Review Article | Published:

Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer

Nature Reviews Cancer volume 17, pages 7992 (2017) | Download Citation

  • A Corrigendum to this article was published on 23 March 2017

This article has been updated

Abstract

Critical driver genomic events in colorectal cancer have been shown to affect the response to targeted agents that were initially developed under the 'one gene, one drug' paradigm of precision medicine. Our current knowledge of the complexity of the cancer genome, clonal evolution patterns under treatment pressure and pharmacodynamic effects of target inhibition support the transition from a one gene, one drug approach to a 'multi-gene, multi-drug' model when making therapeutic decisions. Better characterization of the transcriptomic subtypes of colorectal cancer, encompassing tumour, stromal and immune components, has revealed convergent pathway dependencies that mandate a 'multi-molecular' perspective for the development of therapies to treat this disease.

Key points

  • Molecular alterations fostering the progression of colorectal cancers are acquired early in the carcinogenesis process, and there is inter-connectivity among genomic drivers (gene mutations and chromosomal instability), transcriptomic subtypes (microsatellite instability immune, canonical, metabolic or mesenchymal) and immune signatures (highly immunogenic, poorly immunogenic or inflamed and immune tolerant).

  • Primary and metastatic samples display major similarities at the genomic level: novel gene alterations are usually related to chemotherapy or targeted therapy pressure. More studies on inter-metastatic spatial heterogeneity, molecular shifts at the transcriptomic level and changes in microenvironment markers are needed.

  • Until recently, the evolution of biomarkers for targeted therapies in colorectal cancer has been restrictive, with the identification of multiple negative predictive factors determining the response to epidermal growth factor receptor (EGFR) monoclonal antibodies. At progression to these agents, there is convergent reactivation of MAPK pathway

  • Emerging positive predictive markers for targeted therapies include infrequent genomic events, such as BRAFV600E mutations, ERBB2 amplifications, anaplastic lymphoma kinase (ALK) and neurotrophic receptor tyrosine kinase (NTRK) fusions and alterations in upstream nodes of the WNT pathway, such as ring finger protein 43 (RNF43), zinc and ring finger 3 (ZNRF3) and R-spondin (RSPO) genes. For immune checkpoint inhibitors, promising biomarkers include microsatellite instability and DNA polymerase-ε (POLE) mutations

  • Biomarker–drug co-development has evolved to accommodate a 'multi-molecular, multi-drug' perspective of precision medicine. Novel contexts of vulnerability are likely to be identified, leading to drug-repurposing strategies and combination therapies to halt tumour evolution and tackle minimal residual disease.

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Change history

  • 06 March 2017

    In this article a source of grant funding for one of the authors was omitted from the Acknowledgements section. The online version of the article has been corrected to include: "The work of R.D. was supported by the Grant for Oncology Innovation under the project 'Next generation of clinical trials with matched targeted therapies in colorectal cancer'".

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Acknowledgements

R.D. and J.T. acknowledge the FERO Foundation for supporting research in gastrointestinal malignancies and the Cellex Foundation for providing research facilities and equipment. The work of R.D., S.T. and J.T. was supported by the European Union's Horizon 2020 research and innovation programme 2014–2020 under grant agreement number 635342 (MoTriColor project). The work of S.T. was supported by the University of Leuven (grant GOA/12/2106), the Research Foundation Flanders and the Belgian National Cancer Plan. The work of L.V. was supported by grants from KWF Kankerbestrijding (Dutch Cancer Society) (UVA2014-7245), the European Research Council (ERG-StG 638193) and the Netherlands Organisation for Health Research and Development (Vidi 016.156.308). The work of J.G. was supported by grant U54CA149237 from the US National Cancer Institute. The work of S.C. was supported by the generous philanthropic contributions to the University of Texas MD Anderson Moon Shots Program and Cancer Center Sipport Grants grant 3 P30 CA016672 41. The work of R.D. was supported by the Grant for Oncology Innovation under the project 'Next generation of clinical trials with matched targeted therapies in colorectal cancer'.

Author information

Affiliations

  1. Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona 08035, Spain.

    • Rodrigo Dienstmann
    •  & Josep Tabernero
  2. Sage Bionetworks, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, WA 98109, Seattle, USA.

    • Rodrigo Dienstmann
    •  & Justin Guinney
  3. Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, 1012 WX Amsterdam, The Netherlands.

    • Louis Vermeulen
  4. The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, Texas 77030, USA.

    • Scott Kopetz
  5. Digestive Oncology Unit, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.

    • Sabine Tejpar

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Rodrigo Dienstmann.

Glossary

Early-stage

Tumours that remain localized and have not spread to other parts of the body.

Advanced-stage

Tumours that became metastatic and have spread to other parts of the body.

Sporadic background

Tumours that have no identifiable inherited gene involved in the carcinogenesis process.

Sessile serrated adenomas

Pre-malignant flat (or sessile) polyps, predominantly seen in the right side of the colon. They have been identified as the main precursor lesion in the serrated carcinogenesis process.

Desmoplastic reaction

At histopathological examination, pervasive growth of dense fibrous connective tissue around the tumour.

Trabecular

At histopathological examination, tumours composed of cells structured in a nested pattern.

Mucinous

At histopathological examination, tumours characterized by abundant extracellular accumulation of mucus bound to neoplastic epithelium or stroma.

Papillary

At histopathological examination, tumours demonstrating prominent papillae with fibrovascular cores.

Late-stage neoplasms

Localized tumours that have grown more deeply into nearby tissue or have spread to regional lymph nodes.

Rechallenge

Reintroduction of the same therapy after a drug holiday following disease progression during therapy.

Metachronous disease

Tumours that became metastatic after the diagnosis and treatment of localized disease (usually later than 6 months).

Selective sweeps

These occur when a rare or previously non-existing allele that increases the fitness of the cell — relative to other clonal populations — expands rapidly in frequency as a result of natural selection.

Underpowered

A study with low statistical power of detecting a true effect of practical importance.

Caecum

The first segment of the right colon, an intraperitoneal pouch that connects the ileum with the ascending colon.

Splenic flexure

The first segment of the left colon, a sharp bend under the spleen where the transverse colon joins the descending colon.

Adjuvant

Therapy applied after initial surgical treatment for cancer to avoid tumour relapse.

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DOI

https://doi.org/10.1038/nrc.2016.126

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