maytansine and Carcinoma

Targeting the human epidermal growth factor receptor 2 (HER2) has yielded major advances in breast cancer treatment. Accordingly, it has generated interest in targeting HER2 to treat gynecologic malignancies. Multiple studies have evaluated the rates of HER2 overexpression and/or amplification in ovarian and uterine cancers. HER2 has also been studied as a prognostic factor but resulting data has been contradictory. Moreover, clinical trials of HER2-directed therapies, including trastuzumab, pertuzumab, and lapatinib in ovarian and uterine cancers have been largely disappointing. Current research on HER2 in gynecologic malignancies has focused on identifying mechanisms of resistance and looking further into how HER2 signaling in gynecologic cancers differs from breast cancer. In this review, we highlight the existing data of targeting HER2 in ovarian and uterine carcinomas, many dating back more than a decade, and discuss future directions in pursuing HER2 as a potential target in these diseases.

Topics: Adenocarcinoma, Mucinous; Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma; Endometrial Neoplasms; Female; Genes, erbB-2; Humans; Lapatinib; Maytansine; Molecular Targeted Therapy; Ovarian Neoplasms; Quinazolines; Trastuzumab; Uterine Neoplasms

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Clinical Trials as Topic; Combined Modality Therapy; Female; Genes, erbB-2; Humans; Lapatinib; Mastectomy; Maytansine; Molecular Targeted Therapy; Neoadjuvant Therapy; Neoplasm Micrometastasis; Quinolines; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Taxoids; Trastuzumab

Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy. The objective of this study was to compare the anti-tumor activity of HER2/neu-targeting monoclonal antibodies, trastuzumab (T), pertuzumab (P), combination of trastuzumab and pertuzumab (T+P) and trastuzumab-emtansine (T-DM1) in EOC with high HER2/neu expression.. Primary EOC cell lines were established and cell blocks were analyzed for HER2/neu expression. Cytostatic, apoptotic and antibody-dependent cell-mediated cytotoxicity (ADCC) activities of T, P, T+P and T-DM1 were evaluated in vitro. The in vivo antitumor activity was tested in xenograft models with 3+ HER2/neu expression.. High (3+) HER2/neu expression was detected in 40% of the primary EOC cell lines. T, P, T+P, and T-DM1 were similarly effective in inducing strong ADCC against primary EOC cell lines expressing 3+ HER2/neu. The combination of T and P was more cytostatic when compared with that of T or P used alone (p<0.0001 and p<0.0001, respectively). T-DM1 induced significantly more apoptosis when compared with T+P (p<0.0001). Finally, T-DM1 was significantly more effective in tumor growth inhibition in vivo in EOC xenografts overexpressing HER2/neu when compared to T alone, P alone and T+P (p=0.04).. In vitro and in vivo experiments with 3+ HER2/neu expressing EOC revealed limited anti-tumor activity of T or P. T-DM1 showed superior anti-tumor activity to T and P as single agents and as a combination. Our preclinical data support the design of clinical studies with T-DM1 for the treatment of chemotherapy-resistant EOC overexpressing HER2/neu.

Topics: Adult; Aged; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Drug Combinations; Female; Humans; Maytansine; Mice; Mice, SCID; Middle Aged; Ovarian Neoplasms; Receptor, ErbB-2; Trastuzumab

This is preliminary study assessing the efficacy and safety of concurrent use of radiation therapy (RT) and T-DM1 for the treatment of brain metastases (BM) in patients with HER2-positive metastatic breast cancer (BC). We retrospectively studied 12 patients treated for BM at the Institut Curie in 2014-2015 with T-DM1 and concurrent (4) or sequential (8) radiosurgery with or without whole brain irradiation. The following variables were studied: local control, clinical and radiological response as well as early and late side effects. The mean age of the population was 38 years at the time of diagnosis of BC and 46 years at of BM. All patients were with good PS. The response rate of the concurrent treatment group was 75 % with 1 complete response, 1 partial response, one stable disease and 1 progression. Comparatively, the response rate in the sequential group was as follows: two complete responses, two partial responses, six cases of stable disease and two cases of local progression. No patient experienced interruption of irradiation because of side effects. About 50 % of patients were asymptomatic after treatment. Radiation necrosis was observed in 50 % of patients in the concurrent group and 28.6 % of patients in the sequential group with a similar rate of oedema in the two groups. We found that the combination of T-DM1 and radiosurgery was feasible but can increase the incidence of radiation necrosis. Larger prospective studies with longer follow-up are needed to more clearly evaluate this association.

Topics: Ado-Trastuzumab Emtansine; Adult; Antineoplastic Agents, Immunological; Brain Neoplasms; Breast Neoplasms; Carcinoma; Female; Humans; Maytansine; Middle Aged; Radiosurgery; Receptor, ErbB-2; Retrospective Studies; Trastuzumab; Treatment Outcome; Young Adult

Amplification of c-erbB2 has been reported in over 30% of uterine serous carcinoma (USC) and found to confer poor survival because of high proliferation and increased resistance to therapy. In this study, we evaluated for the first time Trastuzumab emtansine (T-DM1), a novel antibody-drug conjugate, against multiple epidermal growth factor receptor-2 (HER2)-positive USC cells in vitro followed by developing a supportive in vivo model. Fifteen primary USC cell lines were assessed by immunohistochemistry (IHC) and flow cytometry for HER2 protein expression. C-erbB2 gene amplification was evaluated using fluorescent in situ hybridization. Sensitivity to T-DM1 and trastuzumab (T)-induced antibody-dependent cell-mediated cytotoxicity was evaluated in 5-h chromium release assays. T-DM1 and T cytostatic and apoptotic activities were evaluated using flow-cytometry-based proliferation assays. In vivo activity of T-DM1 versus T in USC xenografts in SCID mice was also evaluated. High levels of HER2 protein overexpression and HER2 gene amplification were detected in 33% of USC cell lines. T-DM1 was considerably more effective than trastuzumab in inhibiting cell proliferation and in causing apoptosis (P = 0.004) of USC showing HER2 overexpression. Importantly, T-DM1 was highly active at reducing tumor formation in vivo in USC xenografts overexpressing HER2 (P = 0.04) and mice treated with TDM-1 had significantly longer survival when compared to T-treated mice and control mice (P ≤ 0.0001). T-DM1 shows promising antitumor effect in HER2-positive USC cell lines and USC xenografts and its activity is significantly higher when compared to T. T-DM1 may represent a novel treatment option for HER2-positive USC patients with disease refractory to trastuzumab and traditional chemotherapy.

Topics: Ado-Trastuzumab Emtansine; Aged; Aged, 80 and over; Animals; Antibodies, Monoclonal, Humanized; Antibody-Dependent Cell Cytotoxicity; Antineoplastic Agents; Apoptosis; Carcinoma; Cell Cycle Checkpoints; Cell Proliferation; Disease Models, Animal; Female; Gene Amplification; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Maytansine; Middle Aged; Receptor, ErbB-2; RNA, Messenger; Trastuzumab; Uterine Neoplasms; Xenograft Model Antitumor Assays

Topics: Adenocarcinoma; Adult; Aged; Carcinoma; Drug Evaluation; Female; Humans; Lung Neoplasms; Male; Maytansine; Middle Aged; Neoplasm Metastasis; Oxazines

Topics: Acridines; Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents; Aspartic Acid; Carcinoma; Cell Line; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Evaluation; Female; Humans; Lomustine; Male; Maytansine; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; Organophosphorus Compounds; Phosphonoacetic Acid; Streptozocin; Transplantation, Heterologous; Triazines