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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 (alpha = 0.05, beta = 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.

SUBMITTER: Sparano JA

PROVIDER: S-EPMC2785076 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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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 JA Moulder Stacy S Kazi Aslamuzzaman A Coppola Domenico D Negassa Abdissa A Vahdat Linda L Li Tianhong T Pellegrino Christine C Fineberg Susan S Munster Pam P Malafa Mokenge M Lee David D Hoschander Shira S Hopkins Una U Hershman Dawn D Wright John J JJ Kleer Celina C Merajver Sofia S Sebti Said M SM

Clinical cancer research : an official journal of the American Association for Cancer Research 20090407 8

<h4>Purpose</h4>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.<h4>Experimental design</h4>Forty-fo ...[more]

PMID: 19351752

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Project description:Background:The DNA damaging platinum salts have been explored in the treatment of triple negative breast cancer (TNBC) based on preclinical, and, more recently, clinical evidence of specific susceptibility of TNBC to these agents. Despite the increased toxicity, treatment intensification with polychemotherapy improves response and might be of interest in patients presenting with large primaries. In this trial, we aimed at exploring the efficacy and tolerability of the addition of cisplatin to standard anthracycline-cyclophosphamide backbone in patients with stage IIB/III TNBC. Patients and methods:This is a single arm, single center, non-randomized, phase II trial of stage IIB/III TNBC. Patients received neoadjuvant chemotherapy with cisplatin (50?mg/m2) in combination with doxorubicin (50?mg/m2) and cyclophosphamide (500?mg/m2) every 21?days and for a total of six cycles (CAP). After surgery, adjuvant chemotherapy consisting of docetaxel (75?mg/m2) every 21?days was further provided for four cycles. Primary outcome was pathological complete response in the breast and axilla (pCR; ypT0ypN0). Secondary outcomes were safety, disease-free survival (DFS), and overall survival (OS). Results:Eight (19.5%) out of 41 patients reached a pCR and 35 (85.4%) had a clinical complete or partial response. After a median follow-up of 47.4?months (interquartile range 30.9-61.9), the proportion of patients free of recurrence or death at 3?years was of 51.8% [95% confidence interval (CI) 34.6-66.5%], while the proportion of patients alive at 3?years was of 55.5% (95% CI 37.8-70.1%). Patients with a pCR rate or family history of breast and/or ovarian cancer showed a numerical but statistically non-significant trend for improved DFS and OS. The majority of patients received six cycles of CAP (82.9%). The three most common grade ?3 adverse events were nausea (16.3%), vomiting (14.0%), and neutropenia (9.3%). Febrile neutropenia occurred in three patients (7.0%). Conclusion:Cisplatin in association with doxorubicin and cyclophosphamide was associated with a pCR rate of 19.5% in a cohort of patients with predominantly stage III tumors. The tolerability profile of this combination poses clinical challenges to its general use in clinical practice. Unique Identifier Number:GBECAM 2008/02. NCT Identifier Number:NCT03304756.

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

Publications

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

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