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

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 adding tipifarnib 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 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 (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.

Tipifarnib and farnesyltransferase inhibitors in the treatment of inflammatory breast cancer: is the story over? A review

“…This was greater than the 10%-15% pCR rate in historical controls treated with doxorubicin-cyclophosphamide chemotherapy alone. 90 In the course of the treatment, farnesyltransferase enzyme activity in the tumor was decreased in most patients. Twelve patients with IBC were included in this study; among them, two (17%) achieved breast pCR.…”

“…Tipifarnib was added to a neoadjuvant doxorubicin-cyclophosphamide regimen being given to patients with clinical stage IIB-IIIC breast cancer. 90 Of the total 44 patients, eleven (25%) had a breast pCR. This was greater than the 10%-15% pCR rate in historical controls treated with doxorubicin-cyclophosphamide chemotherapy alone.…”

“…Twelve patients with IBC were included in this study; among them, two (17%) achieved breast pCR. 90 The authors concluded that tipifarnib inhibits farnesyltransferase activity in vivo and enhances the breast pCR rate, which warrants further evaluation. Among biomarkers studied in this trial was expression of RhoA, -B, and -C GTPase proteins in the tumors.…”

“…However, some activity of tipifarnib as a single agent was demonstrated in metastatic BC and in combination with standard neoadjuvant chemotherapy in LABC. 57,90 As discussed earlier, few IBC patients were included in the latter trial, and their outcomes were analyzed as a separate subset without significant difference between IBC and noninflammatory BC. 90 Unfortunately, the sample was too small to draw any meaningful conclusions.…”

Targeting the inflammatory pathways to enhance chemotherapy of cancer

“…77 In a phase II trial of tipifarnib plus neoadjuvant doxorubicin-cyclophosphamide, the biological effects of tipifarnib in primary breast cancers in vivo is associated with downregulation of phospho-STAT3. 78 Pham et al observed that the combination of degrasyn, a novel inhibitor of the in JAK/STAT pathway and bortezomib ©2 0 1 1 L a n d e s B i o s c i e n c e .…”