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Pharmacogenetics of pemetrexed combination therapy in lung cancer: pathway analysis reveals novel toxicity associations

The Pharmacogenomics Journal volume 14, pages 411–417 (2014)Cite this article

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Abstract

Identification of polymorphisms that influence pemetrexed tolerability could lead to individualised treatment regimens and improve quality of life. Twenty-eight polymorphisms within eleven candidate genes were genotyped using the Illumina Human Exome v1.1 BeadChip and tested for their association with the clinical outcomes of non-small cell lung cancer and mesothelioma patients receiving pemetrexed/platinum doublet chemotherapy (n=136). GGH rs11545078 was associated with a reduced incidence of grade ⩾3 toxicity within the first four cycles of therapy (odds ratio (OR) 0.25, P=0.018), as well as reduced grade ⩾3 haematological toxicity (OR 0.13, P=0.048). DHFR rs1650697 conferred an increased risk of grade ⩾3 toxicity (OR 2.14, P=0.034). Furthermore, FOLR3 rs61734430 was associated with an increased likelihood of disease progression at mid-treatment radiological evaluation (OR 4.05, P=0.023). Polymorphisms within SLC19A1 (rs3788189, rs1051298 and rs914232) were associated with overall survival. This study confirms previous pharmacogenetic associations and identifies novel markers of pemetrexed toxicity.

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Acknowledgements

We are grateful for the assistance given by Hamel Patel. We acknowledge the financial support from Guy’s and St Thomas’ Charity, the Purine Metabolic Patient Association (PUMPA) and from the UK Department of Health via the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust. We also acknowledge support from the NIHR BRC for Mental Health at South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, King’s College London. King’s College London is an Experimental Cancer Medicine Centre.

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Author notes

  1. A Corrigan and J L Walker: These authors contributed equally to this work.

Authors and Affiliations

  1. Purine Research Laboratory, GSTS Pathology, Guy’s and St Thomas’ Hospital NHS Foundation Trust, 4th Floor, North Wing, St Thomas Hospital, Lambeth Palace Road, London, UK

    A Corrigan, S Wickramasinghe, M A Hernandez & A M Marinaki

  2. Department of Medical and Molecular Genetics, King’s College London, 8th Floor Tower Wing, Guy’s Hospital, London, UK

    J L Walker & C M Lewis

  3. National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and (Institute of Psychiatry) King’s College London, London, UK

    S J Newhouse & A A Folarin

  4. Department of Gastroenterology, Guy’s and St Thomas’ Hospital NHS Foundation Trust, College House, St Thomas’ Hospital, London, UK

    J D Sanderson

  5. Division of Cancer Studies, King’s College London, Guy’s Hospital, London, UK

    J Spicer

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  1. A Corrigan
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Correspondence to A M Marinaki.

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Corrigan, A., Walker, J., Wickramasinghe, S. et al. Pharmacogenetics of pemetrexed combination therapy in lung cancer: pathway analysis reveals novel toxicity associations. Pharmacogenomics J 14, 411–417 (2014). https://doi.org/10.1038/tpj.2014.13

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