Randomized Phase II Trial of Carboplatin-Paclitaxel Versus Carboplatin-Paclitaxel-Trastuzumab in Uterine Serous Carcinomas That Overexpress Human Epidermal Growth Factor Receptor 2/neu

Abstract

Purpose Uterine serous carcinoma is a rare, aggressive variant of endometrial cancer. Trastuzumab is a humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (HER2)/neu, a receptor overexpressed in 30% of uterine serous carcinoma. This multicenter, randomized phase II trial compared carboplatin-paclitaxel with and without trastuzumab in patients with advanced or recurrent uterine serous carcinoma who overexpress HER2/neu. Methods Eligible patients had primary stage III or IV or recurrent HER2/neu-positive disease. Participants were randomly assigned to receive carboplatin-paclitaxel (control arm) for six cycles with or without intravenous trastuzumab (experimental arm) until progression or unacceptable toxicity. The primary end point was progression-free survival, which was assessed for differences between treatment arms via one-sided log-rank tests. Results From August 2011 to March 2017, 61 patients were randomly assigned. Forty progression-free survival-related events occurred among 58 evaluable participants. Among all patients, median progression-free survival was 8.0 months (control) versus 12.6 months (experimental; P = .005; hazard ratio [HR], 0.44; 90% CI, 0.26 to 0.76). Similarly, median progression-free survival was 9.3 (control) versus 17.9 (experimental) months among 41 patients with stage III or IV disease undergoing primary treatment ( P = .013; HR, 0.40; 90% CI, 0.20 to 0.80) and 6.0 (control) versus 9.2 months (experimental), respectively, among 17 patients with recurrent disease ( P = .003; HR, 0.14; 90% CI, 0.04 to 0.53). Toxicity was not different between treatment arms, and no unexpected safety signals emerged. Conclusion Addition of trastuzumab to carboplatin-paclitaxel was well tolerated and increased progression-free survival. These encouraging results deserve further investigation to determine their impact on overall survival in patients with advanced or recurrent uterine serous carcinoma who overexpress HER2/neu.

HER2 immunohistochemistry in endometrial and ovarian clear cell carcinoma: discordance between antibodies and with in‐situ hybridisation

“…This study included only three endometrial CCCs and did not specify results within this subgroup. Very recently, encouraging results with anti‐HER2 therapy were achieved in a Phase II study on endometrial serous carcinoma, where the addition of trastuzumab to standard chemotherapy increased progression‐free survival in patients with HER2‐positive tumours . In this study, HER2‐positivity was defined as an IHC 3+ score, or IHC 2+ with ISH amplification.…”

Incorporation of molecular characteristics into endometrial cancer management

“…As patients with p53mut EC represent the group with the worst clinical outcomes, identifying targets in p53mut EC is an urgent need. Targeting amplifications of the ERBB2 gene, encoding for human epidermal growth receptor 2 (HER2) and homologous recombination deficiency (HRD), both occurring in p53mut EC, are being explored and show some promise …”

“…Studies investigating the therapeutic potential of trastuzumab as a single agent in HER2 overexpressing EC were not able to demonstrate any prognostic benefit . However, a recent trial including patients with stages III/IV or recurrent HER2 overexpressing serous EC found an increased progression‐free survival (PFS) from 8 to 13 months ( P = 0.005) when trastuzumab was given in combination with carboplatin‐paclitaxel chemotherapy . These findings encourage further investigation on the efficacy of trastuzumab combined with chemotherapy to improve outcomes for patients with advanced or recurrent EC.…”

Green synthesis and cytotoxic activity of dibenzyl α‐hydroxyphosphonates and α‐hydroxyphosphonic acids

“…As observed, the position of the substituent of the aromatic ring might have a greater impact on the cytotoxicity than the substituents (Cl, NO 2 , Me, OMe) themselves. The results obtained on the α‐hydroxyphosphonates are promising, as the in vitro cytotoxic activity in general was within the range of the effect (expressed as IC 50 values) of three well‐known chemotherapeutics, which we also tested against the Mes‐Sa cell line and which are typically applied to treat uterine sarcoma (doxorubicin, 0.36 μmol/L; carboplatin, 24.8 μmol/L; dacarbazine, 349.8 μmol/L) . However, the in vivo tolerability of these structures has to be evaluated.…”