Targeted inhibition of farnesyltransferase in locally advanced breast cancer

A phase I and II trial of tipifarnib plus dose-dense doxorubicin and cyclophosphamide

Joseph A. Sparano, Stacy Moulder, Aslamuzzaman Kazi, Linda Vahdat, Tianhong Li, Christine Pellegrino, Pam Munster, Mokenge Malafa, David Lee, Shira Hoschander, Una Hopkins, Dawn Hershman, John J. Wright, Said M. Sebti

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Purpose: To determine the recommended phase II dose (RPTD) of the farnesyltransferase (FTase) inhibitor tipifarnib when combined with doxorubicin and cyclophosphamide (AC) in patients with advanced breast cancer, the pathologic complete response (pCR) rate after preoperative treatment with four cycles of the combination in locally advanced breast cancer (LABC), and the effect of tipifarnib on primary tumor FTase enzyme activity in vivo. Patients and Methods: Thirty-two patients with metastatic breast cancer (n = 11) or LABC (n = 21) received AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) administered intravenously on day 1 plus tipifarnib (100, 200, or 300 mg bid for 6 to 14 days) without (n = 2) or with (n = 30) granulocyte colony-stimulating factor (G-CSF) for up to four cycles. Patients with LABC underwent surgery after up to four cycles of the combination. Results: When combined with AC every 2 weeks plus G-CSF, the RPTD of tipifarnib was 200 mg bid administered on days 2 to 7. Seven (33%) of 21 patients (95% CI, 15% to 55%) with LABC treated with up to four cycles of the combination at the RPTD had a pCR in the breast at surgery. The five patients had serial biopsies that demonstrated at least 50% FTase enzyme inhibition in the primary tumor (median, 100%; range, 55% to 100%) after tipifarnib. Conclusion: Tipifarnib may be safely combined with dose-dense AC using a dose and schedule that significantly inhibits FTase enzyme activity in human breast cancer in vivo and may enhance the pCR rate after four cycles of preoperative dose-dense AC.

Original languageEnglish (US)
Pages (from-to)3013-3018
Number of pages6
JournalJournal of Clinical Oncology
Volume24
Issue number19
DOIs
StatePublished - Jul 1 2006
Externally publishedYes

Fingerprint

tipifarnib
Farnesyltranstransferase
Doxorubicin
Cyclophosphamide
Breast Neoplasms
Granulocyte Colony-Stimulating Factor
Enzymes
Human Activities
Neoplasms
Appointments and Schedules
Breast
Biopsy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Targeted inhibition of farnesyltransferase in locally advanced breast cancer : A phase I and II trial of tipifarnib plus dose-dense doxorubicin and cyclophosphamide. / Sparano, Joseph A.; Moulder, Stacy; Kazi, Aslamuzzaman; Vahdat, Linda; Li, Tianhong; Pellegrino, Christine; Munster, Pam; Malafa, Mokenge; Lee, David; Hoschander, Shira; Hopkins, Una; Hershman, Dawn; Wright, John J.; Sebti, Said M.

In: Journal of Clinical Oncology, Vol. 24, No. 19, 01.07.2006, p. 3013-3018.

Research output: Contribution to journalArticle

Sparano, JA, Moulder, S, Kazi, A, Vahdat, L, Li, T, Pellegrino, C, Munster, P, Malafa, M, Lee, D, Hoschander, S, Hopkins, U, Hershman, D, Wright, JJ & Sebti, SM 2006, 'Targeted inhibition of farnesyltransferase in locally advanced breast cancer: A phase I and II trial of tipifarnib plus dose-dense doxorubicin and cyclophosphamide', Journal of Clinical Oncology, vol. 24, no. 19, pp. 3013-3018. https://doi.org/10.1200/JCO.2005.04.9114
Sparano, Joseph A. ; Moulder, Stacy ; Kazi, Aslamuzzaman ; Vahdat, Linda ; Li, Tianhong ; Pellegrino, Christine ; Munster, Pam ; Malafa, Mokenge ; Lee, David ; Hoschander, Shira ; Hopkins, Una ; Hershman, Dawn ; Wright, John J. ; Sebti, Said M. / Targeted inhibition of farnesyltransferase in locally advanced breast cancer : A phase I and II trial of tipifarnib plus dose-dense doxorubicin and cyclophosphamide. In: Journal of Clinical Oncology. 2006 ; Vol. 24, No. 19. pp. 3013-3018.
@article{9e82f7b1d47a4915b1c62db9769f35bd,
title = "Targeted inhibition of farnesyltransferase in locally advanced breast cancer: A phase I and II trial of tipifarnib plus dose-dense doxorubicin and cyclophosphamide",
abstract = "Purpose: To determine the recommended phase II dose (RPTD) of the farnesyltransferase (FTase) inhibitor tipifarnib when combined with doxorubicin and cyclophosphamide (AC) in patients with advanced breast cancer, the pathologic complete response (pCR) rate after preoperative treatment with four cycles of the combination in locally advanced breast cancer (LABC), and the effect of tipifarnib on primary tumor FTase enzyme activity in vivo. Patients and Methods: Thirty-two patients with metastatic breast cancer (n = 11) or LABC (n = 21) received AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) administered intravenously on day 1 plus tipifarnib (100, 200, or 300 mg bid for 6 to 14 days) without (n = 2) or with (n = 30) granulocyte colony-stimulating factor (G-CSF) for up to four cycles. Patients with LABC underwent surgery after up to four cycles of the combination. Results: When combined with AC every 2 weeks plus G-CSF, the RPTD of tipifarnib was 200 mg bid administered on days 2 to 7. Seven (33{\%}) of 21 patients (95{\%} CI, 15{\%} to 55{\%}) with LABC treated with up to four cycles of the combination at the RPTD had a pCR in the breast at surgery. The five patients had serial biopsies that demonstrated at least 50{\%} FTase enzyme inhibition in the primary tumor (median, 100{\%}; range, 55{\%} to 100{\%}) after tipifarnib. Conclusion: Tipifarnib may be safely combined with dose-dense AC using a dose and schedule that significantly inhibits FTase enzyme activity in human breast cancer in vivo and may enhance the pCR rate after four cycles of preoperative dose-dense AC.",
author = "Sparano, {Joseph A.} and Stacy Moulder and Aslamuzzaman Kazi and Linda Vahdat and Tianhong Li and Christine Pellegrino and Pam Munster and Mokenge Malafa and David Lee and Shira Hoschander and Una Hopkins and Dawn Hershman and Wright, {John J.} and Sebti, {Said M.}",
year = "2006",
month = "7",
day = "1",
doi = "10.1200/JCO.2005.04.9114",
language = "English (US)",
volume = "24",
pages = "3013--3018",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "19",

}

TY - JOUR

T1 - Targeted inhibition of farnesyltransferase in locally advanced breast cancer

T2 - A phase I and II trial of tipifarnib plus dose-dense doxorubicin and cyclophosphamide

AU - Sparano, Joseph A.

AU - Moulder, Stacy

AU - Kazi, Aslamuzzaman

AU - Vahdat, Linda

AU - Li, Tianhong

AU - Pellegrino, Christine

AU - Munster, Pam

AU - Malafa, Mokenge

AU - Lee, David

AU - Hoschander, Shira

AU - Hopkins, Una

AU - Hershman, Dawn

AU - Wright, John J.

AU - Sebti, Said M.

PY - 2006/7/1

Y1 - 2006/7/1

N2 - Purpose: To determine the recommended phase II dose (RPTD) of the farnesyltransferase (FTase) inhibitor tipifarnib when combined with doxorubicin and cyclophosphamide (AC) in patients with advanced breast cancer, the pathologic complete response (pCR) rate after preoperative treatment with four cycles of the combination in locally advanced breast cancer (LABC), and the effect of tipifarnib on primary tumor FTase enzyme activity in vivo. Patients and Methods: Thirty-two patients with metastatic breast cancer (n = 11) or LABC (n = 21) received AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) administered intravenously on day 1 plus tipifarnib (100, 200, or 300 mg bid for 6 to 14 days) without (n = 2) or with (n = 30) granulocyte colony-stimulating factor (G-CSF) for up to four cycles. Patients with LABC underwent surgery after up to four cycles of the combination. Results: When combined with AC every 2 weeks plus G-CSF, the RPTD of tipifarnib was 200 mg bid administered on days 2 to 7. Seven (33%) of 21 patients (95% CI, 15% to 55%) with LABC treated with up to four cycles of the combination at the RPTD had a pCR in the breast at surgery. The five patients had serial biopsies that demonstrated at least 50% FTase enzyme inhibition in the primary tumor (median, 100%; range, 55% to 100%) after tipifarnib. Conclusion: Tipifarnib may be safely combined with dose-dense AC using a dose and schedule that significantly inhibits FTase enzyme activity in human breast cancer in vivo and may enhance the pCR rate after four cycles of preoperative dose-dense AC.

AB - Purpose: To determine the recommended phase II dose (RPTD) of the farnesyltransferase (FTase) inhibitor tipifarnib when combined with doxorubicin and cyclophosphamide (AC) in patients with advanced breast cancer, the pathologic complete response (pCR) rate after preoperative treatment with four cycles of the combination in locally advanced breast cancer (LABC), and the effect of tipifarnib on primary tumor FTase enzyme activity in vivo. Patients and Methods: Thirty-two patients with metastatic breast cancer (n = 11) or LABC (n = 21) received AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) administered intravenously on day 1 plus tipifarnib (100, 200, or 300 mg bid for 6 to 14 days) without (n = 2) or with (n = 30) granulocyte colony-stimulating factor (G-CSF) for up to four cycles. Patients with LABC underwent surgery after up to four cycles of the combination. Results: When combined with AC every 2 weeks plus G-CSF, the RPTD of tipifarnib was 200 mg bid administered on days 2 to 7. Seven (33%) of 21 patients (95% CI, 15% to 55%) with LABC treated with up to four cycles of the combination at the RPTD had a pCR in the breast at surgery. The five patients had serial biopsies that demonstrated at least 50% FTase enzyme inhibition in the primary tumor (median, 100%; range, 55% to 100%) after tipifarnib. Conclusion: Tipifarnib may be safely combined with dose-dense AC using a dose and schedule that significantly inhibits FTase enzyme activity in human breast cancer in vivo and may enhance the pCR rate after four cycles of preoperative dose-dense AC.

UR - http://www.scopus.com/inward/record.url?scp=33746015951&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33746015951&partnerID=8YFLogxK

U2 - 10.1200/JCO.2005.04.9114

DO - 10.1200/JCO.2005.04.9114

M3 - Article

VL - 24

SP - 3013

EP - 3018

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 19

ER -