doi.org/10.1007/s00432-020-03335-2
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