HSP90 Inhibition Is Effective in Breast Cancer: A Phase II Trial of Tanespimycin (17-AAG) Plus Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab
Shanu Modi,Alison Stopeck,Hannah M. Linden,David B. Solit,Sarat Chandarlapaty,Neal Rosen,Gabriella D'Andrea,Maura N. Dickler,Mary Ellen Moynahan,Steven Sugarman,W. Ma,Sujata Patil,Larry Norton,Alison L. Hannah,Clifford A. Hudis +14 more
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This is the first phase II study to definitively show RECIST-defined responses for 17-AAG in solid tumors and has significant anticancer activity in patients with HER2-positive, metastatic breast cancer previously progressing on trastuzumab.Abstract:
Purpose: HSP90 is a chaperone protein required for the stability of a variety of client proteins. 17-Demethoxygeldanamycin (17-AAG) is a natural product that binds to HSP90 and inhibits its activity, thereby inducing the degradation of these clients. In preclinical studies, HER2 is one of the most sensitive known client proteins of 17-AAG. On the basis of these data and activity in a phase I study, we conducted a phase II study of 17-AAG (tanespimycin) with trastuzumab in advanced trastuzumab-refractory HER2-positive breast cancer. Experimental Design: We enrolled patients with metastatic HER2 + breast cancer whose disease had previously progressed on trastuzumab. All patients received weekly treatment with tanespimycin at 450 mg/m 2 intravenously and trastuzumab at a conventional dose. Therapy was continued until disease progression. The primary endpoint was response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Results: Thirty-one patients were enrolled with a median age of 53 years and a median Karnofsky performance status (KPS) of 90%. The most common toxicities, largely grade 1, were diarrhea, fatigue, nausea, and headache. The overall response rate was 22%, the clinical benefit rate [complete response + partial response + stable disease] was 59%, the median progression-free survival was 6 months (95% CI: 4–9), and the median overall survival was 17 months (95% CI: 16–28). Conclusions: This is the first phase II study to definitively show RECIST-defined responses for 17-AAG in solid tumors. Tanespimycin plus trastuzumab has significant anticancer activity in patients with HER2-positive, metastatic breast cancer previously progressing on trastuzumab. Further research exploring this therapeutic interaction and the activity of HSP90 inhibitors is clearly warranted. Clin Cancer Res; 17(15); 5132–9. ©2011 AACR .read more
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References
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Efficacy and Safety of Trastuzumab as a Single Agent in First-Line Treatment of HER2-Overexpressing Metastatic Breast Cancer
Charles L. Vogel,Melody A. Cobleigh,Debu Tripathy,John Gutheil,Lyndsay Harris,Louis Fehrenbacher,Dennis J. Slamon,Maureen E. Murphy,William Novotny,Michael Burchmore,Steven Shak,Stanford J. Stewart,Michael F. Press +12 more
TL;DR: Single-agent trastuzumab is active and well tolerated as first-line treatment of women with metastatic breast cancer with HER2 3+ overexpression by IHC or gene amplification by FISH.
Use of chemotherapy plus a monoclonal antibody against her2 for metastatic breast cancer that overexpresses her2
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Randomized Study of Lapatinib Alone or in Combination With Trastuzumab in Women With ErbB2-Positive, Trastuzumab-Refractory Metastatic Breast Cancer
Kimberly L. Blackwell,Harold J. Burstein,Anna Maria Storniolo,Hope S. Rugo,George W. Sledge,Maria Koehler,Catherine E. Ellis,Michelle Casey,Svetislava J. Vukelja,Joachim Bischoff,José Baselga,Joyce O'Shaughnessy +11 more
TL;DR: Despite disease progression on prior trastuzumab-based therapy, lapatinib in combination with trastzumab significantly improved PFS and CBR versus lapatinIB alone, thus offering a chemotherapy-free option with an acceptable safety profile to patients with ErbB2-positive MBC.
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Trastuzumab Beyond Progression in Human Epidermal Growth Factor Receptor 2–Positive Advanced Breast Cancer: A German Breast Group 26/Breast International Group 03-05 Study
Gunter von Minckwitz,Andreas du Bois,Marcus Schmidt,Nicolai Maass,Tanja Cufer,Felix E. de Jongh,E. Maartense,Christoph C. Zielinski,Manfred Kaufmann,Wolfgang R. Bauer,Klaus Baumann,Michael R. Clemens,Ralph Duerr,Christoph Uleer,Martin Andersson,Robert Stein,Valentina Nekljudova,Sibylle Loibl +17 more
TL;DR: Continuation of trastuzumab beyond progression was not associated with increased toxicity and showed a significant improvement in overall response and time to progression compared with capecitabine alone in women with HER-2-positive breast cancer who experienced progression during trastzumab treatment.
Journal Article
Herceptin-induced Inhibition of Phosphatidylinositol-3 Kinase and Akt Is Required for Antibody-mediated Effects on p27, Cyclin D1, and Antitumor Action
F. Michael Yakes,Wichai Chinratanalab,Christoph A. Ritter,Walter King,Steven A. Seelig,Carlos L. Arteaga +5 more
TL;DR: Data suggest that changes in cell cycle- and apoptosis-regulatory molecules after HER2 blockade with Herceptin result, at least in part, from the inhibition of Akt, and disabling PI3K and Akt is required for the antitumor effect of HER2 inhibitors.