T-DM1, a novel antibody-drug conjugate, is highly effective against uterine and ovarian carcinosarcomas overexpressing HER2.
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. Eight primary CS cell lines were evaluated for HER2 amplification and protein expression by fluorescence in situ hybridization, immunohistochemistry, flow cytometry and qRT-PCR. Sensitivity to T-DM1-induced antibody-dependent-cell-mediated-cytotoxicity (ADCC) was evaluated in 4-h-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. 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). T-DM1 may represent a novel treatment option for the subset of HER2 positive CS patients with disease refractory to chemotherapy.
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, 06520, USA.
Roberta
R
Nicoletti
Salvatore
S
Lopez
Stefania
S
Bellone
Emiliano
E
Cocco
Carlton L
CL
Schwab
Jonathan D
JD
Black
Floriana
F
Centritto
Liancheng
L
Zhu
Elena
E
Bonazzoli
Natalia
N
Buza
Pei
P
Hui
Delia
D
Mezzanzanica
Silvana
S
Canevari
Peter E
PE
Schwartz
Thomas J
TJ
Rutherford
Alessandro D
AD
Santin
D000080044:Ado-Trastuzumab Emtansine; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002296:Carcinosarcoma / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D018796:Immunoconjugates / Q000494:pharmacology*; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008453:Maytansine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051379:Mice; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000068878:Trastuzumab; D014594:Uterine Neoplasms / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C524056:Erbb2 protein, mouse