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Progress towards individualized treatment of colorectal cancer

Cncer Colorrectal
Colorectal cancer is a leading cause of cancer death worldwide. In the last decade, the median of survival has increased significantly with the introduction of new chemotherapy and biological therapies. Researchers from the Institut d'Oncologia Vall d'Hebron working on molecular identification of predictive factors (such as mutations in KRAS gene, involved in the action of epithelial growth factor) before the selection of chemotherapy, which is going to lead us to the paradigm of individualized treatment of colorectal cancer.

Colorectal cancer is one of the leading causes of cancer mortality worldwide. In the last decade, median overall survival has increased significantly with the introduction of new cytotoxics and biologic therapies. Notably, the definition of molecular markers predicting benefit with epidermal growth factor receptor (EGFR)-targeted agents has led to important advances in the personalized treatment o colorectal cancer.

Data derived from multiple trials have indicated that KRAS mutations can be considered a highly specific negative biomarker of response to anti-EGFR monoclonal antibodies (MoAb). In the first-line setting, retrospective analysis of phase II and III trials comparing standard 5-fluorouracil-based chemotherapy and oxaliplatin or irinotecan with the addition of cetuximab or panitumumab confirmed that the benefit of the MoAb was restricted to patients with KRAS wild-type tumors.

Patients with chemorefractory disease also have survival advantage with EGFR-targeting agents only if KRAS mutation is not found. Importantly, KRAS mutation status concordance between primary tumors and metastatic sites is higher than 90% in multiple series. In addition, there is compelling evidence of the bad prognostic factor of BRAF mutations in colorectal cancer but the predictive value of these mutations for lack of benefit with anti-EGFR MoAbs in the first-line treatment of advanced colorectal cancer has not been demonstrated so far. The predictive value of additional mutations and deregulations of the signalling pathways downstream of the EGFR such as NRAS, PIK3CA or PTEN loss of expression is under intensive investigation.

Prevalence of deregulation of the EGFR pathway and response to monoclonal antibodies that inhibit EGFR in colorectal cancer refractory to standard chemotherapy. With the molecular analysis can identify the subset of patients (15%) having benefit with the use of this therapy (without mutations in KRAS, BRAF, NRAS, PIK3CA or PTEN loss).

Although attempts to identify predictive factors for efficacy to antiangiogenic therapies have been disappointing, further research on this field will maximize their therapeutic index. Candidate on-treatment biomarkers include changes in imaging parameters (perfusion guided magnetic resonance), decrease in circulating endothelial cells and changes in particular circulating measures, such as vascular endothelial growth factor (VEGF).

In addition, status of microsatellite instability (MSI) and molecular markers related to the metabolism of chemotherapy agents has shown promising ability to select patients with higher chances of response to cytotoxic agents. Microsatellite unstable
colorectal cancer cases do not extract any improvement in terms of disease-free or overall survival with adjuvant 5-fluorouracil-based chemotherapy when compared with patients treated with surgery alone. In fact, this treatment in patients with stage II colorectal cancer and MSI tumors could have a detrimental effect.

In the recent years, the predictive value of genomic signatures for benefit of adjuvant chemotherapy in localized
colorectal cancer is being investigated. Different platforms have demonstrated that multigene assays can better quantify the risk of recurrence as compared to conventional clinicopathologic criteria. Further prospective validation studies are of utmost need in this field. To conclude, it is clear that determination of molecular predictive factors before selection of chemotherapy is rapidly approaching us to the paradigm of individualized treatment of colorectal cancer.

Rodrigo Dienstmann
Institut d'Oncologia de la Vall d'Hebron
Unitat de Recerca en Terpia Molecular


"Molecular predictors of response to chemotherapy in colorectal cancer."Dienstmann R, Vilar E, Tabernero J. Cancer J. 2011 Mar-Apr;17(2):114-26.

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