HER2 Overexpression and Trastuzumab Treatment in Advanced Ovarian Cancer

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.^[1] In breast cancer, HER2-positive status is associated with poor prognosis, and also identifies patients who could benefit from anthracycline-based regimens.^[2] 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).^[2] 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.^[1]

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.^[3] The use of targeted therapies such as trastuzumab might potentially improve patient outcome.^[4] 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%)^[5] 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.^[6]

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).

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