BACKGROUND: Taxanes are established in the treatment of metastatic breast cancer (MBC) and early breast cancer (EBC) as potent chemotherapy agents. However, their therapeutic usefulness is limited by de-novo refractoriness or acquired resistance, which are common drawbacks to most anti-cancer cytotoxics. Considering that the taxanes will remain principle chemotherapeutic agents for the treatment of breast cancer, we reviewed known mechanisms of resistance in with an outlook of optimizing their clinical use. METHODS: We searched the PubMed and MEDLINE databases for articles (from inception through to 9th January 2012; last search 10/01/2012) and journals known to publish information relevant to taxane chemotherapy. We imposed no language restrictions. Search terms included: cancer, breast cancer, response, resistance, taxane, paclitaxel, docetaxel, taxol. Due to the possibility of alternative mechanisms of resistance all combination chemotherapy treated data sets were removed from our overview. RESULTS: Over-expression of the MDR-1 gene product Pgp was extensively studied in vitro in association with taxane resistance, but data are conflicting. Similarly, the target components microtubules, which are thought to mediate refractoriness through alterations of the expression pattern of tubulins or microtubule associated proteins and the expression of alternative tubulin isoforms, failed to confirm such associations. Little consensus has been generated for reported associations between taxane-sensitivity and mutated p53, or taxane-resistance and overexpression of Bcl-2, Bcl-xL or NFkB. In contrary sufficient in vitro data support an association of spindle assembly checkpoint (SAC) defects with resistance. Clinical data have been limited and inconsistent, which relate to the variety of methods used, lack of standardization of cut-offs for quantitation, differences in clinical endpoints measured and in methods of tissue collection preparation and storage, and study/patient heterogeneity. The most prominent finding is that pharmaceutical down-regulation of HER-2 appears to reverse the taxane resistance. CONCLUSIONS: Currently no valid practical biomarkers exist that can predict resistance to the taxanes in breast cancer supporting the principle of individualized cancer therapy. The incorporation of several biomarker analyses into prospectively designed studies in this setting are needed.
BACKGROUND:Taxanes are established in the treatment of metastatic breast cancer (MBC) and early breast cancer (EBC) as potent chemotherapy agents. However, their therapeutic usefulness is limited by de-novo refractoriness or acquired resistance, which are common drawbacks to most anti-cancercytotoxics. Considering that the taxanes will remain principle chemotherapeutic agents for the treatment of breast cancer, we reviewed known mechanisms of resistance in with an outlook of optimizing their clinical use. METHODS: We searched the PubMed and MEDLINE databases for articles (from inception through to 9th January 2012; last search 10/01/2012) and journals known to publish information relevant to taxane chemotherapy. We imposed no language restrictions. Search terms included: cancer, breast cancer, response, resistance, taxane, paclitaxel, docetaxel, taxol. Due to the possibility of alternative mechanisms of resistance all combination chemotherapy treated data sets were removed from our overview. RESULTS: Over-expression of the MDR-1 gene product Pgp was extensively studied in vitro in association with taxane resistance, but data are conflicting. Similarly, the target components microtubules, which are thought to mediate refractoriness through alterations of the expression pattern of tubulins or microtubule associated proteins and the expression of alternative tubulin isoforms, failed to confirm such associations. Little consensus has been generated for reported associations between taxane-sensitivity and mutated p53, or taxane-resistance and overexpression of Bcl-2, Bcl-xL or NFkB. In contrary sufficient in vitro data support an association of spindle assembly checkpoint (SAC) defects with resistance. Clinical data have been limited and inconsistent, which relate to the variety of methods used, lack of standardization of cut-offs for quantitation, differences in clinical endpoints measured and in methods of tissue collection preparation and storage, and study/patient heterogeneity. The most prominent finding is that pharmaceutical down-regulation of HER-2 appears to reverse the taxane resistance. CONCLUSIONS: Currently no valid practical biomarkers exist that can predict resistance to the taxanes in breast cancer supporting the principle of individualized cancer therapy. The incorporation of several biomarker analyses into prospectively designed studies in this setting are needed.
Authors: Oluwafunmilayo F Lamidi; Monica Sani; Paolo Lazzari; Matteo Zanda; Ian N Fleming Journal: J Cancer Res Clin Oncol Date: 2015-01-30 Impact factor: 4.553
Authors: Carin K Ingemarsdotter; Laura A Tookman; Ashley Browne; Katrina Pirlo; Rosalind Cutts; Claude Chelela; Karisma F Khurrum; Elaine Y L Leung; Suzanne Dowson; Lee Webber; Iftekhar Khan; Darren Ennis; Nelofer Syed; Tim R Crook; James D Brenton; Michelle Lockley; Iain A McNeish Journal: Mol Oncol Date: 2014-12-29 Impact factor: 6.603
Authors: Guowei Gu; Luca Gelsomino; Kyle R Covington; Amanda R Beyer; John Wang; Yassine Rechoum; Kenneth Huffman; Ryan Carstens; Sebastiano Andò; Suzanne A W Fuqua Journal: Breast Cancer Res Treat Date: 2015-03-28 Impact factor: 4.872
Authors: Balázs Győrffy; Giulia Bottai; Jacqueline Lehmann-Che; György Kéri; László Orfi; Takayuki Iwamoto; Christine Desmedt; Giampaolo Bianchini; Nicholas C Turner; Hugues de Thè; Fabrice André; Christos Sotiriou; Gabriel N Hortobagyi; Angelo Di Leo; Lajos Pusztai; Libero Santarpia Journal: Mol Oncol Date: 2014-01-05 Impact factor: 6.603