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 Journal Article
| Authors: | Modi, S.; Stopeck, A.; Linden, H.; Solit, D.; Chandarlapaty, S.; Rosen, N.; D'Andrea, G.; Dickler, M.; Moynahan, M. E.; Sugarman, S.; Ma, W.; Patil, S.; Norton, L.; Hannah, A. L.; Hudis, C. |
| Article Title: | 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 |
| 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 thedegradationof these clients. In preclinical studies,HER2is one of the most sensitive known client proteins of 17-AAG.On the basis of these data and activity in a phase I study,weconducted 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 progressedontrastuzumab. All patients receivedweekly treatment with tanespimycinat 450mg/m2 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. ©2011 AACR. |
| Keywords: | adult; clinical article; treatment response; aged; disease-free survival; middle aged; overall survival; constipation; fatigue; cancer combination chemotherapy; cancer growth; diarrhea; drug efficacy; drug safety; drug withdrawal; side effect; progression free survival; phase 2 clinical trial; breast cancer; bone marrow suppression; nausea; neuropathy; vomiting; antineoplastic combined chemotherapy protocols; myalgia; breast neoplasms; arthralgia; coughing; dizziness; drug hypersensitivity; dyspnea; drug induced headache; depression; karnofsky performance status; neoplasm metastasis; tanespimycin; heat shock protein 90; hsp90 heat-shock proteins; inhibition kinetics; metastasis potential; trastuzumab; alopecia; genes, erbb-2; tremor; retreatment; benzoquinones; lactams, macrocyclic; breast neoplasms, male; heart ejection fraction; antibodies, monoclonal, humanized |
| Journal Title: | Clinical Cancer Research |
| Volume: | 17 |
| Issue: | 15 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2011-08-01 |
| Start Page: | 5132 |
| End Page: | 5139 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-11-0072 |
| PROVIDER: | scopus |
| PUBMED: | 21558407 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 3 October 2011" - "CODEN: CCREF" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work