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ABSTRACT
Introduction: Outcomes in metastatic colorectal cancer are improving, due to the tailoring of therapy enabled by better understanding of clinical behavior according to molecular subtype.
Areas covered: A review of the literature and recent conference presentations was undertaken on the topic of systemic treatment of metastatic colorectal cancer. This review summarizes expert discussion of the current evidence for therapies in metastatic colorectal cancer (mCRC) based on molecular subgrouping.
Expert opinion: EGFR-targeted and VEGF-targeted antibodies are now routinely incorporated into treatment strategies for mCRC. EGFR-targeted antibodies are restricted to patients with extended RAS wild-type profiles, with evidence that they should be further restricted to patients with left-sided tumors. Clinically distinct treatment pathways based on tumor RAS, BRAF, HER2 and MMR status, are now clinically applicable. Evidence suggests therapy for additional subgroups will soon be defined; the most advanced being for patients with KRAS G12 C mutation and gene TRK fusion defects.
Article Highlights
The treatment strategy for advanced colorectal cancer should include early molecular assessment and multidisciplinary review to determine the optimal systemic options and also the potential for resection of metastasis.
Site of primary is now accepted by a number of guidelines (NCCN, ESMO and Australian NHMRC) as a guide to treatment choice in RAS WT mCRC, with left-sided tumours best treated with an anti-EGFR/chemotherapy combination, and right-sided tumours with bevacizumab/chemotherapy combination
Mismatch repair (MMR) status should be routinely tested in mCRC patients as MMR deficiency predicts benefit from immune checkpoint inhibitors in the treatment-refractory setting with the question remaining re timing and single agent versus combinations.
Patients with BRAF mutations should be considered for combination therapy with anti-EGFR/BRAF ± MEK; the optimal sequencing with other therapies remains unclear
HER2 amplifications may be amenable to treatment with molecularly targeted agents, pending further clinical trial evidence.
New targets such as KRAS G12C and NTRK fusions may lead to further options and improved outcomes.
Circulating tumour DNA (ctDNA) allows real time tumour mutational and burden monitoring and may better inform clinical decision making.
Currently there is evidence that mCRC could be divided into at least 6 distinct clinical/molecular subgroups which have distinct treatment pathways; 1. Left sided RAS WT, 2. Right sided RAS WT, 3. RAS MT, 4. BRAF MT, 5. HER2 over expressed, and 6. dMMR (noting some cross over with BRAF MT).
Acknowledgments
This review represents independent research supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.
Declaration of Interest
David K Lau is the recipient of the Australasian Gastro-Intestinal Trials Group/Merck Clinical Research Fellowship.
Timothy J Price has served on the advisory boards for Merck, Amgen and Roche.
Matthew Burge has served in a consulting and advisory role with Amgen, Roche and Ipsen; received honoraria from Roche, Amgen, Merck KGaA, Servier, Merck Sharp & Dohme; and travel support from Bristol Myers Squibb and Amgen.
Ian Chau has served on advisory boards for AstraZeneca, Bayer, Bristol Myers Squibb, Eli-Lilly, Five Prime Therapeutics, Merck Serono, MSD, Pierre Fabre, Oncologie International and Roche; received research funding from Eli-Lilly, Janssen-Cilag, Merck Serono and Sanofi Oncology and honoraria from Eli Lilly.
Daniel G Haller has served on a speaker’s bureau for Lilly, Amgen and Exilixis.
Jeremy D Shapiro has received travel support from Amgen and Merck Serono.
Marc Peeters has served in a consulting and advisory role, received honoraria and travel support from Servier.
Nick Pavlakis has served on the advisory board for Merck, Roche and Amgen.
Christos S Karapetis has received honoraria from Merck Sharpe & Dohme, and served in a consulting or advisory role with Amgen, AstraZeneca, Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme and Roche.
Niall C Tebbutt has received honoraria from Amgen, Bristol Myers Squibb, Eisai, Merck Sharpe & Dohme and Roche; served in a consulting and advisory role with Amgen, Bristol Myers Squibb, Eisai, Merck Sharpe & Dohme and Roche; and travel support from Bayer and Roche.
Eva Segelov has served in a consulting or advisory role with Ipsen, Merck Sharpe & Dohme; and received travel support from Amgen and Roche.
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.