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Review
. 2020 Jul 24:12:1758835920936089.
doi: 10.1177/1758835920936089. eCollection 2020.

Molecular subtypes and the evolution of treatment management in metastatic colorectal cancer

Giulia Martini  1 , Rodrigo Dienstmann  2 , Javier Ros  3 , Iosune Baraibar  3 , Jose Luis Cuadra-Urteaga  3 , Francesc Salva  3 , Davide Ciardiello  1 , Nuria Mulet  3 , Guillem Argiles  4 , Josep Tabernero  5 , Elena Elez  6
Affiliations
Review

Molecular subtypes and the evolution of treatment management in metastatic colorectal cancer

Giulia Martini et al. Ther Adv Med Oncol. .

Abstract

Colorectal cancer (CRC) is a heterogeneous disease representing a therapeutic challenge, which is further complicated by the common occurrence of several molecular alterations that confer resistance to standard chemotherapy and targeted agents. Mechanisms of resistance have been identified at multiple levels in the epidermal growth factor receptor (EGFR) pathway, including mutations in KRAS, NRAS, and BRAF V600E, and in the HER2 and MET receptors. These alterations represent oncogenic drivers that may co-exist in the same tumor with other primary and acquired alterations via a clonal selection process. Other molecular alterations include DNA damage repair mechanisms and rare kinase fusions, potentially offering a rationale for new therapeutic strategies. In recent years, genomic analysis has been expanded by a more complex study of epigenomic, transcriptomic, and microenvironment features. The Consensus Molecular Subtype (CMS) classification describes four CRC subtypes with distinct biological characteristics that show prognostic and potential predictive value in the clinical setting. Here, we review the panorama of actionable targets in CRC, and the developments in more recent molecular tests, such as liquid biopsy analysis, which are increasingly offering clinicians a means of ensuring optimal tailored treatments for patients with metastatic CRC according to their evolving molecular profile and treatment history.

Keywords: EGFR; RAS; biomarkers; colorectal cancer; molecular classification.

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Conflict of interest statement

Conflict of interest statement: GM, IB, JR, CD, JC, FS, NM declare no conflict of interest. RD: advisory role for Roche; speaker’s fees from Roche, Symphogen, Ipsen, Amgen, Sanofi, MSD, Servier; and direct research funding from Merck. GA: personal financial interests, honoraria for advisory roles, travel grants, research grants (past 5 years) from Hoffman La-Roche, Bristol-Myers Squibb, Bayer, Servier, Amgen, Merck Serono, Menarini; institutional financial interests, honoraria due to investigator contributions to clinical trials from Hoffman La-Roche, Novartis, Boehringer Ingelheim, Boston Pharmaceuticals, Hoffman La Roche, Genentech. JT: personal financial interest in the form of scientific consultancy roles for Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, F. Hoffmann-La Roche Ltd, Sanofi, SeaGen, Seattle Genetics, Servier, Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation Medicine, HalioDX SAS and Roche Diagnostics; institutional financial interest in the form of financial support for clinical trials or contracted research for Agendia BV, Amgen SA, Debiopharm International SA, Janssen-Cilag SA, Mologen AG, Novartis Farmacéutica SA, Pharma Mar, Roche Farma SA, Laboratorios Servier SL and Symphogen A/S. EE: personal financial interests, honoraria for advisory roles, travel grants, research grants (past 5 years) from Hoffman La-Roche, Sanofi Aventis, Amgen, Merck Serono, Servier, MSD, Array Pharmaceuticals, Bristol-Myers Squibb; institutional financial interests, honoraria due to investigator contribution in clinical trials from Hoffman La-Roche, Sanofi Aventis, Amgen, Merck Serono, MSD, Boehringer Ingelheim, AbbVie, Array Pharmaceuticals, Pierre-Fabre, Novartis, Bristol-Myers Squibb, GlaxoSmithKline, Medimmune.

Figures

Figure 1.
Figure 1.
Triple anti-EGFR/BRAF/MEK combination in the BEACON trial. EGFR, epidermal growth factor receptor.
Figure 2.
Figure 2.
Recent anti-HER2 strategies in mCRC. MET tyrosine kinase receptor activation and overexpression have been investigated as a potential mechanism of both primary and acquired resistance to anti-EGFR treatment and BRAF inhibitor combinations in BRAFV600E mutant CRC. Data from in vitro and in vivo studies have shown that CRC xenograft models with MET amplification do not respond to anti-EGFR antibodies. MET amplifications have been found in only a small percentage (1–2%) of the CRC population upfront, but a study found that using NGS liquid biopsies in an anti-EGFR refractory setting the prevalence of MET amplification could rise to 20%. Preliminary studies with MET inhibitors such as SYM015 suggest the resistance could be overcome, with a clear implication for ongoing clinical trials currently exploring these agents. CRC, colorectal cancer; EGFR, epidermal growth factor receptor; mCRC, metastatic colorectal cancer; NGS, next-generation sequencing.
Figure 3.
Figure 3.
CMS classification. CIN, chromosomal instability; CMS, consensus molecular subtypes; DC, dendritic cell; EGFR, epidermal growth factor receptor; MSDC, Myeloid-derived suppressor cells; MSI, microsatellite instability; MSS, microsatellite stability; NK, natural killer; PD-1, programmed cell death protein 1; TGF-β, transforming growth factor beta, Tregs, regulatory T cells.
See this image and copyright information in PMC

References

    1. Dienstmann R, Vermeulen L, Guinney J, et al. Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer. Nat Rev Cancer 2017; 17: 79–92. - PubMed
    1. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990; 61: 759–767. - PubMed
    1. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012; 487: 330–337. - PMC - PubMed
    1. Fakih M, O’Neil B, Price TJ, et al. Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRAS G12C inhibitor, in advanced solid tumors. J Clin Oncol 2019; 37(Suppl. 15): 3003.
    1. Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 2019; 575: 217–223. - PubMed