The Evolving Biomarker Landscape for Treatment Selection in Metastatic Colorectal Cancer

Abstract

The approval of targeted therapies for metastatic colorectal cancer (mCRC) has led to important improvements in patient outcomes. However, it is still necessary to increase individualisation of treatments based on tumour genetic profiles to optimise efficacy, while minimising toxicity. As such, there is currently great focus on the discovery and validation of further biomarkers in mCRC, with many new potential prognostic and predictive markers being identified alongside developments in patient molecular profiling technologies. Here, we review data for validated and emerging biomarkers impacting treatment strategies in mCRC. We completed a structured literature search of the PubMed database to identify relevant publications, limiting for English-language publications published between 1 January 2014 and 11 July 2018. In addition, we performed a manual search of the key general oncology and CRC-focused congresses to identify abstracts reporting emerging mCRC biomarker data, and of ClinicalTrials.gov to identify ongoing clinical trials investigating emerging biomarkers in mCRC and/or molecular-guided clinical trials. There is solid evidence supporting the use of BRAF status as a prognostic biomarker and DYPD, UGT1A1, RAS, and microsatellite instability as predictive biomarkers in mCRC. There are a number of emerging biomarkers that may prove to be clinically relevant in the future to have prognostic (HPP1 methylation), predictive (HER3, microRNAs, anti-angiogenic markers, and CRC intrinsic subtypes), or both prognostic and predictive values (HER2, CpG island methylator phenotype, tumour mutational load, gene fusions, and consensus molecular subtypes). As such, new biomarker-led treatment strategies in addition to anti-epidermal growth factor receptor and anti-angiogenetic treatments are being explored. Biomarkers that are not recommended to be tested in clinical practice or are unlikely to be imminently clinically relevant for mCRC include thymidylate transferase, ERCC1, PIK3CA, and PTEN. We highlight the clinical utility of existing and emerging biomarkers in mCRC and provide recommended treatment strategies according to the biomarker status. An update on ongoing molecular-guided clinical trials is also provided.

Fig. 1

Overview of the main EGFR and VEGF angiogenic signalling cascades. Upon EGFR dimerisation and autophosphorylation, the RAS/BRAF/MEK and PI3K/PTEN/AKT pathways are induced (adapted from [29] under the Creative Commons Attribution License CC BY-NC 3.0 [https://creativecommons.org/licenses/by-nc/3.0/]). Ligand binding to VEGFR-1, VEGFR-2, and VEGFR-3 activates a number of processes that drive angiogenesis. AKT AKR mouse thymoma, BRAF B-rapidly accelerated fibrosarcoma, EGFR epidermal growth factor receptor, ERK extracellular receptor kinase, HER human epidermal growth factor, MEK mitogen-activated protein kinase, mTOR mammalian target of rapamycin, P phosphorylation, PI3K phosphatidylinositol 3-kinase, PIGF phosphatidylinositol-glycan biosynthesis class F, PTEN phosphatase and tensin homolog, RAS rat sarcoma, VEGF vascular endothelial growth factor, VEGFR VEGF receptor

Fig. 2

Possible treatment strategies according to biomarker status in mCRC. ^aWhere maximum tumour shrinkage is the goal; further confirmatory data are needed. Colours indicate possible treatment strategies for tumours with amplified HER2 (pink), mutant BRAF (green), MSI-H (light orange), WT RAS; (yellow) and mutant RAS (orange). Grey shading indicates WT/normal expression/MSS with no treatment recommendations. AMP amplified, B binimetinib, Bev bevacizumab, BRAF B-rapidly accelerated fibrosarcoma, Cmab cetuximab, CT chemotherapy, D dabrafenib, E encorafenib, EGFR epidermal growth factor receptor, FOLFIRI leucovorin, fluorouracil and irinotecan, FOLFOX leucovorin, fluorouracil and oxaliplatin, FOLFOXIRI leucovorin, fluorouracil, irinotecan and oxaliplatin, HER2 human epidermal growth factor 2, Ir irinotecan, L lapatinib, mCRC metastatic colorectal cancer, MSI-H microsatellite instability high, MSS microsatellite stable, MUT mutant, NORM normal, Pmab panitumumab, Pz pertuzumab, RAS rat sarcoma, T trametinib, Tz trastuzumab, V vemurafenib, WT wild type