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06-12-2016 | Colorectal cancer | Article

From tumour heterogeneity to advances in precision treatment of colorectal cancer

Authors:
Cornelis J. A. Punt, Miriam Koopman, Louis Vermeulen

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.

Nat Rev Clin Oncol 2017;14: 235–246. doi:10.1038/nrclinonc.2016.171

Subject terms: Colorectal cancer • Combination drug therapy • Tumour heterogeneity

The progressive development of colorectal cancer (CRC) provides a model of tumour development1, 2, 3, 4. CRC is a heterogeneous and molecularly complex disease. Importantly, it has become clear that developments in molecular staging add clinically relevant prognostic and predictive information to the classic staging system, in which patient with CRC can be classified into four different prognostic groups based on the extent of the primary tumour, the involvement of regional lymph nodes, and the presence/absence of distant metastases. The consequences of this complexity for clinical management of CRC are beginning to materialize. Currently, molecular staging has identified patient subgroups that benefit from novel treatments, as well as subgroups that do not benefit from treatments that were previously considered as standard. In this Review, we will discuss the advances our understanding of CRC development, and the current implications of CRC heterogeneity on diagnosis and treatment of the disease.

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