Phase II study of gefitinib in patients with relapsed or persistent ovarian or primary peritoneal carcinoma and evaluation of epidermal growth factor receptor mutations and immunohistochemical expression: a Gynecologic Oncology Group Study.
ABSTRACT This phase II trial assessed the activity and tolerability of a daily oral dose of 500 mg gefitinib (ZD1839, Iressa) in patients with recurrent or persistent epithelial ovarian or primary peritoneal carcinoma, and explored the clinical value of determining the status of the epidermal growth factor receptor (EGFR).
Primary measure of efficacy was progression-free survival at 6 months. Mutations in exons 18 to 21 of EGFR and/or immunohistochemical expression of EGFR were evaluated in tumor specimens from patients enrolled in this trial as well as from patients not treated with gefitinib.
Twenty-seven of 30 (90%) patients were eligible and evaluable for analysis of gefitinib efficacy and toxicity. Of these, four survived progression-free >6 months with one objective response (4%). The most commonly observed grade 3 toxicities were dermatologic (15%, 4 of 27) and diarrhea (30%, 8 of 27). Specimens from 26 of 26 or 25 of 26 patients were evaluable for immunohistochemical or mutation analysis, respectively. The response rate for patients with EGFR-positive tumors was 9% (1 of 11). EGFR expression was associated with longer progression-free survival (P = 0.008) and possibly longer survival (P = 0.082). The patient with the only objective response had a mutation in the catalytic domain of the tumor's EGFR (P = 0.04). Among 32 invasive tumors from patients not treated with gefitinib, one exhibited a catalytic domain mutation.
Gefitinib was well tolerated but had minimal activity in unscreened patients with recurrent ovarian or primary peritoneal carcinoma. Prescreening patients for activating mutations in EGFR may improve response rate to gefitinib. This report is the first to document activating mutations in catalytic domain of EGFR in 3.5% (2 of 57) of ovarian cancers.
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ABSTRACT: Ovarian cancer is the deadliest cancer among women. About 90% of ovarian cancers are epithelial, (ovarian carcinomas) thought to arise from the ovarian surface epithelium. Diagnosed usually at clinically advanced stages, many patients show poor response to chemotherapy, with resistance and recurrent disease being prevalent. The cell origin and the mechanism of neoplastic transformation of this malignancy are poorly understood. Apoptosis is crucial in normal ovarian development and function; and gonadotropins play a significant role in modulating the expression of several pro-apoptotic and pro-survival genes and other molecules in the ovary. Targeted therapeutic strategies using small molecule protein kinase inhibitors and monoclonal antibodies have been explored in the management of ovarian carcinomas. These molecules, used in combination with chemotherapy, have shown better prognosis in ovarian cancer. With several ongoing clinical trials using kinase inhibitors and the ideal targets being sought after, significant improvements of patients suffering with ovarian carcinomas are expected in the near future. This manuscript aims to review ovarian apoptotic mechanisms and the therapeutic progress in the use of small molecule kinase inhibitors and monoclonal antibodies as targets for inducing apoptosis in ovarian cancer.
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ABSTRACT: We document an EGFR mutation in a patient with papillary renal cell cancer with a history of multiple therapies, including interferon-alpha, interleukin-2, 5-fluorouracil, and interferon-alpha together with 13-cis-retinoic acid, to which floxuridine was later added, and thalidomide maintenance therapy for six years. We provide a succinct review of the PubMed-derived literature on EGFR mutations in diverse tumors, which indicates that a subset of patients with various tumor types may harbor EGFR mutations. A 32-year old woman with sporadic, metastatic papillary renal cancer was found to harbor an EGFR kinase domain mutation in addition to the MET kinase mutation typically found in this disease. Since lung cancer patients with EGFR mutations often respond well to EGFR inhibitor therapy and EGFR mutations occur in a variety of tumors, it should be worthwhile to assess EGFR status prospectively in other tumors and study the results of treatment with EGFR inhibitors in these patients.Molecular oncology 03/2010; 4(4):306-8. DOI:10.1016/j.molonc.2010.03.002 · 5.94 Impact Factor
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ABSTRACT: The epidermal growth factor receptor is overexpressed in up to 60% of ovarian epithelial malignancies. EGFR regulates complex cellular events due to the large number of ligands, dimerization partners, and diverse signaling pathways engaged. In ovarian cancer, EGFR activation is associated with increased malignant tumor phenotype and poorer patient outcome. However, unlike some other EGFR-positive solid tumors, treatment of ovarian tumors with anti-EGFR agents has induced minimal response. While the amount of information regarding EGFR-mediated signaling is considerable, current data provides little insight for the lack of efficacy of anti-EGFR agents in ovarian cancer. More comprehensive, systematic, and well-defined approaches are needed to dissect the roles that EGFR plays in the complex signaling processes in ovarian cancer as well as to identify biomarkers that can accurately predict sensitivity toward EGFR-targeted therapeutic agents. This new knowledge could facilitate the development of rational combinatorial therapies to sensitize tumor cells toward EGFR-targeted therapies.Journal of Oncology 01/2010; 2010(1687-8450):568938. DOI:10.1155/2010/568938