Hgfr And Fgr2: Their Roles 1 In Progression And Metastasis Of Esophageal Cancer

Esophageal cancer (EC) is the sixth leading cause of malignancy-related death in the world. The disease is characterized by two types of histologies: esophageal squamous cell cancer (ESCC) and esophageal adenocarcinoma (EAC), which are the most common in the Western world. While alcohol has proven to lead to ESCC, it has not been associated with EAC. Progressive dysphagia (first with solids, followed by liquids) and rapid involuntary weight loss are the two most common symptoms, which make most patients seek medical attention. Most patients have a long period of symptoms before they seek care. At diagnosis, ~50% of the patients already have metastasis. The treatment of gastroesophageal cancers continues to pose significant clinical challenges for various defined reasons. The majority of patients fail intensive and toxic multimodality therapy for locoregional disease, and systemic chemotherapy for metastatic carcinoma gives short-term benefits only. Our understanding of the molecular pathology of gastroesophageal cancers has considerably increased during the recent years, leading to the development of novel targeted therapeutic agents that have proven to be promising in improving the patients’ survival with minimal adverse events. Receptor tyrosine kinases (RTKs) play pivotal role(s) in the formation, maintenance, growth, and differentiation of the malignant cells encompassing both histological types of EC. Malignancies treated with chemotherapy/radiation therapy face the challenge of developing resistance and increasing the aggressive nature of cancerous cells leading to undesirable recurrence. In peer-reviewed literature, an array of RTKs have been described in ESCC, and more recently, they are being assessed for their therapeutic utility. Notably, structures of hepatocyte growth factor receptor (HGFR) and fibroblast growth factors receptor 2 (FGR2) are two of the many prominent RTKs studies thus far. In this chapter, we thoroughly discuss the clinical characteristics of the disease and structure-functional aspects of various RTKs with focus on HGFR and FGR2 as it relates to the translational and clinical outcomes of EC

Functional Consequences And Clinical Significance Of Tyrosine Kinase Inhibitors In Advanced Colorectal Cancer

Colorectal cancer (CRC) is an important public health issue as the 5-year prognosis is \u3c20% for newly diagnosed metastatic CRC (mCRC). In recent years, screening modalities have led to early detection of the disease, which has shown some promise for improved survival. The advancements in adjunctive treatments and aggressive surgical treatment are also partly responsible for this success, but the deeper understanding of carcinogenesis and targeted molecular therapy has made a stronger impact with the emergence of newer targets in the recent past. Particularly, the development and FDA approval of newer drugs, including capecitabine, irinotecan, oxaliplatin, monoclonal antibodies that block either VEGF (bevacizumab, aflibercept, and ramucirumab) or the EGFR (cetuximab and panitumumab), and most recently, trifluridine/tipiracil and regorafenib (TAS-102), have been remarkable in this area of research. The clinical benefits of these drugs are now generally acceptable/established for mCRC patients, with the median overall survival of \u3e30 months. Currently, limitation in the effectiveness of tyrosine kinase inhibitors (TKIs) is due to (i) combination chemotherapy use that necessitates lowering of the dose density for toxicity profile management, and (ii) these drugs have mainly been developed in molecularly unselected population. The main challenge now is the identification of more reliable and 116 specific predictive biomarkers for selecting the most suitable therapy for mCRC. So far, the only well-established/reliable biomarker for mCRC treatment is RAS mutational status, which predicts negative response to anti-EGFR therapy. Current recommendation for the BRAF mutational status has also been given by the NCCN and the ESMO. Unlike VEGF inhibitor therapy, the resistance mechanisms in the EGFR inhibitor therapy are well understood, as are the drugs blocking the downstream RAS-MAPK pathway. Notably, a number of clinical trials on targeting the RAS signaling pathway have revealed promising efficacy in chemo-refractory mCRC. This chapter discusses the role of TKIs in advanced CRC from both translational and clinical research points of view

Data-Driven Harmonization of 2022 Who and ICC Classifications of Myelodysplastic Syndromes/Neoplasms (MDS): A Study By the International Consortium for MDS (icMDS)

Background. The inclusion of gene mutations and chromosomal abnormalities in the 2022 WHO and ICC Classifications of MDS has enhanced diagnostic precision and is expected to improve clinical decision-making process. Although these two systems share similarities, clinically relevant discrepancies still exist and potentially cause inconsistency in their adoption in a clinical setting. In this study on behalf of the International Consortium for MDS (icMDS), we adopted a data-driven approach to provide a harmonization roadmap between the 2022 WHO and ICC classification for MDS. A modified Delphi Process consensus approach is currently ongoing among icMDS experts to finalize a harmonized MDS classification scheme. Methods. We analyzed retrospective international cohorts of patients with a diagnosis of MDS (n=7017) and AML (n=1002) according to WHO 2016 criteria. Hierarchical Dirichlet Processes were applied to define clusters capturing broad dependencies among all gene mutations and cytogenetic abnormalities. To investigate the features of importance and their impact on the clustering process, we employed the SHapley Additive exPlanations approach (SHAP). This allowed to define harmonized labels for each clinical entity. The clinical relevance of the unsupervised clustering was assessed through the analysis of phenotypic features and outcomes among each group. ( Blood 2022;140: 9828-9830) Results. Patients' characteristics are summarized in Table 1. We identified 9 clusters, defined by specific genomic features. The cluster of highest hierarchical importance was characterized by biallelic inactivation of TP53 (biTP53). According to SHAP analysis, bi TP53 was defined as 2 or more TP53 mutations, or 1 mutation with copy number loss or cnLOH. Most patients assigned to bi TP53 cluster had TP53 VAF>10% (77.9%) and complex karyotype (70.1%). Assignment to bi TP53 cluster was irrespective of blast count. Patients with monoallelic TP53 mutation segregated into other clusters. Hierarchically, the second cluster included patients with del(5q). SHAP analysis highlighted 5q deletion alone, or with one other chromosomal abnormality other than -7, and absence of bi TP53, as the most relevant features. Most of these patients had blast counts <5% (88.1%). The third distinct cluster included patients with SF3B1 mutations (in the absence of concurrent del(7q), abn3q26.2, complex karyotype or RUNX1 mutation). Most patients with MDS and SF3B1 mutation had <5% blasts (94.2%). Common co-mutated variants in the SF3B1 cluster included mutant DNMT3A (25.2%) and TET2 (38.3%). Morphologically defined MDS cases (i.e., not meeting criteria for bi TP53, del(5q) or SF3B1) were preferentially assigned to the following additional clusters: SF3B1 and concurrent higher-risk mutations (e.g., RUNX1 and ASXL1); SRSF2 and concomitant TET2 mutations; U2AF1 mutations with del(20q), del(7q) or -7; SRSF2 with TET2 mutations and co-mutational patterns including RUNX1 and ASXL1; and AML-like genomic signatures. Our analyses suggest that morphologically defined MDS is characterized by a large heterogeneity in terms of mutation profiles, not entirely captured by the presence of unilineage versus multilineage dysplasia, percentage of bone marrow blasts, and presence of hypocellularity and fibrosis. To better investigate the continuum between high risk MDS (i.e., patients with ≥10% blasts) and AML, an exploratory comparison was made using a cohort of AML (defined according to WHO 2016) patients analyzed using the same statistical methods. Only a partial overlap in genetic signatures was observed between MDS with ≥10% blasts and AML. However, similarities were observed between the AML-like MDS clusters (characterized by mutant NPM1, bZIP CEBPA, and Core Binding Factor abnormalities) and AML clusters defined by the same genetic signature, thus supporting the classification of these entities as AML, irrespective of blast count. Conclusion. Our study demonstrated the utility of a data-driven approach based on advanced statistical methods to generate a harmonized classification for MDS. Table 2 shows a provisional, hierarchical classification algorithm. Further refinement of entity labels and classification criteria is the subject of the ongoing modified Delphi Process consensus approach among icMDS experts