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A phase II and pharmacodynamic study of gefitinib in patients with refractory or recurrent epithelial ovarian cancer

Posadas, Edwin M. ; Liel, Meghan S. ; Kwitkowski, Virginia ; Minasian, Lori ; Godwin, Andrew K. ; Hussain, Mahrukh M. ; Espina, Virginia ; Wood, Bradford J. ; Steinberg, Seth M. ; Kohn, Elise C.

Cancer, 2007-04, Vol.109 (7), p.1323-1330 [Periódico revisado por pares]

Hoboken: Wiley Subscription Services, Inc., A Wiley Company

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Título:
A phase II and pharmacodynamic study of gefitinib in patients with refractory or recurrent epithelial ovarian cancer
Autor: Posadas, Edwin M. ; Liel, Meghan S. ; Kwitkowski, Virginia ; Minasian, Lori ; Godwin, Andrew K. ; Hussain, Mahrukh M. ; Espina, Virginia ; Wood, Bradford J. ; Steinberg, Seth M. ; Kohn, Elise C.
Assuntos: Adenocarcinoma, Clear Cell - drug therapy ; Adenocarcinoma, Clear Cell - genetics ; Adenocarcinoma, Clear Cell - metabolism ; Adult ; Aged ; Antineoplastic Agents - therapeutic use ; Biological and medical sciences ; Carcinoma, Endometrioid - drug therapy ; Carcinoma, Endometrioid - genetics ; Carcinoma, Endometrioid - metabolism ; Carcinoma, Papillary - drug therapy ; Carcinoma, Papillary - genetics ; Carcinoma, Papillary - metabolism ; Cystadenocarcinoma, Serous - drug therapy ; Cystadenocarcinoma, Serous - genetics ; Cystadenocarcinoma, Serous - metabolism ; Disease-Free Survival ; epidermal growth factor receptor ; Female ; Female genital diseases ; gefitinib ; Gynecology. Andrology. Obstetrics ; Humans ; Medical sciences ; Middle Aged ; Mitogen-Activated Protein Kinase 1 - metabolism ; Neoplasm Recurrence, Local - drug therapy ; Neoplasms, Glandular and Epithelial - drug therapy ; Neoplasms, Glandular and Epithelial - genetics ; Neoplasms, Glandular and Epithelial - metabolism ; ovarian cancer ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - genetics ; Ovarian Neoplasms - metabolism ; Phosphorylation - drug effects ; Polymerase Chain Reaction ; Prospective Studies ; protein array ; proteomics ; Proto-Oncogene Proteins c-akt - metabolism ; Quinazolines - therapeutic use ; Receptor, Epidermal Growth Factor - antagonists & inhibitors ; Receptor, Epidermal Growth Factor - genetics ; Signal Transduction ; Time Factors ; Treatment Outcome ; Tumors
É parte de: Cancer, 2007-04, Vol.109 (7), p.1323-1330
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This is a US government work and, as such, is in the public domain in the United States of America.
Descrição: BACKGROUND The primary objective of this study was to evaluate the biochemical effects of gefitinib on its target signal‐transduction pathways in patients with recurrent epithelial ovarian cancer (EOC). The secondary objectives included assessing clinical activity and toxicity and determining the association between biochemical and clinical outcomes. METHODS Twenty‐four heavily pretreated patients with EOC who had good end‐organ function and performance status and who had measurable disease received gefitinib 500 mg daily. Prospectively planned core‐needle tumor biopsies were obtained before treatment and after 4 weeks. Protein expression of total and phosphorylated (p) epidermal growth factor receptor (EGFR), protein kinase B (AKT), and extracellular regulated kinase (ERK) was quantified in microdissected tumor cells using tissue lysate array proteomics. RESULTS All tumor samples had detectable levels of EGFR and p‐EGFR. A decrease in the quantity of both EGFR and p‐EGFR was observed with gefitinib therapy in >50% of patients. This was not associated with clinical benefit, nor were responses observed. However, trends for increased gastrointestinal and skin toxicity were observed with greater phosphorylation or quantities of EGFR, ERK, and AKT in tumor samples (P ≤ .05). Gefitinib had limited clinical activity as monotherapy despite documented target inhibition. CONCLUSIONS The results from this study demonstrated that gefitinib inhibited the phosphorylation of EGFR in EOC tumor cells, providing proof of target in a clinical setting. Combinatorial therapy with molecular therapeutics against complementary targets may prove successful. Cancer 2007. Published 2007 by the American Cancer Society. Gefitinib treatment for ovarian cancer inhibited the activity of the epidermal growth factor receptor (EGFR) in >50% of the patients in this study. The modulation of EGFR activity was correlated with gefitinib toxicity, and the current results indicated that EGFR inhibition is inadequate as a sole molecular therapeutic target in ovarian cancer.
Editor: Hoboken: Wiley Subscription Services, Inc., A Wiley Company
Idioma: Inglês

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A phase II and pharmacodynamic study of gefitinib in patients with refractory or recurrent epithelial ovarian cancer

Posadas, Edwin M. ; Liel, Meghan S. ; Kwitkowski, Virginia ; Minasian, Lori ; Godwin, Andrew K. ; Hussain, Mahrukh M. ; Espina, Virginia ; Wood, Bradford J. ; Steinberg, Seth M. ; Kohn, Elise C.

Hoboken: Wiley Subscription Services, Inc., A Wiley Company

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