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Clinical Cancer Research Vol. 12, 5496-5502, September 15, 2006
© 2006 American Association for Cancer Research

Cancer Therapy: Clinical

Pharmacogenetics of Capecitabine in Advanced Breast Cancer Patients

Rémy Largillier1, Marie-Christine Etienne-Grimaldi1, Jean-Louis Formento1, Joseph Ciccolini2, Jean-François Nebbia1, Aurélie Ginot1, Mireille Francoual1, Nicole Renée1, Jean-Marc Ferrero1, Cyril Foa1, Moïse Namer1, Bruno Lacarelle2 and Gérard Milano1

Authors' Affiliations: 1 Centre Antoine Lacassagne, Nice, France and 2 Pharmacokinetic Unit, La Timone University Hospital, Marseille, France

Requests for reprints: Gérard Milano, Oncopharmacology Unit, Centre Antoine Lacassagne, 33 Avenue de Valombrose, 06189 Nice Cedex 2, France. Phone: 33-4-92-03-15-53; Fax: 33-4-93-81-71-31; E-mail: gerard.milano{at}nice.fnclcc.fr.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: Germinal gene polymorphisms can explain a part of the interpatient pharmacodynamic variability of anticancer drugs, particularly fluoropyrimidines. Genes for which polymorphisms may potentially influence pharmacodynamics of fluoropyrimidines, including capecitabine, are thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), and dihydropyrimidine dehydrogenase (DPD).

Experimental design: The aim of this prospective pilot study was to analyze the effect of TS, MTHFR, and DPD gene polymorphisms on toxicity and efficacy in advanced breast cancer patients receiving capecitabine as monotherapy. Germinal polymorphisms of TS (6 bp deletion in the 3' region and 28 bp repeats, including G>C mutation in the 5' region), MTHFR (677C>T and 1298A>C), and DPD (IVS14 + 1G>A) were determined in 105 consecutive patients.

Results: A trend toward a higher global toxicity grade 3 and 4 was observed in patients homozygous for the TS 3RG allele compared with patients heterozygous for the 3RG allele or patients not carrying the 3RG allele (50% versus 19% versus 13% respectively, P = 0.064). The sole patient bearing the DPD IVS14 + 1G>A mutation (heterozygous) deceased from hematologic toxicity. The median response duration was 5.8 months (95% confidence interval, 4.3-7.2). Duration of response was significantly shortened in patients homozygous for the 3RG allele compared with others (P = 0.037).

Conclusions: The present data suggest that 3RG3RG breast cancer patients are not good candidates for capecitabine therapy. In addition, attention should be paid to DPD deficiency in breast cancer patients receiving capecitabine. These preliminary data require further confirmation on a larger number of patients.

Capecitabine (Xeloda) is an oral prodrug of 5-fluorouracil (5-FU), which has been developed to provide a more selective and less toxic alternative to 5-FU (1). Following a three-step activation cascade, capecitabine is converted to its active metabolite, 5-FU, by thymidine phosphorylase (Fig. 1 ). Higher levels of expression of this enzyme have been found in tumors and liver compared with normal healthy tissue (2). Clinical experience with capecitabine has proven to be a valuable substitute for 5-FU in colorectal and breast cancer and is now a standard treatment in these tumors, both as single agent or in combination therapy (2). The most common dose-limiting adverse effects associated with capecitabine monotherapy are hyperbilirubinemia, diarrhea, and hand-foot syndrome. Myelosuppression, fatigue, and nausea have also been reported (2). Germinal gene polymorphisms can explain part of the interpatient pharmacodynamic variability of anticancer drugs, particularly fluoropyrimidines (3, 4). Individual analysis of targeted genetic factors could thus contribute to improve prediction of pharmacodynamic events in terms of response and/or toxicity.


Figure 1
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  		Fig. 1. Metabolic pathways of capecitabine and pharmacologically related targets. 5-10 CH=FH4, 5-10 methenyltetrahydrofolate; 5-10 CH2FH4, 5-10 methylene-tetrahydrofolate; 5-CH3FH4, 5-methyltetrahydrofolate; 5-CHOFH4 (FA), 5-formyltetrahydrofolate; DHFR, dihydrofolate reductase; FdUMP, 5-fluorodeoxyuridine 5'-monophosphate; FdUrd, 5-fluorodeoxyuridine; FH2, dihydrofolate; FH4, tetrahydrofolate; MS, methionine synthase; TK, thymidine kinase; TP, thymidine phosphorylase.

 
Regarding the pharmacogenetics of fluoropyrimidines, one of the most promising target genes is the one encoding for thymidylate synthase (TS) because elevated TS expression or activity is a well-known mechanism of resistance to 5-FU (5, 6). A genetic polymorphism in the 5' regulatory region of the TS gene promoter (Fig. 2 ), consisting of either double (2R) or triple (3R) repeats of a 28 bp sequence (7), has been shown to influence TS expression, with higher expression in 3R/3R tumors relative to 2R/2R (8). Two E-box binding sites for upstream stimulatory factor (USF) have been found within the 3R allele, and one within the 2R allele. Experimental studies have shown that transcriptional regulation of TS is dependent on USF protein binding within the repeats (9). The presence of a G->C mutation in the E-box of the second repeat of the 3R allele alters the USF protein binding, thus decreasing transcriptional activation (9). A second TS polymorphism consisting of a 6 bp deletion at bp 1,494 in the 3' untranslated region has also been reported without any clear effect on TS expression (10). Several clinical studies have shown the potential contribution of the above TS germinal polymorphism in the prediction of tumor responsiveness and/or toxicity following treatment by fluoropyrimidines (11).


Figure 2
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  		Fig. 2. Description of reported polymorphisms within the 5' region of the TYMS gene. Two E-box binding sites for USF were found within the 3R allele and one within the 2R allele. Experimental studies have shown that transcriptional regulation of TS is dependent on USF protein binding within the repeats. The presence of a G->C mutation in the E-box of the second repeat of the 3R allele alters the USF protein binding, thus decreasing transcriptional activation.

 
Optimal efficacy of fluoropyrimidines requires elevated intratumoral concentrations of 5-10-methylenetetrahydrofolate (CH2FH4; ref. 12). Intracellular CH2FH4 concentration is mainly controlled by the enzyme methylenetetrahydrofolate reductase (MTHFR), which irreversibly converts CH2FH4 into 5-methyltetrahydrofolate (Fig. 1). Two MTHFR single nucleotide polymorphisms (677C>T and 1298A>C) are associated with low enzyme activity (13, 14). Because a loss in MTHFR enzymatic activity may theoretically favor an increase in intracellular CH2FH4 concentrations, one can hypothesize that patients exhibiting mutated MTHFR genotypes may be more sensitive to fluoropyrimidine cytotoxicity than patients bearing the wild-type genotype. Accordingly, preclinical (15) and clinical studies (16, 17) have suggested that these MTHFR gene polymorphisms may influence fluoropyrimidine responsiveness.

The marked interpatient variability in dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme of 5-FU catabolism, is an additional factor influencing fluoropyrimidine pharmacodynamics (Fig. 1). Several studies have underlined the role of DPD deficiency in the development of severe 5-FU–related toxicity (18, 19). DPD abnormalities can be explained, at least in part, by germinal polymorphisms (18). Analysis of the prevalence of the various DPYD gene mutations indicated that the IVS14 + 1G>A mutation is the most common functional mutation (19, 20), with a prevalence as low as 0.9% in the general Caucasian population. This mutation, leading to the skipping of the whole of exon 14 (165 bp), results in the complete loss of DPD activity in the event of homozygosity (21).

The influence of the above-mentioned gene polymorphisms on the pharmacodynamics of capecitabine has not been widely investigated thus far. The aim of this prospective pilot study was thus to investigate the relevance of TS, MTHFR, and DPD gene polymorphisms on capecitabine-related toxicity and efficacy, in a cohort of 105 consecutive advanced breast cancer patients receiving capecitabine as monotherapy.


   Materials and Methods
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 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Patients
This prospective pilot study, conducted from January 2003 to June 2004, included 105 consecutive advanced breast cancer patients from our Cancer Institute (mean age 61 years, range 33-84 years) receiving oral capecitabine alone (days 1-14 every 3 weeks). According to ethic laws, patients gave consent for tissue collection and analyses. Mean initial capecitabine dose was 2,020 mg/m2/d (range 690-2,580 mg/m2/d). Dose was subsequently reduced at the second and third cycle in 13 patients (mean 1,990 mg/m2/d) and 11 patients (mean 1,940 mg/m2/d), respectively. The median number of cycles was seven (range 1-38). Toxicity was evaluated at first and third cycle, according to National Cancer Institute of Canada Common Toxicity Criteria, as defined in a previous capecitabine trial (22). Response to treatment was evaluated according to Response Evaluation Criteria in Solid Tumors criteria (23). Duration of response was computed from the start of capecitabine until disease progression. Patient characteristics are depicted in Table 1 . Constitutional gene polymorphisms were analyzed on DNA extracted from 9 mL total blood (Paxgene Blood DNA kit, Preanalytics).


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  		Table 1. Description of patients (n = 105)

 
TS genotype analysis
TS 5' polymorphism. Double and triple 28 bp repeats were analyzed by PCR (3% agarose gel, 500 ng genomic DNA). Expected fragment sizes were 220 bp for 2R and 248 bp for 3R. The G->C mutation within the second repeat of the 3R allele suppresses a restriction site and was detected by PCR-RFLP using the HaeIII restriction enzyme, as previously described (9). The influence of the mutation was then analyzed by considering the number of E-box binding sites likely to bind USF proteins, because transcriptional regulation of TS is dependent on USF protein binding (9). We thus defined class 2, class 3, and class 4 TS 5' genotypes as those corresponding to two, three, or four theoretical E-box binding sites (Fig. 2).

TS 3' polymorphism. A fragment containing the 6 bp deletion was amplified by PCR from 100 ng genomic DNA. Expected fragment sizes (110 bp for the wild-type and 104 bp for the variant allele) were separated by electrophoresis on a 4% high-resolution Metaphor agarose gel (15).

MTHFR genotype analysis
MTHFR variants 677C>T (Ala->Val) and 1298A>C (Glu->Ala) were analyzed simultaneously by means of melting curve analyses on Light Cycler (Roche, Meylan, France), as previously described by us (15). MTHFR variant identification was based on the fact that the melting temperature of the DNA/probe complex is lower in the event of DNA/probe T/C mismatch at nucleotide 677 or DNA/probe C/A mismatch at nucleotide 1298.

DPD genotype analysis
The IVS14 + 1G>A mutation (splice site) in the DPYD gene introduces a restriction site and was detected by PCR-RFLP using the NdeI restriction enzyme, as previously described (20). The digested PCR fragments were separated on a 3% agarose gel and visualized with ethidium bromide. The wild-type allele corresponded to two fragments at 181 and 17 bp and the mutated allele corresponded to three fragments at 154, 27, and 17 bp, respectively (20).

Statistics
The relationship between the capecitabine dose (mg/m2/d) and the grade of global toxicity (defined as the maximum observed grade whatever the toxicity pattern) was analyzed by means of Spearman correlation. Relationships between genotypes (wt/wt versus wt/mut versus mut/mut) and the occurrence of grade 3 and 4 global toxicity were analyzed by means of {chi}2 tests, using an exact test method so as to estimate the exact two-sided P value. Response duration was analyzed according to the Kaplan-Meier method. Median follow-up of the present studied population of patients was 6.7 months. The influence of the various tested variables on response duration was assessed by means of Cox regression analysis (for continuous variables) or log-rank test (for categorical variables). Statistics were done on SPSS software, version 13.1 (SPSS, Inc., Chicago, IL).


   Results
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 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Genotype distribution. Distribution of the 28 bp tandem repeat TS genotype was 17.3% 2R2R, 50% 2R3R, and 32.7% 3R3R. Distribution of TS 5' genotype, including the G>C mutation along with TS 3' genotype, is depicted in Table 2 ; distribution of MTHFR genotypes 677C>T and 1298A>C is depicted in Table 2. Distributions of MTHFR (677C>T and 1298A>C) and TS (5' and 3' regions) genotypes agree with those predicted by the Hardy-Weinberg equilibrium. Combined analysis of 677C>T and 1298A>C MTHFR genotypes showed fewer than expected mutated patients for both variants (no patient mut/mut in both positions), suggesting a linkage desequilibrium between 677 and 1,298 variants ({chi}2, P < 0.001). As regards the IVS14 + 1 mutation in the DPYD gene, only 1 of 105 patients carried this mutation (heterozygous patient; see the case report).


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  		Table 2. Distribution of TS and MTHFR genotypes

 
Analysis of toxicity. At first cycle, grade 3 and 4 toxicities were 6.2% for nausea-vomiting, 6.1% for hematotoxicity, 5.2% for diarrhea and for hand-foot syndrome, 2.1% for mucositis, and 0% for alopecia and cardiotoxicity (Table 3 ). At the third cycle, the incidence of grade 3 and 4 hand-foot syndrome increased (9.9%), whereas that of nausea-vomiting, hematotoxicity, and mucositis decreased (Table 3). The global toxicity, defined as the highest grade observed whatever the toxicity pattern, was 17.9% and 13.0% for grade 3 to 4 at first and third cycle, respectively. The global toxicity grade was not linked to the capecitabine administered dose (Spearman correlation: P = 0.14 and 0.76 at first and third cycle, respectively).


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  		Table 3. Description of toxicities

 
Analysis of the influence of TS 5' genotype on the global toxicity revealed, at first, capecitabine cycle only, a trend toward a higher grade 3 and 4 toxicity incidence in patients bearing class 4 genotype, relative to those belonging to class 3 or class 2 (50% versus 19.4% versus 13.0% toxicity rate, P = 0.064; Table 4 ). Interestingly, when considering only the 28 bp tandem repeats (i.e., 2R2R versus 2R3R versus 3R3R), TS genotype was not related to toxicity (Table 4). Similarly, TS gene polymorphism in the 3' region and MTHFR genotypes 677C>T and 1298A>C were not related to toxicity (Table 4).


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  		Table 4. Relationships between the analyzed gene polymorphisms and the global toxicity observed at first cycle

 
Case report. The case is that of a 58-year-old breast cancer patient with hepatic metastasis, who had received no previous treatment by fluoropyrimidines. Capecitabine monotherapy was administered at a daily dose of 1,820 mg/m2 (starting on day 0). She stopped capecitabine treatment on day 12. On day 14, she was hospitalized due to grade 4 hematologic toxicity (febrile neutropenia grade 4, thrombocytopenia grade 3), grade 3 digestive toxicity (diarrhea and mucositis), and grade 2 hand-foot syndrome. The patient was transferred to the intensive care unit and deceased on day 20. Two days before starting treatment, a blood sampling was done and lymphocytic DPD activity was measured. DPD activity was subnormal, at 142 pmol/min/mg protein, corresponding to the 18th percentile of a previous cancer patient population study (24). Interestingly, this patient carried the IVS14 + 1G>A mutation (heterozygous). In addition, the ratio of uracil to dihydrouracil in plasma was subsequently measured as a surrogate marker of DPD activity (the higher the ratio, the lower the activity; ref. 25). This uracil/dihydrouracil ratio was high, with a value of 4.9, strongly suggesting a DPD deficiency (25), when compared with the Gaussian distribution of previously measured ratios in a nonselected cancer population (n = 60, mean = 1.4). The 5' TS genotype of this patient was 3RC3RG (class 3).

Analysis of response. One hundred and two patients out of the 105 were assessable for clinical response. The best response, achieved after a median of three capecitabine cycles (extremes 1-8), were the following: 5 complete responses, 28 partial responses, 39 stabilizations, and 30 progressions. A total of 76 patients ultimately progressed following treatment. Capecitabine was stopped in 88 patients for the following reasons: 70 for disease progression, 13 for severe toxicity, 3 for death, and 2 for nonobservance.

The median response duration was 5.8 months (95% confidence interval, 4.3-7.2). Univariate analyses (Cox analysis or log-rank test when appropriate) revealed that only estradiol receptor status (P < 0.0001), patient age (P = 0.032), and TS 5' genotype class (P = 0.037) were significantly related to response duration (Table 5 ). Of note, for TS 5' genotype, patients belonging to class 4 exhibited a dramatically short duration of response under capecitabine treatment (Fig. 3 ). In contrast, when considering only the 28 bp tandem repeats (i.e., 2R2R versus 2R3R versus 3R3R), TS genotype did not influence duration of response (Table 5). In a multivariate Cox analysis, including estrogen receptor status (P = 0.002) and patient age (P = 0.037), TS 5' class was no longer significant (P = 0.40).


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  		Table 5. Univariate analyses of response duration

 

Figure 3
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  		Fig. 3. Plot of cumulative time to progression according to the TS 5' genotype class. Black dashed line, class 2 patients (n = 58, 41 events, median time to progression 7.4 months). Gray dashed line, class 3 patients (n = 36, 27 events, median time to progression 4.8 months). Black line, class 4 patients (n = 7, 7 events, median time to progression 3.8 months). Vertical bars, censored observations. P value of the log-rank test was 0.037.

 

   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
Different approaches are available to identify and validate predictive markers of anticancer treatment pharmacodynamics. These predictive markers generally include the measurement of drug targets and modulators, the analysis of drug-relevant gene polymorphisms, and the exploration of whole genome expression using DNA array and proteomic tools. In this respect, the majority of clinical studies concerning fluoropyrimidines have been conducted on advanced colorectal cancer (26). In addition, recent data have shown that expression of tumoral determinants like TS, DPD, or thymidine phosphorylase may predict response and/or toxicity to capecitabine in advanced colorectal cancer (27) and ovarian cancer patients (28). However, the limitations of tumoral phenotyping are the need to obtain a representative tumor sample, the risk of analytic variability due to tissue sample handling, and the unavoidable intratumor heterogeneity. Conversely, the advantages of pharmacogenetics lie mainly in the possibility to perform genotyping on normal tissue (germinal polymorphism) along with the stability of DNA. Promising pharmacogenetic data have been reported from the analysis of TS, DPD, and MTHFR gene polymorphisms, which can predict for pharmacodynamic events in colorectal cancer patients receiving 5-FU–based chemotherapy (11, 16, 17, 19, 20).

The introduction of capecitabine treatment has led to the substitution of i.v. 5-FU with a comparable efficacy and reduced toxicity (1, 2). Capecitabine treatment is, however, not devoid of toxicity, this being especially true for the specific hand-foot syndrome with functional and cosmetic effects, particularly in breast cancer patients (29). As the potential clinical role of capecitabine-related gene polymorphisms has not thus far been reported in breast cancer, we conducted a prospective pilot study aimed at examining the potential interest of TS, MTHFR, and DPD gene polymorphisms in 105 consecutive advanced breast cancer patients receiving capecitabine as monotherapy at our institute. Present patients were representative of a general population of advanced breast cancer patients (Table 1). For this pharmacogenetic-pharmacodynamics study, it was important that the drug was given as a single therapy because the presence of concomitant cytotoxic agents could also participate in the global pharmacodynamic events and thus limit the conclusions drawn from the capecitabine-related gene polymorphisms.

Two main results emerged from the present study. The first concerns the effect of DPD abnormalities. Toxic deaths have been reported following capecitabine treatment of advanced breast cancer in elderly women (30), but with no mention of DPD deficiency in these cases. More recently, a case report of lethal toxicity after capecitabine plus oxaliplatin administration was reported in a 58-year-old male patient treated for multifocal hepatocarcinoma (31). The patient was not carrying the IVS14 + 1G>A DPD mutation but exhibited an abnormal uracil/dihydrouracil ratio with a value at 5.0, close to that of the present case report. Our case report clearly identifies DPD deficiency as a source of life-threatening toxicity under capecitabine treatment. It is thus clear that major DPD abnormalities may be responsible for severe toxicities under capecitabine-based chemotherapy. Because capecitabine generates low circulating 5-FU levels (32), it is unlikely that the severe DPD-related toxicity could be attributed to 5-FU overexposure in the blood. A more plausible explanation may lie in the intracellular detoxifying role of DPD. In fact, in the event of marked DPD deficiency, one could anticipate intracellular metabolic imbalance with intracellular overexposure to locally produced 5-FU within normal proliferating cells. Women are at risk of severe toxicity under fluoropyrimidines (33). Prospective studies have shown that women exhibit lower DPD activity than men (24). It is thus advisable to pay more attention to DPD deficiency in breast cancer patients receiving capecitabine. It is not yet clear how to solve the problem of systematic detection of these patients at risk. The determination of the uracil/dihydrouracil plasma ratio (25, 34) may represent a valuable alternative approach that needs to be prospectively validated. The recently described [13C]uracil breath test could also be interesting in this respect (35).

The second main result arising from the present study is the finding on TS gene polymorphisms. It is worth stressing that patients carrying the TS 5'genotype class 4 (3RG3RG genotype) were prone to rapid disease progression (Fig. 3). This observation was statistically significant and concords with the observation that the 3RG allele of TS gene favors transcriptional activation and thus TS expression (7–9, 36). We also observed that, at the first capecitabine cycle, patients bearing the 3RG3RG genotype developed ~3-fold more grade 3 and 4 toxicity than other patients (Table 4). To our knowledge, thus far, only one retrospective study, conducted on a small set of 24 metastatic colorectal cancer patients, has investigated the influence of germinal TS 5' polymorphism on capecitabine pharmacodynamics (37). However, the G->C mutation was not determined. In line with the present study, the authors reported a lower response rate to capecitabine in patients bearing the TS genotype associated with higher TS expression (i.e., 3R3R) relative to 2R2R (37). It must be borne in mind that intracellular TS expression may have a dual role in tumor evolution. As a 5-FU target, high TS expression is related to 5-FU resistance (5). On the other hand, elevated TS expression reflects tumor aggressiveness and can also be an indicator of unfavorable prognosis (38). Altogether, these preliminary data suggest that patients bearing 3RG3RG TS genotype are not good candidates for capecitabine therapy. Due to the presently limited number of patients with 3RG3RG genotype, further confirmatory studies are needed to confirm the role of TS 5' gene polymorphism on capecitabine toxicity and efficacy. It is hoped that the present pilot study will stimulate such studies, which could open future trials aimed at evaluating the effect of a strategy for selecting capecitabine-treated patients based on pharmacogenetics.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 2/13/06; revised 4/11/06; accepted 6/29/06.


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 Materials and Methods
 Results
 Discussion
 References
 

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