Unexpected immunohistochemical localization of deoxycytidine kinase.
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Antigen-Antibody Reactions↗
Biomedical subjects
John Mackey
Publications and source records attributed to John Mackey.
Life-threatening complications from doxorubicin-docetaxel chemotherapy for breast cancer.
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Antineoplastic Combined Chemotherapy Protocols↗
Adjuvant docetaxel for node-positive breast cancer.
BACKGROUND: We compared docetaxel plus doxorubicin and cyclophosphamide (TAC) with fluorouracil plus doxorubicin and cyclophosphamide (FAC) as adjuvant chemotherapy for operable node-positive breast cancer. METHODS: We randomly assigned 1491 women with axillary node-positive breast cancer to six cycles of treatment with either TAC or FAC as adjuvant chemotherapy after surgery. The primary end point was disease-free survival. RESULTS: At a median follow-up of 55 months, the estimated rates of disease-free survival at five years were 75 percent among the 745 patients randomly assigned to receive TAC and 68 percent among the 746 randomly assigned to receive FAC, representing a 28 percent reduction in the risk of relapse (P=0.001) in the TAC group. The estimated rates of overall survival at five years were 87 percent and 81 percent, respectively. Treatment with TAC resulted in a 30 percent reduction in the risk of death (P=0.008). The incidence of grade 3 or 4 neutropenia was 65.5 percent in the TAC group and 49.3 percent in the FAC group (P<0.001); rates of febrile neutropenia were 24.7 percent and 2.5 percent, respectively (P<0.001). Grade 3 or 4 infections occurred in 3.9 percent of the patients who received TAC and 2.2 percent of those who received FAC (P=0.05); no deaths occurred as a result of infection. Two patients in each group died during treatment. Congestive heart failure and acute myeloid leukemia occurred in less than 2 percent of the patients in each group. Quality-of-life scores decreased during chemotherapy but returned to baseline levels after treatment. CONCLUSIONS: Adjuvant chemotherapy with TAC, as compared with FAC, significantly improves the rates of disease-free and overall survival among women with operable node-positive breast cancer.
Adult↗
Selection of adjuvant chemotherapy for treatment of node-positive breast cancer.
Over the past two decades, several studies have suggested that regimens that contain anthracyclines are more effective than those that do not. A meta-analysis by the 2005 Early Breast Cancer Trialists' Collaborative Group confirmed that about 6 months of anthracycline-based polychemotherapy in the adjuvant setting reduced the yearly death rate from breast cancer by about 38% for women younger than 50 years and by 20% for women aged 50-69 years. Although this meta-analysis found that survival was better with regimens that contain anthracycline than with regimens based on cyclophosphamide, methotrexate, and fluorouracil, the best use of anthracycline-based regimens remains unclear. Adjuvant regimens in use can be categorised into three groups: standard-dose anthracycline; escalated-dose epirubicin; and anthracyclines and taxanes. The duration of treatment and combination of dose and drugs varies between these three categories. We reviewed the three types of regimen to establish which provide a better outcome in terms of safety, efficacy, cost, and convenience to patients. We found that both escalated-dose epirubicin and anthracycline-taxane regimens were most effective in terms of disease-free survival and overall survival. Of the specific anthracycline-based regimens, the docetaxel, doxorubicin, and cyclophosphamide regimen (TAC); the fluorouracil, 100 mg epirubicin, and cyclophosphamide regimen (FEC100); and the cyclophosphamide, epirubicin, and fluorouracil regimen (CEF) produced the greatest proportional decreases in 5-year death rate.
Aged↗
Class III beta-tubulin expression in tumor cells predicts response and outcome in patients with non-small cell lung cancer receiving paclitaxel.
Both fundamental and clinical studies suggest that class III beta-tubulin expression is associated with resistance to taxanes and constitutes a prognostic factor in several solid tumors. In this study, we assessed the prognostic and predictive value of class III beta-tubulin in tumors of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) treated with paclitaxel-based or other regimens that did not include tubulin-binding agents. Expression of class III beta-tubulin was examined immunohistochemically in 91 tumor samples obtained before treatment from patients with stage III and IV NSCLC, including 47 who received paclitaxel-based regimens and 44 who received regimens without tubulin-binding agents. Response to chemotherapy, progression-free survival, and overall survival were correlated with the expression of class III beta-tubulin protein. The response rate was 37.5% (16 responses among 45 evaluable patients) among patients receiving paclitaxel. Patients whose tumors expressed low levels of class III beta-tubulin isotype had a better response rate, longer progression-free survival, and overall survival (P < 0.001, 0.004, and 0.002, respectively), whereas this variable was not found to be predictive in patients receiving regimens without tubulin-binding agents. A multivariate analysis taking into account sex, age, histology, stage, and class III beta-tubulin confirmed that low-level class III beta-tubulin expression was independently correlated with progression-free survival (P = 0.003) and overall survival (P = 0.003). These findings suggest that the expression levels of class III beta-tubulin in tumor cells is predictive of response to therapy and patient outcome in patients with NSCLC receiving paclitaxel-based chemotherapy but is not a general prognostic factor in this patient population.
Adult↗
Characterization of a gemcitabine-resistant murine leukemic cell line: reversion of in vitro resistance by a mononucleotide prodrug.
Resistance to cytotoxic nucleoside analogues is a major problem in cancer treatment. The cellular mechanisms involved in this phenomenon have been studied for several years, and some factors have been identified. Various strategies to overcome resistance have been suggested, but none has yet shown efficacy in vivo. We developed a gemcitabine-resistant cell line (L1210 10K) from the murine leukemic L1210 strain (L1210 wt) by continuous exposure to increasing concentrations of gemcitabine. L1210 10K is highly resistant to gemcitabine (14,833-fold), 1-beta-D-arabinofuranosylcytosine (ara-C; 2,100-fold), troxacitabine (>200-fold), and cladribine (160-fold) and slightly resistant to trimidox (7.22-fold), but does not display cross-resistance to fludarabine or nonnucleoside anticancer drugs. Deoxycytidine kinase mRNA was not detected by quantitative real-time reverse transcription-PCR in L1210 10K cells, whereas expression of thymidine kinase 1 and ribonucleotide reductase subunit R2 gene was moderately reduced. L1210 10K cells also demonstrated in vivo resistance to nucleoside analogues: gemcitabine- or ara-C-treated mice carrying L1210 10K had significantly shorter survival than gemcitabine- or ara-C-treated mice carrying L1210 wt (P < 0.05). UA911, a mononucleotide prodrug (pronucleotide) of ara-C was found to significantly sensitize L1210 10K cells in vitro. These results suggest that reduced deoxycytidine kinase expression is a mechanism of resistance to gemcitabine that is relevant in vivo and can be circumvented by a prodrug approach.
Animals↗
Predictive models for breast cancer susceptibility from multiple single nucleotide polymorphisms.
Hereditary predisposition and causative environmental exposures have long been recognized in human malignancies. In most instances, cancer cases occur sporadically, suggesting that environmental influences are critical in determining cancer risk. To test the influence of genetic polymorphisms on breast cancer risk, we have measured 98 single nucleotide polymorphisms (SNPs) distributed over 45 genes of potential relevance to breast cancer etiology in 174 patients and have compared these with matched normal controls. Using machine learning techniques such as support vector machines (SVMs), decision trees, and naïve Bayes, we identified a subset of three SNPs as key discriminators between breast cancer and controls. The SVMs performed maximally among predictive models, achieving 69% predictive power in distinguishing between the two groups, compared with a 50% baseline predictive power obtained from the data after repeated random permutation of class labels (individuals with cancer or controls). However, the simpler naïve Bayes model as well as the decision tree model performed quite similarly to the SVM. The three SNP sites most useful in this model were (a) the +4536T/C site of the aldosterone synthase gene CYP11B2 at amino acid residue 386 Val/Ala (T/C) (rs4541); (b) the +4328C/G site of the aryl hydrocarbon hydroxylase CYP1B1 at amino acid residue 293 Leu/Val (C/G) (rs5292); and (c) the +4449C/T site of the transcription factor BCL6 at amino acid 387 Asp/Asp (rs1056932). No single SNP site on its own could achieve more than 60% in predictive accuracy. We have shown that multiple SNP sites from different genes over distant parts of the genome are better at identifying breast cancer patients than any one SNP alone. As high-throughput technology for SNPs improves and as more SNPs are identified, it is likely that much higher predictive accuracy will be achieved and a useful clinical tool developed.
Algorithms↗
Use of trastuzumab beyond disease progression: observations from a retrospective review of case histories.
HER2 overexpression is associated with poor breast cancer prognosis and is the target for the humanized monoclonal antibody trastuzumab. This novel agent, when administered until disease progression in combination with chemotherapy, extends the survival of women with HER2-positive metastatic breast cancer (MBC). However, the optimal duration of trastuzumab therapy remains to be confirmed. We conducted a retrospective case review study of women with HER2-positive MBC who continued to receive trastuzumab beyond disease progression. Objectives were to assess whether treatment beyond disease progression shows any evidence of efficacy and to evaluate the feasibility of this approach. One hundred five patients (median age, 47 years; range, 24-77 years) were identified in 13 centers. Women had received </=6 chemotherapy regimens (median, 1) before trastuzumab therapy. Median survival from first trastuzumab dose was 29 months. The overall response rate to trastuzumab alone or with a taxane as the first regimen was 39%; a further 30% of patients had stable disease as the best response. These rates were 36% and 38% after a second regimen of trastuzumab alone or with paclitaxel or vinorelbine was administered. Some patients responded to both the first and second regimens; others responded to the second regimen after the first had failed. Twenty-two patients experienced cardiac events, of whom 18 received >/=1 more trastuzumab regimen. Trastuzumab treatment beyond progression appears to be of value, producing responses and clinical benefit, and is well tolerated without significant cardiac toxicity. The feasibility of this approach warrants examination in prospective trials.
Adult↗
Nucleoside anticancer drugs: the role of nucleoside transporters in resistance to cancer chemotherapy.
The clinical efficacy of anticancer nucleoside drugs depends on a complex interplay of transporters mediating entry of nucleoside drugs into cells, efflux mechanisms that remove drugs from intracellular compartments and cellular metabolism to active metabolites. Nucleoside transporters (NTs) are important determinants for salvage of preformed nucleosides and mediated uptake of antimetabolite nucleoside drugs into target cells. The focus of this review is the two families of human nucleoside transporters (hENTs, hCNTs) and their role in transport of cytotoxic chemotherapeutic nucleoside drugs. Resistance to anticancer nucleoside drugs is a major clinical problem in which NTs have been implicated. Single nucleotide polymorphisms (SNPs) in drug transporters may contribute to interindividual variation in response to nucleoside drugs. In this review, we give an overview of the functional and molecular characteristics of human NTs and their potential role in resistance to nucleoside drugs and discuss the potential use of genetic polymorphism analyses for NTs to address drug resistance.
Antineoplastic Agents↗
Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial.
BACKGROUND: The goal of the current study was to compare the long-term (25-month) safety and efficacy of zoledronic acid with pamidronate in patients with bone lesions secondary to advanced breast carcinoma or multiple myeloma. METHODS: Patients (n = 1648) were randomized to receive 4 mg or 8 mg (reduced to 4 mg) zoledronic acid as a 15-minute infusion or to receive 90 mg pamidronate as a 2-hour infusion every 3-4 weeks for 24 months. The primary endpoint was the proportion of patients with at least 1 skeletal-related event (SRE), defined as pathologic fracture, spinal cord compression, radiation therapy, or surgery to bone. Secondary analyses included time to first SRE, skeletal morbidity rate, and multiple-event analysis. Hypercalcemia of malignancy (HCM) was included as an SRE in some secondary analyses. RESULTS: After 25 months of follow-up, zoledronic acid reduced the overall proportion of patients with an SRE and reduced the skeletal morbidity rate similar to pamidronate. Compared with pamidronate, zoledronic acid (4 mg) reduced the overall risk of developing skeletal complications (including HCM) by an additional 16% (P = 0.030). In patients with breast carcinoma, zoledronic acid (4 mg) was significantly more effective than pamidronate, reducing the risk of SREs by an additional 20% (P = 0.025) compared with pamidronate and by an additional 30% in patients receiving hormonal therapy (P = 0.009). Zoledronic acid (4 mg) and pamidronate were tolerated equally well. The most common adverse events included bone pain, nausea, and fatigue. CONCLUSIONS: Long-term follow-up data confirm that zoledronic acid was more effective than pamidronate in reducing the risk of skeletal complications in patients with bone metastases from breast carcinoma and was of similar efficacy in patients with multiple myeloma.
Bone Diseases↗
Clinically validated benchmarking of normalisation techniques for two-colour oligonucleotide spotted microarray slides.
Acquisition of microarray data is prone to systematic errors. A correction, called normalisation, must be applied to the data before further analysis is performed. With many normalisation techniques published and in use, the best way of executing this correction remains an open question. In this study, a variety of single-slide normalisation techniques, and different parameter settings for these techniques, were compared over many replicated microarray experiments. Different normalisation techniques were assessed through the distribution of the standard deviation of replicates from one biological sample across different slides. It is shown that local normalisation outperformed global normalisation, and intensity-based 'LOWESS' outperformed trimmed mean and median normalisation techniques. Overall, the top performing normalisation technique was a print-tip-based LOWESS with zero robust iterations. Lastly, we validated this evaluation methodology by examining the ability to predict oestrogen receptor-positive and -negative breast cancer samples with data that had been normalised using different techniques.
Algorithms↗
Phase III trial comparing granulocyte colony-stimulating factor to leridistim in the prevention of neutropenic complications in breast cancer patients treated with docetaxel/doxorubicin/cyclophosphamide: results of the BCIRG 004 trial.
This randomized, double-blind, phase III trial compared granulocyte colony-stimulating factor (G-CSF; filgrastim) and leridistim (formerly myelopoietin), a chimeric dual agonist that binds both G-CSF and interleukin-3 receptors, for the prevention of neutropenic complications in patients with breast cancer receiving TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy. Patients with metastatic (44%) or localized breast cancer (56%) were randomized to G-CSF 5 microg/kg subcutaneously (s.c.) daily (n = 135), leridistim 5 microg/kg s.c. daily (n = 139), or leridistim 10 microg/kg s.c. every other day alternating with placebo (n = 139). Following administration of TAC (docetaxel 75 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2) on day 1, patients received growth factor beginning on day 2 until the postnadir absolute neutrophil count exceeded 1500 cells/ microL. Chemotherapy cycles were repeated every 21 days. The incidence of febrile neutropenia was 7% in the G-CSF arm, 19% in the daily leridistim arm (P = 0.003 for comparison with G-CSF) and 22% in the alternate-day leridistim arm (P < 0.001 for comparison with G-CSF). There was no significant difference between treatment arms in the cumulative percentage of patients experiencing grade 4 neutropenia at some point during therapy (85%-88%). However, grade 4 neutropenia occurred in 53% of cycles in the G-CSF cohort, 61% of cycles in the daily leridistim group (P = 0.063 for comparison with G-CSF), and 63% of cycles in the alternate-day leridistim group (P = 0.015 for comparison with G-CSF). We conclude that G-CSF is superior to leridistim in the prevention of febrile neutropenia in patients with advanced breast cancer receiving TAC chemotherapy. The up-front prophylactic use of G-CSF is a reasonable supportive therapy for patients treated with docetaxel/anthracycline-based combination chemotherapy.
Adult↗