Phase II Trial of Tipifarnib plus Neoadjuvant Doxorubicin-Cyclophosphamide in Patients with Clinical Stage IIB-IIIC Breast Cancer

New York Cancer Consortium, including the Montefiore-Einstein Cancer Center, Montefiore Medical Center, Bronx, New York 10461, USA.
Clinical Cancer Research (Impact Factor: 8.72). 05/2009; 15(8):2942-8. DOI: 10.1158/1078-0432.CCR-08-2658
Source: PubMed


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 adding tipifarnib to preoperative chemotherapy increased the pathologic complete response rate (pCR) at surgery, and determined whether biomarkers predictive of pCR could be identified.
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 during the 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 (alpha = 0.05, beta = 0.10).
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).
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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Available from: Una Hopkins, Aug 17, 2014
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    • "The known farnesylated proteins include members of the Ras superfamily of GTPases (e.g., H-Ras, K-Ras, N-Ras) (Kho et al., 2004), the precursor proteins of the nuclear lamin A (Young et al., 2005; Chang et al., 2012), and members of the DnaJ chaperone proteins (Kampinga and Craig, 2010; Stark et al., 2014). Geranylgeranylated GTPases include the Rho family of proteins, treatments of pancreatic (90% K-Ras mutations), lung, and colon carcinomas (∼30% K-Ras mutations) (Lerner et al., 1997; Sparano et al., 2009). "
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    • "The drugs chosen for this study are relatively non-toxic, work by different mechanisms and can readily be utilized for a clinical trial. Atorvastatin and celecoxib are in broad clinical use and tipifarnib is a farnesyl transferase inhibitor that has been extensively tested in clinical trials (9–12). To the best of our knowledge the simultaneous targeting of Ras and COX-2 pathways in pancreatic cancer growth is novel. "
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    • "The FTI Tipifarnib (Zarnestra, R115777) has been evaluated for the treatment of myeloid malignancy, including for elderly patients with acute myelogenous leukemia (AML) [6,12]. Moreover, Tipifarnib has shown promising results in coadjutant therapies for breast cancer [13]. The FTI Lonafarnib have shown efficacy in melanoma cells that develop resistance to Sorafenib, a pan-Raf inhibitor [14]. "
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