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Journal ArticleDOI

5-Fluorouracil degradation rate as a predictive biomarker of toxicity in breast cancer patients treated with capecitabine.

04 Mar 2020-Journal of Oncology Pharmacy Practice (J Oncol Pharm Pract)-Vol. 26, Iss: 8, pp 1836-1842

TL;DR: The pre-treatment evaluation of 5-fluorouracil degradation rate allows to identify breast cancer patients at high risk for severe 5-FU toxicity, as well as predicting G3–4 toxicity occurrence.

AbstractCapecitabine is an oral prodrug of 5-fluorouracil with a relevant role in the treatment of breast cancer. Severe and unexpected toxicities related to capecitabine are not rare, and the identificati...

Topics: Capecitabine (69%), Fluorouracil (55%), Breast cancer (54%)

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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Original Article
5-Fluorouracil degradation rate as a
predictive biomarker of toxicity in breast
cancer patients treated with capecitabine
Andrea Botticelli
1
, Simone Scagnoli
1
, Michela Roberto
2
,
Luana Lionetto
2
, Bruna Cerbelli
2
, Maurizio Simmaco
3
and
Paolo Marchetti
4
Abstract
Capecitabine is an oral prodrug of 5-fluorouracil with a relevant role in the treatment of breast cancer. Severe and
unexpected toxicities related to capecitabine are not rare, and the identification of biomarkers is challenging.
We evaluate the relationship between dihydropyrimidine dehydrogenase, thymidylate synthase enhancer region and
methylenetetrahydrofolate reductase polymorphisms, 5-fluorouracil degradation rate and the onset of G3–4 toxicities in
breast cancer patients. Genetic polymorphisms and the 5-fluorouracil degradation rate of breast cancer patients treated
with capecitabine were retrospectively studied. Genetic markers and the 5-fluorouracil degradation rate were corre-
lated with the reported toxicities. Thirty-seven patients with a median age of 58 years old treated with capecitabine for
stages II–IV breast cancer were included in this study. Overall, 34 (91.9%) patients suffered from at least an episode of
any grade toxicity while nine patients had G3–4 toxicity. Homozygous methylenetetrahydrofolate reductase 677TT was
found to be significantly related to haematological toxicity (OR ¼ 6.5 [95% IC 1.1–37.5], P ¼ 0.04). Three patients had
a degradation rate less than 0.86 ng/mL/106 cells/min and three patients greater than 2.1 ng/mL/106 cells/min. At a
univariate logistic regression analysis, an altered value of 5-fluorouracil degradation rate (values < 0.86 or >2.10 ng/mL/
106 cells/min) increased the risk of G3–4 adverse events (OR ¼ 10.40 [95% IC: 1.48–7.99], P ¼ 0.02). A multivariate logistic
regression analysis, adjusted for age, comorbidity and CAPE-regimen, confirmed the role of 5-fluorouracil degradation rate
as a predictor of G3–4 toxicity occurrence (OR ¼ 10.9 [95% IC 1.2–96.2], P ¼ 0.03). The pre-treatment evaluation of
5-fluorouracil degradation rate allows to identify breast cancer patients at high risk for severe 5-FU toxicity.
Keywords
5-FU degradation rate , breast cancer, capecitabine, chemotherapy toxicity, polymorphism
Date received: 26 May 2019; revised: 13 December 2019; accepted: 15 January 2020
Introduction
Capecitabine is an oral prodrug of 5-fluorouracil
(5-FU), enzymatically activated by timidina phosphor-
ylase 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 5
0
deoxy-5-fluorocytidine and then to
5
0
deoxy-5-fluorouridine (5
0
DFUR) by cytidine deam-
inase. Finally, the enzyme thymidine phosphorylase
converts 5
0
DFUR to 5-FU both in normal and
tumour tissues. However, after an oral dose of capeci-
tabine, the concentration of 5-FU in tumor tissue is
higher than in adjacent healthy tissue, as result of an
higher activity of Thymidine phosphorylase (TP).
2
Oral
administration seems to be preferred by patients and
allows to avoid complications and costs linked to 5-FU
IV infusion.
3
1
Azienda Policlinico Umberto I Roma, Roma, Italy
2
Azienda Ospedaliera Sant’Andrea, Roma, Lazio, Italy
3
Department of Neurosciences, Mental Health and Sensory Organs
(NESMOS), Sapienza University of Rome, Roma, Italy
4
Department of Medical Oncology, St Andrea University Hospital, Rome,
Italy
Corresponding author:
Simone Scagnoli, Azienda Policlinico, Umberto I Viale del Policlinico, 155
Roma, Roma 00161, Italy.
Email: simone.scagnoli@hotmail.it
J Oncol Pharm Practice
0(0) 1–7
! The Author(s) 2020
Article reuse guidelines:
sagepub.com/journals-permissions
DOI: 10.1177/1078155220904999
journals.sagepub.com/home/opp

In advanced breast cancer (ABC), the efficacy and
safety of capecitabine have been demonstrated both as
monotherapy and in combination with other drugs.
Several studies have demonstrated the efficacy of cape-
citabine at the dose of 1250 or 1000 mg/m
2
twice
daily for 14 over 21 days in metastatic breast cancer
patients.
4,5
The oral prodrug has also been tested in
an older population of patients (>65 years old) result-
ing effective and well tolerated at the dose of
1000 mg/m
2
.
6
Capecitabine is a landmark treatment
also in HER2þ metastatic disease in association
with lapatinib, after initial progression to first or
second line.
7
Conversely, the role of capecitabine in the adjuvant
setting is still uncertain. Several trials of adjuvant cape-
citabine administered in combination with other effec-
tive drugs did not show an advantage over regimens
without capecitabine.
8,9
Recently, in the CRATE
study, about 900 patients with HER2 negative breast
cancer with residual disease after standard neoadjuvant
chemotherapy have been randomized to receive adju-
vant capecitabine or no treatment (control group).
The results showed improvement in disease-free surviv-
al (74.1% vs. 67.6%r at 5 years, respectively, HR 0.70,
p: 0.01) and overall survival (OS) (89.2% vs. 83.6%
respectively, HR 0.59; P ¼ 0. 01) in treatment group
and even more significant in TNBC subgroup.
10
As
expected, the addition of capecitabine caused
treatment-related toxicities.
11,12
Regardless cancer primary site and setting of treat-
ment, however, capecitabine is related with several high
grade toxicities, some of them with quick onset and
unexpected severity.
13
Diarrhea is the most common,
adverse event that occurs in 55–60% of patients, with a
severe grade 3 or 4 of toxicity in about 12–15%. Other
common GI adverse events are nausea and vomiting.
Moreover, haematological adverse events like neutro-
penia, anaemia and thrombocytopenia are very
common during the treatment. Finally, skin reactions
are common: rash and hand&foot syndrome are fre-
quent but also severe skin toxicities such as Stevens–
Johnson syndrome and toxic epidermal necrolysis are
reported.
14–16
In view of the wide use of capecitabine in breast
cancer, the identification of predictive factors for
capecitabine-related toxicities is a pressing need. Pre-
emptive identification of patients that will develop
severe toxicities is still an open issue. Several tests
have been developed to identify those patients with
alterations in 5-FU metabolism that can lead to
undue and unexpected toxicities. We previously dem-
onstrated that the evaluation of dihydropyrimidine
dehydrogenase (DPYD) polymorphisms and the
5-FU degradation rate (5FUDR) can help to distin-
guish patients prone to develop severe side effects in
colorectal and gastric patients treated with 5-FU in
both adjuvant and metastatic setting.
17
The aim of our study is to explore the association
between 5FUDR, DPYD, thymidylate synthase
enhancer region (TSER) and methylenetet rahydrofo-
late reductase (MTHFR) polymorphisms and toxicities
in breast cancer patients treated with capecitabine.
Patients and methods
Patients
Clinical data of 37 patients treated for locally advanced
and metastatic breast cancer at our institutions were
retrospectively collected. Inclusion criteria were: 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. Exclusion criteria were: PS 2 or
more at baseline, less than one month of treatment
with capecitabine and patient lost at follow up during
treatment with capecitabine. As a clinical practice,
CAPE was used at 1000–1250 mg/mq twice daily for
14 days followed by a seven-day rest period. We per-
formed a monthly assessment of treatment toxicity
according to the National Cancer Institute-Common
Terminology Criteria for Adverse Events version 5
(CTCAE v.5, 2017). Patien ts were instructed to
report and were usually asked for common toxicities
during follow-up visits. Total toxicity was defined as
the percentage of patients who suffered from at least
one adverse event irrespective of type and grade. 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
our Institution to perform genotype analysis and eval-
uate 5FUDR on peripheral blood cells. Genotyping of
DPYD GIVS14A (rs3918290), MTHFR C677T
(rs1801133) and A1298C (rs1801131) SNPs was per-
formed by pyro-sequencing technology. PCR analysis
was used for genotyping TSER polymorphism
(rs34743033). The individual 5FUDR was assessed by
a liquid chromatography–tandem mass spectrometry
on peripheral blood mononuclear cells (PBMC).
5FUDR is determined in vitro by measuring the
decrease of a fixed amount of 5-FU (10 mg/mL) added
to a solution of PBMC, after 2 h incubation, expressed
as nanogram per millilitre of 5-FU degraded per
minute 10 cells. The assay is composed of three
steps: (1) PBMC isolation from peripheral blood, (2)
2 Journal of Oncology Pharmacy Practice 0(0)

PBMC incubation with 5-FU in vitro and (3) determi-
nation 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. As previously reported,
patients were categorized in three groups according
to their 5FUDR value: below the fifth centile (poor
metabolizers–PMs), above the 95th centile (ultra-rapid
metabolizers–UMs) and within the 5–95th centile (0.85–
2.2 ng/mL/106 cells/min) (extensive metabolizers–EM).
Statistical analysis
SPSS statistical software, Version 24 (SPSS Inc.
Chicago, Illinois, USA), was used. Each MTHFR gen-
otypes C677T (CC, CT and TT) and A1298C (AA, AC,
CC), TSER genotypes (2 R/2R, 2 R/3R, 3 R/3R) and
DPYD (GG/GA) were tested. The v
2
test and t test
for unpaired data were applied to compare the frequen-
cies and mean, respectively. Genotype variant associa-
tion with toxicity events was first analysed using
univariate logistic regression and further by a multi var-
iate 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). A P value < 0.05 was considered
as statistically significant.
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. A 25% dose
reduction was done in nine cases (24.3%), and the
treatment was prematurely stopped in six (16.2%)
patients due to G1–4 GI (40%) and haematological
(60%) adverse events. The most common treatment-
related adverse events are reported in Figure 1.
CAPE was administered with an adjuvant intent in
16 (43.2%) patients and in 21 (56.8%) patients affected
by ABC, and it was administered alone or in combina-
tion with other drugs in 15 (40.5%) and 22 (59.5%)
cases, respectively. Overall, 34 (91.9%) patients suf-
fered from at least an episode of any grade toxicity
while 9 (24.3%) patients had G3–4 toxicity. No toxic
death was reported. 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. Besides, capecitabine plus navelbine regi-
men showed a higher incidence of any grade haemato-
logical toxicity and G1–2 GI toxicity than capecitabine
alone or in combination with lapatinib (Figure 2).
Pharmacogenetic variant analyses
The distribution of the analysed genotypes did not
deviate from Hardy–Weinberg equilibrium (DPYD,
P ¼ 0.9, MTHFR 677, P ¼ 0.86; MTHFR 1298,
P ¼ 0.50; TSER, P ¼ 0.87). Homozygous DPYD
Table 1. Clinicopathological parameters of patients.
Parameter Number %
Total 37 100
Median age years (range) 58 (34–79)
Comorbidity
<2 32 86.5
2 5 13.5
Stage
II–III 16 43.2
IV 21 56.8
Estrogen receptor
Median (range) 80 (0–100)
Negative 11 30.6
Progesteron receptor
Median (range) 49.5 (0–90)
Negative 10 27.8
Her2/neu
Positive 10 27.0
Negative 27 73.0
Grading
1 2 5.4
2 6 16.2
3 22 59.5
Missing 7 18.9
Ki 67 expression
Median (range) 32 (7–89)
Capecitabine-based therapy
Mono-chemotherapy 15 40.5
Plus navelbine 17 46.0
Plus lapatinib 5 13.5
TSER
2R/2R 7 18.9
3R/3R 14 37.8
2R/3R 14 37.8
Missing 2 5.4
MTHFR 677
CC 11 29.7
CT 19 51.4
TT 6 16.2
Missing 1 2.7
MTHFR 1298
AA 17 45.9
AC 15 40.5
CC 5 13.5
5FU degradation value
EM 31 83.8
PM 3 8.1
UP 3 8.1
5FU: 5-fluorouracil; EM: extensive metabolizer; PM: poor metabolizer,
UM: ultra-rapid metabolizer.
Botticelli et al. 3

IVS14 þ 1G > A SNP nor heterozygous DPYD was
not observed in the cohort. Homozygous MTHFR
677TT was found to be significantly related to haema-
tological toxicity (OR ¼ 6.5 [95% IC 1.1–37.5],
P ¼ 0.04). However, no association was detected
between each other SNPs and toxicity (Table 2).
Overall, the mean value SD of 5FUDR was 1.45
0.45 (range: 0.49–2.50) ng/mL/106 cells/min. Three
patients had a degradation rate less than 0.86 ng/mL/
106 cells/min (PMs) and three patients greater than
2.1 ng/mL/106 cells/min (UMs). No association was
found between 5FUDR and either TSER or MTHFR
genotypes (Table 3). At a univariate logistic regression
analysis, an altered value of 5FUDR (values < 0.86 or
>2.10 ng/mL/106 cells/min) increased the risk of G3–4
adverse events (OR ¼ 10.40 [95% IC: 1.48–7.99],
P ¼ 0.02) (Table 2). A multivariate logistic regression
analysis, adjusted for age, comorbidity and CAPE reg-
imen, confirmed the role of 5FUDR as a predictor
of G3–4 toxicity occurrence (OR ¼ 10.9 [95% IC 1.2–
96.2], P ¼ 0.03.
Discussion
Several enzymes are involved in the capecitabine
metabolism.
19
The dihydropyrimidine dehydrogenase
enzyme (DPD) metabolizes about 80% of the admin-
istered 5-FU into the inactive metabolite 5,6-dihydro-5-
fluorouracil. The remaining 20% is converted into
active metabolites that cause the inhibition of thymidy-
late synthase (TYMS) and RNA/DNA damage.
20
Several genotypes of the DPD have been associated
Leucopenia
Neutropenia
Anaemia Nausea Vomit Constipation Diarrhoea Mucositis
Hand-foot
syndrome
G1–G2
2661772944
G3G4
042110402
0
2
4
6
8
10
12
14
16
18
N. of patients
Figure 1. Most common toxicities in study population.
G1–G2 G3–G4 G1–G2 G3–G4 G1–G2 G3–G4
Haematological toxicity Gastrointestinal toxicity Hand-foot syndrome
CAPE
408422
CAPE plus Nvb
7410210
CAPE plus lapatinib
003110
0
2
4
6
8
10
12
N. of patients
Figure 2. Type and severity of toxicity according to the therapeutic scheme administered.
4 Journal of Oncology Pharmacy Practice 0(0)

with reduced enzyme activity that could lead to severe
toxic adverse events of capecitabine or fluoropyrimi-
dine.
21
The most used pharmacogenetic test to predict
DPD activity is base d on the detection of IVS14 þ
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.
22
Moreover, a decreased value of 5FUDR is linked to
DPYD haplotype, and it could be related to adverse
events development;
23
however, this polymorphism has
a low frequency. Other enzymes are involved in 5-FU
metabolism, and their polymorphisms could result in
increased and unexpected toxicities such as MTHFR,
one of the most relevant enzyme that regulates intra-
cellular folate levels that affect DNA synthesis and
methylation and TYMS.
24,25
The single-nucleotide polymorphisms (SNPs) of
MTHFR 677 C > T and 1298 A > C are clinically
relevant and have been associated with the toxicity
of 5-FU.
26
Moreover, variations of the TSER in the
promoter of TYMS gene have been related to both
survival/response outcomes and toxicities in patients
affected by colorectal cancer treated with 5-FU-based
chemotherapy.
27–30
Finally, we previously described
a non-genomic assay that seems to be able to predict
5-FU toxicity by the assessment of the 5FUDR in the
PBMC.
31
This parameter indicates the amount of drug
consumed by cells in a time unit and reflexes the result
of the entire 5-FU degradation metabolism, not only a
single enzyme activity.
32
Applying the assay on colo-
rectal patients, we previously described two different
classes of patients with a higher risk to develop 5-FU
unexpected toxicities: poor metabolizers and ultrarapid
metabolizers.
33,34
Besides, we showed that 5FUDR is
associated with progression-free survival in metastatic
colorectal patients with an advantage for ultra/poor
metabolizers versus normal metabolizers.
35
Up to now, no data were available on the correla-
tion between 5FUDR and DPD/MTHFR/TSER poly-
morphism and cape citabine-related toxicity specifically
in breast cancer patients. Hence, we carried out a ret-
rospective study aimed to evaluate the impact of each
of the fol lowing gene polymorphisms MTHFR C667T,
MTHFR A1298C, DPYD IVS14 þ 1G > A, TSER and
the 5-fluorouracil degradation rate (5-FUDR) on
toxicities in breast cancer patients treated with capeci-
tabine. Our hypothesis was that ultra/poor metabolizer
patients have a higher percentage of total adverse
events.
Our results suggest that 5FUDR is a possible
predictor of G3–4 toxicity in both metastatic and
non-metastatic breast cancer patients treated with
capecitabine. UMs and PMs patients developed
higher rate of severe toxicities compared with NM,
and these results are similar to our previous findings
on colorectal cancer patients treated with capecitabine,
Table 3. Incidence of toxicity by patients genotype and 5FUDR.
Biomarker Genotype N
Haematoxicity
(G1–4)
(%)
OR
(95% CI) P
GI toxicity
(G1–4)
(%)
OR
(95% CI) P
HFS
(G1–4)
(%)
OR
(95% CI) P
G3–4
Toxicity
(%)
OR
(95% CI) P
MTHFR
C677T
CC 11 18 91 35 36
CT 16 56 75 6 21
TT 6 66 6.5 (1.1–37.5) 0.04 83 0.3 (0.1–3.3) 0.35 20 0.2 (0.1–1.2) 0.08 17 0.4 (0.1–2.1) 0.30
MTHFR
A1298C
AA 15 53 73 21 29
AC 14 43 85 7 13
CC 5 20 0.5 (0.1–2.0) 0.33 100 3.1 (0.5–19.8) 0.23 40 0.7 (0.1–4.0) 0.67 40 0.6 (0.1–2.7) 0.50
TSER 3R/3R 7 43 86 0 29
2R/3R 12 42 83 25 29
2R/2R 13 54 1.2 (0.2–6.6) 0.81 77 0.6 (0.1–6.8) 0.73 23 1.5 (0.2–8.9) 0.65 14 0.7 (0.1–4.4) 0.68
5-FU
dRate
NM 28 43 1.3 (0.2–7.8) 86 22 16 10.4 (1.5–72.9)
PM 3 33 67 0.3 (0.1–2.4) 0 67
UM 3 67 0.75 67 0.28 0 0.0 0.99 67 0.02
Bold- significant difference in G3-4 toxicities between normal metabolizers (NM) and ultra/poor metabolizers (PM/UM) (p ¼ 0.02).
Table 2. 5FUDR descriptive statistics by demographic and
genetic characteristics.
N
5FUDR
(mean value SD) P
Age
<60 years 19 1.39 0.51 0.26
70 years 18 1.56 0.37
MTHFR C677T
CC 11 1.56 0.63 0.72
CT 19 1.42 0.39
TT 6 1.48 0.28
MTHFR A1298C
AA 17 1.57 0.45 0.14
AC 15 1.47 0.36
CC 5 1.12 0.57
TSER
3R3R 7 1.30 0.47 0.60
2R3R 14 1.51 0.41
2R2R 14 1.46 0.43
Botticelli et al. 5

Citations
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Journal ArticleDOI
TL;DR: Issues and barriers to implementing precision dosing approaches for 5FU and capecitabine are identified and discussed with possible solutions proposed.
Abstract: Despite advances in targeted cancer therapy, the fluoropyrimidines 5-fluorouracil (5FU) and capecitabine continue to play an important role in oncology. Historically, dosing of these drugs has been based on body surface area. This approach has been demonstrated to be an imprecise way to determine the optimal dose for a patient. Evidence in the literature has demonstrated that precision dosing approaches, such as DPD enzyme activity testing and, in the case of intravenous 5FU, pharmacokinetic guided dosing, can reduce toxicity and yield better patient outcomes. However, despite the evidence, there has not been uniform adoption of these approaches in the clinical setting. When a drug such as 5FU has been used clinically for many decades, it may be difficult to change clinical practice. With the aim of facilitating change of practice, issues and barriers to implementing precision dosing approaches for 5FU and capecitabine are identified and discussed with possible solutions proposed.

4 citations


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    [...]


Journal ArticleDOI
Abstract: Drug–drug interactions (DDIs) can affect both treatment efficacy and toxicity. We used Drug-PIN® (Personalized Interactions Network) software in colorectal cancer (CRC) patients to evaluate drug–drug–gene interactions (DDGIs), defined as the combination of DDIs and individual genetic polymorphisms. Inclusion criteria were: (i) stage II-IV CRC; (ii) ECOG PS (Performance status sec. Eastern coperative oncology group) ≤2; (iii) ≥5 concomitant drugs; and (iv) adequate renal, hepatic, and bone marrow function. The Drug-PIN® system analyzes interactions between active and/or pro-drug forms by integrating biochemical, demographic, and genomic data from 110 SNPs. We selected DDI, DrugPin1, and DrugPin2 scores, resulting from concomitant medication interactions, concomitant medications, and SNP profiles, and DrugPin1 added to chemotherapy drugs, respectively. Thirty-four patients, taking a median of seven concomitant medications, were included. The median DrugPin1 and DrugPin2 scores were 42.6 and 77.7, respectively. In 13 patients, the DrugPin2 score was two-fold higher than the DrugPin1 score, with 7 (54%) of these patients experiencing severe toxicity that required hospitalization. On chi-squared testing for any toxicity, a doubled DrugPin2 score (p = 0.001) was significantly related to G3–G4 toxicity. Drug-PIN® software may prevent severe adverse events, decrease hospitalizations, and improve survival in cancer patients.

2 citations


Journal ArticleDOI
TL;DR: The synergistic interactions observed in MDA-MB-231 correlated with an activation of p38 MAPK, inhibition of FAK, increased expression of apoptogenic markers, prolongation of S-phase of cell cycle, and destabilization of actin network.
Abstract: Background: The combination effect of 5-fluorouracil (5-FU) with either CX-4945 or a new inhibitor of protein kinase CK2, namely 14B (4,5,6,7-tetrabromo-1-(3-bromopropyl)-2-methyl-1H-benzimidazole), on the viability of MCF-7 and triple-negative MDA-MB-231 breast cancer cell lines was studied. Methods: Combination index (CI) values were determined using an MTT-based assay and the Chou-Talalay model. The effect of the tested drug combinations on pro-apoptotic properties and cell cycle progression was examined using flow cytometry. The activation of FAK, p38 MAPK, and ERK1/2 kinases and the expression of selected pro-apoptotic markers in MDA-MB-231 cell line after the combined treatment were evaluated by the western blot method. Confocal microscopy was used to examine actin network in MDA-MB-231. Results: Our results showed that a synergistic effect (CI < 1) occurred in MDA-MB-231 after treatment with both combinations of 5-FU with 14B or CX-4945, whereas the combination of 5-FU and 14B evoked an antagonistic effect in MCF-7. We conclude that the synergistic interactions (CI < 1) observed for both the combinations of 5-FU and 14B or CX-4945 in MDA-MB-231 correlated with an activation of p38 MAPK, inhibition of FAK, increased expression of apoptogenic markers, prolongation of S-phase of cell cycle, and destabilization of actin network. Conclusions: The obtained results support the recent observation that CK2 inhibitors can improve 5-FU-based anticancer therapy and FAK kinase can be an attractive molecular target in breast cancer therapy.

1 citations


Cites background from "5-Fluorouracil degradation rate as ..."

  • ...Due to its cytotoxicity [8] and resistance occurrence, 5-FU is one of the most commonly used TS-directed anticancer drugs applied in combination with other chemotherapy compounds for the treatment of various cancers, including breast cancer [9,10]....

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Journal ArticleDOI
Abstract: Breast cancer (BC) is the second most common cancer in women globally after lung cancer. Presently, the most important approach for BC treatment consists of surgery, followed by radiotherapy and chemotherapy. The latter therapeutic methods are often unsuccessful in the treatment of BC because of their various side effects and the damage incurred to healthy tissues and organs. Currently, numerous nanoparticles (NPs) have been identified and synthesized to selectively target BC cells without causing any impairments to the adjacent normal tissues or organs. Based on an exploratory study, this comprehensive review aims to provide information on engineered NPs and their payloads as promising tools in the treatment of BC. Therapeutic drugs or natural bioactive compounds generally incorporate engineered NPs of ideal sizes and shapes to enhance their solubility, circulatory half-life, and biodistribution, while reducing their side effects and immunogenicity. Furthermore, ligands such as peptides, antibodies, and nucleic acids on the surface of NPs precisely target BC cells. Studies on the synthesis of engineered NPs and their impact on BC were obtained from PubMed, Science Direct, and Google Scholar. This review provides insights on the importance of engineered NPs and their methodology for validation as a next-generation platform with preventive and therapeutic effects against BC.

Journal ArticleDOI
Abstract: The perpetual lack of advanced strategies to prevent aggressive breast cancer with multiple categories represents challenging scientific society problems. Reduced graphene oxide- can treat disease, which was recently investigated due to its ability to induce apoptosis-based death. This research tested the chemotherapeutics in vitro efficacy of reduced graphene oxide embedded with gold and silver nanoparticles toward drug-sensitive breast cancer cells (MCF-7) and their cytotoxicity. Synthesis of the Au-Ag/rGO–5FU nanocomposites has been conducted using a wet chemical approach with chitosan aid as a pore directing and capping agent. The particle structure and morphology well characterized using different systems. HR-TEM shows a narrow-sized distribution of less than 100 nm, which is proper for cell membranes and medical use. The physical combination of the nanocomposite and 5-FU drug has been conducted mechanically using wet chemistry. The Au/Ag/rGO-5FU material's high activity enables it to produce reactive oxygen radicals, which display a potential against MCF-7 cell lines. All the results, including those obtained via cytometry, use the combination of Au/Ag/rGO–5FU to show a more substantial anticancer influence and more drug stability than pure 5-FU.

References
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Journal ArticleDOI
TL;DR: This work has shown that novel genes identified in DNA microarray profiling have the potential to identify novel genes that are involved in mediating resistance to 5-FU, and these genes might prove to be therapeutically valuable as new targets for chemotherapy, or as predictive biomarkers of response to5-FU-based chemotherapy.
Abstract: 5-fluorouracil (5-FU) is widely used in the treatment of cancer. Over the past 20 years, increased understanding of the mechanism of action of 5-FU has led to the development of strategies that increase its anticancer activity. Despite these advances, drug resistance remains a significant limitation to the clinical use of 5-FU. Emerging technologies, such as DNA microarray profiling, have the potential to identify novel genes that are involved in mediating resistance to 5-FU. Such target genes might prove to be therapeutically valuable as new targets for chemotherapy, or as predictive biomarkers of response to 5-FU-based chemotherapy.

3,575 citations


"5-Fluorouracil degradation rate as ..." refers background in this paper

  • ...The remaining 20% is converted into active metabolites that cause the inhibition of thymidylate synthase (TYMS) and RNA/DNA damage.(20) Several genotypes of the DPD have been associated Leucopenia Neutropenia Anaemia Nausea Vomit Constipation Diarrhoea Mucositis Hand-foot syndrome...

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Journal ArticleDOI
TL;DR: Lapatinib plus capecitabine is superior to cape citabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab.
Abstract: A b s t r ac t The interim analysis of time to progression met specified criteria for early reporting on the basis of superiority in the combination-therapy group. The hazard ratio for the independently assessed time to progression was 0.49 (95% confidence interval, 0.34 to 0.71; P<0.001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group. This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events. Conclusions Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2- positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab. (ClinicalTrials.gov number, NCT00078572.)

2,932 citations


"5-Fluorouracil degradation rate as ..." refers background in this paper

  • ...Capecitabine is a landmark treatment also in HER2þ metastatic disease in association with lapatinib, after initial progression to first or second line.(7) Conversely, the role of capecitabine in the adjuvant setting is still uncertain....

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Journal ArticleDOI
TL;DR: Capecitabine, which is finally converted to 5-FU by dThdPase in tumours, should be much safer and more effective than5-FU, and this was indeed the case in the HCT116 human colon cancer and the MX-1 breast cancer xenograft models.
Abstract: Capecitabine (N4-pentyloxycarbonyl-5′-deoxy-5-fluorocytidine) is a novel oral fluoropyrimidine carbamate, which is converted to 5-fluorouracil (5-FU) selectively in tumours through a cascade of three enzymes. The present study investigated tissue localisation of the three enzymes in humans, which was helpful for us to design the compound. Carboxylesterase was almost exclusively located in the liver and hepatoma, but not in other tumours and normal tissue adjacent to the tumours. Cytidine (Cyd) deaminase was located in high concentrations in the liver and various types of solid tumours. Finally, thymidine phosphorylase (dThdPase) was also more concentrated in various types of tumour tissues than in normal tissues. These unique tissue localisation patterns enabled us to design capecitabine. Oral capecitabine would pass intact through the intestinal tract, but would be converted first by carboxylesterase to 5′-deoxy-5-fluorocytidine (5′-dFCyd) in the liver, then by Cyd deaminase to 5′-deoxy-5-fluorouridine (5′-dFUrd) in the liver and tumour tissues and finally by dThdPase to 5-FU in tumours. In cultures of human cancer cell lines, the highest level of cytotoxicity was shown by 5-FU itself, followed by 5′-dFUrd. Capecitabine and 5′-dFCyd had weak cytotoxic activity only at high concentrations. The cytotoxicity of the intermediate metabolites 5′-dFCyd and 5′-dFUrd was suppressed by inhibitors of Cyd deaminase and dThdPase, respectively, indicating that these metabolites become effective only after their conversion to 5-FU. Capecitabine, which is finally converted to 5-FU by dThdPase in tumours, should be much safer and more effective than 5-FU, and this was indeed the case in the HCT116 human colon cancer and the MX-1 breast cancer xenograft models.

1,170 citations


"5-Fluorouracil degradation rate as ..." refers background in this paper

  • ...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....

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Journal ArticleDOI
TL;DR: Capecitabine is a novel fluoropyrimidine carbamate rationally designed to generate 5-fluorouracil preferentially in tumors, which is explained to a great extent by the activity of TP in colorectal tumor tissue, (the enzyme responsible for the conversion of 5′-DFUR to 5-FU), which is approximately four times that in adjacent healthy tissue.
Abstract: Purpose: Capecitabine (Xeloda) is a novel fluoropyrimidine carbamate rationally designed to generate 5-fluorouracil (5-FU) preferentially in tumors. The purpose of this study was to demonstrate the preferential activation of capecitabine, after oral administration, in tumor in colorectal cancer patients, by the comparison of 5-FU concentrations in tumor tissues, healthy tissues and plasma. Methods: Nineteen patients requiring surgical resection of primary tumor and/or liver metastases received 1,255 mg/m2 of capecitabine twice daily p.o. for 5–7 days prior to surgery. On the day of surgery, samples of tumor tissue, adjacent healthy tissue and blood samples were collected simultaneously from each patient, 2 to 12 h after the last dose of capecitabine had been administered. Concentrations of 5-FU in various tissues and plasma were determined by HPLC. The activities of the enzymes (CD, TP and DPD) involved in the formation and catabolism of 5-FU were measured in tissue homogenates, by catabolic assays. Results: The ratio of 5-FU concentrations in tumor to adjacent healthy tissue (T/H) was used as the primary marker for the preferential activation of capecitabine in tumor. In primary colorectal tumors, the concentration of 5-FU was on average 3.2 times higher than in adjacent healthy tissue (P=0.002). The mean liver metastasis/healthy tissue 5-FU concentration ratio was 1.4 (P=0.49, not statistically different). The mean tissue/plasma 5-FU concentration ratios exceeded 20 for colorectal tumor and ranged from 8 to 10 for other tissues. Conclusions: The results demonstrated the preferential activation of capecitabine to 5-FU in colorectal tumor, after oral administration to patients. This is explained to a great extent by the activity of TP in colorectal tumor tissue, (the enzyme responsible for the conversion of 5′-DFUR to 5-FU), which is approximately four times that in adjacent healthy tissue. In the liver, TP activity is approximately equal in metastatic and healthy tissue, which explains the lack of preferential activation of capecitabine in these tissues.

630 citations


"5-Fluorouracil degradation rate as ..." refers background in this paper

  • ...However, after an oral dose of capecitabine, the concentration of 5-FU in tumor tissue is higher than in adjacent healthy tissue, as result of an higher activity of Thymidine phosphorylase (TP).(2) Oral administration seems to be preferred by patients and allows to avoid complications and costs linked to 5-FU IV infusion....

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Journal ArticleDOI
TL;DR: After standard neoadjuvant chemotherapy containing anthracycline, taxane, or both, the addition of adjuvant capecitabine therapy was safe and effective in prolonging disease‐free survival and overall survival among patients with HER2‐negative breast cancer who had residual invasive disease on pathological testing.
Abstract: BackgroundPatients who have residual invasive carcinoma after the receipt of neoadjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2)–negative breast cancer have poor prognoses. The benefit of adjuvant chemotherapy in these patients remains unclear. MethodsWe randomly assigned 910 patients with HER2-negative residual invasive breast cancer after neoadjuvant chemotherapy (containing anthracycline, taxane, or both) to receive standard postsurgical treatment either with capecitabine or without (control). The primary end point was disease-free survival. Secondary end points included overall survival. ResultsThe result of the prespecified interim analysis met the primary end point, so this trial was terminated early. The final analysis showed that disease-free survival was longer in the capecitabine group than in the control group (74.1% vs. 67.6% of the patients were alive and free from recurrence or second cancer at 5 years; hazard ratio for recurrence, second cancer, or death, 0.70; 95% ...

588 citations


"5-Fluorouracil degradation rate as ..." refers result in this paper

  • ...01) in treatment group and even more significant in TNBC subgroup.(10) As expected, the addition of capecitabine caused treatment-related toxicities....

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Frequently Asked Questions (1)
Q1. What are the contributions in "5-fluorouracil degradation rate as a predictive biomarker of toxicity in breast cancer patients treated with capecitabine" ?

Genetic polymorphisms and the 5-fluorouracil degradation rate of breast cancer patients treated with capecitabine were retrospectively studied. Genetic markers and the 5-fluorouracil degradation rate were correlated with the reported toxicities. Thirty-seven patients with a median age of 58 years old treated with capecitabine for stages II–IV breast cancer were included in this study.