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
Notes: --- - "Cited By (since 1996): 1" - "Export Date: 3 October 2011" - "CODEN: CCREF" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Sujata Patil
    383 Patil
  2. Mary Ellen Moynahan
    100 Moynahan
  3. Clifford Hudis
    843 Hudis
  4. Larry Norton
    567 Norton
  5. Neal Rosen
    363 Rosen
  6. David Solit
    431 Solit
  7. Maura N Dickler
    237 Dickler
  8. Weining Ma
    20 Ma
  9. Shanu Modi
    132 Modi