ABSTRACT
Immunotherapy has demonstrated a role in the therapeutic landscape of a small subset of patients with colorectal carcinoma (CRC) that harbor a microsatellite instability (MSI-H) status due to a deficient DNA mismatch repair (dMMR) system. The remarkable responses to immune checkpoint inhibitors (ICIs) are now being tested in the neoadjuvant setting in localized CRC, where the dMMR/MSI-H status can be found in up to 15% of patients, with remarkable results obtained in NICHE2 and 3 trials, among others. This case series aims to report our experience at a tertiary center and provide a comprehensive analysis of the possible questions and challenges to overcome if ICIs were established as standard of care in a neoadjuvant setting, as well as the potential role they may have as conversion therapy not only in locoregional advanced CRC but also in oligometastatic disease.
Subject(s)
Colorectal Neoplasms , Microsatellite Instability , Humans , Immunotherapy , Research , Neoadjuvant Therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/therapyABSTRACT
Colorectal cancer (CRC) is the third most frequent cancer and the second most common cause of cancer-related death in Europe. High microsatellite instability (MSI-H) due to a deficient DNA mismatch repair (dMMR) system can be found in 5% of metastatic CRC (mCRC) and has been established as a biomarker of response to immunotherapy in these tumors. Therefore, immune checkpoint inhibitors (ICIs) in mCRC with these characteristics were evaluated with results showing remarkable response rates and durations of response. The majority of mCRC cases have high levels of DNA mismatch repair proteins (pMMR) with consequent microsatellite stability or low instability (MSS or MSI-low), associated with an inherent resistance to ICIs. This review aims to provide a comprehensive analysis of the possible approaches to overcome the mechanisms of resistance and evaluates potential biomarkers to establish the role of ICIs in pMMR/MSS/MSI-L (MSS) mCRC.
ABSTRACT
Tyrosine kinase receptors (TKR) comprise more than 60 molecules that play an essential role in the molecular pathways, leading to cell survival and differentiation. Consequently, genetic alterations of TKRs may lead to tumorigenesis and, therefore, cancer development. The discovery and improvement of tyrosine kinase inhibitors (TKI) against TKRs have entailed an important step in the knowledge-expansion of tumor physiopathology as well as an improvement in the cancer treatment based on molecular alterations over many tumor types. The purpose of this review is to provide a comprehensive review of the different families of TKRs and their role in the expansion of tumor cells and how TKIs can stop these pathways to tumorigenesis, in combination or not with other therapies. The increasing growth of this landscape is driving us to strengthen the development of precision oncology with clinical trials based on molecular-based therapy over a histology-based one, with promising preliminary results.
Subject(s)
Neoplasms/metabolism , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/metabolism , Anaplastic Lymphoma Kinase/metabolism , Carcinogenesis , ErbB Receptors/metabolism , Humans , Immunotherapy , Ligands , Neovascularization, Pathologic , Phosphorylation , Precision Medicine , Protein-Tyrosine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-kit/metabolism , Receptor, ErbB-2/metabolism , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Receptor, trkA/metabolism , Signal TransductionABSTRACT
Thyroid cancer represents a heterogenous disease whose incidence has increased in the last decades. Although three main different subtypes have been described, molecular characterization is progressively being included in the diagnostic and therapeutic algorithm of these patients. In fact, thyroid cancer is a landmark in the oncological approach to solid tumors as it harbors key genetic alterations driving tumor progression that have been demonstrated to be potential actionable targets. Within this promising and rapid changing scenario, current efforts are directed to improve tumor characterization for an accurate guidance in the therapeutic management. In this sense, it is strongly recommended to perform tissue genotyping to patients that are going to be considered for systemic therapy in order to select the adequate treatment, according to recent clinical trials data. Overall, the aim of this article is to provide a comprehensive review on the molecular biology of thyroid cancer focusing on the key role of tyrosine kinases. Additionally, from a clinical point of view, we provide a thorough perspective, current and future, in the treatment landscape of this tumor.
