5-Fluorouracil degradation rate as a predictive biomarker of toxicity in breast cancer patients treated with capecitabine.
Summary (2 min read)
Introduction
- Capecitabine is an oral prodrug of 5-fluorouracil (5-FU), enzymatically activated by timidina phosphorylase in tumour tissue, that was rationally designed to mimic continuous infusion 5-FU.1 Capecitabine is rapidly absorbed from the gastrointestinal (GI) tract and metabolized by carboxylesterase in liver, and it is converted to 50 deoxy-5-fluorocytidine and then to 50 deoxy-5-fluorouridine (50 DFUR) by cytidine deaminase.
- In advanced breast cancer (ABC), the efficacy and safety of capecitabine have been demonstrated both as monotherapy and in combination with other drugs.
- Several trials of adjuvant capecitabine administered in combination with other effective drugs did not show an advantage over regimens without capecitabine.
- Finally, skin reactions are common: rash and hand&foot syndrome are frequent but also severe skin toxicities such as Stevens– Johnson syndrome and toxic epidermal necrolysis are reported.
- The authors previously demonstrated that the evaluation of dihydropyrimidine dehydrogenase (DPYD) polymorphisms and the 5-FU degradation rate (5FUDR) can help to distinguish patients prone to develop severe side effects in colorectal and gastric patients treated with 5-FU in both adjuvant and metastatic setting.
Patients
- Clinical data of 37 patients treated for locally advanced and metastatic breast cancer at their institutions were retrospectively collected.
- Age >18 years old, diagnosis of metastatic breast cancer, previous treatment with capecitabine for metastatic breast cancer, PS 0-1 at baseline, absence of liver or kidney impairment, also known as Inclusion criteria were.
- The authors performed a monthly assessment of treatment toxicity according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 5 (CTCAE v.5, 2017).
- Patients were instructed to report and were usually asked for common toxicities during follow-up visits.
- The study was conducted in accordance with the Declaration of Helsinki and the protocol approved by the institutional (Sapienza University) ethical committee.
Methods
- Peripheral blood samples from all patients enrolled were collected at the baseline as clinical practice in their Institution to perform genotype analysis and evaluate 5FUDR on peripheral blood cells.
- The individual 5FUDR was assessed by a liquid chromatography–tandem mass spectrometry on peripheral blood mononuclear cells (PBMC).
- The assay is composed of three steps: (1) PBMC isolation from peripheral blood, (2) PBMC incubation with 5-FU in vitro and (3) determination of 5-FU amount to calculate the degradation rate.
- 18 5FUDR is the result of the whole intracellular metabolizing process, regardless the presence or not of a single enzyme alterations.
Statistical analysis
- SPSS statistical software, Version 24 (SPSS Inc. Chicago, Illinois, USA), was used.
- The v2 test and t test for unpaired data were applied to compare the frequencies and mean, respectively.
- Genotype variant association with toxicity events was first analysed using univariate logistic regression and further by a multivariate logistic regression including patient age ( 60 vs. <60 years old), comorbidity ( 2 vs. <2) and type of chemotherapy regimen (CAPE alone vs. CAPE plus navelbine/lapatinib).
Results
- Overall, 37 Caucasian patients with a median age of 58 years old (range 34–79) treated with CAPE-based chemotherapy for stage II–IV breast cancer were included in this study.
- Their baseline and demographic characteristics are shown in Table 1.
- The frequency of toxicity (73.7 vs. 77.3% and 26.7 vs. 22.7% for any grade and G3–4 toxicity, respectively) did not differ between patients who received CAPE alone or in combination with other drugs.
Pharmacogenetic variant analyses
- Homozygous DPYD IVS14þ 1G>A SNP nor heterozygous DPYD was not observed in the cohort.
- No association was found between 5FUDR and either TSER or MTHFR genotypes (Table 3).
Discussion
- Several enzymes are involved in the capecitabine metabolism.
- The dihydropyrimidine dehydrogenase enzyme (DPD) metabolizes about 80% of the administered 5-FU into the inactive metabolite 5,6-dihydro-5fluorouracil.
- 1G>A polymorphism in the DPYD gene, which leads to the production of an inactive protein and severe toxicity in about one-half of carrier patients.
- 33,34 Besides, the authors showed that 5FUDR is associated with progression-free survival in metastatic colorectal patients with an advantage for ultra/poor metabolizers versus normal metabolizers.
- Hence, the authors carried out a retrospective study aimed to evaluate the impact of each of the following gene polymorphisms MTHFR C667T, MTHFR A1298C, DPYD IVS14þ 1G>A, TSER and the 5-fluorouracil degradation rate (5-FUDR) on toxicities in breast cancer patients treated with capecitabine.
MTHFR
- Suggesting a predictive value of 5FU-degradation regardless of cancer origin and stage.
- 1G>A polymorphism in the DPYD gene, but this alteration has a low frequency, and it is not present in some of the patients with severe toxicity.
- In the adjuvant setting, a test able to predict severe toxicities in these particular setting is crucial in order to avoid reduced dose, delayed administration or interruption of therapy and to maintain dose intensity.
- Finally, their study has some relevant limitations: it is a retrospective and monocentric study and the population is limited.
- The authors highlight the importance of conducting prospective studies on larger sample size and on a homogeneous population in order to evaluate the 5FUDR impact on both toxicities and outcome.
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