Germline polymorphisms in patients with advanced nonsmall cell lung cancer receiving first-line platinum-gemcitabine chemotherapy

A prospective clinical study

Authors

  • Markus Joerger MD, PhD,

    Corresponding author
    1. Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, the Netherlands
    2. Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
    3. Department of Oncology and Hematology, Cantonal Hospital, St. Gallen, Switzerland
    • Department of Oncology and Hematology, Cantonal Hospital, Rorschacherstr. 95, 9007 St. Gallen, Switzerland

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    • Fax: (011) 41-71-4942563

  • Sjaak A. Burgers MD,

    1. Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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  • Paul Baas MD,

    1. Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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  • Egbert F. Smit MD,

    1. Department of Pulmonary Diseases, Vrije University Medical Center, Amsterdam, the Netherlands
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  • Tjeerd J. Haitjema MD,

    1. Department of Pulmonary Diseases, Alkmaar Medical Center, Alkmaar, the Netherlands
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  • Martin P. L. Bard MD,

    1. Department of Pulmonary Diseases, Kennemer Hospital, Haarlem, the Netherlands
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  • Valerie D. Doodeman,

    1. Department of Molecular Biology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, the Netherlands
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  • Paul H. M. Smits PhD,

    1. Department of Molecular Biology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, the Netherlands
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  • Andrew Vincent PhD,

    1. Biometrics Department, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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  • Alwin D. R. Huitema PhD,

    1. Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, the Netherlands
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  • Jos H. Beijnen PhD,

    1. Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, the Netherlands
    2. Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
    3. Faculty of Science, Department of Pharmaceutical Sciences, Division of Biomedical Analysis, Department of Drug Toxicology, Utrecht University, Utrecht, the Netherlands
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  • Jan H. M. Schellens MD

    1. Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
    2. Faculty of Science, Department of Pharmaceutical Sciences, Division of Biomedical Analysis, Department of Drug Toxicology, Utrecht University, Utrecht, the Netherlands
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Abstract

BACKGROUND:

The authors assessed the impact of germline polymorphisms on clinical outcome in patients with advanced nonsmall cell lung cancer (NSCLC) who received platinum-gemcitabine (PG) chemotherapy.

METHODS:

In total, 137 patients with stage IIIB/IV NSCLC were included who received first-line PG chemotherapy (74% of patients received cisplatin, and 26% received carboplatin). Twenty-three germline polymorphisms that were identified in peripheral blood samples were analyzed for progression-free survival (PFS), treatment response, overall survival (OS), and toxicity.

RESULTS:

The median PFS was 5.8 months, the median OS was 10.2 months, and 44 patients (32%) had a partial treatment response. Carriers of the excision repair cross-complementation group 1 (ERCC1) mutant thymine (T) allele had a lower treatment response rate (29% vs 52%; P = .02), shorter PFS (adjusted hazard ratio [HR], 1.60; P = .04), and shorter OS (adjusted HR, 1.54; P = .05) compared with carriers of the wild-type cytosine/cytosine (CC) genotype. The xeroderma pigmentosum group A member 10 (XPD10) mutant adenine (A) allele (adjusted HR, 0.64; P = .04) and the x-ray cross-complementing group 1 (XRCC1) mutant guanine (G) allele (adjusted HR, 0.51; P = .02) also were independent predictors of OS. Carriers of the mutant adenosine triphosphate-dependent DNA helicase Q1 (RECQ1) C allele or the mutant cytidine deaminase (CDA) C allele were more likely to experience severe leukocytopenia (26% vs 10% [P = .03] and 28% vs 11% [P = .02], respectively) compared with wild-type genotype carriers. Patients who carried the homozygous mutant glutathione S-transferase π 1(GSTP1) GG genotype were at considerable risk for severe platinum-associated polyneuropathy (18% vs 3% in wild-type vs heterozygous mutant patients, respectively; P = .01).

CONCLUSIONS:

To the authors' knowledge, this is the first prospective study to date in patients with advanced NSCLC describing predictive germline polymorphisms not only for the clinical activity of PG chemotherapy (ERCC1, XPD10) but also for its toxicity (GSTP1, RECQ1, CDA). Nonplatinum-containing chemotherapy in carriers of the ERCC1 T allele or the XPD10 G allele should be studied prospectively. Cancer 2012;. © 2011 American Cancer Society.

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