Phase II trial of tipifarnib plus neoadjuvant doxorubicin-cyclophosphamide in patients with clinical stage IIB-IIIC breast cancer

Joseph A. Sparano, Stacy Moulder, Aslamuzzaman Kazi, Domenico Coppola, Abdissa Negassa, Linda Vahdat, Tianhong Li, Christine Pellegrino, Susan A. Fineberg, Pam Munster, Mokenge Malafa, David Lee, Shira Hoschander, Una Hopkins, Dawn Hershman, John J. Wright, Celina Kleer, Sofia Merajver, Said M. Sebti

Research output: Contribution to journalArticle

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Abstract

Purpose: Tipifarnib is a farnesyl transferase (FTase) inhibitor that has activity in metastatic breast cancer and enhances the efficacy of cytotoxic agents in preclinical models. We evaluated the biological effects of tipifarnib in primary breast cancers in vivo, whether addingtipifarnib to preoperative chemotherapy increased the pathologic complete response rate (pCR) at surgery, and determined whether biomarkers predictive of pCR could be identified. Experimental Design: Forty-four patients with stage IIB-IIIC breast cancer received up to four cycles of neoadjuvant doxorubicin-cyclophosphamide (AC) every 2 weeks plus tipifarnib and filgrastim followed by surgery. Enzymatic assays measuring FTase activity and Western blotting for phospho (p) -signal transducer and activator of transcription 3 (STAT3), phospho-extracellular signal-regulated kinase, p-AKT, and p27 were done in 11 patients who agreed to optional tissue biopsies before therapy and 2 hours after the final dose of tipifarnib duringthe first cycle, and predictive biomarkers were evaluated by immunohistochemistry in 33 patients. The trial was powered to detect an improvement in breast pCR rate of 10% or less expected for AC alone to 25% for AC-tipifarnib (a =0.05, b = 0.10). Results: Eleven patients had a breast pCR (25%; 95% confidence interval, 13-40%). FTase enzyme activity decreased in all patients (median, 91%; range, 24-100%) and p-STAT3 expression decreased in 7 of 9 (77%) patients. Low tumor Ki-67 expression (below the median of 60%) at baseline was significantly associated with resistance to therapy (P = 0.01). Conclusion: Tipifarnib inhibits FTase activity in human breast tumors in vivo, is associated with down-regulation of p-STAT3, and enhances the breast pCR rate, thus meriting further evaluation.

Original languageEnglish (US)
Pages (from-to)2942-2948
Number of pages7
JournalClinical Cancer Research
Volume15
Issue number8
DOIs
StatePublished - Apr 15 2009

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tipifarnib
Doxorubicin
Cyclophosphamide
Breast Neoplasms
Transferases
STAT3 Transcription Factor
Breast
Biomarkers
Extracellular Signal-Regulated MAP Kinases
Cytotoxins
Enzyme Assays
Human Activities
Research Design
Down-Regulation
Western Blotting
Immunohistochemistry
Confidence Intervals
Biopsy
Drug Therapy
Enzymes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase II trial of tipifarnib plus neoadjuvant doxorubicin-cyclophosphamide in patients with clinical stage IIB-IIIC breast cancer. / Sparano, Joseph A.; Moulder, Stacy; Kazi, Aslamuzzaman; Coppola, Domenico; Negassa, Abdissa; Vahdat, Linda; Li, Tianhong; Pellegrino, Christine; Fineberg, Susan A.; Munster, Pam; Malafa, Mokenge; Lee, David; Hoschander, Shira; Hopkins, Una; Hershman, Dawn; Wright, John J.; Kleer, Celina; Merajver, Sofia; Sebti, Said M.

In: Clinical Cancer Research, Vol. 15, No. 8, 15.04.2009, p. 2942-2948.

Research output: Contribution to journalArticle

Sparano, JA, Moulder, S, Kazi, A, Coppola, D, Negassa, A, Vahdat, L, Li, T, Pellegrino, C, Fineberg, SA, Munster, P, Malafa, M, Lee, D, Hoschander, S, Hopkins, U, Hershman, D, Wright, JJ, Kleer, C, Merajver, S & Sebti, SM 2009, 'Phase II trial of tipifarnib plus neoadjuvant doxorubicin-cyclophosphamide in patients with clinical stage IIB-IIIC breast cancer', Clinical Cancer Research, vol. 15, no. 8, pp. 2942-2948. https://doi.org/10.1158/1078-0432.CCR-08-2658
Sparano, Joseph A. ; Moulder, Stacy ; Kazi, Aslamuzzaman ; Coppola, Domenico ; Negassa, Abdissa ; Vahdat, Linda ; Li, Tianhong ; Pellegrino, Christine ; Fineberg, Susan A. ; Munster, Pam ; Malafa, Mokenge ; Lee, David ; Hoschander, Shira ; Hopkins, Una ; Hershman, Dawn ; Wright, John J. ; Kleer, Celina ; Merajver, Sofia ; Sebti, Said M. / Phase II trial of tipifarnib plus neoadjuvant doxorubicin-cyclophosphamide in patients with clinical stage IIB-IIIC breast cancer. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 8. pp. 2942-2948.
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abstract = "Purpose: Tipifarnib is a farnesyl transferase (FTase) inhibitor that has activity in metastatic breast cancer and enhances the efficacy of cytotoxic agents in preclinical models. We evaluated the biological effects of tipifarnib in primary breast cancers in vivo, whether addingtipifarnib to preoperative chemotherapy increased the pathologic complete response rate (pCR) at surgery, and determined whether biomarkers predictive of pCR could be identified. Experimental Design: Forty-four patients with stage IIB-IIIC breast cancer received up to four cycles of neoadjuvant doxorubicin-cyclophosphamide (AC) every 2 weeks plus tipifarnib and filgrastim followed by surgery. Enzymatic assays measuring FTase activity and Western blotting for phospho (p) -signal transducer and activator of transcription 3 (STAT3), phospho-extracellular signal-regulated kinase, p-AKT, and p27 were done in 11 patients who agreed to optional tissue biopsies before therapy and 2 hours after the final dose of tipifarnib duringthe first cycle, and predictive biomarkers were evaluated by immunohistochemistry in 33 patients. The trial was powered to detect an improvement in breast pCR rate of 10{\%} or less expected for AC alone to 25{\%} for AC-tipifarnib (a =0.05, b = 0.10). Results: Eleven patients had a breast pCR (25{\%}; 95{\%} confidence interval, 13-40{\%}). FTase enzyme activity decreased in all patients (median, 91{\%}; range, 24-100{\%}) and p-STAT3 expression decreased in 7 of 9 (77{\%}) patients. Low tumor Ki-67 expression (below the median of 60{\%}) at baseline was significantly associated with resistance to therapy (P = 0.01). Conclusion: Tipifarnib inhibits FTase activity in human breast tumors in vivo, is associated with down-regulation of p-STAT3, and enhances the breast pCR rate, thus meriting further evaluation.",
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T1 - Phase II trial of tipifarnib plus neoadjuvant doxorubicin-cyclophosphamide in patients with clinical stage IIB-IIIC breast cancer

AU - Sparano, Joseph A.

AU - Moulder, Stacy

AU - Kazi, Aslamuzzaman

AU - Coppola, Domenico

AU - Negassa, Abdissa

AU - Vahdat, Linda

AU - Li, Tianhong

AU - Pellegrino, Christine

AU - Fineberg, Susan A.

AU - Munster, Pam

AU - Malafa, Mokenge

AU - Lee, David

AU - Hoschander, Shira

AU - Hopkins, Una

AU - Hershman, Dawn

AU - Wright, John J.

AU - Kleer, Celina

AU - Merajver, Sofia

AU - Sebti, Said M.

PY - 2009/4/15

Y1 - 2009/4/15

N2 - Purpose: Tipifarnib is a farnesyl transferase (FTase) inhibitor that has activity in metastatic breast cancer and enhances the efficacy of cytotoxic agents in preclinical models. We evaluated the biological effects of tipifarnib in primary breast cancers in vivo, whether addingtipifarnib to preoperative chemotherapy increased the pathologic complete response rate (pCR) at surgery, and determined whether biomarkers predictive of pCR could be identified. Experimental Design: Forty-four patients with stage IIB-IIIC breast cancer received up to four cycles of neoadjuvant doxorubicin-cyclophosphamide (AC) every 2 weeks plus tipifarnib and filgrastim followed by surgery. Enzymatic assays measuring FTase activity and Western blotting for phospho (p) -signal transducer and activator of transcription 3 (STAT3), phospho-extracellular signal-regulated kinase, p-AKT, and p27 were done in 11 patients who agreed to optional tissue biopsies before therapy and 2 hours after the final dose of tipifarnib duringthe first cycle, and predictive biomarkers were evaluated by immunohistochemistry in 33 patients. The trial was powered to detect an improvement in breast pCR rate of 10% or less expected for AC alone to 25% for AC-tipifarnib (a =0.05, b = 0.10). Results: Eleven patients had a breast pCR (25%; 95% confidence interval, 13-40%). FTase enzyme activity decreased in all patients (median, 91%; range, 24-100%) and p-STAT3 expression decreased in 7 of 9 (77%) patients. Low tumor Ki-67 expression (below the median of 60%) at baseline was significantly associated with resistance to therapy (P = 0.01). Conclusion: Tipifarnib inhibits FTase activity in human breast tumors in vivo, is associated with down-regulation of p-STAT3, and enhances the breast pCR rate, thus meriting further evaluation.

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