Publications (2)12.29 Total impact
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Article: Phase I assessment of new mechanism-based pharmacodynamic biomarkers for MLN8054, a small-molecule inhibitor of Aurora A kinase.
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ABSTRACT: The mitotic kinase Aurora A is an important therapeutic target for cancer therapy. This study evaluated new mechanism-based pharmacodynamic biomarkers in cancer patients in two phase I studies of MLN8054, a small-molecule inhibitor of Aurora A kinase. Patients with advanced solid tumors received MLN8054 orally for 7 consecutive days in escalating dose cohorts, with skin and tumor biopsies obtained before and after dosing. Skin biopsies were evaluated for increased mitotic cells within the basal epithelium. Tumor biopsies were assessed for accumulation of mitotic cells within proliferative tumor regions. Several patients in the highest dose cohorts showed marked increases in the skin mitotic index after dosing. Although some tumors exhibited increases in mitotic cells after dosing, others displayed decreases, a variable outcome consistent with dual mechanisms of mitotic arrest and mitotic slippage induced by antimitotics in tumors. To provide a clearer picture, mitotic cell chromosome alignment and spindle bipolarity, new biomarkers of Aurora A inhibition that act independently of mitotic arrest or slippage, were assessed in the tumor biopsies. Several patients, primarily in the highest dose cohorts, had marked decreases in the percentage of mitotic cells with aligned chromosomes and bipolar spindles after dosing. Evidence existed for an exposure-effect relationship for mitotic cells with defects in chromosome alignment and spindle bipolarity that indicated a biologically active dose range. Outcomes of pharmacodynamic assays from skin and tumor biopsies were concordant in several patients. Together, these new pharmacodynamic assays provide evidence for Aurora A inhibition by MLN8054 in patient skin and tumor tissues.Cancer Research 02/2011; 71(3):675-85. · 7.86 Impact Factor -
Article: Optimal delivery of anthracycline-based chemotherapy in the adjuvant setting improves outcome of breast cancer patients.
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ABSTRACT: To evaluate the dose-response effect of an adjuvant anthracycline-based non-taxane chemotherapy in early breast cancer patients. This was a retrospective database analysis. Selection criteria included patients treated for early breast cancer from years 1980 to 2000 with an adjuvant anthracycline-based non-taxane chemotherapy. The delivery of chemotherapy was assessed through the number of delayed cycles, the number of delayed days and the relative dose intensity (RDI) administered (>or= 85%, <85%). Seven hundred and ninety-three breast cancer patients were included. The Kaplan-Meier disease-free survival (DFS) was affected by the number of delayed cycles (P<0.0001), the number of delayed days (P<0.0001) and the RDI (P=0.0029). The Kaplan-Meier overall survival (OS) was also affected by the number of delayed cycles (P=0.0008) and days (P=0.0115), as well as the RDI (P=0.0055). The Cox regression models showed that, when the number of nodes affected and the hormonal receptor status were controlled, all the study variables maintained their significance on DFS, but not on OS. The dose-response effect is a crucial factor in the administration of anthracycline-based non-taxane schedules for the adjuvant treatment of early breast cancer. Delays and/or reductions of chemotherapy should be avoided if possible to achieve the maximal benefit.Breast Cancer Research and Treatment 05/2008; 114(3):479-84. · 4.43 Impact Factor
