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 T Stopeck, Hannah Linden, David Solit, Sarat Chandarlapaty, Neal Rosen, Gabriella D'Andrea, Maura Dickler, Mary E. Moynahan, Steven Sugarman, Weining Ma, Sujata Patil, Larry Norton, Alison L. Hannah, Clifford Hudis

Research output: Contribution to journalArticle

283 Citations (Scopus)

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/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.

Original languageEnglish (US)
Pages (from-to)5132-5139
Number of pages8
JournalClinical Cancer Research
Volume17
Issue number15
DOIs
StatePublished - Aug 1 2011

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tanespimycin
Breast Neoplasms
Therapeutic Human Experimentation
Karnofsky Performance Status
Protein Stability
Biological Products
Nausea
Disease-Free Survival
Fatigue
Headache
Disease Progression
Trastuzumab
Diarrhea
Proteins
Research Design

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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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. / Modi, Shanu; Stopeck, Alison T; Linden, Hannah; Solit, David; Chandarlapaty, Sarat; Rosen, Neal; D'Andrea, Gabriella; Dickler, Maura; Moynahan, Mary E.; Sugarman, Steven; Ma, Weining; Patil, Sujata; Norton, Larry; Hannah, Alison L.; Hudis, Clifford.

In: Clinical Cancer Research, Vol. 17, No. 15, 01.08.2011, p. 5132-5139.

Research output: Contribution to journalArticle

Modi, S, Stopeck, AT, Linden, H, Solit, D, Chandarlapaty, S, Rosen, N, D'Andrea, G, Dickler, M, Moynahan, ME, Sugarman, S, Ma, W, Patil, S, Norton, L, Hannah, AL & Hudis, C 2011, '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', Clinical Cancer Research, vol. 17, no. 15, pp. 5132-5139. https://doi.org/10.1158/1078-0432.CCR-11-0072
Modi, Shanu ; Stopeck, Alison T ; Linden, Hannah ; Solit, David ; Chandarlapaty, Sarat ; Rosen, Neal ; D'Andrea, Gabriella ; Dickler, Maura ; Moynahan, Mary E. ; Sugarman, Steven ; Ma, Weining ; Patil, Sujata ; Norton, Larry ; Hannah, Alison L. ; Hudis, Clifford. / 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. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 15. pp. 5132-5139.
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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/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.",
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AU - Stopeck, Alison T

AU - Linden, Hannah

AU - Solit, David

AU - Chandarlapaty, Sarat

AU - Rosen, Neal

AU - D'Andrea, Gabriella

AU - Dickler, Maura

AU - Moynahan, Mary E.

AU - Sugarman, Steven

AU - Ma, Weining

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