Enrique Sanz-Garcia

Current and advancing treatments for metastatic colorectal cancer.

Introduction: Colorectal cancer (CRC) is one of the leading causes of cancer deaths worldwide. Despite the introduction of several new drugs targeting the vascular endothelial growth factor or epidermal growth factor receptor (EGFR) signaling pathways, survival and disease control in metastatic CRC remains poor. Areas covered: Chemotherapy based on fluoropyrimidines and irinotecan or oxaliplatin has been the cornerstone of CRC standard of care for several decades. Optimal regimens are selected according to toxicity profiles and patient characteristics. The addition of targeted drugs inhibiting angiogenesis, notably bevacizumab, aflibercept and ramucirumab, has improved chemotherapy outcomes in metastatic CRC. Anti-EGFR agents, cetuximab and panitumumab, in combination with chemotherapy have also improved survival in patients with wild-type RAS tumors. In the refractory setting, there are emerging drugs such as regorafenib or TAS-102 that also have demonstrated impact on outcomes. Expert opinion: Drugs targeting signaling pathways involved in tumorigenesis improve patient outcomes over chemotherapy alone. Determining the most suitable combination and sequence should be carefully selected, with studies yet to provide a definitive solution to this unknown. Molecular mechanisms of colorectal cancer are at the forefront of research. Knowledge in this domain will help overcome resistance to therapies and introduce new drugs in the personalized CRC therapeutic scenario.

Prognosis and Therapeutic Implications for Emerging Colorectal Cancer Subtypes

Although colorectal cancer was one of the first solid tumors to be characterized at the molecular level, a consensus biological classification for researchers and clinicians is lacking. Prognosis and therapy are mainly defined on the basis of patient characteristics and histopathological findings, despite studies showing that, according to mutation and gene-expression profiles, the evolution of colorectal cancer differs substantially, probably because of the high heterogeneity of the disease. In this paper we review the original molecular classifications of colorectal cancer, microsatellite and chromosomal unstable tumors, and more recent attempts to characterize the disease by using intrinsic gene expression clustering methods. These have identified at least three subtypes with different hypermutation, proliferation, and epithelial and mesenchymal features. Furthermore, we discuss preliminary data from evaluation of the potential effect of colorectal cancer subtype on prognosis and treatment response.

Pharmacokinetic and pharmacodynamic evaluation of aflibercept for the treatment of colorectal cancer

Introduction: Colorectal cancer (CRC) is currently one of the most lethal and prevalent tumors worldwide. Prognosis in the metastatic setting remains poor despite therapeutic advances. In addition to chemotherapy, new drugs have recently been developed targeting signaling pathways involved in tumor growth, differentiation and angiogenesis. Aflibercept, a recombinant protein derived from VEGF receptors 1 and 2, also targets this angiogenesis pathway but via a different mechanism, acting as VEGF decoy, thus blocking other VEGFs. Areas covered: A comprehensive review of preclinical studies with aflibercept in cell lines and xenografts of different tumor types is presented. Aflibercept safety, pharmacokinetics and pharmacodynamics data from Phase I studies in solid tumor patients are discussed. Implications of Phase II studies and the pivotal Phase III VELOUR trial of second-line treatment in metastatic CRC (mCRC) patients evaluating aflibercept alone or combined with chemotherapy are also described. Expert opinion: In this challenging field, aflibercept offers a good option for oxaliplatin-refractory mCRC patients when combined with irinotecan and 5-fluorouracil irrespective of prior anti-angiogenic treatment. Therapeutic management may be further advanced by characterization of patients with predictive biomarkers and molecular profiles to improve benefit with this treatment.