Abstract
The development of personalised therapy and mechanism-targeted agents in oncology mandates the identification of the patient populations most likely to benefit from therapy. This paper discusses the increasing evidence as to the heterogeneity of the group of diseases called colorectal cancer. Differences in the aetiology and epidemiology of proximal and distal cancers are reflected in different clinical behaviour, histopathology, and molecular characteristics of these tumours. This may impact response both to standard cytotoxic therapies and mechanism-targeted agents. This disease heterogeneity leads to challenges in the design of clinical trials to assess novel therapies in the treatment of “colorectal cancer.”
Highlights
Incremental improvements in the outcome of patients with metastatic colorectal cancer have been seen over the last 20 years as initially new cytotoxic agents, and more recently agents targeting the biological abnormalities of the cancer (mechanism-targeted agents (MTAs)) are integrated into routine clinical practice [1]
Most colorectal cancers are histologically classified as adenocarcinomas, which can be further stratified according to the grade of the tumour, which is related to subsequent prognosis
This CIMP-associated MSI-H molecular phenotype is more commonly found in patients over 70, in women, in proximal cancers and is associated with B-Raf mutations (63.5% in this population versus 5% in chromosomal instability (CIN) cancers and 1% in Lynch syndrome cancers [41])
Summary
Incremental improvements in the outcome of patients with metastatic colorectal cancer have been seen over the last 20 years as initially new cytotoxic agents, and more recently agents targeting the biological abnormalities of the cancer (mechanism-targeted agents (MTAs)) are integrated into routine clinical practice [1]. Improving the classification of CRC may enable better estimation of prognosis and identify the patients most likely to respond to novel targeted agents This change in approach from selecting therapy purely on the basis of the primary site of origin to a more stratified approach has perhaps best been exemplified by work done in the treatment of breast cancer [2]. Similar advances have been made in the molecular classification of other cancers (e.g., nonsmall cell lung cancer, diffuse large B-cell lymphoma [4, 5]) and is being advocated in the treatment of CRC [6] This obviously has important implications in the design and interpretation of trials of novel therapeutics in these areas. This paper will discuss the advances that have been made in anatomical, histological, and molecular classification of CRC and the potential impact on trial design of novel therapeutics
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