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Genomic stratification beyond Ras/B‐Raf in colorectal liver metastasis patients treated with hepatic arterial infusion
BACKGROUND: Resection of colorectal liver metastases (CLM) can cure disease, but many patients with extensive disease cannot be fully resected and others recur following surgery. Hepatic arterial infusion (HAI) chemotherapy can convert extensive liver disease to a resectable state or decrease recurr...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825986/ https://www.ncbi.nlm.nih.gov/pubmed/31503397 http://dx.doi.org/10.1002/cam4.2415 |
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author | Smith, J. Joshua Chatila, Walid K. Sanchez‐Vega, Francisco Datta, Jashodeep Connell, Louise C. Szeglin, Bryan C. Basunia, Azfar Boucher, Taryn M. Hauser, Haley Wasserman, Isaac Wu, Chao Cercek, Andrea Hechtman, Jaclyn F. Madden, Chris Jarnagin, William R. Garcia‐Aguilar, Julio D'Angelica, Michael I. Yaeger, Rona Schultz, Nikolaus Kemeny, Nancy E. |
author_facet | Smith, J. Joshua Chatila, Walid K. Sanchez‐Vega, Francisco Datta, Jashodeep Connell, Louise C. Szeglin, Bryan C. Basunia, Azfar Boucher, Taryn M. Hauser, Haley Wasserman, Isaac Wu, Chao Cercek, Andrea Hechtman, Jaclyn F. Madden, Chris Jarnagin, William R. Garcia‐Aguilar, Julio D'Angelica, Michael I. Yaeger, Rona Schultz, Nikolaus Kemeny, Nancy E. |
author_sort | Smith, J. Joshua |
collection | PubMed |
description | BACKGROUND: Resection of colorectal liver metastases (CLM) can cure disease, but many patients with extensive disease cannot be fully resected and others recur following surgery. Hepatic arterial infusion (HAI) chemotherapy can convert extensive liver disease to a resectable state or decrease recurrence risk, but response varies and no biomarkers currently exist to identify patients most likely to benefit. METHODS: We performed a retrospective cohort study of CLM patients receiving HAI chemotherapy whose tumors underwent MSK‐IMPACT sequencing. The frequency of oncogenic alterations and their association with overall survival (OS) and objective response rate were analyzed at the individual gene and signaling pathway levels. RESULTS: Three hundred and seventy patients met inclusion criteria: 189 (51.1%) who underwent colorectal liver metastasectomy followed by HAI + systemic therapy (Adjuvant cohort), and 181 (48.9%) with unresectable CLM (Metastatic cohort) who received HAI + systemic therapy, consisting of 63 (34.8%) with extrahepatic disease and 118 (65.2%) with liver‐restricted disease. Genomic alterations were similar in each cohort, and no individual gene or pathway was significantly associated with objective response. Patients in the adjuvant cohort with concurrent Ras/B‐Raf alteration and SMAD4 inactivation had worse prognosis while in the metastatic cohort patients with co‐alteration of Ras/B‐Raf and TP53 had worse OS. Similar findings were observed in a validation cohort. CONCLUSIONS: Concurrently altered Ras/B‐Raf and SMAD4 mutations were associated with worse survival in resectable patients, while concurrent Ras/B‐Raf and TP53 alterations were associated with worse survival in unresectable patients. The mutual exclusivity of Ras/B‐Raf, SMAD4, and TP53 may have prognostic value for CLM patients receiving HAI. |
format | Online Article Text |
id | pubmed-6825986 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-68259862019-11-07 Genomic stratification beyond Ras/B‐Raf in colorectal liver metastasis patients treated with hepatic arterial infusion Smith, J. Joshua Chatila, Walid K. Sanchez‐Vega, Francisco Datta, Jashodeep Connell, Louise C. Szeglin, Bryan C. Basunia, Azfar Boucher, Taryn M. Hauser, Haley Wasserman, Isaac Wu, Chao Cercek, Andrea Hechtman, Jaclyn F. Madden, Chris Jarnagin, William R. Garcia‐Aguilar, Julio D'Angelica, Michael I. Yaeger, Rona Schultz, Nikolaus Kemeny, Nancy E. Cancer Med Clinical Cancer Research BACKGROUND: Resection of colorectal liver metastases (CLM) can cure disease, but many patients with extensive disease cannot be fully resected and others recur following surgery. Hepatic arterial infusion (HAI) chemotherapy can convert extensive liver disease to a resectable state or decrease recurrence risk, but response varies and no biomarkers currently exist to identify patients most likely to benefit. METHODS: We performed a retrospective cohort study of CLM patients receiving HAI chemotherapy whose tumors underwent MSK‐IMPACT sequencing. The frequency of oncogenic alterations and their association with overall survival (OS) and objective response rate were analyzed at the individual gene and signaling pathway levels. RESULTS: Three hundred and seventy patients met inclusion criteria: 189 (51.1%) who underwent colorectal liver metastasectomy followed by HAI + systemic therapy (Adjuvant cohort), and 181 (48.9%) with unresectable CLM (Metastatic cohort) who received HAI + systemic therapy, consisting of 63 (34.8%) with extrahepatic disease and 118 (65.2%) with liver‐restricted disease. Genomic alterations were similar in each cohort, and no individual gene or pathway was significantly associated with objective response. Patients in the adjuvant cohort with concurrent Ras/B‐Raf alteration and SMAD4 inactivation had worse prognosis while in the metastatic cohort patients with co‐alteration of Ras/B‐Raf and TP53 had worse OS. Similar findings were observed in a validation cohort. CONCLUSIONS: Concurrently altered Ras/B‐Raf and SMAD4 mutations were associated with worse survival in resectable patients, while concurrent Ras/B‐Raf and TP53 alterations were associated with worse survival in unresectable patients. The mutual exclusivity of Ras/B‐Raf, SMAD4, and TP53 may have prognostic value for CLM patients receiving HAI. John Wiley and Sons Inc. 2019-09-10 /pmc/articles/PMC6825986/ /pubmed/31503397 http://dx.doi.org/10.1002/cam4.2415 Text en © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Clinical Cancer Research Smith, J. Joshua Chatila, Walid K. Sanchez‐Vega, Francisco Datta, Jashodeep Connell, Louise C. Szeglin, Bryan C. Basunia, Azfar Boucher, Taryn M. Hauser, Haley Wasserman, Isaac Wu, Chao Cercek, Andrea Hechtman, Jaclyn F. Madden, Chris Jarnagin, William R. Garcia‐Aguilar, Julio D'Angelica, Michael I. Yaeger, Rona Schultz, Nikolaus Kemeny, Nancy E. Genomic stratification beyond Ras/B‐Raf in colorectal liver metastasis patients treated with hepatic arterial infusion |
title | Genomic stratification beyond Ras/B‐Raf in colorectal liver metastasis patients treated with hepatic arterial infusion |
title_full | Genomic stratification beyond Ras/B‐Raf in colorectal liver metastasis patients treated with hepatic arterial infusion |
title_fullStr | Genomic stratification beyond Ras/B‐Raf in colorectal liver metastasis patients treated with hepatic arterial infusion |
title_full_unstemmed | Genomic stratification beyond Ras/B‐Raf in colorectal liver metastasis patients treated with hepatic arterial infusion |
title_short | Genomic stratification beyond Ras/B‐Raf in colorectal liver metastasis patients treated with hepatic arterial infusion |
title_sort | genomic stratification beyond ras/b‐raf in colorectal liver metastasis patients treated with hepatic arterial infusion |
topic | Clinical Cancer Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825986/ https://www.ncbi.nlm.nih.gov/pubmed/31503397 http://dx.doi.org/10.1002/cam4.2415 |
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