Patient-Tailored Treatments with Anti-EGFR Monoclonal Antibodies in Advanced Colorectal Cancer: KRAS and Beyond

Abstract

Personalized medicine emphasizes the practice of considering individual patient characteristics as opposed to that centered on standards derived from epidemiological studies which, by definition, do not take into account the variability of individuals within a given population. When applied to oncology, personalized medicine is an even more complex concept because it extends the variability beyond the individual patient to the individual tumor. Indeed, the great genotypic and phenotypic variability (both in primary and metastatic sites of cancer) the development of targeted therapies, and the growing availability of biological assays complicate the scenario of personalized medicine in the oncological field. In this paper we review the results of anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) therapy in metastatic colorectal cancer (mCRC) in the context of tumor biology, delineating the future prospects of patient-tailored medicine in this area. In particular, we deal with EGFR inhibition by Cetuximab, a chimeric mouse human IgG1 mAb, and panitumumab, a fully human IgG2 mAb. We discuss the clinical impact of anti-EGFR mAbs on wild-type (WT) KRAS mCRC, also taking into account the feasibility of novel multi-marker approaches to treatment decision-making, aimed at increasing the predictive power of pre-therapy biomarkers. Experimental topics and fields of ongoing research, such as targeting microRNAs (miRNAs) with novel anticancer drugs and epigenetics in CRC are also addressed.

Comparative Study of 17-AAG and NVP-AUY922 in Pancreatic and Colorectal Cancer Cells: Are There Common Determinants of Sensitivity?

“…These types of cancer are highly dependent on the epidermal growth factor receptor (EGFR) signaling pathway. Overexpression of EGFR is common in pancreatic adenocarcinoma [31] and novel therapies in metastatic colorectal cancer include antibodies targeted against the EGFR, such as panitumumab and cetuximab [32]. EGFR belongs to the HER family of transmembrane tyrosine kinase receptors, which include HER2 (ErbB2/Neu), HER3 (ErbB3), and HER4 (ErbB4).…”

Response of the Insulin-Like Growth Factor (IGF) System to IGF-IR Inhibition and Androgen Deprivation in a Neoadjuvant Prostate Cancer Trial: Effects of Obesity and Androgen Deprivation

“…One fundamental limitation of failed clinical trials is the inability to determine the basis for the lack of efficacy. As strikingly demonstrated in the cases of the targeted agents gefitinib for lung cancer and panitumumab or cetuximab for colon cancer, the likelihood of efficacy is strongly predicted by the presence of epidermal growth factor receptor (gefitinib) or K-Ras (panitumumab and cetuximab) mutations, respectively (37,38). This need for patient selection is likely inherent to the specificity of these targeted agents, compared to the less selective effects of traditional chemotherapy agents.…”

Reciprocal regulation between microRNAs and epigenetic machinery in colorectal cancer

“…Evidence has demonstrated that miRNAs act either as tumour suppressors by suppressing the expression of target oncogenes, or as proto-oncogenes by inhibiting the expression of tumour suppressor genes (TSGs) (21)(22)(23)(24). Both effects correlate with cancer development and its progression in CRC (11,25,26).…”