Article

A phase 2 trial of erlotinib in patients with previously treated squamous cell and adenocarcinoma of the esophagus.

Gastrointestinal Oncology Service/Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Cancer (Impact Factor: 4.9). 04/2011; 117(7):1409-14. DOI: 10.1002/cncr.25602
Source: PubMed

ABSTRACT Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) have activity in solid tumors. The authors evaluated an oral EGFR TKI, erlotinib, in patients with previously treated esophageal cancer.
Thirty patients with measurable, metastatic cancer of the esophageal and gastroesophageal junction received 150 mg erlotinib daily. EGFR-negative tumors (6 patients; 20%) and EGFR-over expressing tumors (24 patients; 80%) were treated. Most patients were men (70%) with adenocarcinoma (57%) and had received previous chemotherapy (97%).
Two partial responses were observe d in the EGFR-positive cohort (2 of 24 patients; 8%), and no responses were observed in the EGFR-negative cohort (0 of 6 patients). Reponses were limited to patients who had squamous cell carcinoma (2 of 13 patients; 15%; response duration, 5.5-7 months). The time to tumor progression was longer in patients who had squamous cell carcinoma (3.3 months; range, 1-24 months) compared with patients who had adenocarcinoma (1.6 months; range, 1-6 months; P = .026). Therapy was tolerable with the expected toxicity of skin rash (grade 1-2, 67%; grade 3, 10%).
Erlotinib had limited activity in patients with esophageal cancer, and responses and some protracted stable disease were observed in those with squamous cell carcinoma. Efficacy according to EGFR status could not be assessed given the rarity of EGFR-negative tumors. The current results indicated that further evaluation of this agent in squamous cell carcinoma is warranted. Cancer 2011. © 2010 American Cancer Society.

0 Bookmarks
 · 
245 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: ErbB family receptor tyrosine kinases (ErbBs) play a role in cell adhesion and migration and are frequently overexpressed in esophageal squamous cell carcinomas (ESCCs) or esophageal adenocarcinomas (EACs). Targeting ErbBs by tyrosine kinase inhibitors (TKIs) may therefore limit esophageal cancer cell migration. Here, we studied the impact of TKIs on ErbB dimerization, cell signaling pathways, and cell migration in three esophageal cell lines: OE21 (ESCC), OE33 (EAC), and Het-1A (non-neoplastic esophageal epithelium). In OE21 cells, the TKIs erlotinib, gefitinib, and lapatinib slightly affected epidermal growth factor receptor EGFR/EGFR, but not EGFR/HER2 dimerization as detected by in situ proximity ligation assay (in situ PLA). Still, TKIs inhibited ERK1/2, Akt, STAT3, and RhoA activity in OE21 cells, as assessed by Western blot, antibody arrays, and Rho GTPase effector pull-down assays. This was accompanied by reduced OE21 cell migration, induction of focal adhesions, and actin cytoskeleton reorganization, as shown by Oris™ migration assay and focal adhesion kinase (FAK)/phalloidin staining. In contrast, in OE33 cells, only lapatinib decreased STAT5, Src family kinase (SFK), and FAK activity as well as β-catenin expression. This impeded cell migration and induced morphological changes in OE33 cells. No alterations were seen for the non-neoplastic Het-1A cells. Thus, we identified the ErbB signaling network as regulator of esophageal cancer cell's actin cytoskeleton, focal adhesions, and cell migration. ErbB targeted TKIs therefore also limit ESCC and EAC cell motility and migration.
    Journal of Molecular Medicine 08/2014; DOI:10.1007/s00109-014-1187-5 · 4.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: It has previously been shown that gefitinib-treated patients with epidermal growth factor receptor (EGFR) gene amplification or high polysomy had a statistically significant improvement in response, time to progression, and survival in non-small cell lung cancer (NSCLC). Only few studies utilizing anti-EGFR treatment in advanced esophageal adenocarcinomas have been performed and the results have been heterogeneous. The aim of this study was to evaluate EGFR-targeted therapy with gefitinib in esophageal adenocarcinoma with a high EGFR polysomy.
    Langenbeck s Archives of Surgery 07/2014; DOI:10.1007/s00423-014-1235-1 · 2.16 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Gastric cancer is the one of the major causes of cancer-related death, especially in Asia. Gastric adenocarcinoma, the most common type of gastric cancer, is heterogeneous and its incidence and cause varies widely with geographical regions, gender, ethnicity, and diet. Since unique mutations have been observed in individual human cancer samples, identification and characterization of the molecular alterations underlying individual gastric adenocarcinomas is a critical step for developing more effective, personalized therapies. Until recently, identifying genetic mutations on an individual basis by DNA sequencing remained a daunting task. Recent advances in new next-generation DNA sequencing technologies, such as the semiconductor-based Ion Torrent sequencing platform, makes DNA sequencing cheaper, faster, and more reliable. In this study, we aim to identify genetic mutations in the genes which are targeted by drugs in clinical use or are under development in individual human gastric adenocarcinoma samples using Ion Torrent sequencing. We sequenced 737 loci from 45 cancer-related genes in 238 human gastric adenocarcinoma samples using the Ion Torrent Ampliseq Cancer Panel. The sequencing analysis revealed a high occurrence of mutations along the TP53 locus (9.7%) in our sample set. Thus, this study indicates the utility of a cost and time efficient tool such as Ion Torrent sequencing to screen cancer mutations for the development of personalized cancer therapy.
    PLoS ONE 01/2014; 9(7):e100442. DOI:10.1371/journal.pone.0100442 · 3.53 Impact Factor

Full-text (2 Sources)

Download
0 Downloads
Available from
Feb 28, 2015