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

Irene Dehghan-Paz,¹ Dora Il'yasova,² Kenneth L van Golen,³ Lydia Usha<sup>1

1</sup>Division of Hematology and Oncology, Rush University Medical Center, Chicago, IL, USA; ²Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA; ³Department of Biological Sciences, University of Delaware, Newark, DE, USA


Abstract: Inflammatory breast cancer (IBC) is a rare but aggressive form of breast cancer with unique clinicopathological features and poor prognosis. Its epidemiology is distinct from noninflammatory locally advanced breast cancer (LABC), which points to different etiology. With the advent of multimodality treatment for LABC, the outcomes for women with IBC have improved, but remain significantly inferior to outcomes for noninflammatory LABC. This review focuses on new research in epidemiology and molecular pathways characteristic for IBC. One of the critical carcinogenic events apparently driving the development and progression of IBC is activation of the RhoC protein, which is a part of the Ras oncogene superfamily. These proteins, like other Ras proteins, require posttranslational prenylation for their activation and transfer to cell membranes. Farnesylation is a common type of prenlyation that can be blocked with a new class of drugs – farnesyltransferase inhibitors. The most advanced farnesyltransferase inhibitor in development, tipifarnib, has been evaluated in Phase II clinical trials as monotherapy and in combination with antihormonal agents and trastuzumab in metastatic and locally advanced breast cancer. A few tumor responses have been observed in these trials, but not enough to warrant a Phase III trial. Potential combinations of tipifarnib with other novel agents targeting enzymes downstream to RhoC are reviewed. Some of these drugs, such as imatinib and crizotinib, are already commercially available. Others like perifosine and anti-vascular endothelial growth factor 3 antibody are currently under development. Innovative trial designs to address this rare type of cancer are discussed.

Keywords: inflammatory breast cancer, farnesyltransferase inhibitors, tipifarnib, Rho proteins, clinical trials