Are Pathogenic Germline Variants in Metastatic Melanoma Associated with Resistance to Combined Immunotherapy?
Background: Combined immunotherapy has significantly improved survival of patients with advanced melanoma, but there are still patients that do not benefit from it. Early biomarkers that indicate potential resistance would be highly relevant for these patients. Methods: We comprehensively analyzed t...
Main Authors: | , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2020-04-01
|
Series: | Cancers |
Subjects: | |
Online Access: | https://www.mdpi.com/2072-6694/12/5/1101 |
id |
doaj-c40adf035bd747cb8e2e23ca9cd9ee16 |
---|---|
record_format |
Article |
spelling |
doaj-c40adf035bd747cb8e2e23ca9cd9ee162020-11-25T03:20:19ZengMDPI AGCancers2072-66942020-04-01121101110110.3390/cancers12051101Are Pathogenic Germline Variants in Metastatic Melanoma Associated with Resistance to Combined Immunotherapy?Teresa Amaral0Martin Schulze1Tobias Sinnberg2Maike Nieser3Peter Martus4Florian Battke5Claus Garbe6Saskia Biskup7Andrea Forschner8Center for Dermatooncology, Department of Dermatology, University Hospital Tuebingen, Eberhard Karls University, 72076 Tuebingen, GermanyPractice for Human Genetics, 72076 Tuebingen, GermanyCenter for Dermatooncology, Department of Dermatology, University Hospital Tuebingen, Eberhard Karls University, 72076 Tuebingen, GermanyPractice for Human Genetics, 72076 Tuebingen, GermanyInstitute for Clinical Epidemiology and applied Biostatistics (IKEaB), Eberhard Karls University, 72076 Tuebingen, GermanyCenter for Genomics and Transcriptomics (CeGaT) GmbH, 72076 Tuebingen, GermanyCenter for Dermatooncology, Department of Dermatology, University Hospital Tuebingen, Eberhard Karls University, 72076 Tuebingen, GermanyPractice for Human Genetics, 72076 Tuebingen, GermanyCenter for Dermatooncology, Department of Dermatology, University Hospital Tuebingen, Eberhard Karls University, 72076 Tuebingen, GermanyBackground: Combined immunotherapy has significantly improved survival of patients with advanced melanoma, but there are still patients that do not benefit from it. Early biomarkers that indicate potential resistance would be highly relevant for these patients. Methods: We comprehensively analyzed tumor and blood samples from patients with advanced melanoma, treated with combined immunotherapy and performed descriptive and survival analysis. Results: Fifty-nine patients with a median follow-up of 13 months (inter quartile range (IQR) 11–15) were included. Interestingly, nine patients were found to have pathogenic or likely pathogenic (P/LP) germline variants in one of these genes: BRCA2, POLE, WRN, FANCI, CDKN2A, BAP1, PALB2 and RAD54B. Most of them are involved in DNA repair mechanisms. Patients with P/LP germline variants had a significantly shorter progression-free survival (PFS) and melanoma specific survival (MSS) compared to patients without P/LP germline variants (HR = 2.16; 95% CI: 1.01–4.64; <i>p</i> = 0.048 and HR = 3.21; 95% CI: 1.31–7.87; <i>p</i> = 0.011, respectively). None of the patients with a P/LP germline variant responded to combined immunotherapy. In the multivariate Cox-regression analysis, presence of a P/LP germline variant, S100B and lactate dehydrogenase (LDH) remained independently significant factors for MSS (<i>p</i> = 0.036; <i>p </i>= 0.044 and <i>p </i>= 0.001, respectively). Conclusions: The presence of P/LP germline variants was associated with resistance to combined immunotherapy in our cohort. As genes involved in DNA repair mechanisms are also involved in lymphocyte development and T-cell differentiation, a P/LP germline variant in these genes may preclude an antitumor immune response.https://www.mdpi.com/2072-6694/12/5/1101pathogenic/likely pathogenic germline variantimmune checkpoint inhibitorsadvanced melanomaresistance to immunotherapy |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Teresa Amaral Martin Schulze Tobias Sinnberg Maike Nieser Peter Martus Florian Battke Claus Garbe Saskia Biskup Andrea Forschner |
spellingShingle |
Teresa Amaral Martin Schulze Tobias Sinnberg Maike Nieser Peter Martus Florian Battke Claus Garbe Saskia Biskup Andrea Forschner Are Pathogenic Germline Variants in Metastatic Melanoma Associated with Resistance to Combined Immunotherapy? Cancers pathogenic/likely pathogenic germline variant immune checkpoint inhibitors advanced melanoma resistance to immunotherapy |
author_facet |
Teresa Amaral Martin Schulze Tobias Sinnberg Maike Nieser Peter Martus Florian Battke Claus Garbe Saskia Biskup Andrea Forschner |
author_sort |
Teresa Amaral |
title |
Are Pathogenic Germline Variants in Metastatic Melanoma Associated with Resistance to Combined Immunotherapy? |
title_short |
Are Pathogenic Germline Variants in Metastatic Melanoma Associated with Resistance to Combined Immunotherapy? |
title_full |
Are Pathogenic Germline Variants in Metastatic Melanoma Associated with Resistance to Combined Immunotherapy? |
title_fullStr |
Are Pathogenic Germline Variants in Metastatic Melanoma Associated with Resistance to Combined Immunotherapy? |
title_full_unstemmed |
Are Pathogenic Germline Variants in Metastatic Melanoma Associated with Resistance to Combined Immunotherapy? |
title_sort |
are pathogenic germline variants in metastatic melanoma associated with resistance to combined immunotherapy? |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2020-04-01 |
description |
Background: Combined immunotherapy has significantly improved survival of patients with advanced melanoma, but there are still patients that do not benefit from it. Early biomarkers that indicate potential resistance would be highly relevant for these patients. Methods: We comprehensively analyzed tumor and blood samples from patients with advanced melanoma, treated with combined immunotherapy and performed descriptive and survival analysis. Results: Fifty-nine patients with a median follow-up of 13 months (inter quartile range (IQR) 11–15) were included. Interestingly, nine patients were found to have pathogenic or likely pathogenic (P/LP) germline variants in one of these genes: BRCA2, POLE, WRN, FANCI, CDKN2A, BAP1, PALB2 and RAD54B. Most of them are involved in DNA repair mechanisms. Patients with P/LP germline variants had a significantly shorter progression-free survival (PFS) and melanoma specific survival (MSS) compared to patients without P/LP germline variants (HR = 2.16; 95% CI: 1.01–4.64; <i>p</i> = 0.048 and HR = 3.21; 95% CI: 1.31–7.87; <i>p</i> = 0.011, respectively). None of the patients with a P/LP germline variant responded to combined immunotherapy. In the multivariate Cox-regression analysis, presence of a P/LP germline variant, S100B and lactate dehydrogenase (LDH) remained independently significant factors for MSS (<i>p</i> = 0.036; <i>p </i>= 0.044 and <i>p </i>= 0.001, respectively). Conclusions: The presence of P/LP germline variants was associated with resistance to combined immunotherapy in our cohort. As genes involved in DNA repair mechanisms are also involved in lymphocyte development and T-cell differentiation, a P/LP germline variant in these genes may preclude an antitumor immune response. |
topic |
pathogenic/likely pathogenic germline variant immune checkpoint inhibitors advanced melanoma resistance to immunotherapy |
url |
https://www.mdpi.com/2072-6694/12/5/1101 |
work_keys_str_mv |
AT teresaamaral arepathogenicgermlinevariantsinmetastaticmelanomaassociatedwithresistancetocombinedimmunotherapy AT martinschulze arepathogenicgermlinevariantsinmetastaticmelanomaassociatedwithresistancetocombinedimmunotherapy AT tobiassinnberg arepathogenicgermlinevariantsinmetastaticmelanomaassociatedwithresistancetocombinedimmunotherapy AT maikenieser arepathogenicgermlinevariantsinmetastaticmelanomaassociatedwithresistancetocombinedimmunotherapy AT petermartus arepathogenicgermlinevariantsinmetastaticmelanomaassociatedwithresistancetocombinedimmunotherapy AT florianbattke arepathogenicgermlinevariantsinmetastaticmelanomaassociatedwithresistancetocombinedimmunotherapy AT clausgarbe arepathogenicgermlinevariantsinmetastaticmelanomaassociatedwithresistancetocombinedimmunotherapy AT saskiabiskup arepathogenicgermlinevariantsinmetastaticmelanomaassociatedwithresistancetocombinedimmunotherapy AT andreaforschner arepathogenicgermlinevariantsinmetastaticmelanomaassociatedwithresistancetocombinedimmunotherapy |
_version_ |
1724618167967285248 |