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  P3.02 - Poster Session 3 - Novel Cancer Genes and Pathways (ID 149)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

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    P3.02-003 - ATP7A is a novel determinant of toxicity and response in advanced non-small cell lung cancer patients receiving paclitaxel and carboplatin (ID 700)

    09:30 - 09:30  |  Author(s): A. McLachlan
    • Abstract

    Background
    Genetic variability can influence the pharmacokinetics and pharmacodynamics of paclitaxel and carboplatin in patients with non-small cell lung cancer (NSCLC). Additionally, the prevalence of genetic variations often differs between ethnic groups and may account for observed interethnic variability in drug efficacy. We aimed to undertake a pharmacogenomic investigation to account for patient variability in order to improve dosing and patient selection in NSCLC.

    Methods
    76 advanced NSCLC patients from Caucasian (n = 50) and Asian (n = 26) ethnicity were prospectively recruited into the study at Concord Repatriation General Hospital from 2007-2011. All patients received paclitaxel (175mg/m[2]) and carboplatin (target AUC 6 mg/mL•min) for an intended 6 cycles. A candidate gene approach was used to select single nucleotide polymorphisms (SNPs) for pharmacogenomic analysis. HPLC with population pharmacokinetic modelling (NONMEM) was used to obtain pharmacokinetic data (n = 61). Toxicities were assessed according to CTCAE v 4.0 and response was measured by CT scans according to RECIST criteria. Blood DNA was genotyped by the Australian Genetics Research Facility using a MassARRAY® iPLEX Gold system on a Sequenom mass spectrometer. SNPs were assessed for linkage disequilibrium, Hardy-Weinberg equilibrium and interethnic differences in allele frequency. Regression analysis was undertaken to associate SNPs with drug pharmacokinetics, toxicities and response.

    Results
    42 SNPs from 21 genes were selected and genotyped in patients. Regression analysis identified 12 SNPs significantly associated to paclitaxel pharmacokinetics, patient toxicities and response. SNPs rs2306283 and rs11615, in SLCO1B1 and ERCC1 respectively, associated with paclitaxel clearance. Previously published SNPs in CYP2C8, CYP1B1, ABCB1, ABCC10, SLCO2B1, GSTP1, ATP7A, ERCC1 and CCND1 were found to be associated with patient toxicities. Three SNPs, rs2306283, rs1056836 and rs2306168, encoded by SLCOB1, CYP1B1 and SLCO2B1 respectively, had interethnic difference in SNP prevalence and associated to patient outcomes. SNP rs2227291 in ATP7A associated with patient response and to nausea and anaemia.

    Conclusion
    The study associated various SNPs to drug pharmacokinetics, patient toxicities and response which could be integrated into future personalisation efforts of paclitaxel and carboplatin. Furthermore, SNPs with interethnic differences may provide clues to understand interethnic variability in drug efficacy. Finally, a novel SNP identified in ATP7A associated with patient response and toxicity. The ATP7A gene encodes a protein that has been linked to resistance to platinum based drugs, however, the SNP has unknown functional effects which require further elucidation.