Update on Gastroesophageal Adenocarcinoma Targeted Therapies.
Ontology highlight
ABSTRACT:
SUBMITTER: Maron SB
PROVIDER: S-EPMC5446061 | biostudies-literature | 2017 Jun
REPOSITORIES: biostudies-literature
Publications
Update on Gastroesophageal Adenocarcinoma Targeted Therapies.
Maron Steven B SB Catenacci Daniel V T DVT
Hematology/oncology clinics of North America 20170601 3
Gastroesophageal cancer (GEC) remains a major cause of cancer-related mortality worldwide. Although the incidence of distal gastric adenocarcinoma (GC) is declining in the United States, proximal esophagogastric junction adenocarcinoma (EGJ) incidence is rising. GC and EGJ, together, are treated uniformly in the metastatic setting as GEC. Overall survival in the metastatic setting remains poor, with few molecular targeted approaches having been successfully incorporated into routine care to date ...[more]
Similar Datasets
Project description:Gastroesophageal adenocarcinomas (GEA) are devastating diseases with stark global presence. Over the past 10 years, there have been minimal improvements in treatment approach despite numerous clinical trials. Here, we review recent progress toward understanding the molecular features of these cancers and the diagnostic and therapeutic challenges posed by their intrinsic genomic instability and heterogeneity. We highlight the potential of genomic heterogeneity to influence clinical trial outcomes for targeted therapies and emphasize the need for comprehensive molecular profiling to guide treatment selection and adapt treatment to resistance and genomic evolution. Revising our clinical approach to GEA by leveraging genomic advances will be integral to the success of current and future treatments, especially as novel targets become therapeutically tractable. SIGNIFICANCE: GEAs are deadly cancers with few treatment options. Characterization of the genomic landscape of these cancers has revealed considerable genetic diversity and spatial heterogeneity. Understanding these fundamental properties of GEA will be critical for overcoming barriers to the development of novel, more effective therapeutic strategies.
| S-EPMC7232941 | biostudies-literature
Project description:Previous anti-EGFR trials in unselected patients with gastroesophageal adenocarcinoma (GEA) were resoundingly negative. We identified EGFR amplification in 5% (19/363) of patients at the University of Chicago, including 6% (8/140) who were prospectively screened with intention-to-treat using anti-EGFR therapy. Seven patients received ?1 dose of treatment: three first-line FOLFOX plus ABT-806, one second-line FOLFIRI plus cetuximab, and three third/fourth-line cetuximab alone. Treatment achieved objective response in 58% (4/7) and disease control in 100% (7/7) with a median progression-free survival of 10 months. Pretreatment and posttreatment tumor next-generation sequencing (NGS), serial plasma circulating tumor DNA (ctDNA) NGS, and tumor IHC/FISH for EGFR revealed preexisting and/or acquired genomic events, including EGFR-negative clones, PTEN deletion, KRAS amplification/mutation, NRAS, MYC, and HER2 amplification, and GNAS mutations serving as mechanisms of resistance. Two evaluable patients demonstrated interval increase of CD3+ infiltrate, including one who demonstrated increased NKp46+, and PD-L1 IHC expression from baseline, suggesting an immune therapeutic mechanism of action. EGFR amplification predicted benefit from anti-EGFR therapy, albeit until various resistance mechanisms emerged.Significance: This paper highlights the role of EGFR inhibitors in EGFR-amplified GEA-despite negative results in prior unselected phase III trials. Using serial ctDNA and tissue NGS, we identified mechanisms of primary and acquired resistance in all patients, as well as potential contribution of antibody-dependent cell-mediated cytotoxicity to their clinical benefit. Cancer Discov; 8(6); 696-713. ©2018 AACR.See related commentary by Strickler, p. 679This article is highlighted in the In This Issue feature, p. 663.
| S-EPMC5984701 | biostudies-literature
Project description:Chordomas are rare, locally aggressive skull base neoplasms known for local recurrence and not-infrequent treatment failure. Current evidence supports the role of maximal safe surgical resection. In addition to open skull-base approaches, the endoscopic endonasal approach to clival chordomas has been reported with favorable albeit early results. Adjuvant radiation is prescribed following complete resection, alternatively for gross residual disease or at the time of recurrence. The modalities of adjuvant radiation therapy reported vary widely and include proton-beam, carbon-ion, fractionated photon radiotherapy, and photon and gamma-knife radiosurgery. As of now, no direct comparison is available, and high-level evidence demonstrating superiority of one modality over another is lacking. While systemic therapies have yet to form part of any first-line therapy for chordomas, a number of targeted agents have been evaluated to date that inhibit specific molecules and their respective pathways known to be implicated in chordomas. These include EGFR (erlotinib, gefitinib, lapatinib), PDGFR (imatinib), mTOR (rapamycin), and VEGF (bevacizumab). This article provides an update of the current multimodality treatment of cranial base chordomas, with an emphasis on how current understanding of molecular pathogenesis provides a framework for the development of novel targeted approaches.
| S-EPMC4451853 | biostudies-literature
Project description:Progress has been made in the treatment of gastrointestinal cancers through advances in systemic therapies, surgical interventions, and radiation therapy. At the Multi-Disciplinary Patient Care in Gastrointestinal Oncology conference, the faculty members of the Penn State Health Milton S. Hershey Medical Center presented a variety of topics that focused on this sub-specialty. This conference paper highlights the new development in systemic treatment of various malignant diseases in the digestive system. Results of the recent clinical trials that investigated the clinical efficacy of pegylated hyaluronidase, napabucasin, and L-asparaginase in pancreatic carcinoma are presented. The use of peri-operative chemotherapy comprised of 5-fluorouracil or capecitabine, leucovorin, oxaliplatin, and docetaxel (FLOT), and immunotherapy including pembrolizumab, nivolumab, and ipilimumab in gastroesophageal carcinoma are discussed. Data from clinical trials that investigated the targeted therapeutics including nivolumab, ramucirumab, lenvatinib, and BLU-554 are reported. The role of adjuvant capecitabine in resected biliary tract carcinoma (BTC) and nab-paclitaxel in combination with gemcitabine and cisplatin in advanced BTC are presented. In colorectal carcinoma, the efficacy of nivolumab, adjuvant FOLFOX or CAPOX, irinotecan/cetuximab/vemurafenib, and trifluridine/tipiracil/bevacizumab, is examined. In summary, some of the above systemic therapies have become or are expected to become new standard of care, while the others demonstrate the potential of becoming new treatment options.
| S-EPMC5874691 | biostudies-literature
Project description:PURPOSE OF REVIEW:The article reviews the evolution of targeted therapies for clear cell renal cell carcinoma (RCC) and recent developments in the field. The vast majority of work in kidney cancer deals with clear cell RCC, which is the most common variant of this malignancy. The identification of loss of function of the von Hippel-Lindau protein as the basis for clear cell RCC, in addition to the well designed clinical trials that have ensued, provide an outstanding model for the development of mechanism-based targeted therapy in cancer. RECENT FINDINGS:The treatment of advanced and metastatic RCC continues to be a major challenge for uro-oncologists despite the approval of six targeted therapies over the past 5 years. This rapid growth in therapeutic options has brought much needed improvements in overall and progression-free survival, although durable complete responses are rare. However, the plurality of treatments also poses challenges in terms of selecting the best therapy for a given patient, designing trials with appropriate comparison arms and endpoints, identifying well tolerated and effective drug combinations or sequences, and determining the role of targeted therapies in the neoadjuvant and adjuvant settings. SUMMARY:Vascular endothelial growth factor and mammalian target of rapamycin-targeted therapies continue to play a critical role in the management of advanced and metastatic RCC. Ongoing research to identify novel agents continues to build upon the work done during the elucidation of the von Hippel-Lindau/clear cell RCC pathway. It is hoped that ongoing and planned studies will enable development of therapeutic regimens that will incorporate agents with improved toxicity and better efficacy as well as defining a role for a multidisciplinary approach to the management of advanced RCC.
| S-EPMC3488422 | biostudies-literature
Project description:Recently, the global incidence of gastric/gastroesophageal junction (G/GEJ) cancer has remained high. China is also a large country with a high gastric cancer (GC) incidence rate, where the cases of GC account for 40% of all cases worldwide. More than 90% of GEJ cancers are the adenocarcinoma pathological type. Patients with early-stage G/GEJ adenocarcinoma may have a better prognosis after surgery. In contrast, patients with advanced metastatic G/GEJ adenocarcinoma usually choose comprehensive treatment based on systemic pharmacotherapy, but the subsequent long-term survival is not optimistic. The discovery of various biomarkers, especially microsatellite instability (MSI), programmed cell death-ligand 1 (PD-L1), human epidermal growth factor receptor 2 (HER2), tumor mutational burden (TMB) and Epstein-Barr virus (EBV), has led to the identification of an increasing number of targeted populations and has greatly improved the clinical efficacy of treatments for G/GEJ adenocarcinoma. The ToGA trial added trastuzumab to standard chemotherapy, showed improved survival of patients with HER2-positive advanced G/GEJ adenocarcinoma and brought these patients into a new era of HER2-targeted therapy. Moreover, many HER2-targeted agents have been developed and studied in patients with advanced HER2-positive G/GEJ adenocarcinoma who have demonstrated excellent clinical outcomes. However, many patients experience disease progression with HER2-targeted therapy; hence, new anti-HER2 drugs keep being developed, significantly reducing HER2 resistance. This paper reviews HER2-targeted drugs for advanced metastatic G/GEJ adenocarcinoma, potential resistance mechanisms and future directions.
| S-EPMC9524015 | biostudies-literature
Project description:We aimed to characterize the genomic profiles of adenocarcinomas in the gastroesophageal junction in relation to cancers in the esophagus and the stomach. Profiles of gains/losses as well as gene expression profiles were obtained from 27 gastroesophageal adenocarcinomas using 32k high-resolution array-based comparative genomic hybridization (aCGH) and 27k oligo gene expression arrays and putative target genes were validated in an extended series. Adenocarcinomas in the distal esophagus and the gastroesophageal junction showed strong similarities with the most common gains at 20q13, 8q24, 1q21-q23, 5p15, 13q34, and 12q13, whereas different profiles with gains at 5p15, 7p22, 2q35, and 13q34 characterized gastric cancers. CDK6 and EGFR were identified as putative target genes in cancers of the esophagus and the gastroesophageal junction with upregulation in one quarter of the tumors. Gains/losses and gene expression profiles show strong similarity between cancers in the distal esophagus and the gastroesophageal junction with frequent upregulation of CDK6 and EGFR, whereas gastric cancer displays distinct genetic changes. These data suggest that molecular diagnostics and targeted therapies can be applied to adenocarcinomas of the distal esophagus and gastroesophageal junction alike. Three types of gastroesophageal adenocarcinomas; 7 distal esophageal (EA) tumors, 9 junctional (JA) and 7 proximal stomach cancers (GA) was genomically profiled using tiling 32k BAC-arrays. Two replicates of tumors IDs 1-EA-CGH (replicate 1-EA-CGH-2), 12-EA-CGH (replicate 12-EA-CGH-2) and 18-EA-CGH (replicate 18-EA-CGH-2). Reference samples consist of a pool of male DNA (Promega, Madison, WI, USA).
2010-06-24 | E-GEOD-22524 | biostudies-arrayexpress
Project description:Metastatic pancreatic ductal adenocarcinoma (PDAC) is a major health burden due to its increasing incidence and poor prognosis. PDAC is characterized by a low tumor mutational burden, and its molecular pathogenesis is driven by Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. Response to DNA damage through homologous repair is defective in 15% of tumors. Chemotherapy using FOLFIRINOX (folinic acid, fluorouracil, irinotecan, oxaliplatin) or gemcitabine-nab-paclitaxel significantly improves life expectancy, but the median overall survival remains <1 year. Targeted therapies are not efficient in the overall population of patients with metastatic PDAC. Improvements in overall survival or progression-free survival, however, have been demonstrated in subgroups carrying certain mutations. Maintenance therapy with poly-ADP-ribose polymerase (PARP) inhibitors increases progression-free survival in patients with germline mutations in BRCA1/2. Sotorasib shows signs of efficacy against tumors carrying the KRAS G12C mutation, and targeted therapies may also benefit patients with KRAS-wild-type PDAC. Combining targeted therapies with chemotherapy holds promise because of potential synergistic effects. These associations, however, have not yet demonstrated clinical benefit. Checkpoint inhibitors are not effective against metastatic PDAC. Combined immunotherapies attempt to restore their efficacy but have not succeeded yet. Other immunotherapies are emerging such as therapeutic vaccines or chimeric antigen receptor (CAR) T cells, but these strategies remain to be evaluated in large trials. In the future, treatment personalization based on tumor-derived organoids could potentially further improve treatment efficiency.
| S-EPMC9674888 | biostudies-literature
Project description:There have been significant advances in the understanding of the biology and treatment of non-small-cell lung cancer (NSCLC) during the past few years. A number of molecularly targeted agents are in the clinic or in development for patients with advanced NSCLC. We are beginning to understand the mechanisms of acquired resistance after exposure to tyrosine kinase inhibitors in patients with oncogene addicted NSCLC. The advent of next-generation sequencing has enabled to study comprehensively genomic alterations in lung cancer. Finally, early results from immune checkpoint inhibitors are very encouraging. This review summarizes recent advances in the area of cancer genomics, targeted therapies, and immunotherapy.
| S-EPMC4346098 | biostudies-literature
Project description:HER2-targeted therapy with the HER2 monoclonal antibody trastuzumab has achieved impressive outcomes in the first-line settings of patients with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma overexpressing HER2. However, considering that a substantial proportion of those patients eventually relapses, as well as the relatively limited performance of those agents in second-line settings, a deeper understanding of resistance mechanisms is needed for enhanced guidance for patients' therapeutic selection in the second-line setting and beyond. In this review, we highlight trastuzumab's (HER2-targeting agent) performance in patients with gastric or GEJ cancer, with insight into mechanisms of resistance. We also discuss the new integration of PD-1 inhibitor pembrolizumab into the trastuzumab for gastric cancer frontline regimen, the latest addition of trastuzumab deruxtecan to the treatment armamentarium, and the potential of pipeline HER2-targeting approaches and combinations in patients with gastric or GEJ adenocarcinoma.
| S-EPMC10448730 | biostudies-literature