T-DM1, a novel antibody-drug conjugate, is highly effective against uterine and ovarian carcinosarcomas overexpressing HER2

Abstract

Introduction Ovarian and uterine carcinosarcoma (CS) are characterized by their aggressive clinical behavior and poor prognosis. We evaluated the efficacy of trastuzumab-emtansine (T-DM1), against primary HER2 positive and HER2 negative CS cell lines in vitro and in vivo. Methods Eight primary CS cell lines were evaluated for HER2 amplification and protein expression by FISH, immunohistochemistry, flow cytometry and qRT-PCR. Sensitivity to T-DM1-induced antibody-dependent-cell-mediated-cytotoxicity (ADCC) was evaluated in 4-hr-chromium-release-assays. T-DM1 cytostatic and apoptotic activities were evaluated using flow cytometry based proliferation assays. In vivo activity of T-DM1 was also evaluated. Results HER2 protein overexpression and gene amplification were detected in 25% (2/8) of the primary CS cell lines. T-DM1 and T were similarly effective in inducing strong ADCC against CS overexpressing HER2 at 3+ levels. In contrast, T-DM1 was dramatically more effective than T in inhibiting cell proliferation (P<0.0001) and in inducing G2/M phase cell cycle arrest in the HER2 expressing cell lines (shift of G2/M: mean ± SEM from 14.87 ± 1.23% to 66.57 ± 4.56%, P<0.0001). Importantly, T-DM1 was highly active at reducing tumor formation in vivo in CS xenografts overexpressing HER2 (P=0.0001 and P<0.0001 compared to T and vehicle respectively) with a significantly longer survival when compared to T and vehicle mice (P=0.008 and P=0.0001 respectively). Conclusion T-DM1 may represent a novel treatment option for the subset of HER2 positive CS patients with disease refractory to chemotherapy.

SYD985, a Novel Duocarmycin-Based HER2-Targeting Antibody–Drug Conjugate, Shows Antitumor Activity in Uterine and Ovarian Carcinosarcoma with HER2/Neu Expression

“…In Nicoletti’s study, T-DM1 and T were similarly effective in inducing strong ADCC against CS overexpressing HER2 at 3+ levels. In contrast, T-DM1 was dramatically more effective than T in inhibiting cell proliferation and, more importantly, in reducing tumor formation in CS xenografts overexpressing HER2 with a significantly longer survival when compared to T (44). Unfortunately, the activity of TDM-1 was evlauted in this study only against HER2/neu 3+ CS by IHC and c-erbB gene amplified endometrial cancer cell lines.…”

“…In an effort to optimize the use of HER2 blockade in the next phase of CS treatment and meaningfully alter patient outcomes, multiple groups including our own, have investigated the frequency of HER2 expression in uterine and ovarian CS with a reported range of overexpression of 25%–56% (32–34, 43, 44). Along these lines, Nicoletti et al, recently compared the activity of T-DM1 and Trastuzumab (T) against HER2 positive and negative primary CS cell lines in vitro followed by developing a supportive CS in vivo model.…”

“Carcinosarcoma of the ovary, fallopian tube, and peritoneum: Prognostic factors and treatment modalities”

“…T-DM1, a combination of traztuzumab (anti-HER2/ neu) and mertansine (microtubule polymerization inhibitor) was recently demonstrated by Nicoletti et al [51] to be highly effective at targeting and killing HER2/neu OCS in a mouse model. Guzzo et al [52] reported HER2/neu gene and protein expression in primary carcinosarcoma cell lines and demonstrated trastuzumab-mediated antibody-dependent cellular cytotoxicity against uterine and ovarian carcinosarcomas in vitro.…”

Epithelial Ovarian Cancers: On-Target is Better than Near-Target

“…In another study by the GINECO group, HER 2 was found to be amplified in 6.8% of patients [93]. Many preclinical studies have shown the efficacy of HER2 targeting agents in ovarian cell lines [94][95][96]. In the clinical setting, a phase II trial was undertaken, where the eligible patients had 2/3+ IHC score for HER2.…”

“…So, they concluded that the role of trastuzumab in ovarian cancer is limited because of the low levels of expression of HER2 as well as the low response rates [97]. Trastuzumab emtansine (T-DM1) has also shown to be effective in ovarian cancer cell lines, but there is lack of any meaningful clinical data [95].…”