Michael Pohl1, Wolff Schmiegel. 1. Department of Medicine, Universitx00E4;tsklinikum Knappschaftskrankenhaus, Bochum, Germany.
Abstract
BACKGROUND: Colorectal cancer (CRC) is the third most common cancer type in Western countries. Significant progress has been made in the last decade in the therapy of metastatic CRC (mCRC) with a median overall survival (OS) of patients exceeding 30 months. The integration of biologic targeted therapies and anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MABs) in the treatment of patients with genomically selected all-RAS wild-type mCRC leads to a significant progress in advanced incurable disease state. After the introduction of the anti-VEGF MAB bevacizumab, the FDA approved with ramucirumab the second antiangiogenic MAB for the mCRC treatment. Further new drugs are on the horizon and new diagnostic tools will be introduced soon. KEY MESSAGES: Molecular heterogeneity of mCRC has been recognized as pivotal in the evolution of clonal populations during anti-EGFR therapies. Mutations in RAS genes predict a lack of response to anti-EGFR MABs. Mutations in the mitogen-activated protein kinase-phosphoinositide 3-kinase pathways like BRAF or PIK3CA mutations or HER2/ERBB2 or MET amplifications bypass EGFR signaling and also may confer resistance to anti-EGFR MABs. HER2/ERBB2 amplification is a further driver of resistance to anti-EGFR MABs in mCRC. The phase II study of HER2 Amplification for Colo-Rectal Cancer Enhanced Stratification (HERACLES) discovers that a dual HER2-targeted therapy may be an option for HER2-amplified mCRC. The mismatch repair deficiency predicts responsiveness to an immune checkpoint blockade with the anti-PD-1 immune checkpoint inhibitor pembrolizumab. CONCLUSIONS: The understanding of primary (de novo) and secondary (acquired) resistance to anti-EGFR therapies, new targeted therapies, immuno-oncology and about predictive biomarkers in mCRC is guiding the development of rational therapeutic strategies. Combinations of targeted therapies are necessary to effectively treat drug-resistant cancers. Liquid biopsy is an upcoming new tool in the primary diagnosis and follow-up analysis of mutations in circulating tumor DNA.
BACKGROUND:Colorectal cancer (CRC) is the third most common cancer type in Western countries. Significant progress has been made in the last decade in the therapy of metastatic CRC (mCRC) with a median overall survival (OS) of patients exceeding 30 months. The integration of biologic targeted therapies and anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MABs) in the treatment of patients with genomically selected all-RAS wild-type mCRC leads to a significant progress in advanced incurable disease state. After the introduction of the anti-VEGF MAB bevacizumab, the FDA approved with ramucirumab the second antiangiogenic MAB for the mCRC treatment. Further new drugs are on the horizon and new diagnostic tools will be introduced soon. KEY MESSAGES: Molecular heterogeneity of mCRC has been recognized as pivotal in the evolution of clonal populations during anti-EGFR therapies. Mutations in RAS genes predict a lack of response to anti-EGFR MABs. Mutations in the mitogen-activated protein kinase-phosphoinositide 3-kinase pathways like BRAF or PIK3CA mutations or HER2/ERBB2 or MET amplifications bypass EGFR signaling and also may confer resistance to anti-EGFR MABs. HER2/ERBB2 amplification is a further driver of resistance to anti-EGFR MABs in mCRC. The phase II study of HER2 Amplification for Colo-Rectal Cancer Enhanced Stratification (HERACLES) discovers that a dual HER2-targeted therapy may be an option for HER2-amplified mCRC. The mismatch repair deficiency predicts responsiveness to an immune checkpoint blockade with the anti-PD-1 immune checkpoint inhibitor pembrolizumab. CONCLUSIONS: The understanding of primary (de novo) and secondary (acquired) resistance to anti-EGFR therapies, new targeted therapies, immuno-oncology and about predictive biomarkers in mCRC is guiding the development of rational therapeutic strategies. Combinations of targeted therapies are necessary to effectively treat drug-resistant cancers. Liquid biopsy is an upcoming new tool in the primary diagnosis and follow-up analysis of mutations in circulating tumor DNA.
Authors: Tamás Sticz; Anna Molnár; Titanilla Dankó; Zoltán Hujber; Gábor Petővári; Noémi Nagy; Gyula Végső; László Kopper; Anna Sebestyén Journal: Pathol Oncol Res Date: 2018-06-07 Impact factor: 3.201
Authors: Koji Taniguchi; Toshiro Moroishi; Petrus R de Jong; Michal Krawczyk; Britta Moyo Grebbin; Huiyan Luo; Rui-Hua Xu; Nicole Golob-Schwarzl; Caroline Schweiger; Kepeng Wang; Giuseppe Di Caro; Ying Feng; Eric R Fearon; Eyal Raz; Lukas Kenner; Henner F Farin; Kun-Liang Guan; Johannes Haybaeck; Christian Datz; Kang Zhang; Michael Karin Journal: Proc Natl Acad Sci U S A Date: 2017-01-27 Impact factor: 11.205