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Poster session 01

71P - Capecitabine-induced adverse events: A pharmacogenetic study beyond DPYD

Date

10 Sep 2022

Session

Poster session 01

Topics

Translational Research;  Genetic and Genomic Testing, Counseling

Tumour Site

Oesophageal Cancer;  Colon and Rectal Cancer;  Head and Neck Cancers

Presenters

Mirjam De With

Citation

Annals of Oncology (2022) 33 (suppl_7): S27-S54. 10.1016/annonc/annonc1037

Authors

M. De With1, L. Van Doorn2, D. Maasland2, T. Mulder3, S. El Bouazzaoui3, R.H. Mathijssen2, R.H.N. Van Schaik3, S. Bins2

Author affiliations

  • 1 Medical Oncology And Clinical Chemistry Department, Erasmus MC Cancer Institute, 3015 GD - Rotterdam/NL
  • 2 Medical Oncology Department, Erasmus MC Cancer Institute, 3015 GD - Rotterdam/NL
  • 3 Clinical Chemistry Department, Erasmus MC, 3015 GD - Rotterdam/NL
More

Abstract 71P

Background

Capecitabine treatment is frequently accompanied by adverse events such as hand-foot syndrome (HFS), leading to interruption --or even discontinuation-- of treatment in approximately 26% of patients. These adverse events can be mitigated with pre-emptive dose reductions in case of single nucleotide polymorphisms (SNPs) in DPYD, encoding the main fluoropyrimidine-metabolizing enzyme dihydropyrimidine dehydrogenase. However, HFS still occurs in 53-77% of patients treated with capecitabine. In this study, we investigated if SNPs in other genes involved in capecitabine metabolism are predictive for capecitabine-induced HFS.

Methods

Consecutive patients treated with capecitabine at the Erasmus MC Cancer Institute since 2008 were enrolled if they gave written informed consent in the Code-Geno study (MEC02-1002) or M14DPD study (MEC15-358). Prospectively collected blood samples were genotyped for SNPs in CES1 (rs2244613, rs2244614, rs3217164), CES2 (rs2241409, rs11075646), and CDA (rs2072671, rs603412, rs10916825). HFS was graded according to the Common Terminology Criteria for Adverse Events version 5.0. Associations between SNPs or baseline factors (age, sex and ECOG PS) and HFS with P ≤ 0.10 were tested multivariable by logistic regression and internally validated by bootstrapping.

Results

In total, 446 patients were eligible for analysis. 146 patients (32.7%) developed HFS, of which 77 patients (17.3%) developed HFS ≥ grade 2. In 130 patients (29.1%), capecitabine dose was reduced or treatment was prematurely discontinued due to HFS. CES1 1165-33C>A (rs2244613) and CDA 266+242A>G (rs10916825) variant allele carriers were at higher risk of HFS ≥ grade 2 (OR 1.9; 95% CI 1.1-3.3; P = 0.027 and OR 1.9; 95% CI 1.1-3.2; P = 0.024, respectively) in multivariable analysis.

Conclusions

In this study, we have found CES1 1165-33C>A (rs2244613) and CDA 266+242A>G (rs10916825) as potential biomarker in the prediction of HFS grade 2 or higher. Clinicians should be aware of this association and prospective studies should investigate the right strategy to reduce the risk of HFS during capecitabine treatment in carriers of these SNPs.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

R.H. Mathijssen: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Servier; Financial Interests, Personal, Other, Patent pending: Pamgene; Financial Interests, Institutional, Other, Investigator-initiated research: Astellas, Bayer, Boehringer Ingelheim, Cristal Therapeutics, Pamgene, Pfizer, Novartis, Roche, Servier. All other authors have declared no conflicts of interest.

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