A Meaning Of the Perifosine

Intense effort has been devoted to identification of novel therapeutic targets for TNBC; however, the molecular heterogeneity and complex biology of TNBC pose significant challenges to development of targeted agents. Some progress has been made in classifying TNBC into subtypes with differing gene expression profiles,63?and?64 but the therapeutic implications are yet Perifosine to be elucidated. Pathways and agents being examined in clinical trials include antiangiogenic agents, EGFR, and PARP inhibitors, as well as PI3K, Src, and CDKs. Angiogenesis is an essential step for tumor growth and metastasis, and vascular endothelial growth factors (VEGFs), particularly VEGF-A, are among the most prominent factors in inducing pathological angiogenesis.65 Compared with other breast cancer subtypes, TNBC has been associated with?significantly higher levels of intratumor VEGF-A expression,66 which provides a rationale for evaluation of anti-VEGF agents in the treatment of TNBC, even though these agents are not necessarily classified as bona fide targeted therapeutics. Bevacizumab (Avastin; Genentech) is a humanized monoclonal antibody directed against VEGF-A. In initial studies of bevacizumab in breast cancer, performed in unselected patients with metastatic HER2? disease, the addition of bevacizumab to standard chemotherapy improved ORR and PFS, but not OS.60, 67, 68?and?69 Three randomized, placebo-controlled phase III trials of bevacizumab were conducted in the first-line metastatic setting: the Vasopressin Receptor E2100 trial (with paclitaxel),67 the Avado trial (with docetaxel),68 and the Ribbon 1 trial (with an anthracycline-, taxane-, or capecitabine-based regimen).60 In the subgroup analysis within LY2835219 each individual trial, patients with TNBC had considerable improvement in ORR and PFS in the E2100 and the Avado trials,67?and?68 but no significant improvement was observed in the Ribbon 1 trial.60 A meta-analysis was performed that included 621 patients with TNBC enrolled in these three trials (chemotherapy alone, n = 258; chemotherapy in combination with bevacizumab, n = 363). A significant improvement was observed in PFS (8.1 months versus 5.4 months; HR = 0.65; P