HER2/neu as a Potential Target for Immunotherapy in Gynecologic Carcinosarcomas

Abstract

Carcinosarcomas of the female genital tract are rare tumors with aggressive clinical behavior. Trastuzumab, a humanized monoclonal antibody, acts by binding to HER2/neu extracellular domain and exhibits therapeutic efficacy in HER2/neu over-expressing cancers. Two uterine carcinosarcomas (UMMT-ARK-1, UMMT-ARK-2) and two ovarian carcinosarcomas (OMMT-ARK-1, OMMT-ARK-2) were established as primary tumor cell lines in vitro and evaluated for HER2/neu expression by immunohistochemistry (IHC), fluorescent-in-situ-hybridization-analysis (FISH), quantitative-real-time-polymerase-chain-reaction and for membrane-bound-complement-regulatory-proteins (mCRP) CD46, CD55 and CD59 by flow-cytometry. Sensitivity to trastuzumab-dependent-cell-mediated-cytotoxicity (ADCC) and complement-dependent-cytotoxicity (CDC) was studied in 5-hour-chromium-release-assays. HER2/neu expression was demonstrated in OMMT-ARK-1 and OMMT-ARK-2. OMMT-ARK-2 demonstrated amplification of the c-erbB2 gene by FISH and a high sensitivity to ADCC (mean killing 45.6%; range: 32.3–72.6%). Lower level of killing was detected against the FISH-negative OMMT-ARK-1 cell line (mean 26.5%; range: 21.0–31.8%). CD46, CD55 and CD59 mCRP were expressed at high levels in all primary MMT cell lines and all these tumors were found highly resistant to CDC with or without trastuzumab. Addition of untreated and heat-inactivated-plasma did not significantly decrease ADCC against OMMT-ARK-2 cell line suggesting that while the cell line is highly resistant to complement, irrelevant IgG do not significantly alter the ability of trastuzumab to mediate ADCC. Our results suggest that HER2/neu may represent a novel target for the immunotherapy of a subset of human carcinosarcomas refractory to salvage chemotherapy.

“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.…”

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

“…Carcinosarcomas can arise in the ovary, cervix or uterus. Previously published data from the SEER database suggests that age adjusted rate of carcinosarcoma development in the uterus is 0.6/100,000 and in the ovary 0.19/100,000 (4). Despite aggressive surgical and adjuvant therapy, 5 year survival rates for uterine carcinosarcoma are approximately 60% for early (stage I/II) disease and 9–22% for more advanced disease (5).…”

“…These genetic landscape results are consistent with previous clinical/pathological studies showing that the epithelial component of the carcinosarcoma drives the growth and proliferation of these rare and biologically aggressive gynecologic cancers. Because of the reported overexpression and/or gene amplification of HER2 in over one third of uterine serous carcinoma (12, 13) which represents the high grade epithelial component of a large number of gynecologic CS (10), HER2 may represent an attractive target for anticancer therapy (4). …”

Neratinib shows efficacy in the treatment of HER2 amplified carcinosarcoma in vitro and in vivo

“…Carcinosarcomas can arise in the ovary, cervix or uterus. Previously published data from the SEER data base suggests that age adjusted rate of carcinosarcoma development in the uterus is 0.6/100,000 and in the ovary 0.19/100,000 [2]. Despite aggressive surgical and adjuvant therapy 5 year survival rates for uterine carcinosarcoma are approximately 60% for early (stage I/II) disease and 9–22% for more advanced disease [3].…”