Introduction

Capecitabine (brand name Xeloda) is a chemotherapy agent that belongs to the drug class of fluoropyrimidines. It is widely used in the treatment of several malignancies including colon cancer, metastatic colorectal cancer, and metastatic breast cancer. Capecitabine is a prodrug that is enzymatically converted to its active form, fluorouracil (also called 5-fluorouracil), which acts as an antimetabolite to slow tumor growth.

The DPYD gene encodes dihydropyrimidine dehydrogenase (DPD), an enzyme that catalyzes the rate-limiting step in fluorouracil metabolism. Dihydropyrimidine dehydrogenase inactivates 80–90% of 5-fluorouracil (5-FU) into 5,6-dihydro-fluorouracil. Genetic variants in the DPYD gene can lead to enzymes with reduced or absent activity. Individuals who have at least one copy of a nonfunctional DPYD variant (for example, c.1905+1G>A (formerly *2A; rs3918290) or c.1679T>G (p.I560S; formerly *13; rs55886062)) will not be able to metabolize fluorouracil at normal rates. Consequently, these individuals are at risk of potentially life-threatening fluorouracil toxicity, such as bone marrow suppression, gastrointestinal toxicity and, rarely, neurotoxicity. The prevalence of DPD partial deficiency varies in different populations but is approximately 3–5%. There is an FDA-approved antidote for 5-FU overdose: uridine triacetate. Overdose can occur in individuals with partial DPD deficiency taking either capecitabine or 5-FU.

The FDA-approved drug label for capecitabine states that no capecitabine dose has been proven safe in individuals with absent DPD activity, and that there is insufficient data to recommend a specific dose in individuals with partial DPD activity as measured by any specific test (Table 1) (1).

The Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) have published dosing recommendations for fluoropyrimidines (capecitabine and fluorouracil) based on DPYD genotype (Tables 2 and 3). Both recommendations include dose reductions for intermediate metabolizers (with reduced enzyme activity), and avoiding fluorouracil and choosing an alternative agent for poor metabolizers (with absent enzyme activity) (2, 3, 4).

Drug Class: Fluoropyrimidines

Fluoropyrimidines are a class of antimetabolite drugs that are widely used in the treatment of cancer. Currently, there are 3 types of fluoropyrimidines in clinical use: capecitabine (oral – pill) and 5-fluorouracil (5-FU – IV), which are licensed for use in the US, and tegafur, which is not available in the US. Capecitabine and tegafur are both active precursors of fluorouracil.

Fluoropyrimidines are thought to exert their chemotherapeutic effects through several active metabolites. The main mechanism of action is thought to be the inhibition of thymidylate synthase, which plays an important part in the folate-homocysteine cycle, and purine and pyrimidine synthesis pathways. Active metabolites can also be incorporated into RNA and DNA, ultimately leading to cell death (7). Based on their mechanism of action, fluoropyrimidines are teratogenic, as they can cause fetal harm when administered to a pregnant woman (8).

Approximately 10–40% of individuals develop severe and potentially life-threatening toxicity early during treatment with fluoropyrimidines (9). This toxicity typically leads to an interruption or discontinuation of potentially effective anticancer therapy and may require an emergency room visit or hospitalization in severe instances (10).

The inter-individual variation in the occurrence and severity of adverse events in individuals receiving fluoropyrimidines can be partly explained by clinical factors, such as age and gender. However, much of the variability in adverse events remains unexplained (11).

Of the genetic factors thought to contribute to fluoropyrimidine intolerance, the DPYD gene has been the most studied. This gene encodes the primary enzyme involved in breaking down fluoropyrimidines to inactive metabolites. Individuals who have DPD deficiency have a significantly increased risk of severe fluoropyrimidine toxicity, and the stratification of individuals based on DPYD genotype may help prevent adverse events (12, 13, 14, 15, 16, 17).

Drug: Capecitabine

Capecitabine is a chemotherapy used as an adjunct treatment for colon cancer, and as either monotherapy or part of combination therapy for metastatic colorectal cancer, metastatic breast cancer, pancreatic cancer, esophageal cancer, head and neck cancers and neuroendocrine tumors (NETs) (1, 18, 19, 20, 21).

Capecitabine is an orally administered prodrug, which is converted to its active form, fluorouracil, by thymidine phosphorylase, an enzyme that can be found in higher concentrations in tumors compared to normal tissue and plasma. Fluorouracil (5-flourouracil, 5-FU) is structurally similar to pyrimidines, and the enzyme that catalyzes the rate-limiting step in the breakdown of pyrimidines (DPD) also catalyzes the rate-limiting step in 5-FU catabolism. Dihydropyrimidine dehydrogenase catalyzes the conversion of fluorouracil to the non-cytotoxic dihydrofluorouracil (22).

Once capecitabine is activated to 5-FU, further metabolism generates 5-fluoro-2’-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These 2 metabolites achieve cell injury by different mechanisms. The FdUMP targets thymidylate synthase (TS), inhibiting synthesis of an important DNA precursor. The FUTP is incorporated into RNA, leading to inhibition of RNA processing and protein synthesis. (1)

Uridine triacetate (brand name Vistogard) was approved December 11, 2015 as an antidote for fluorouracil and capecitabine overdose (23). Exogenous uridine competes with 5-FU for incorporation into RNA, thus diluting the toxic effects of high 5-FU levels. Uridine triacetate is 4–6-fold higher in bioavailability than equimolar doses of uridine (24).

Uridine triacetate is meant for overdose treatment of adults or children, however, it can be considered in situations of individuals with pharmacogenetic deficiency, which is technically an overdose (25, 26). The high cost of a single course of uridine triacetate therapy has been cited as a potential barrier to therapy. Nevertheless, 94% of clinical trial individuals treated with uridine triacetate survived the overdose event, a notable improvement over the historic mortality rate of 84% (24).

Symptomatic DPD deficiency is a rare autosomal recessive disorder with a wide range of symptoms, ranging from no symptoms or signs to severe neurological problems. In affected individuals, the absent or greatly reduced DPD activity results in uracil and thymine accumulating in the blood, urine, and cerebrospinal fluid. Neurological symptoms typically manifest in early childhood and include seizures, small head size, and delayed cognitive and motor development (27).

Symptomatic DPD deficiency is typically caused by homozygous inactivation of DPYD; whereas individuals who are heterozygotes tend to be asymptomatic. However, all individuals with less than 70% DPD activity are considered at risk for the development of severe drug toxicity when treated with fluoropyrimidines (28). Signs of capecitabine toxicity include severe diarrhea, severe mucositis, neutropenia, hand-foot syndrome, and neurotoxicity (1).

Capecitabine can cause fetal harm when administered to a pregnant woman; however, the limited human data are not sufficient to inform the drug-associated risk during pregnancy. There is also no information regarding the presence of capecitabine in human milk, or its effects on milk production the breast-fed infant. The FDA label advises that women should not breastfeed during treatment with capecitabine nor for 2 weeks following the final dose. (1)

Safety and efficacy of capecitabine in pediatric individuals has not been established. Additional monitoring and precautions should be employed when administering capecitabine in the elderly and individuals with mild to moderate hepatic dysfunction. Individuals with moderate and severe renal impairment have demonstrated higher exposure for capecitabine and its metabolites when compared to individuals with normal renal function. (1)

Gene: DPYD

The DPYD gene encodes the enzyme DPD, which catalyzes the first and rate-limiting step in the breakdown of the pyrimidine nucleotides thymine and uracil. Dihydropyrimidine dehydrogenase also catalyzes the rate-limiting step in the breakdown of fluoropyrimidines.

Many DPYD variants have been described, although only a few have been demonstrated to influence DPD enzyme activity. When no variant is detected (formerly known as *1), it is associated with normal enzyme activity. Individuals who have 2 copies of DPYD alleles with normal activity are known as “normal metabolizers” and have fully functional DPD enzyme activity (Table 4). The DPYD alleles c.1601G>A (*4, rs1801158), c.1627G>A (*5, rs1801159), c.2194G>A (*6, rs1801160), and c.85T>C (*9A, rs1801265) are also considered to have normal activity (29). Historically, variant haplotypes in DPYD have been identified by their star (*) allele names. However, the Pharmacogene Variation Database (PharmVar) now identifies these alleles by their dbSNP “rs” allele identifier or cDNA change based on the NM_000110.3 transcript, DPYD mRNA variant 1. All 3 of these identifiers are provided in the Nomenclature for Selected DPYD alleles table below.

The nonfunctional DPYD variants that have been associated with absent DPD activity and an increased risk of toxicity with fluoropyrimidines include c.1905+1G>A (*2A, rs3918290) and c.1679T>G (*13, rs55886062) (22). Variants with decreased function include rs67376798 (c.2846A>T) and HapB3, which also are associated with an increased risk of fluoropyrimidine toxicity. The most well-studied variant is DPYD c.1905+1G>A (*2A, rs3918290), in which a single nucleotide substitution at the invariant splice donor site of intron 14 leads to exon 14 skipping, resulting in the production of a truncated protein with no enzyme activity.

Individuals who have one normal function and one decreased function or no function DPYD alleles are known as “intermediate metabolizers”. Individuals with 2 decreased function alleles are also categorized as intermediate metabolizers, as they have partial DPD deficiency and are at increased risk of capecitabine toxicity. And individuals who have a combination of nonfunctional DPYD alleles, or decreased function DPYD alleles, or both are known as “poor metabolizers”, as they have complete DPD deficiency and are at very high risk of capecitabine toxicity.

Activity scores may be used to distinguish between the various DPYD alleles and their functionality (Table 5). The use of activity scores may result in differentiated individualized dosing advice for fluoropyrimidines, which is beneficial for reducing toxic side effects while maintaining efficacy (16).

Overall, the prevalence of individuals who are heterozygous for nonfunctional variant DPYD alleles (partially DPD deficient) and at risk of severe drug reactions is estimated to be as high as 5–8%, but this varies in different populations (9, 28, 31, 32, 33, 34, 35). In Caucasians, approximately 3–5% of have partial DPD deficiency and 0.2% have complete DPD deficiency (32). Recent studies suggest that ~8% of Caucasians have at least one of the 4 best-known altered-function alleles (36).

In African-Americans, the prevalence of decreased DPD enzyme activity is 8% (35). It is notable that despite being well studied, DPYD c.1905+1G>A (*2A, rs3918290) is very rare in individuals of African ancestry (37). One study did note that the normal function c.85T>C (*9A, rs1801265) variant was present in 49% of African-American samples (38). The rs115232898 (c.557A>G) variant allele with reduced function was detected in 2.6% of African-heritage Brazilians (39).

Studies of Egyptian and Tunisian populations suggest the allelic frequencies for DPYD variants in in these 2 countries are similar to Caucasian variant allele frequencies (40, 41). The frequency of the poor-metabolizer rs67376798 (c.2846A>T) allele in Mestizo and Native Mexican populations is rare, but not significantly different than in MXL (Mexican Ancestry from Los Angeles USA) or CEU (Utah Residents (CEPH) with Northern and Western European Ancestry) populations in the 1000 genomes project (42).

Asian populations have slightly different allele frequencies as compared to African and European populations. The frequency of the c.85T>C (*9A, rs1801265) normal function variant was slightly lower in Han Chinese, Korean and Japanese populations, particularly compared to Africans, though the frequency of the c.2657G>A (*9B, rs1801267) normal function variant and c.295_298delTCAT (*7, rs72549309), c.703C>T (*8, rs1801266), and c.2983G>T (*10, rs1801268) no function alleles were similar across these groups (38). The c.1905+1G>A (*2A/*2B, rs3918290) and c.1679T>G (*13, rs55886062) no function alleles were not detected in a study of Hmong and East Asian descent individuals, underscoring the rarity of these alleles (43). An analysis of multiple genotyping studies in South Asian populations found that the normal function rs2297595 (c.496A>G) allele was prevalent in south Asia (44).

Most individuals in the US are not screened for DPD deficiency before starting fluorouracil therapy (45). In contrast, the European Medicines Agency recommends testing for DPD deficiency before initiating treatment with any fluorouracil related chemotherapy (37).

Gene: TYMS

Emerging studies and reports suggest that genetic variation at another locus may also affect 5-FU efficacy and toxicity—TYMS. This gene encodes TS, which catalyzes the methylation of deoxyuridylate to deoxythymidylate. This reaction is a rate-limiting step in the production of an essential DNA synthesis precursor. The TS expression correlates with sensitivity to 5-FU and the TS enzyme one of the targets of 5-FU(46). While this functional link to 5-FU metabolism and tumor response has been demonstrated in multiple studies, the impact of specific genetic variants in TYMS is less clear (46, 47, 48, 49). The TYMS alleles have been reported in a handful of studies as being associated with increased toxicity and anti-tumor cell response with fluoropyrimidines.

The rs45445694 polymorphism is the defining variant of the TYMS “2R” allele, which has been associated with clinical response and severe toxicity events, either in homozygosity or heterozygosity (25, 50, 51, 52). This allele is in the 5’UTR and is a duplication a 28 base pair (bp) repeat. This same locus can have variable tandem repeats between 0 and 9 copies, and studies suggest that increased copy numbers of the repeat are associated with increased TYMS expression and TS protein levels (53).

One additional variant in TYMS has been found in association with adverse reactions to fluoropyrimidine therapy: a 3'UTR 9 bp-indel (rs11280056) (51, 53). There are conflicting reports as to whether this is a 6- or 9-bp-indel. One variant (rs2853542) within the TYMS enhancer region in the context of the 28bp tandem repeat triplication, called 3RG or 3RC based on the specific nucleotide present, has also been reported in association with neurotoxicity during 5-FU treatment (54). The presence of the C nucleotide at rs2853542 has been associated with decreased expression of TYMS mRNA (55).

PharmGKB has described TYMS as a Very Important Pharmacogene, though the level of evidence for TYMS and capecitabine/5-fluorouracil interaction is limited (PharmGKB “level 3”) (53). CPIC also views this interaction as having limited evidence and thus provides no prescribing recommendations for these pharmacogenetic variants (56).

Linking Gene Variation with Treatment Response

Standard doses of fluorouracil increase the risk of severe toxicity in individuals who have specific DPYD variant alleles. No dose of capecitabine is safe in individuals with absent DPD activity (1, 57). Multiple studies have found that preemptive DPYD screening for individuals with cancer can significantly improve individual safety (10, 36, 58, 59, 60, 61, 62, 63, 64). Additionally, prospective genotyping decreased chemotherapy toxicities and was cost effective (10).

At least one case report indicated that the cost of administering uridine triacetate and palliative care following an adverse, overdose reaction to 5-FU was roughly $180,000 USD (25). This is significantly higher than the cost of most pre-emptive pharmacogenetic tests.

Genetic Testing

The NIH Genetic Testing Registry, GTR, displays genetic tests that are available for the DPYD gene, TYMS gene, and the capecitabine drug response. The DPYD*2A variant is the most commonly tested. Tests available for clinical practice include full gene sequencing and targeted panel-based testing of selected variants. In cases where a targeted panel is used, only those specific variants are examined, A negative result does not mean the individual does not have DPD deficiency. Clinicians should refer to the specific testing laboratory for complete information on the test. CPIC provides a table of minor allele frequencies for DPYD variants per ethnic populations, which may be useful when determining what type of test or panel will be most informative for any individual (5).

Biochemical genetic tests may also be used, which assess the level of activity of the DPD enzyme. These tests include biochemical assays such as analyte testing (for example, measuring the amount of thymine and uracil in the urine or blood) or an enzyme assay (for example, directly measuring the activity of DPD using RNA extracted from blood cells and measuring the DPD mRNA copy number) (65, 66, 67).

The GTR provides a list of biochemical tests that assess the levels of thymine and uracil analytes, and the activity of the enzyme dihydropyrimidine dehydrogenase.

Therapeutic Recommendations based on Genotype

This section contains excerpted¹ information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

Nomenclature for Selected DPYD Alleles

Acknowledgments

The authors would like to thank Peter H. O’Donnell, MD, Associate Professor of Medicine, Section of Hematology/Oncology, Department of Medicine, Deputy Director, Center for Personalized Therapeutics, Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, IL, USA; Natalie Reizine, MD, Hematology and Oncology Fellow, Clinical Pharmacology and Pharmacogenomics Fellow, University of Chicago Medicine, Chicago, IL, USA; and Chara Stavraka, MD, MRCP, PhD, NIHR Academic Clinical Fellow & Specialist Registrar in Medical Oncology, King’s College London/Guy's and St Thomas' NHS Foundation Trust, London, UK for reviewing this summary.

2016 Edition

The author would like to thank Linda Henricks, PharmD, and Professor Jan HM Schellens, MD PhD, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Mohamed Nagy, Clinical Pharmacist, Head of the Personalised Medication Management Unit, Department of Pharmaceutical Services, Children's Cancer Hospital, Cairo, Egypt; and Emily K. Pauli, Director of Research, Clearview Cancer Institute, Huntsville, AL, USA for reviewing this summary.

Version history

To view the 2016 version of this summary (created on 15 September 2016) please click here.

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