Schilder RJ, Sill MW, Chen X, Darcy KM, Decesare SL, Lewandowski G, Lee RB, Arciero CA, Wu H, Godwin AKPhase 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. Clin Cancer Res 11: 5539-5548
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.
"Tyrosine kinase inhibitors such as erlonitib and gefitinib have been successfully directed against the EGFR (Sirotnak et al., 2000; Sirotnak, 2003). Phase 2 clinical trials with gefinitib in patients with advanced recurrent ovarian carcinomas showed very little activity, although the drug was well tolerated (Schilder et al., 2005). Phase 3 trials with erlonitib, however did not show any significant improvement in activity (Vergote et al., 2013). "
[Show abstract][Hide abstract] 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.
"Erlotinib and gefitinib, both small-molecule inhibitors, have been examined in patients with recurrent ovarian cancer. Single-agent Phase II studies of both drugs have been disappointing, with poor response rates noted (6% for erlotinib26; 0%–4% for gefitinib27,28). Even when patients had detectable levels of target EGFR and phospho-EGFR, which were decreased with gefitinib therapy, there was no clinically associated benefit.29 Phase II studies combining erlotinib or gefitinib with cytotoxic chemotherapies did demonstrate significant clinical response. "
[Show abstract][Hide abstract] ABSTRACT: Epithelial ovarian cancer is typically found in its advanced stages, where a combination of surgical debulking and platinum/taxane-based chemotherapy is recommended. Although over 70%-80% of patients achieve remission, a significant proportion develop recurrence of their disease. Additional cytotoxic chemotherapy, as well as surgery, is typically used to manage disease recurrence. Therapies that target specific pathways in cancer cells are rapidly developing in the laboratory and are increasingly being studied in patients with ovarian cancer. We review the current status of novel therapies in the management of epithelial ovarian cancer.
"The epidermal growth factor receptor (EGFR) family is commonly overexpressed in ovarian cancer and has been associated with a negative prognosis; however, limited efficacy has been observed with molecules targeted to the EGFR pathway. Gefitinib and erlotinib, which are inhibitors of EGFR, stabilized disease in 11%–44% of patients with ovarian cancer but produced objective regression in only 4%–6% of cases [38, 39]. The effect of EGFR inhibitors might be reduced by activation of the RAS-MAPK signalling pathway, as happens in colorectal cancers . "
[Show abstract][Hide abstract] ABSTRACT: Ovarian cancer is sensitive to chemotherapy with platinum compounds; however, the therapy success rate is significantly lowered by a high incidence of recurrence and by the acquisition of drug resistance. These negative outcomes mainly depend on altered apoptotic and drug resistance pathways, determining the need for the design of new therapeutic strategies to improve patient survival. This challenge has become even more critical because it has been recognized that hindering uncontrolled cell growth is not sufficient as the only curative approach. In fact, while current therapies are mostly conceived to impair survival of highly proliferating cells, several lines of research are now focusing on cancer-specific features to specifically target malignant cells with the aim of avoiding drug resistance and reducing adverse effects. Recently, great interest has been generated by the identification of metabolic reprogramming mechanisms occurring in cancer cells, such as the increase in glycolysis levels. In this light, pharmacologic manipulation of relevant pathways involved in cancer-specific metabolism and drug resistance could prove an effective approach to treat ovarian cancer patients.
Journal of Oncology 03/2012; 2012:382159. DOI:10.1155/2012/382159
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