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From tumour heterogeneity to advances in precision treatment of colorectal cancer

Key Points

  • Colorectal cancer is a heterogeneous disease, at the intertumoural and intratumoural level, with molecularly-defined subgroups that differ in their prognosis and response to treatment

  • Currently, only DNA mismatch-repair status, RAS-mutation and possibly BRAF-mutation status influence clinical decision-making, although the number of prognostic/predictive biomarkers is increasing

  • A transcriptome-based classification of CRC into four consensus molecular subtypes, which differ in their biology and prognosis, and probably also in their responsiveness to treatment, has been reported

  • International collaborations and innovative study designs are warranted to drive progress in the clinical development of subgroup-specific treatments

Abstract

In recent years, the high heterogeneity of colorectal cancer (CRC) has become evident. Hence, biomarkers need to be developed that enable the stratification of patients with CRC into different prognostic subgroups and in relation to response to therapies, according to the distinctive tumour biology. Currently, only RAS-mutation status is used routinely as a negative predictive marker to avoid treatment with anti-EGFR agents in patients with metastatic CRC, and mismatch-repair status can guide the use of adjuvant chemotherapy in patients with early stage colon cancer. Advances in molecular biology over the past decade have enabled a better understanding of the development of CRC, as well as the more-precise use of innovative targeted therapies for this disease, and include three fundamental achievements. First, the availability of large databases to capture and store the genomic landscape of patients with CRC, providing information on the genes that are frequently deregulated in CRC. Second, the possibility of using gene-expression profiling to differentiate the subtypes of CRC into prognostic groups. Third, results from highly sensitive next-generation sequencing analyses have led to an appreciation of the extensive intratumoural heterogeneity of CRC. Herein, we discuss these advances and place them into the clinical context, and present the novel targets and therapeutic opportunities that are on the horizon.

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Figure 1: Proposed landscape of molecularly targeted treatments for metastatic colorectal cancer.

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Acknowledgements

L.V. is supported by KWF grants (UVA2011-4969 and UVA2014-7245), a Worldwide Cancer Research grant (14–1164), a Maag Lever Darm Stichting grant (MLDS-CDG 14–03), the European Research Council (ERG-StG 638193), and a NWO Vidi grant (917.15.308).

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All authors contributed equally to researching data, discussing the article content, writing, revising and editing the manuscript before submission.

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Correspondence to Cornelis J. A. Punt.

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C.J.A.P. has an advisory role for Servier and Nordic Pharma. M.K. has an advisory role for Servier. L.V. declares no competing interests.

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Punt, C., Koopman, M. & Vermeulen, L. From tumour heterogeneity to advances in precision treatment of colorectal cancer. Nat Rev Clin Oncol 14, 235–246 (2017). https://doi.org/10.1038/nrclinonc.2016.171

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