MOLECULAR MARKERS FOR CAPECITABINE THERAPY: A REVIEW

MOLECULAR MARKERS FOR CAPECITABINE THERAPY: A REVIEW

Ramalakshmi ^*1, S. Kavimani ², Satish Srineevas ³, V. Vetriselvi ⁴ and LVKS Bhaskar ⁵

K. College of Pharmacy¹, Gerugambakkam, Chennai, Tamilnadu, India

Department of Pharmacology ², Mother Theresa Post Graduate & Research Institute of Health sciences, Puducherry, India

Department of Radiation Oncology ³, Department of Human Genetics ⁴, Sri Ramachandra University, Porur, Chennai, Tamilnadu - 600116, India

Sickle Cell Institute Chhattisgarh Genetic Lab ⁵, Department of Biochemistry, Pt. JNM Medical College, Raipur, Chhattisgarh, India

ABSTRACT: Capecitabine an oral prodrug of 5- fluorouracil is widely used for the treatment of variety of solid tumors, particularly colorectal cancer. However it is not devoid of toxicities and may limit therapy. A little is known about predictors of toxicity, response and survival in patients treated with capecitabine. The pharmacogenetic testing methods can identify such variants and thus indicate those patients who are at risk for adverse effects with capecitabine. Various studies have been carried out to assess the various genetic predictive and prognostic markers with treatment. The purpose of this review is to describe the comprehensive reports and draw conclusion with the available information on capecitabine pharmacogenetics and future directions on ongoing research.  An extensive literature search was carried out on the genes encoding the enzymes involved in the metabolism of capecitabine. Overall, evidence indicates multiple genes associated with the response/toxicity with capecitabine therapy, however majority of reports indicate DPD deficiency as a source of life-threatening toxic effects. Hence, prospective studies correlating the enzymes and the concentration of the drug and its metabolites in the body are needed before validated SNP tests can enter routine clinical practice.

Keywords: Capecitabine, Pharmacogenetic, Polymorphism, Toxicity, Molecular Marker

INTRODUCTION: Capecitabine (CAP), carbomate of fluropyrimidine is an orally administered anti neoplastic agent. It was synthesized in 1990s by Japanese researchers as an oral formulation designed to overcome the toxicity of 5'-deoxy-5-fluorouridine (5′d5-FUrd) ¹.

This 5′d5-FUrd is related to GI toxicity, attributed to the liberation of 5FU in the small intestine under the action of thymidine phosphorylase (TP) ². Thus CAP was designed as a prodrug of 5′d5-FUrd that crosses the GI barrier intact and is rapidly and almost completely absorbed ³.

The anti tumor activity is related to fluorouracil which is a fluorinated pyrimidine antimetabolite that inhibits thymidylate synthetase, blocking the methylation of deoxyuridylic acid to thymidylic acid, interfering with DNA, and to a lesser degree, RNA synthesis ⁴. Fluorouracil appears to be phase specific for the G₁ and S phases of the cell cycle.

Capecitabine is FDA-approved for: Adjuvant in colorectal cancer Stage III Dukes' C & used as first-line monotherapy and in metastatic colorectal cancer as well. If appropriate, it is used in combination with docetaxel, after failure of anthracycline-based treatment in metastatic breast cancer. It is also used as monotherapy, if the patient has failed paclitaxel-based and anthracycline-based treatment has failed or cannot be continued for other reasons (i.e., the patient has already received the maximum lifetime dose of an anthracycline).

In the UK, capecitabine is approved by the National Institute for Health and Clinical Excellence (NICE) for colon and colorectal cancer, and locally advanced or metastatic breast cancer.⁵ On March 29, 2007, the European Commission approved Capecitabine, in combination with platinum-based therapy (with or without epirubicin), for the first-line treatment of advanced stomach cancer. Unlabeled it is used in the treatment of CNS lesions for metastatic breast cancer, esophageal cancer, gastric cancer, hepatobiliary cancers (advanced), neuroendocrine (pancreatic/islet cell) tumors (metastatic or unresectable), ovarian cancer (platinum-refractory), pancreatic cancer (metastatic), unknown primary cancer.

 Dosing:

The first line treatment of metastatic colorectal cancer patients on whom single agent capecitabine therapy is preferred, the approved FDA dose is 1,250 mg/m² which is given orally twice daily, over  12 hours interval for 14 days followed by a period of rest for 1 week. The FDA has also approved the same dose as colorectal cancer for metastatic breast cancer patients who have developed resistance to both anthracycline and taxane based regimens or in whom any further anthracycline therapy is contraindicated, as single agent therapy. Additionally, the approved combination regimen with docetaxel 75 mg/m²  as a 1-hour IV infusion on the first day for metastatic breast cancer patients, in whom prior anthracycline therapy has failed and 1,250 mg/m² capecitabine administered orally twice a day for the first 2 weeks of every 3-week cycle. In prostate, renal cell, ovarian and pancreatic cancers, the majority of evidence is from smaller, Phase II trials, and efficacy has been mostly in the form of partial response and stable disease. Combination therapy in these patients appears to be more beneficial than single-agent capecitabine. ⁶ Further, based on tolerability dosage modifications are recommended. ⁷ The ideal dosing of capecitabine varies as regional differences have been seen in the tolerance of oral fluoropyrimidines.⁸ The product data recommends the tablets should be administered within 30 minutes of a meal; this may decrease gastrointestinal discomfort.

 Toxicities with capecitabine:

Capecitabine is not devoid of toxicities. It poses a risk of adverse effects, some of which can be serious and dose limiting. The predominant adverse effects observed with capecitabine include hand and foot syndrome, Stomatitis, nausea, vomiting and diarrhoea. The Toxicity Profile of Capecitabine monotherapy is tabulated in the Table 1.

TABLE 1: TOXICITY PROFILE CAPECITABINE MONOTHERAPY IN COLON AND RECTAL CANCERS

In its standard dose schedule of capecitabine is 2000 mg/ m² per day (days 1–14) and oxaliplatin 130 mg /m² (day 1) every 3 weeks (CAPOX 2000), the reported rate of grades 3 and 4 diarrhoea rate was about 20% ^14-17. This severe diarrhoea rate further increased when CAPOX 2000 was combined with cetuximab ¹⁸. Differential reports of toxicities by patients from different racial groups were observed. Regional differences in tolerability of capecitabine as adjuvant therapy was noted with toxicities being worse in the US population compared with rest of the world ^{19, 20} and whereas in Chinese population a much higher incidence of serious hand-foot syndrome and a lower rate of severe diarrhoea were observed¹².

Pharmacogenetics:

Although in recent years, there has been a vast improvement in the outcome of patients, present day protocols are still limited by the unpredictable response to the drug and to its severe toxic effects. The different responses to a particular drug are not only due to the specific clinic pathological features of the patients but also ethnic origins and particular genotype of a single individual. Here, we provide an overview of the known polymorphism present in the genes which codify for key metabolic factors involved in the mechanism of action of the drugs responsible for significant toxicity with capecitabine

FIG. 1: CAPECITABINE IN ITS METABOLIC PATHWAY

5'-DFUR ,5'-deoxy-5-fluorouridine ; 5'-DFCR, 5'-Deoxy-5-fluorocytidine; 5-dUrd, 5-fluorodeoxyuridine ; 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.

 Carboxylesterases:

Carboxylesterases (CES) are members of the α/β hydrolase fold family and are a group of enzymes that function in the metabolism of ester and amide prodrugs to their free acid forms ²¹. They are ubiquitously expressed, but levels are highest in the small intestine, liver, and lungs. There are five genes of carboxylesterases reported in humans, named CES1-CES5. CES1 substrates generally contain a large acyl and a small alcohol group, while substrates for CES2 contain a small acyl and a large alcohol moiety. Carboxylesterases hydrolyze capecitabine's carbamate side chain to form 5′-deoxy-5-fluorocytidine (5′-DFCR). Both CES1A1 and CES2 are responsible for the activation of capecitabine, whereas CES3 plays little role in 5′-DFCR formation. For the first time N Ribelles et al reported an association between a polymorphism in the CES2 gene(CDD 943insC and CES 2 Exon 3 6046 G/A)  and the efficacy of capecitabine with a non-statistically significant higher incidence of grade 3 hand-foot syndrome (HFS) (p=0.07) and grade 3-4 diarrhoea (p=0.09), respectively.

It was also observed  that the patients heterozygous or homozygous for the polymorphism CES 2 5UTR 823 C/G exhibited a significantly greater response rate to capecitabine, and time to progression of disease (59%, 8.7 months) than patients with the wild type gene sequence (32%; 5.3 months) ²².

 Thymidine phosphorylase:

Thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor (PD-ECGF), is an enzyme expressed in many normal tissues and cells with a key role in pyrimidine salvage pathway that recovers pyrimidine nucleosides formed during RNA or DNA degradation ²³. TP catalyzes the conversion of thymidine, deoxyuridine and their analogs to their respective bases and 2-deoxyribose-1- phosphates. Furthermore, TP is often overexpressed in tumor sites. The high TP activity in the tumor can selectively activate the 5FU prodrug 5'-deoxy-5-fluorouridine to 5FU. ²⁴ Thymidinephosphorylase is located at chromosome 22 in the region of q13.33. cDNA is approximately 1.8 kb long, consisting of 10 exons in a 4.3 kb region .^{25, 26} TP is highly expressed in liver tissues.

Thymidine phosphorylase is upregulated in a wide variety of solid tumors such as breast, bladder, gastric, colorectal, pancreatic, lung and esophageal cancer ^27-31. Several literatures shows a correlation between the TP expression level with tumor angiogenesis,  growth and progression illustrating that TP promotes tumor growth and metastasis by preventing apoptosis and inducing angiogenesis.^{32, 33}

As TP is the rate-limiting enzyme for the activation of capecitabine, it might be a useful predictor of tumor response to capecitabine-based chemotherapy. Reports of a study by bokos et al confer that Median ratio TP/DPD of patients with proven pathological "response" (downstaging of the disease) was higher than the "no response" group, 4.40 and 1.42, respectively (P = 0.0001) indicating that Thymidine phosphorylase to dihydropyrimidine dehydrogenase ratio as a predictive factor of response to preoperative chemoradiation with capecitabine in patients with advanced rectal cancer ³⁴.

Similarly, Meropol et al. assessed in the tissues from primary and metastatic sites for TP protein expression in patients with previously untreated metastatic CRC on irinotecan plus capecitabine chemotherapy and concluded that  the objective tumor response to chemotherapy was associated with high TP expression in primary tumors (OR: 4.77; 95% CI: 1.25-18.18), with a similar trend in metastases (OR: 8.67; 95% CI: 0.95-79.1). These reports seem to indicate that TP expression might be a predictive marker for response. In addition, overall survival (OS) was also based on TP expression. The median survival in TP-expressing primary tumors was 28.2 months (95% CI: 15.5--39.8 months) compared to 14.9 months (95% CI: 9.0--20.5) in patients with TP-negative primary tumors. ³⁵

Another  study by Petrioli R et a indicated a significant associated with  high TP expression in metastatic tissue with  response to treatment (P=0.019), and also with a trend towards a better median progression-free survival and overall survival compared with patients expressing low TP (P=0.056; P=0.073) suggesting that patients with high levels of intratumoral TP expression were the ideal candidates for capecitabine-based chemotherapy patients with metastatic colorectal cancer treated with continuous oral capecitabine and biweekly oxaliplatin ³⁶. Lindskog EB et al reports that high TP gene expression in non-microdissected tumour tissues of patients with advanced colorectal cancer correlates with longer time to progression.³⁷

Several studies report a correlation between elevated TP (as measured by either IHC or ELISA) and benefit with high response rate in gastric cancer patients and breast cancer on capecitabine based therapy as well.^38-43 These findings support the potentially predictive role of TP and a promising marker that can give helpful information to benefit from capecitabine-based chemotherapy.

Palmar-plantar erythordysesthesia (PPE) is the most common toxicity of capecitabine. Saif M W et al showed no significant association of PPE with higher tumor thymidine phosphorylase in patients receiving capecitabine. ⁴⁴ With an extensive literature survey, it was observed that TP plays a dual role in cancer development and therapy. On the one hand, TP activity is necessary for the activation and in contrast, high levels of TP in tumor tissues are correlated with a poor prognosis because of higher tumor aggressiveness. This apparently opposite effect of TP illustrates the complexity of this marker in tumor progression and in the clinical response to capecitabine therapy and strongly suggesting the involvement of other markers.

 Cytidine Deaminase:

The human CDA spans approximately 30 kB and consists of 4 exons. No splice variant was reported. The CDA gene encodes an enzyme involved in the pyrimidine salvage pathway and catalyzes irreversibly the hydrolytic deamination of cytidine and deoxycytidine into uridine and deoxyuridine, respectively ⁴⁵. In addition, CDA plays an essential role in the metabolism of a number of antitumor cytosine nucleoside analogues, leading to their pharmacologic activation to 5-FU.Few case reports indicate the association of CDA with toxicity. A report by Mercier at al suggests severe toxicity with capecitabine linked to CDA without the deficiency Of DPD. ⁴⁶ A study by Caronia et al. investigated the association between grade 3 HFS and the genes involved in capecitabine metabolism and found that the deleted allele of rs3215400 showed an increased allele-specific expression and was significantly associated with an increased risk of capecitabine-induced HFS. ⁴⁷

 Thymidylate Synthase:

The prime target for 5FU is thymidylate synthase (TS). TS in association with a methyl cofactor, catalyses the conversion deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). by methylation.

In a trial by Uchida K et al involving predominantly pre-treated colorectal cancer patients, higher levels of TS mRNA expression appeared to have a predictive value in identifying those subjects with a greater probability of early disease progression during treatment with XELOX ⁴⁸and a study by lee et al reports that the median PFS was significantly lower in patients with high TS (6.6 vs. 3.0 months; P = 0.017) ⁴². Another study by Lee S et al showed that high expression of TS and TP was associated with a higher RR than was low expression of TS and TP (54.1 vs 40.5%, P=0.022) in advanced oesophageal squamous cell carcinoma with capecitabine and cisplatin therapy.⁴⁹ Study reports of Agustin A. Garcia, et al indicated  severe nausea/vomiting  associated with TS expression (P = 0.039), but not with other severe toxicities⁵⁰. The results of a recent study presented by Martinez-Balibrea et al and Spindler K L et al reported a less pronounced impact of the TS and ERCC1 genotypes on XELOX efficacy compared with the outcome of an 5-FU-oxaliplatin infusional regimen (FUOX) ^{51, 52}. Among the three common polymorphisms associated with altered TS gene expression the variable number of tandem repeats (VNTR) polymorphism in 5’untranslated region mainly leads to double or triple tandem repeats (2R or 3R) of a 28-bp sequence. These repeats are found in Caucasians, Asians and Africans. The Four, five or nine tandem repeats have also been described for this polymorphism. A low TS levels in vitro and in tumour tissue samples were observed with homozygous 2R/2R genotype.^{53, 54} A deletion of 6 bp in the TS gene has been associated with decreased TS expression ⁵⁵. Several studies indicate association between treatment outcome and TS polymorphism which is depicted in Table 2 .^57-59

 TABLE 2: SUMMARY OF PUBLISHED LITERATURE ON TS POLYMORPHISM WITH CAPECITABINE

In the second repeat of the 3R allele, a SNP resulting in a G>C change has been observed.  Increased gene expression and protein levels have been associated with the G allele of this SNP. Another common polymorphism has been reported at position 1494 in the 3’UTR of TS ⁵⁹. 3’UTRs modulate gene regulation at a posttranscriptional level through control of mRNA stability. A 6-bp insertion/deletion (indel) polymorphism in TS 3’R is associated with decreased TS mRNA stability in vitro and reduced expression of TS protein in colorectal tumor tissue ⁶⁰. According to a study by A Loganayagam et al the presence of a homozygous del/del genotype approximately doubled the risk of grade 3–4 toxicity ⁶¹. However, other studies have failed to show an association  between a homozygous del/del genotype and severe toxicity ^62-64.

Methylenetetrahydrofolate Reductase:

An important enzyme in the folate pathway is Methylenetetrahydrofolate reductase (MTHFR) which converts 5,10-Methylenetetrahydrofolate (5,10-MTHF) to 5-methyltetrahydrofolate.An increased levels of 5,10-MTHF available for inhibiting TS has been linked to reduction in  enzyme activity and therefore leading to increased efficacy of 5-FU.⁶⁵  The two common polymorphism of MTHFR gene are 677c>T and 1298A>C are known to reduce the enzyme activity leading to a decreased pool of methyl THF and associated with hyperhomocysteine particularly in folate deficiency ⁶⁶. The 677c>T transition at exon 4 causes an amino acid substitution from alanine to valine at codon 222 within the catalytic region of the enzyme.the677c>T variants MTHFR TT genotype show-30% of the enzyme activity found among those with wild type(CC). While individuals who are heterozygous for mutation CT have -65% of wild type enzyme activity. Individuals with the TT genotype, particularly if combined with a diet low in folate, have elevated plasma homocysteine levels.

The A1298C polymorphism, resulting in an amino acid change of glutamine to alanine, also leads to reduced enzyme activity of the minor allele; however, this is to a lesser extent than for the 677T allele.⁶⁵ Studies related to the association of these genotypes with reponse/toxities with capecitabine is represented in the Table 3.

TABLE 3: SUMMARY OF PUBLISHED LITERATURE ON MTHFR POLYMORPHISM WITH CAPECITABINE

Dihydropyrimidine Dehydrogenase:

Dihydropyrimidine dehydrogenase (DPD) acts in the degradation of 5-FU and a rate limiting enzyme accounting for more than 80% in its catabolism. The clearance of 5FU depends on DPD activity. Hence, reduced DPD activity leads to both increased toxicity and efficacy of the drug ⁷⁰. Till date at atleast 30 polymorphism in DPD gene have been described ⁷¹. In two studies Common genetic polymorphisms in the DPD gene (DPD-C1896T, DPD-T85C, DPD-A496G, DPD-A557G, DPD-A1627G, DPD-T3351C, DPD-G3649A, DPD-A3844G and DPD-T3856C) leading to altered enzyme activity were examined. These studies reveal no significant associations between DPD genotype and toxicity or response. ^{72, 73}. The most common polymorphism is DPYD*2A,G>A splice site transition that causes skipping of exon 14 has been found in upto 40-50% of people with partial or complete DPD deficiency. The point mutation G to A in the invariant slice donor site leads to skipping of exon 14 immediately upstream of the mutated splice donor site in the process of DPD prem RNA splicing segment coding the aminoacid 581-635⁷⁴. Patients heterozygous for this polymorphism have low DPD activity and developing toxicity is represented in Table 4 and several case reports also indicate toxicity with DPD deficiency ^81-85.

 TABLE 4: SUMMARY OF DPD POLYMORPHISM AND ASSOCIATED TOXICITIES WITH CAPECITABINE

The simultaneous presence of variants DPYD*2A and 2846A>T was shown to be lethal in several cases shortly after initiation of treatment with fluoropyrimidine. ^{86, 87} Deenen et al. found that 100% of patients carrying the IVS14+1 polymorphism developed severe toxicity.⁸⁸ Measuring DPYD activity has been suggested to be a better biomarker for fluoropyrimidine-induced toxicity than DPYD genotyping, although recent findings confirm that genotyping and haplotyping could be acceptable options for stratifying patients according to risk of toxicity ⁸⁹ or establishing dose recommendations for  capecitabine and  as shown by the Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association.⁹⁰

Recently Recommended dosing of fluoropyrimidines by DPD phenotype has been laid ⁹¹, Hélène Blasco et al indicated that, once this deficiency has been identified on the basis of both DPD genotype and phenotype with capecitabine, it is possible to tailor 5-FU dose in DPD-deficient patients, using TDM ⁹². However a study by Garcia AA et al expression of DPD was not associated with any of the severe toxicities.⁹³ Saif MW et al reports discoloration of his palms consistent with HFS, contrary to the pattern and degree of HFS reported in the current guidelines as proposed in the drug insert. This case suggests that the pattern of cutaneous manifestations varying in patients with different ethnic backgrounds, especially whites Versus non-whites with the normal limits of DPD.⁹⁴

 A study by Vallböhmer D et al reports a Higher gene expression levels of DPD were associated with resistance to capecitabine (P=0.032). Patients with a lower mRNA amount of DPD (<or=0.46) had a longer progression-free survival compared with patients that had a higher mRNA amount (8.0 vs. 3.3 months; adjusted P=0.048; log-rank test).⁹⁵ Nishimura G et al reports patients with high TP but low DPD had the best disease-free survival, whereas the low TP but high DPD group had the worst survival in colorectal cancer patients on capecitabine.⁹⁶

 CONCLUSION: Predicting response and limiting drug induced toxicity are two important challenges faced by clinicians in the treatment of colorectal cancer. The introduction of genetic testing individualize treatment regimens will hope fully allow better response prediction and limit drug induced toxicity leading to improved patient outcomes. Determination of polymorphisms in metabolizing enzymes before the administration of chemotherapy could offer new strategies for optimizing the treatment of individual patients. However, phase wise studies on large population simultaneously accounting for other co variables should be carried out for predicting and confirming the effects of multiple genetic factors.

 DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST:

No potential conflicts of interest were disclosed.

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