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The Evolutionary Landscape of Treatment for BRAF(V600E) Mutant Metastatic Colorectal Cancer

SIMPLE SUMMARY: The BRAF(V600E) mutation accounts for 8–10% of metastatic colorectal cancer (mCRC) patients and it is an established prognostic factor. Median overall survival of this subset of patients is indeed so poor that it is similar to first line PFS of patients without this molecular alterat...

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Autores principales: Mauri, Gianluca, Bonazzina, Erica, Amatu, Alessio, Tosi, Federica, Bencardino, Katia, Gori, Viviana, Massihnia, Daniela, Cipani, Tiziana, Spina, Francesco, Ghezzi, Silvia, Siena, Salvatore, Sartore-Bianchi, Andrea
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795863/
https://www.ncbi.nlm.nih.gov/pubmed/33406649
http://dx.doi.org/10.3390/cancers13010137
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author Mauri, Gianluca
Bonazzina, Erica
Amatu, Alessio
Tosi, Federica
Bencardino, Katia
Gori, Viviana
Massihnia, Daniela
Cipani, Tiziana
Spina, Francesco
Ghezzi, Silvia
Siena, Salvatore
Sartore-Bianchi, Andrea
author_facet Mauri, Gianluca
Bonazzina, Erica
Amatu, Alessio
Tosi, Federica
Bencardino, Katia
Gori, Viviana
Massihnia, Daniela
Cipani, Tiziana
Spina, Francesco
Ghezzi, Silvia
Siena, Salvatore
Sartore-Bianchi, Andrea
author_sort Mauri, Gianluca
collection PubMed
description SIMPLE SUMMARY: The BRAF(V600E) mutation accounts for 8–10% of metastatic colorectal cancer (mCRC) patients and it is an established prognostic factor. Median overall survival of this subset of patients is indeed so poor that it is similar to first line PFS of patients without this molecular alteration. An exception is represented by patients displaying concomitant MSI-H status who can benefit from immunotherapy with checkpoint inhibitors (CPIs). Recently, a targeted therapy with the combination of encorafenib and cetuximab provided for the first time a survival gain and thus translation in the clinic, even though acquired resistance limits the possibility of more than an incremental benefit. Many studies exploiting other different strategies are ongoing. In this review we present current therapies specifically headed to BRAF(V600E) mutant mCRC and systematically review ongoing clinical trials identifying different approaches under investigations: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. ABSTRACT: The BRAF(V600E) mutation is found in 8–10% of metastatic colorectal cancer (mCRC) patients and it is recognized as a poor prognostic factor with a median overall survival inferior to 20 months. At present, besides immune checkpoint inhibitors (CPIs) for those tumors with concomitant MSI-H status, recommended treatment options include cytotoxic chemotherapy + anti-VEGF in the first line setting, and a combination of EGFR and a BRAF inhibitor (cetuximab plus encorafenib) in second line. However, even with the latter targeted approach, acquired resistance limits the possibility of more than an incremental benefit and survival is still dismal. In this review, we discuss current treatment options for this subset of patients and perform a systematic review of ongoing clinical trials. Overall, we identified six emerging strategies: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. In the future, the integration of new therapeutic strategies targeting key players in the BRAF(V600E) oncogenic pathways with current treatment approach based on cytotoxic chemotherapy and surgery is likely to redefine the treatment landscape of these CRC patients.
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spelling pubmed-77958632021-01-10 The Evolutionary Landscape of Treatment for BRAF(V600E) Mutant Metastatic Colorectal Cancer Mauri, Gianluca Bonazzina, Erica Amatu, Alessio Tosi, Federica Bencardino, Katia Gori, Viviana Massihnia, Daniela Cipani, Tiziana Spina, Francesco Ghezzi, Silvia Siena, Salvatore Sartore-Bianchi, Andrea Cancers (Basel) Review SIMPLE SUMMARY: The BRAF(V600E) mutation accounts for 8–10% of metastatic colorectal cancer (mCRC) patients and it is an established prognostic factor. Median overall survival of this subset of patients is indeed so poor that it is similar to first line PFS of patients without this molecular alteration. An exception is represented by patients displaying concomitant MSI-H status who can benefit from immunotherapy with checkpoint inhibitors (CPIs). Recently, a targeted therapy with the combination of encorafenib and cetuximab provided for the first time a survival gain and thus translation in the clinic, even though acquired resistance limits the possibility of more than an incremental benefit. Many studies exploiting other different strategies are ongoing. In this review we present current therapies specifically headed to BRAF(V600E) mutant mCRC and systematically review ongoing clinical trials identifying different approaches under investigations: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. ABSTRACT: The BRAF(V600E) mutation is found in 8–10% of metastatic colorectal cancer (mCRC) patients and it is recognized as a poor prognostic factor with a median overall survival inferior to 20 months. At present, besides immune checkpoint inhibitors (CPIs) for those tumors with concomitant MSI-H status, recommended treatment options include cytotoxic chemotherapy + anti-VEGF in the first line setting, and a combination of EGFR and a BRAF inhibitor (cetuximab plus encorafenib) in second line. However, even with the latter targeted approach, acquired resistance limits the possibility of more than an incremental benefit and survival is still dismal. In this review, we discuss current treatment options for this subset of patients and perform a systematic review of ongoing clinical trials. Overall, we identified six emerging strategies: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. In the future, the integration of new therapeutic strategies targeting key players in the BRAF(V600E) oncogenic pathways with current treatment approach based on cytotoxic chemotherapy and surgery is likely to redefine the treatment landscape of these CRC patients. MDPI 2021-01-04 /pmc/articles/PMC7795863/ /pubmed/33406649 http://dx.doi.org/10.3390/cancers13010137 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Mauri, Gianluca
Bonazzina, Erica
Amatu, Alessio
Tosi, Federica
Bencardino, Katia
Gori, Viviana
Massihnia, Daniela
Cipani, Tiziana
Spina, Francesco
Ghezzi, Silvia
Siena, Salvatore
Sartore-Bianchi, Andrea
The Evolutionary Landscape of Treatment for BRAF(V600E) Mutant Metastatic Colorectal Cancer
title The Evolutionary Landscape of Treatment for BRAF(V600E) Mutant Metastatic Colorectal Cancer
title_full The Evolutionary Landscape of Treatment for BRAF(V600E) Mutant Metastatic Colorectal Cancer
title_fullStr The Evolutionary Landscape of Treatment for BRAF(V600E) Mutant Metastatic Colorectal Cancer
title_full_unstemmed The Evolutionary Landscape of Treatment for BRAF(V600E) Mutant Metastatic Colorectal Cancer
title_short The Evolutionary Landscape of Treatment for BRAF(V600E) Mutant Metastatic Colorectal Cancer
title_sort evolutionary landscape of treatment for braf(v600e) mutant metastatic colorectal cancer
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795863/
https://www.ncbi.nlm.nih.gov/pubmed/33406649
http://dx.doi.org/10.3390/cancers13010137
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