Phase II Trial of Tipifarnib plus Neoadjuvant Doxorubicin-Cyclophosphamide in Patients with Clinical Stage IIB-IIIC Breast Cancer
Year: 2009
Type: article
Study design: Clinical Trial
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.
Source: Clinical Cancer Research
Authors: Joseph A. Sparano, Stacy Moulder, Aslamuzzaman Kazi, Domenico Coppola, Abdissa Negassa, Linda Vahdat, Tianhong Li, Christine Pellegrino, Susan Fineberg, Pam Munster, Mokenge Malafa, David Lee, Shira Hoschander, Una Hopkins, Dawn Hershman, John J. Wright, Celina Kleer, Sofia Merajver, Said M. Sebti
Institutions: Montefiore Medical Center, Yeshiva University, Montefiore Einstein Comprehensive Cancer Center, University of South Florida, Moffitt Cancer Center, Weill Cornell Medicine, Weill Cornell Medical Center, Columbia University Irving Medical Center, Columbia University, National Institutes of Health, National Cancer Institute, University of Michigan
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2122900341