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Cancer Therapy: Clinical

Rationally Designed Pharmacogenomic Treatment Using Concurrent Capecitabine and Radiotherapy for Glioblastoma; Gene Expression Profiles Associated with Outcome

Jessica M. Grunda, John Fiveash, Cheryl A. Palmer, Alan Cantor, Hassan M. Fathallah-Shaykh, L. Burt Nabors and Martin R. Johnson
Jessica M. Grunda
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John Fiveash
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Cheryl A. Palmer
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Alan Cantor
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Hassan M. Fathallah-Shaykh
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L. Burt Nabors
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Martin R. Johnson
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DOI: 10.1158/1078-0432.CCR-09-3151 Published May 2010
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  • Fig. 1.
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    Fig. 1.

    Patient treatment schematic with capecitabine and radiotherapy.

  • Fig. 2.

    Results of SSPCA. Kaplan-Meier plots representing all evaluable (n = 13), poor outcome (n = 6), and good outcome (n = 7) patient groups with median (A) TTP of 247 d (—), 199 d (


    ), and 300 d (


    ) and (B) OS of 430 d (—), 303 d (


    ), and 520 d (


    ), respectively.

  • Fig. 3.
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    Fig. 3.

    Heat map of the eight-gene expression–based predictor model of patient outcome to capecitabine and radiotherapy treatment.

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  • Table 1.

    Demographics of the 18 enrolled evaluable patients

    Characteristic
    Age, y
        Median49
        Range18-78
    Sex, n
        Male15
        Female3
    Karnofsky performance status, %
        Median80
        Range60-100
    Race, n (%)
        White18 (100)
        Black
        Asian
    Histology, n (%)
        Glioblastoma multiforme18 (100)
  • Table 2.

    Genes associated with GBM patient TTP

    Accession no.GeneDescriptionHazard ratio*P
    Capecitabine metabolism genes
        NM_001033RRM1Ribonucleotide reductase M12.300.002
        NM_000110DPYDDihydropyrimidine dehydrogenase1.230.002
        NM_012474UCK2Uridine-cytidine kinase 22.140.004
        NM_001905CTPSCTP synthase19.630.009
        NM_004955SLC29A1Solute carrier family 29, member 11.060.010
        NM_001953TPThymidine phosphorylase (ECGF1)1.110.010
        NM_001785CDACytidine deaminase1.660.020
    Radiation response genes
        NM_002875RAD51RAD51 homolog1.060.007
        NM_002524NRASNeuroblastoma RAS1.490.007
        NM_005432XRCC3XRCC36.050.008
        NM_012415RAD54BRAD54 homolog B1.210.009
        NM_005732RAD50RAD50 homolog1.620.009
        NM_003401XRCC4XRCC41.280.010
        NM_001641APEX1APEX nuclease 12.200.012
        NM_000124ERCC6ERCC61.900.013
        NM_014481APEX2APEX nuclease 21.740.018
        NM_021141XRCC5XRCC52.480.019
        NM_000251MSH2mutS homolog 237.500.022
        NM_006297XRCC1XRCC11.350.023

    NOTE: Cox regression analysis was used to assess the association between TTP and each individual gene expression value, adjusted for age and dose.

    • ↵*Hazard ratio > 1: higher gene expression, shorter time-to-progression; hazard ratio < 1: higher gene expression, longer time-to-progression; hazard ratio = 1: no association.

  • Table 3.

    Genes associated with GBM patient OS

    Accession no.GeneDescriptionHazard ratio*P
    Capecitabine metabolism genes
        NM_001921DCTDdCMP deaminase51.150.005
        NM_003258TK1Thymidine kinase 1156.730.006
        NM_000110DPYDDihydropyrimidine dehydrogenase1.210.006
        NM_001033RRM1Ribonucleotide reductase M11.930.007
        NM_001034RRM2Ribonucleotide reductase M21.040.008
        NM_001905CTPSCTP synthase40.100.008
        NM_012474UCK2Uridine-cytidine kinase 21.600.024
    Radiation response genes
        NM_002875RAD51RAD51 homolog1.080.003
        NM_012415RAD54BRAD54 homolog B1.220.013
        NM_006297XRCC1XRCC11.450.014
        NM_004958mTORMechanistic target of rapamycin (FRAP1)6.550.020
        NM_001274CHEK1CHK1 checkpoint homolog1.740.025

    NOTE: Cox regression analysis was used to assess the association between OS and each individual gene expression value, adjusted for age and dose.

    • ↵*Hazard ratio > 1: higher gene expression, shorter survival; hazard ratio < 1: higher gene expression, longer survival; hazard ratio = 1: no association.

  • Table 4.

    Gene expression statistics for the poor outcome and good outcome patient subgroups

    GenePoor outcomeGood outcomeFold change*P
    Ave.MinMaxAve.MinMax
    RAD54B14.607.4720.864.602.917.063.170.002
    mTOR1.951.242.511.000.641.371.950.003
    DCTD1.390.711.800.610.310.992.280.004
    APEX25.982.837.293.161.795.151.890.006
    TK10.700.461.170.240.060.722.960.006
    RRM298.0473.82132.7349.5012.7188.051.980.007
    SLC29A158.1231.1583.0427.9916.5256.602.080.015
    ERCC64.902.498.542.071.083.112.370.029
    • ↵*Expression fold change relative to the poor outcome patient subgroup.

Additional Files

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Clinical Cancer Research: 16 (10)
May 2010
Volume 16, Issue 10
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Rationally Designed Pharmacogenomic Treatment Using Concurrent Capecitabine and Radiotherapy for Glioblastoma; Gene Expression Profiles Associated with Outcome
Jessica M. Grunda, John Fiveash, Cheryl A. Palmer, Alan Cantor, Hassan M. Fathallah-Shaykh, L. Burt Nabors and Martin R. Johnson
Clin Cancer Res May 15 2010 (16) (10) 2890-2898; DOI: 10.1158/1078-0432.CCR-09-3151

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Rationally Designed Pharmacogenomic Treatment Using Concurrent Capecitabine and Radiotherapy for Glioblastoma; Gene Expression Profiles Associated with Outcome
Jessica M. Grunda, John Fiveash, Cheryl A. Palmer, Alan Cantor, Hassan M. Fathallah-Shaykh, L. Burt Nabors and Martin R. Johnson
Clin Cancer Res May 15 2010 (16) (10) 2890-2898; DOI: 10.1158/1078-0432.CCR-09-3151
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