Breast cancer (BC) is the most common malignancy in women. It is classified into a few major molecular subtypes according to hormone and growth factor receptor expression. Over the past few years, substantial advances have been made in the discovery of new drugs for treating BC. Improved understanding of the biologic heterogeneity of BC has allowed the development of more effective and individualized approach to treatment. In this review, we provide an update about the current treatment strategy and discuss the various emerging novel therapies for the major molecular subtypes of BC. A brief account of the clinical development of inhibitors of poly(ADP-ribose) polymerase, cyclin-dependent kinases 4 and 6, phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway, histone deacetylation, multi-targeting tyrosine kinases, and immune checkpoints for personalized treatment of BC is included. However, no targeted drug has been approved for the most aggressive subtype-triple negative breast cancer (TNBC). Thus, we discuss the heterogeneity of TNBC and how molecular subtyping of TNBC may help drug discovery for this deadly disease. The emergence of drug resistance also poses threat to the successful development of targeted therapy in various molecular subtypes of BC. New clinical trials should incorporate advanced methods to identify changes induced by drug treatment, which may be associated with the upregulation of compensatory signaling pathways in drug resistant cancer cells.

/pdf/recent-advances-in-the-treatment-of-breast-cancer-4s2y0zq4xx.pdf

Recent Advances in the Treatment of Breast Cancer

Mode of action of docetaxel – a basis for combination with novel anticancer agents

Urokinase-type plasminogen activator (uPA) binds to the uPA receptor (uPAR) and activates the Ras-extracellular signal-regulated kinase (ERK) signaling pathway in many different cell types. In this study, we demonstrated that endogenously produced uPA functions as a major determinant of the basal level of activated ERK in MDA-MB-231 breast cancer cells. When these cells were cultured in the presence of antibodies that block the binding of uPA to uPAR, the level of phosphorylated ERK decreased substantially. Furthermore, conditioned medium from MDA-MB-231 cells activated ERK in MCF-7 cells and this response was blocked by uPA-specific antibody. The mitogen-activated protein kinase kinase inhibitor, PD098059, decreased expression of uPA and uPAR in MDA-MB-231 cells. Thus, uPA and the uPAR-ERK signaling pathway form a positive feedback loop in these cells. When this feedback loop was disrupted with uPA- or uPAR-specific antibody, uPA mRNA-specific antisense oligodeoxynucleotides or PD098059, cell growth was inhibited and apoptosis was promoted, as determined by the increase in cytoplasmic nucleosomes and caspase-3 activity. Treating the cells simultaneously with PD098059 and uPA- or uPAR-specific antibody did not further promote apoptosis, compared with either reagent added separately, supporting the hypothesis that uPAR and ERK are components of the same cell growth/survival-regulatory pathway. The ability of uPA to signal through uPAR, maintain an elevated basal level of activated ERK and inhibit apoptosis represents a novel mechanism whereby the uPA-uPAR system may affect breast cancer progression in vivo.

Endogenously produced urokinase-type plasminogen activator is a major determinant of the basal level of activated ERK/MAP kinase and prevents apoptosis in MDA-MB-231 breast cancer cells.

The role of HER2 in early breast cancer metastasis and the origins of resistance to HER2-targeted therapies.

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 ( α = 0.05, β = 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.

https://clincancerres.aacrjournals.org/content/clincanres/15/8/2942.full.pdf

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

Human solid tumors develop multiple genetic abnormalities that accumulate progressively in individual cells during the course of tumor evolution. We sought to determine whether there are specific sequences of occurrence of these progressive evolutionary changes in human breast cancers by performing correlated cell-by-cell measurements of cell DNA content, p53 protein, Her-2/neu protein, and ras protein by multiparameter flow cytometry in 56 primary tumor samples obtained at surgery. In addition, p53 allelic loss and Her-2/neu gene amplification were determined by fluorescence in situ hybridization in cells from the same samples. We reasoned that if there is a specific order in which genetic changes occur, the same early changes would be found consistently in the cells with the fewest abnormalities. We reasoned further that late-developing abnormalities would not occur alone in individual cells but would almost always be found together with the early changes inherited by the same cells. By these criteria, abnormalities involving p53 generally occurred early in the course of development of invasive breast cancers, whereas ras protein overexpression was found to be a late-occurring phenomenon. Within individual tumors, cellular p53 overexpression was often observed alone in individual cells, whereas ras protein overexpression was rarely observed in the absence of p53 overexpression and/or Her-2/neu overexpression in the same cells. Furthermore, the intracellular level of each abnormally expressed protein was found to increase progressively as new abnormalities were acquired. Infiltrating ductal carcinomas exhibited characteristic phenotypic patterns in which p53 allelic loss and/or p53 protein overexpression, Her-2/neu amplification and/or overexpression, aneuploidy, and ras overexpression accumulated within individual cells. However, this pattern was not a prominent feature of lobular breast cancers. All six lobular breast cancers studied were diploid. p53 allelic loss and/or early p53 overexpression, and late ras cooverexpression in the same cells were less common in lobular breast cancers than in infiltrating ductal carcinomas. Although Her-21neu overexpression was a common finding in lobular breast cancers, Her-2/neu amplification was not observed in these tumors.

https://clincancerres.aacrjournals.org/content/clincanres/6/1/112.full.pdf

Correlations Among p53, Her-2/neu, and ras Overexpression and Aneuploidy by Multiparameter Flow Cytometry in Human Breast Cancer: Evidence for a Common Phenotypic Evolutionary Pattern in Infiltrating Ductal Carcinomas

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Correlations Among p53, Her-2/neu, and ras Overexpression and Aneuploidy by Multiparameter Flow Cytometry in Human Breast Cancer: Evidence for a Common Phenotypic Evolutionary Pattern in Infiltrating Ductal Carcinomas