Abstract and Introduction
Background: Variable rates of HER2 protein overexpression and gene amplification have been reported in advanced ovarian cancers (AOC). Trastuzumab, tested only as a single agent, has been shown to achieve 7% response in heavily pretreated patients with AOC with 3+ and 2+ HER2 immunostaining by immunohistochemistry (IHC). Th e GINECO trial explored the combination of trastuzumab with paclitaxel and carboplatin in patients with resistant AOC (< 6 months) and HER2 gene amplification.
Patients and Methods: A total of 320 patients with AOC were centrally screened for HER2 status (243 patients in fi rst line, 77 in relapse). All positive (IHC 3+) and doubtful (IHC 2+) cases were screened by fl uorescence in situ hybridization (FISH). Patients with HER2 gene amplification, normal left ventricular ejection fraction (LVEF), and resistant relapse after first- or second-line paclitaxel/carboplatin chemotherapy received paclitaxel (175 mg/m2 for 3 hours), carboplatin (AUC 5), and trastuzumab (8 mg/kg first course, 6 mg/kg subsequent courses) every 3 weeks.
Results: Twenty patients (6.4%) had HER2-positive disease by immunohistochemistry and FISH. Only 7 (32%) patients (median age, 56 years; range, 48-68 years) met eligibility criteria; they had measurable lesions (n = 4) or elevated cancer antigen 125 level and non-measurable lesions (n = 3). Three had complete response (6, 7+, and 24+ months) and 2 had stable disease (3 months). Toxicity was moderate: febrile neutropenia, grade 3 infection, grade 2 neurotoxicity, and decreased LVEF after 23 cycles of trastuzumab were observed in 1 patient each.
Conclusion: HER2 overexpression/amplification is low (6.4%) in patients with AOC. In this small prospective cohort of 7 patients with resistant AOC, 3 achieved complete remission when adding trastuzumab to conventional chemotherapy, suggesting that trastuzumab combined with carbolatin and paclitaxel is able to reverse platinum resistance in HER2-positive AOC.
The HER2 proto-oncogene encodes a protein of the epidermal growth factor receptor (EGFR) tyrosine kinase family. Overexpression of HER2 initiates intracellular signaling pathways involved in cell proliferation, differentiation, migration, and apoptosis. In breast cancer, HER2-positive status is associated with poor prognosis, and also identifies patients who could benefit from anthracycline-based regimens. HER2 overexpression, which is observed in 25%-30% of patients with metastatic breast cancer (MBC), is correlated with more aggressive disease and shortened disease-free and overall survival (OS). These properties, with preclinical data, support a pathogenic role for HER2 in HER2-overexpressing tumors. In patients with MBC and HER2/neu overexpression or HER2 amplification, a combination of the humanized anti-HER2 monoclonal antibody trastuzumab and a taxane, with or without carboplatin, has been shown to be highly active.
Despite a typically good response to first-line combination chemotherapy, the prognosis of patients with advanced ovarian cancer (AOC) remains poor because of acquired chemotherapy resistance. The use of targeted therapies such as trastuzumab might potentially improve patient outcome. HER2 overexpression/amplification has been reported in ovarian cancer, but the exact percentage of HER2-positive tumors varies widely in the literature (between 8% and 66%) and is associated with poor clinical outcome. Treatment with trastuzumab monotherapy has been reported to induce a poor response (7%) in heavily pretreated patients with AOC with moderate (2+) or high (3+) HER2 overexpression.
The GINECO group launched the present clinical trial (TCHerceptin1) in order to investigate the efficacy and tolerance of trastuzumab in combination with paclitaxel and carboplatin in patients with HER2-positive (fluorescence in situ hybridization [FISH] positive) ovarian cancer progressing under taxane/carboplatin chemotherapy or in early relapse (< 6 months).
Clin Ovarian Cancer. 2008;1(1):54-59. © 2008 CIG Media Group, LP
Cite this: HER2 Overexpression/Amplification and Trastuzumab Treatment in Advanced Ovarian Cancer: A GINECO Phase II Study - Medscape - Jun 01, 2008.