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Genetic polymorphism in ATIC is associated with effectiveness and toxicity of pemetrexed in non-small-cell lung cancer
  1. Sabine Visser1,2,3,
  2. Stijn Koolen4,5,
  3. Nadine van Donk6,
  4. Nico van Walree2,
  5. Cor van der Leest2,
  6. Robin Cornelissen1,
  7. Ron van Schaik6,
  8. Ron Mathijssen4,
  9. Joachim Aerts1,
  10. Bruno H Stricker3,7
  1. 1 Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
  2. 2 Department of Pulmonary Medicine, Amphia Hospital, Breda, the Netherlands
  3. 3 Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands
  4. 4 Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
  5. 5 Department of Hospital Pharmacy, Erasmus MC, Rotterdam, the Netherlands
  6. 6 Department of Clinical Chemistry, Erasmus MC, Rotterdam, the Netherlands
  7. 7 Netherlands Healthcare Inspectorate, Heerlen, Utrecht, The Netherlands
  1. Correspondence to Dr Bruno H Stricker, Department of Epidemiology, Erasmus Medical Center, 3000 CA Rotterdam, Zuid-Holland, Netherlands; b.stricker{at}


Patients with advanced non-small-cell lung cancer who are treated with pemetrexed display a wide variation in clinical response and toxicity. In this prospective, multicentre cohort study, we investigated the association with treatment effectiveness and toxicity of 10 polymorphisms in nine candidate genes, covering the folate pathway (MTHFR), cell transport (SLC19A1/ABCC2/ABCC4), intracellular metabolism (FPGS/GGH) and target enzymes (TYMS/DHFR/ATIC) of pemetrexed. Adjusted for sex, ECOG performance score and disease stage, the association between ATIC (rs12995526) and overall survival (HR 1.59, 95% CI 1.06 to 2.39) was significant. Regarding toxicity, this ATIC polymorphism was significantly associated with severe laboratory (p=0.014) and clinical (p=0.016) chemotherapy-related adverse events, severe neutropenia (p=0.007) and all-grade diarrhoea (p=0.034) in multivariable analyses.

  • lung cancer chemotherapy
  • lung cancer
  • clinical epidemiology
  • non-small cell lung cancer

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  • Contributors SV, RM, SK, JA and BHS were involved in study design. SV, CvdL, NvW and RC were involved in recruiting patients and collecting data. Genetic analyses were performed by RvS and NvD and pharmacogenetic analyses by SV and SK. Statistical analyses were performed by SV and BHS. All authors were involved in data interpretation and manuscript writing.

  • Funding This work was supported by ZonMw, the Netherlands (grant number 152001017, Biomarkers for improving the cost-effectiveness and safety of pemetrexed). For a part of the research, funding was received from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement number 116 030. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.

  • Competing interests JA reports personal fees and non-financial support from Eli Lilly, outside the submitted work. In addition, JA has a patent allogenic tumor cell lysate licensed to Amphera pending, and a patent for combination immunotherapy in cancer and biomarker for immunotherapy pending; BHS reports grants from ZonMw during the conduct of the study.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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