Biomarker-guided therapy for colorectal cancer: strength in complexity

Abstract

The number of molecularly stratified treatment options available to patients with colorectal cancer (CRC) is increasing, with a parallel rise in the use of biomarkers to guide prognostication and treatment decision-making. The increase in both the number of biomarkers and their use has resulted in a progressively complex situation, evident both from the extensive interactions between biomarkers and from their sometimes complex associations with patient prognosis and treatment benefit. Current and emerging biomarkers also reflect the genomic complexity of CRC, and include a wide range of aberrations such as point mutations, amplifications, fusions and hypermutator phenotypes, in addition to global gene expression subtypes. In this Review, we provide an overview of current and emerging clinically relevant biomarkers and their role in the management of patients with CRC, illustrating the intricacies of biomarker interactions and the growing treatment opportunities created by the availability of comprehensive molecular profiling.

Key points

  • The expanded use of biomarkers to guide the treatment of patients with colorectal cancer has revealed a level of complexity arising from interactions between different biomarkers.

  • An improved understanding of the causes of primary resistance might increase response rates among patients receiving targeted therapies and enable more-effective drug combinations, exemplified by mutations in the MAPK signalling pathway for EGFR-targeted and/or BRAF-targeted therapies.

  • Immune checkpoint inhibition has provided the largest contribution to the increased use of molecularly guided therapies, and biomarkers that complement patient stratification by microsatellite instability status are likely to provide further benefit.

  • Biomarkers that indicate a poor prognosis have motivated the search for more effective therapies for specific molecular subgroups; these biomarkers typically have a limited prevalence, but their accumulation could expand the eligibility for, and benefit from, targeted treatment.

  • Some colorectal cancers harbour more than one molecular target and treatment sequencing in relation to both standard and targeted therapies is a growing challenge.

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Fig. 1: Clinical implications of biomarker interactions in CRC.
Fig. 2: Optimization of immunotherapy in CRC.
Fig. 3: Treatment options and biomarker interactions in metastatic CRCs.

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Acknowledgements

This work was supported by grants from the Norwegian Cancer Society (project numbers 6824048–2016 and 182759–2016), the Research Council of Norway (project number 250993), South-Eastern Norway Regional Health Authority (project numbers 2016123 and 2017102) and the NIH (project numbers R01 CA218230, R01 CA184843 and R01 CA187238).

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Correspondence to Anita Sveen.

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A.S. and R.A.L. are co-inventors of a pending patent application (Attorney Docket Number: INVEN-35063/US-1/PRO) regarding the use of HSP90 inhibitors in relation to the consensus molecular subtypes of colorectal cancer. S.K. is a co-inventor of a pending patent application regarding a clinical classifier for the consensus molecular subtypes of colorectal cancer.

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Sveen, A., Kopetz, S. & Lothe, R.A. Biomarker-guided therapy for colorectal cancer: strength in complexity. Nat Rev Clin Oncol 17, 11–32 (2020). https://doi.org/10.1038/s41571-019-0241-1

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