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Comprehensive Molecular Characterization of Soft Tissue Sarcoma for Prediction of Pazopanib-Based Treatment Response
PURPOSE: Even though pazopanib, a multitargeted tyrosine kinase inhibitor, has been approved for refractory soft tissue sarcoma (STS), little is known about the molecular determinants of the response to pazopanib. We performed integrative molecular characterization to identify potential predictors o...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Korean Cancer Association
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10101793/ https://www.ncbi.nlm.nih.gov/pubmed/36164943 http://dx.doi.org/10.4143/crt.2022.251 |
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author | Hong, Jung Yong Cho, Hee Jin Yun, Kum-Hee Lee, Young Han Kim, Seung Hyun Baek, Wooyeol Kim, Sang Kyum Lee, Yurimi Choi, Yoon-La Kwon, Minsuk Kim, Hyo Song Lee, Jeeyun |
author_facet | Hong, Jung Yong Cho, Hee Jin Yun, Kum-Hee Lee, Young Han Kim, Seung Hyun Baek, Wooyeol Kim, Sang Kyum Lee, Yurimi Choi, Yoon-La Kwon, Minsuk Kim, Hyo Song Lee, Jeeyun |
author_sort | Hong, Jung Yong |
collection | PubMed |
description | PURPOSE: Even though pazopanib, a multitargeted tyrosine kinase inhibitor, has been approved for refractory soft tissue sarcoma (STS), little is known about the molecular determinants of the response to pazopanib. We performed integrative molecular characterization to identify potential predictors of pazopanib efficacy. MATERIALS AND METHODS: We obtained fresh pre-treatment tumor tissue from 35 patients with advanced STS receiving pazopanib-based treatment. Among those, 18 (51.4%) received pazopanib monotherapy, and the remaining 17 (48.6%) received pazopanib in combination with durvalumab, programmed death-ligand 1 blockade. Whole-exome and transcriptome sequencing were performed for each tumor and patient germline DNA. RESULTS: Of the 35 patients receiving pazopanib-based treatment, nine achieved a partial response (PR), resulting in an objective response rate (ORR) of 27.3%, and the median progression-free survival (PFS) was 6.0 months. Patients with CDK4 amplification (copy ratio tumor to normal > 2) exhibited shorter PFS (3.7 vs. 7.9 months, p=2.09×10(−4)) and a poorer response (ORR; 0% vs. 33.3%) compared to those without a gene amplification (copy ratio ≤ 2). Moreover, non-responders demonstrated transcriptional activation of CDK4 via DNA amplification, resulting in cell cycle activation. In the durvalumab combination cohort, seven of the 17 patients (41.2%) achieved a PR, and gene expression analysis revealed that durvalumab responders exhibited high immune/stromal cell infiltration, mainly comprising natural killer cells, compared to non-responders as well as increased expression of CD19, a B-cell marker. CONCLUSION: Despite the limitation of heterogeneity in the study population and treatment, we identified possible molecular predictors of pazopanib efficacy that can be employed in future clinical trials aimed at evaluating therapeutic strategies. |
format | Online Article Text |
id | pubmed-10101793 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Korean Cancer Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-101017932023-04-15 Comprehensive Molecular Characterization of Soft Tissue Sarcoma for Prediction of Pazopanib-Based Treatment Response Hong, Jung Yong Cho, Hee Jin Yun, Kum-Hee Lee, Young Han Kim, Seung Hyun Baek, Wooyeol Kim, Sang Kyum Lee, Yurimi Choi, Yoon-La Kwon, Minsuk Kim, Hyo Song Lee, Jeeyun Cancer Res Treat Original Article PURPOSE: Even though pazopanib, a multitargeted tyrosine kinase inhibitor, has been approved for refractory soft tissue sarcoma (STS), little is known about the molecular determinants of the response to pazopanib. We performed integrative molecular characterization to identify potential predictors of pazopanib efficacy. MATERIALS AND METHODS: We obtained fresh pre-treatment tumor tissue from 35 patients with advanced STS receiving pazopanib-based treatment. Among those, 18 (51.4%) received pazopanib monotherapy, and the remaining 17 (48.6%) received pazopanib in combination with durvalumab, programmed death-ligand 1 blockade. Whole-exome and transcriptome sequencing were performed for each tumor and patient germline DNA. RESULTS: Of the 35 patients receiving pazopanib-based treatment, nine achieved a partial response (PR), resulting in an objective response rate (ORR) of 27.3%, and the median progression-free survival (PFS) was 6.0 months. Patients with CDK4 amplification (copy ratio tumor to normal > 2) exhibited shorter PFS (3.7 vs. 7.9 months, p=2.09×10(−4)) and a poorer response (ORR; 0% vs. 33.3%) compared to those without a gene amplification (copy ratio ≤ 2). Moreover, non-responders demonstrated transcriptional activation of CDK4 via DNA amplification, resulting in cell cycle activation. In the durvalumab combination cohort, seven of the 17 patients (41.2%) achieved a PR, and gene expression analysis revealed that durvalumab responders exhibited high immune/stromal cell infiltration, mainly comprising natural killer cells, compared to non-responders as well as increased expression of CD19, a B-cell marker. CONCLUSION: Despite the limitation of heterogeneity in the study population and treatment, we identified possible molecular predictors of pazopanib efficacy that can be employed in future clinical trials aimed at evaluating therapeutic strategies. Korean Cancer Association 2023-04 2022-09-27 /pmc/articles/PMC10101793/ /pubmed/36164943 http://dx.doi.org/10.4143/crt.2022.251 Text en Copyright © 2023 by the Korean Cancer Association https://creativecommons.org/licenses/by-nc/4.0/This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Hong, Jung Yong Cho, Hee Jin Yun, Kum-Hee Lee, Young Han Kim, Seung Hyun Baek, Wooyeol Kim, Sang Kyum Lee, Yurimi Choi, Yoon-La Kwon, Minsuk Kim, Hyo Song Lee, Jeeyun Comprehensive Molecular Characterization of Soft Tissue Sarcoma for Prediction of Pazopanib-Based Treatment Response |
title | Comprehensive Molecular Characterization of Soft Tissue Sarcoma for Prediction of Pazopanib-Based Treatment Response |
title_full | Comprehensive Molecular Characterization of Soft Tissue Sarcoma for Prediction of Pazopanib-Based Treatment Response |
title_fullStr | Comprehensive Molecular Characterization of Soft Tissue Sarcoma for Prediction of Pazopanib-Based Treatment Response |
title_full_unstemmed | Comprehensive Molecular Characterization of Soft Tissue Sarcoma for Prediction of Pazopanib-Based Treatment Response |
title_short | Comprehensive Molecular Characterization of Soft Tissue Sarcoma for Prediction of Pazopanib-Based Treatment Response |
title_sort | comprehensive molecular characterization of soft tissue sarcoma for prediction of pazopanib-based treatment response |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10101793/ https://www.ncbi.nlm.nih.gov/pubmed/36164943 http://dx.doi.org/10.4143/crt.2022.251 |
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