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

Our plain-English summary of Pharmacogenetics of pemetrexed combination therapy in lung cancer: pathway analysis reveals novel toxicity associations, by A. Corrigan, J.L. Walker, S. Wickramasinghe, et al (The Pharmacogenomics Journal, 2014).

The study

• Authors: A. Corrigan, J.L. Walker, S. Wickramasinghe, M.A. Hernandez, S.J. Newhouse, A.A. Folarin, C.M. Lewis, J.D. Sanderson, J. Spicer, A.M. Marinaki
• Journal: The Pharmacogenomics Journal
• Published: 2014;14(5):411-7
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This retrospective pharmacogenetic study at Guy's and St Thomas' Hospitals NHS Foundation Trust recruited 136 patients: 94 with advanced non-small cell lung cancer and 42 with malignant mesothelioma, all given pemetrexed at a standard dose of 500 mg per square metre with cisplatin (63.2%) or carboplatin (36.8%); two patients had first-cycle dose reductions of 20% and 25%. Twenty-eight polymorphisms in eleven pemetrexed-pathway genes were genotyped using an exome chip and TaqMan assays and tested against toxicity, response and survival. Across the first four cycles, 44.7% (59/132) of patients had grade 3 or higher treatment-related toxicity. The GGH rs11545078 minor T allele was associated with less grade 3 or 4 toxicity in cycles 1-4 (odds ratio 0.245, 95% CI 0.078 to 0.774, P=0.0165), while DHFR rs1650697 was associated with more (odds ratio 2.204, 95% CI 1.093 to 4.444, P=0.0272). FOLR3 rs61734430 T allele carriers more often had progressive disease at mid-treatment scan (OR 3.80, 95% CI 1.15 to 12.53, P=0.029). Three SLC19A1 variants and MTHFR rs1801133 were associated with overall survival. No correction for multiple testing was applied.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: retrospective pharmacogenetic (candidate-gene association) study
• Who was studied: 136 patients treated at Guy's and St Thomas' Hospitals NHS Foundation Trust, London: 94 (69.1%) with advanced non-small cell lung cancer and 42 (30.9%) with malignant mesothelioma; 132 included in toxicity analyses, 113 in response analyses, 136 in survival analyses
• Exposure: Pemetrexed at a standard initial dose of 500 mg per square metre, except two patients given 20% and 25% first-cycle dose reductions for age and renal function, combined with cisplatin or carboplatin; the genetic exposures were 28 polymorphisms in 11 pemetrexed-pathway genes (SLC19A1, FOLR3, FPGS, GGH, DHFR, GART, MTHFR, MTHFD1, MTR, SHMT2, ERCC2)
• Main results:
  • Cisplatin was the combination agent for 63.2% of participants and carboplatin for 36.8%
  • 44.7% (59/132) of patients had grade 3 or higher treatment-related toxicity across the first four cycles; haematological and gastrointestinal toxicities were most frequent (25.8% and 11.4%)
  • GGH rs11545078 minor T allele: lower odds of grade 3 or 4 toxicity in cycles 1-2 (OR 0.099, P=0.027) and cycles 1-4 (OR 0.25, P=0.017)
  • GGH rs11545078 T allele and severe haematological toxicity over cycles 1-4: OR 0.129, 95% CI 0.017 to 0.998, P=0.0498
  • DHFR rs1650697 CT or TT genotypes: increased grade 3 or 4 toxicity in cycles 1-4, OR 2.20 (table: 2.204, 95% CI 1.093-4.444), P=0.027
  • FOLR3 rs61734430 T allele carriers: increased likelihood of progressive disease at mid-treatment scan, OR 3.80 (95% CI 1.15-12.53), P=0.029 (113 patients with response data)
  • Overall survival: MTHFR rs1801133 CT+TT HR 1.56 (1.01-2.44, P=0.048); SLC19A1 rs3788189 AC+CC HR 1.71 (1.07-2.73, P=0.026); rs1051298 CT+TT HR 1.76 (1.11-2.78, P=0.016); rs914232 AA HR 1.99 (1.21-3.27, P=0.007)
  • No polymorphism studied was significantly associated with progression-free survival; the ERCC2 rs13181 C allele and gastrointestinal toxicity did not reach significance (P=0.051, OR 0.30)
• The authors' conclusion: The authors concluded that the study replicated previously reported pharmacogenetic associations and, using exome chip genotyping, identified novel variants influencing pemetrexed therapy outcomes, with future studies needed to test such markers for personalising therapy
• Limitations the authors state:
  • The exome chip omitted many intronic variants previously linked to pemetrexed outcomes, although these were genotyped by other methods
  • No correction for multiple testing was applied; the study was exploratory and used P less than 0.05 as the significance threshold
  • The study was retrospective, and apart from ERCC2 the authors did not consider pharmacogenetic influences on the concomitant platinum therapy
  • The MTHFR rs1801133 survival finding contradicted a previous study, was of marginal significance and may reflect the smaller cohort size

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Lung Cancer, Quality of Life, Non-Small Cell Lung Cancer, Mesothelioma, Chemotherapy, Odds Ratio, Disease Progression.

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