The role of personalized medicine in metastatic colorectal cancer: an evolving landscape

Abstract

Advances in the treatment of metastatic colorectal cancer have led to an improvement in survival from 12 months with fluorouracil monotherapy to approximately 2 years. This is partly as a result of the addition of irinotecan and oxaliplatin, but is also due to the use of monoclonal antibodies against the epidermal growth factor receptor (EGFR) and antiangiogenic drugs such as bevacizumab. However, there are significant molecular differences between tumours which can affect both prognosis and response to treatment. Personalized medicine aims to tailor treatment according to the characteristics of the individual patient and is now a clinical reality as testing for KRAS mutations to guide treatment with the anti-EGFR monoclonal antibodies cetuximab and panitumumab is now part of routine clinical practice. However, not all patients who are KRAS wild type respond to anti-EGFR therapy and a validated biomarker for antiangiogenic therapy is still lacking. Therefore, other biomarkers are needed to assist with predicting response to both existing drugs as well as to drugs currently under investigation. This review summarizes the molecular biology of colorectal cancer, focusing on the genetic features that are currently most clinically relevant. Current and emerging biomarkers are reviewed along with their roles in selecting patients for targeted treatment with currently licensed therapies and drugs being evaluated in clinical trials. The value of predictive biomarkers of chemosensitivity and potential future treatment strategies are also discussed.

Keywords: biomarker; colorectal cancer; personalized medicine; targeted therapy.

Figure 1.

Cell signalling pathways in colorectal cancer. AKT, protein kinase B; APC, adenomatous polyposis coli; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; Fz, Frizzled receptor; HER2, human epidermal growth factor receptor 2; IGF, insulin-like growth factor; mTOR, mammalian target of rapamycin; MEK, mitogen-activated protein kinase kinase; MYC, v-myc myelocytomatosis viral oncogene homolog (avian); PI3K, phosphoinositol 3 kinase; PTEN, phosphatase and tensin homolog; TCF, T cell factor; VEGF, vascular endothelial growth factor.