colorectal cancer
Kweekel, D.M.
Citation
Kweekel, D. M. (2009, May 26). Pharmacogenetics of irinotecan and oxaliplatin in advanced colorectal cancer. Retrieved from https://hdl.handle.net/1887/13820
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden Downloaded from: https://hdl.handle.net/1887/13820
Note: To cite this publication please use the final published version (if applicable).
GENERAL INTRODUCTION
COLORECTAL CANCER
Colorectal cancer is one of the main causes of cancer-related death, accounting for 677,000 deaths each year worldwide 1. In the Netherlands, colorectal cancer is diagnosed in 9,000 persons per year. With nearly 12% of all cancer-related deaths colorectal cancer is a major health problem 2.
It is thought that cancer arises from one single cell, that transforms into a tumor cell through a multistage process. A number of factors contribute to this process, including internal factors (eg. age, genetic diversity) and external agents (eg. diet, smoking habit, infections). The first step in the process of tumor formation in the colon generally involves mutations in the APC gene. This mutation is followed by alterations in other genes (like K-RAS, TP53) that play a role in tumor growth, invasiveness and the ability to metastasize 3. On a histological level, a number of changes take place in the epithelium. Mutation in stem cells of colonic crypts (small, crater-like openings in the epithelium) may give rise to a cell line that, through a multi-stage process, proliferates into a visible lesion, the adenomatous polyp. This polyp may ultimately give rise to a colorectal adenocarcinoma.
If diagnosed early, colorectal tumors can be cured by a radical resection. Patients with high- risk colon cancer receive additional adjuvant chemotherapy, depending on the stage of the tumor. Unfortunately, a large number of patients are diagnosed with (distant) metastases either during follow-up or at first presentation. A small subset of patients with metastases confined to a single organ (mostly the liver) may be cured by resection. However, for the majority of patients with metastatic disease the only treatment option is palliative systemic treatment, which has shown to significantly prolong the median overall survival.
PALLIATIVE CHEMOTHERAPY
In the past decade, new chemotherapeutic agents for colorectal cancer have become available, such as irinotecan and oxaliplatin. These agents are generally used in combination with intravenous combination of fluorouracil (5-FU) / leucovorin (LV), or the oral prodrug capecitabine. The use of irinotecan and oxaliplatin in combination with 5FU/LV has helped to improve the overall median survival in metastatic colorectal cancer patients from 11-12 months (using 5-FU/LV alone) to 17-19 months. However, one may argue that these survival times may not be fully comparable, since nowadays patients are diagnosed earlier and receive chemotherapy in earlier stages of advanced disease 4. The availability of new targeted agents such as bevacizumab and cetuximab may further improve the median survival to 20 months or more.
Although beneficial in several aspects, the use of chemotherapy has its disadvantages. One important issue is the fact that its efficacy is largely unpredictable, and that patients who do not benefit from chemotherapy are exposed to the risk of toxicity that may even be life-threatening.
For the assessment of the efficacy of chemotherapy several endpoints may be used. One option is to assess the objective response rate by measuring the tumor dimensions using CT- or MRI imaging, based on the Response Evaluation Criteria in Solid Tumors (RECIST) 5 or WHO criteria. However, an objective response does not always predict the magnitude of patient benefit in terms of progression-free survival (PFS) or overall survival (OS) 6.
CAIRO trial design
Randomisation
Regimen A Regimen B
Capecitabine 1250mg/m2 b.i.d.
on days 1-14, every 3 weeks
Irinotecan 350mg/m2 once every 3 weeks
Capecitabine 1000mg/m2 b.i.d.
on days 1-14, every 3 weeks Plus
Oxaliplatin 130mg/m2 once every 3 weeks
Capecitabine 1000mg/m2 b.i.d.
on days 1-14, every 3 weeks Plus
Irinotecan 250mg/m2 once every 3 weeks
Capecitabine 1000mg/m2 b.i.d.
on days 1-14, every 3 weeks Plus
Oxaliplatin 130mg/m2 once every 3 weeks
Figure 1
CAIRO trial design. The efficacy and toxicity of sequential (regimen A) and combinational (regimen B) chemotherapy are studied in advanced colorectal cancer patients.
Historically, OS has been used as the primary endpoint in advanced colorectal cancer clinical trials. However, the availability of salvage treatments has made OS less suitable to test the efficacy in first-line of a single drug or regimen, and for this purpose PFS is more commonly used nowadays. 7. Retrospective studies have shown that PFS is an acceptable surrogate parameter for OS in advanced colorectal cancer 8.
Other important aspects of chemotherapy are its timing, duration and the use of either sequential or concomitant use of cytotoxic agents 4. There is some evidence that starting chemotherapy in asymptomatic patients helps to preserve performance status, which is an important prognostic factor for treatment efficacy and toxicity. The optimal duration of chemotherapy is unknown, and once a regimen has proven to be effective with acceptable toxicity, patients and their doctors are usually reluctant to interrupt treatment. However, in some studies it was shown that treatment may be interrupted until progression without compromising survival. Two clinical trials have investigated the use of sequential versus combination chemotherapy. The rationale behind this design is that salvage treatments were not a prospective part of previous trials with combination therapy, and imbalances in these salvage treatments could explain the observed survival benefits. The FOCUS study of the U.K. Medical Research Council (MRC) investigated the sequential versus the combined
use of either irinotecan or oxaliplatin, and the results showed no significant benefit for combination treatment 9. The CAIRO study of the Dutch Colorectal Cancer Group (DCCG) investigated the sequential versus the combined use with three effective cytotoxics (figure 1).
In this study capecitabine was used as a fluoropyrimidine instead of 5FU, which has become common practice in many countries. Combination treatment did not result in a significant overall survival benefit, and it was concluded that sequential treatment remained a valid treatment option10. As expected, combination treatment did result in a longer median PFS and higher objective response rate. In the following paragraphs, the chemotherapeutic agents that form the cornerstone of palliative chemotherapy in colorectal cancer are discussed:
capecitabine, irinotecan and oxaliplatin.
CAPECITABINE
Capecitabine (CAP, Xeloda®), is an oral prodrug of 5-FU. It is hepatically metabolized by carboxylesterases (CES) to 5-deoxy-5-fluorocytidine, that in turn is transformed into 5-deoxyfluorouridine via cytidine deaminase (figure 2). This compound is then metabolized to 5-FU by pyrimidine nucleoside phosphorylase, primarily at the tumor site. After its formation, 5-FU is activated to 5- fluorouridine triphosphate (FUTP) and to 5-fluoro-deoxyuridine monophosphate (5-FdUMP), that binds covalently to thymidylate synthase (TS) with the folate cofactor. This inhibits the production of deoxythymidylate monophosphate (dTMP), the precursor of thymidine triphosphate, which is essential for the synthesis of DNA. Shortage of thymidine triphosphate inhibits cell division. In addition, FUTP is mistakenly incorporated into new RNA instead of uridine triphosphate, thereby affecting RNA processing and protein synthesis. The main toxic effects of capecitabine include diarrhea and hand-foot syndrome, which manifests as a (painful) swelling, sensory abnormalities and erythema in the palms of the hands and soles of the feet 11. Finally, 5-FU is inactivated to dihydro-5-fluorouracil (FUH2) by dihydropyrimidine-dehydrogenase (DPD), and is further metabolized to various other compounds that are also relatively nontoxic and are excreted in urine. The rate of 5-FU inactivation is dependent on DPD status, and DPD-deficiency may lead to increased risk of capecitabine toxicity 12. A number of genetic variations in the DPD gene have been described, that seem to influence DPD activity 13.
However, these genetic variations are rare (<1% combined incidence) and multiple variations need to be genotyped in order to establish DPD status.
The presence of folate cofactor, 5,10-methylenetetrahydrofolate (MTHF) is essential for TS inhibition by 5-FdUMP. Intracellular MTHF levels are regulated by MTHFR (methylene tetrahydrofolate reductase) and the reduced folate carrier (RFC). There is some evidence that genetic variations (or single nucleotide polymorphisms, SNPs) in the MTHFR gene may influence enzyme function and, hence, intracellular MTHF levels 14. The C677T SNP causes the amino acid substitution Ala>Val in the MTHFR enzyme. The ‘mutant’ enzyme has 30%
enzyme capacity compared to the normal, or ‘wild-type’, enzyme 15. Another MTHFR SNP, A1298C, has less pronounced effects on enzyme activity 16. There is some evidence that the C677T SNP influences treatment efficacy in colorectal cancer patients receiving 5-FU (or analogues) 17. The G80A SNP in the RFC gene is highly prevalent in the general population and was found to be associated with plasma folate levels in colorectal cancer patients 18.
In addition to MTHFR activity, expression of TS enzyme is an important factor influencing the therapeutic efficacy of TS inhibitors, like capecitabine. A variable number of 28 basepair repeats in the TS gene enhancer region determines TS enzyme production 19. This genetic variation usually consists of 2 or 3 ‘repeats’, or R. Patients with the 2R/2R genotype have a lower TS expression compared to those with a 2R/3R or 3R/3R genotype. Research suggested that treatment with 5-FU or its analogues was more effective in patients with the 2R/2R genotype 20. Apart from the number of repeats, there is a polymorphic site at position 12 of this 28 basepair sequence. It was suggested that the G>C substitution at this site results in lower TS expression 21;22. Studies indicate that patients with the 3R/3R genotype, but a G>C substitution at both alleles, have the same expression as individuals with a 2R/2R genotype. In addition, a 6 basepair deletion at nucleotide 1494 is described. This deletion probably results in production of a less stable mRNA encoding for the TS enzyme, which may influence capecitabine efficacy in patients with this deletion 22.
5-FU
5-deoxyfluorouridine capecitabine 5-deoxy-5- fluorocytidine
CES
cytidine deaminase pyrimidine nucleoside phophorylase
DPD
RNA FUTP FUH2
5-FdUMP MTHF
dUMP dTMP
DNA synthesis TS
Figure 2
Capecitabine metabolism. CES: carboxylesterases; 5-FU: fluorouracil; DPD: dihydropyrimidine dehydrogenase;
FUTP: 5-fluorouridine triphosphate; FUH2: dihydro-5-fluorouracil; 5-FdUMP: 5-fluoro-deoxyuridine monophosphate; MTHF: methylene tetrahydrofolate; TS: thymidylate synthase; dUMP: deoxyuridine monophosphate; dTMP: deoxythymidine monophosphate.
IRINOTECAN
The prodrug irinotecan (Campto®) is metabolized into an active metabolite by carboxylesterases in the liver. The active metabolite, SN-38, binds the nuclear enzyme topo-isomerase I, which is essential for DNA synthesis and replication. SN-38 is subject to glucuronidation by several UGT1A (UDP-glucuronosyl transferase) isoforms. At least nine functional isoforms of UGT1A exist, which are all splice variants of a single mRNA product.
Each isoform is encoded by a unique first exon, followed by 4 shared exons. UGT1A1 plays an important role in the biotransformation of SN-38. Its expression is regulated by the number of TA repeats in the gene promoter region, which can vary between 5 and 8. Patients with 7 TA repeats in both alleles (TA7/7, or UGT1A1*28 homozygotes) have a lower irinotecan glucuronidation capacity compared to wild-type (TA6/6) patients, and hence are exposed to a higher risk of toxicity 23. The main toxic effects of irinotecan include diarrhea and (febrile) neutropenia, of which the incidence depends in part on patient characteristics such as age, performance status, prior therapies, and UGT1A1 genotype 24.
APC
NPC
irinotecan
SN38
M4
TOPO-1
SN38-G
SN38-G
irinotecan -glucuronidase UGT1A1
UGT1A6 UGT1A7 UGT1A9 CYP3A4
hCE2
CYP3A4 CYP3A5
hCE1 hCE2
SN38
extracellular
intracellular
ABCG2 ABCC2
ABCC1
ABCB1
Figure 3
Schematic representation of the metabolic pathway and transport mechanisms of irinotecan and its metabolites.
APC, NPC, M4 and SN38; metabolites of irinotecan. hCE; human carboxylesterase. SN38-G; glucuronidation product of SN38. TOPO-1; topo-isomerase 1, the SN38 target enzyme. ABCB1, ABCC1, ABCC2, ABCG2;
transporting peptides of the ATP binding cassette (ABC) transporter family.
Other members of the UGT1A enzyme family may glucuronidate SN-38 as well, although some show a lower enzyme capacity for this reaction: UGT1A6, UGT1A7 and UGT1A9.
All UGT1A isoforms are encoded by the same gene, and genetic variations in one isoform may be linked to variations in other isoforms, depending on genetic descent. As a result, pharmacogenetic analysis of these UGT1A isoforms is difficult. Besides the UGT1A family, other enzymes play a role in the distribution of SN-38 on a cellular level. These include CYP3A4, CYP3A5 (cytochrome P450) and P-glycoprotein muti-drug resistance proteins MDR1 (alternatively called ATP-binding cassette transporter ABCB1), ABCC1, ABCC2 and ABCG2 (figure 3) 25-27. The C1236T and C3435T SNPs in the ABCB1 gene are in linkage disequilibrium. Patients carrying the ABCB1 1236T allele show an increased systemic exposure to both irinotecan and SN-38, presumably as a result of enterohepatic recirculation of SN-38 28. In this process, SN-38 glucuronides excreted in the intestine are deglucuronidated by bacterial glucuronidases, resulting in a release of SN-38 that is reabsorbed into the systemic circulation 29. In a study of non-small cell lung cancer, patients with the ABCB1 3435TT genotype showed a different pharmacokinetic profile of SN-38 glucuronide 26. In addition, grade 3 diarrhea in this study occurred more frequently in 3435TT individuals.
ABCG2, which also plays an important role in the cellular transport of irinotecan and its metabolites, has a non-conservative genetic variation (C421A or Lys141Gln) that was found to be associated with irinotecan resistance 30.
OXALIPLATIN
In the palliative treatment of colorectal cancer platinum (Pt) derivatives are generally ineffective, with the exception of oxaliplatin, which shows no cross-resistance with other compounds such as cisplatin and carboplatin. Oxaliplatin has a unique 1,2- diaminocyclohexane (DACH) group and a bidentate oxalate ligand, which dissociates in vivo through hydrolysis (figure 4). The oxalate ligand is responsible for one of the major adverse effects of oxaliplatin, a (cumulative) sensory neuropathy 31. Hydrolysis of the oxalate group results in a Pt-DACH diaquo intermediate that is capable of DNA adduct formation.
Initially, only monoadducts of Pt-DACH are formed, but in time these are converted into biadducts, or crosslinks. The adducts are bulky and modify the 3-dimensional DNA structure, which inhibits normal DNA repair processes, ultimately leading to cell cycle arrest and apoptosis 32. Also, oxaliplatin seems to interfere on the level of biomolecules and RNA synthesis 33;34. Competing with DNA adduct formation are cellular detoxicification processes, which include conjugation of the Pt-DACH diaquo intermediate to methionine, cysteine or glutatione. The latter conjugation is catalyzed by glutathione-S-transferase pi 1 (GSTP1). A SNP at codon 105 (Ile>Val) was found to result in formation of GSTP1 enzyme that is less capable of carcinogen detoxicification, and to confer a significant survival benefit in colorectal cancer patients treated with an oxaliplatin-based regimen 35;36.
Oxaliplatin crosslinks are removed by DNA repair mechanisms, primarily by the nucleotide excision repair (NER) and base excision repair (BER) enzymes. One of the BER enzymes, XRCC1 (X-ray repair cross-complementing group 1 enzyme), is involved in the detection of strand breaks. An amino acid substitution at site 399 (Arg>Gln) was found to influence oxaliplatin/5-FU therapy efficacy in advanced colorectal cancer 37. Of the NER enzymes, ERCC2 (excision repair cross-complementing group 2) is most widely known. Gross defects
in this gene cause Xeroderma Pigmentosum (XP), a disease that makes patients extremely sensitive to UV-light and confers a 1000-fold enhanced risk to develop cancer 38;39. Milder ERCC2 variations are highly prevalent in the general population, for example amino acid substitutions at site 751 (Lys>Gln) or 321 (Asp>Asn). Both amino acid substitutions are nonetheless associated with differences in DNA repair capacity 38. ERCC1, another NER enzyme, was found to be crucial for the repair of interstrand crosslinks. Together with its cofactor ERCC4 (or XPF), its forms an endonuclease. This endonuclease complex makes a double incision at the damaged DNA site, followed by DNA resynthesis and ligation. ERCC1 function appears to be essential, as gross ERCC1 defects are incompatible with life 40-42. However, the T496C SNP (resulting in the conservative AAT>AAC substitution of codon 118) is highly prevalent and may be associated with either RNA stability or decreased expression 43. This may explain an association between the T496C SNP and overall survival in advanced colorectal tumor patients treated with oxaliplatin-based chemotherapy 44. Finally, as apoptosis plays an important role in the antitumor effects of oxaliplatin, SNPs in p53 may influence oxaliplatin efficacy as well. A non-conservative substitution at site 72 (Arg>Pro) results in a less stable p53 protein. As a consequence, production of the mutant protein is shown to result in a lower capacity for apoptosis induction 45.
Figure 4
Oxaliplatin metabolism. First, the oxalate dissociates from the Pt-DACH structure. Then, oxaliplatin is hydrolyzed into the diaquo intermediate, which is the active compound. The diaquo intermediate forms DNA adducts and interferes with RNA synthesis. Cellular detoxification processes compete with adduct formation, including conjugation to glutathione. Once conjugated, oxaliplatin is excreted from the cell and eliminated from the body.
SCOPE OF THIS THESIS
In the following chapters, we will focus on the palliative treatment of advanced colorectal carcinoma with capecitabine, irinotecan and oxaliplatin. In our pharmacogenetic studies, we investigated the potential associations of germline genetic variations with the efficacy or toxicity of treatment. One may argue that in case of efficacy, it would be better to focus on tumor rather than germline genetics. However, tumor DNA is generally difficult to obtain as compared to whole blood for germline genotyping. In addition, germline DNA is uniform, whereas during tumorigenesis multiple changes occur in DNA, resulting in heterogeneity of cancerous tissue. In tumor tissue sampling it is therefore extremely important to make sure no stromal cells are included. Finally, tumor DNA in paraffin embedded samples is fragmented due to the use of formalin, and this still remains an issue despite evolving new techniques.
In the first part of this thesis, we made a selection of SNPs that are relevant in the pharmacogenetic research of colorectal cancer, and genotyped these in paired tumor tissue and blood samples of 149 colorectal cancer patients (Chapter 3). The selected SNPs were located in different chomosomal regions, and included variations in the ATP-binding cassette proteins ABCB1 and ABCG2 (involved in irinotecan pharmacokinetics), in the DNA repair enzymes ERCC1, ERCC2 and XRCC1 (involved in platinum DNA crosslink repair), and in folate pathway enzymes that influence the effects of 5-FU and its prodrugs (MTHFR, RFC).
In Chapter 2, we describe our efforts in developing a combined, fast and reliable genotyping assay of the G399A and A576delA polymorphisms in the XRCC1 gene.
In the second part, we focus on irinotecan. First, we present an overview of clinical and pharmacogenetic factors that have been described to influence irinotecan toxicity (Chapter 4). One of the main toxicities of irinotecan, neutropenia, was shown to be associated with the UGT1A1*28 homozygote genotype 46;47. However, it was not known whether this genotype is also associated with febrile neutropenia, a more relevant clinical endpoint compared to (often uncomplicated) neutropenia. Also, one may hypothesize that irinotecan efficacy in patients with the UGT1A1*28 genotype is increased because of impaired SN-38 metabolism.
We therefore investigated the association of febrile neutropenia and drug efficacy with the UGT1A1 genotype in Chapter 5. The irinotecan product label recommends a dose reduction in patients homozygous for the UGT1A1*28 allele, however the effects of this strategy (on toxicity or efficacy) have not yet been tested prospectively. Therefore, we also studied differences in dose intensity among the three UGT1A1 genotype groups. In Chapter 6, we investigated the GSTP1 Ile105Val SNP with regard to irinotecan efficacy in terms of progression-free survival. The rationale of this study was based upon the in vitro correlation between nuclear GSTP1 expression and irinotecan cytotoxicity described by Goto et al. 48 The Ile>Val transition occurs in GSTP1 binding site, resulting in different interaction with various compounds. As a result, if the mutant protein is produced instead of wild-type protein, this may mimick a lower expression of wild-type enzyme, as in Goto’s experiments.
We hypothesized that for this reason, patients with the mutant genotype may experience an increased benefit of irinotecan.
In the third part of this thesis, the main focus is on oxaliplatin. We provide an overview of pharmacogenetic, pharmacokinetic and pharmacodynamic data on this platinum derivative (Chapter 7). In Chapter 8, we transfected ERCC1 negative cells with an ERCC1 gene, containing either the codon 118C or 118T genotype. These in vitro experiments were performed in order to establish whether cell survival or DNA repair after oxaliplatin exposure depends on this genetic variation, as was suggested by other authors 49. In addition, we studied the PFS and ERCC1 protein expression in paraffin-embedded tumor samples of previously genotyped colorectal cancer patients, because both were reported to be associated with the ERCC1 C118T SNP 49-52. In chapter 9 we describe our investigations on the cumulative neurotoxicity and efficacy of oxaliplatin. GSTP1 is involved in the pharmacokinetics of oxaliplatin by conjugation of the Pt-DACH compound to glutathione. Through this mechanism, mutant GSTP1 may result in higher intracellular platinum levels, and may therefore be associated with increased efficacy and (neuro)toxicity. Other authors have found conflicting results, reporting either a superior survival in GSTP1 homozygote mutants 36, or no association of genotype with survival 53;54. Similarly, data on cumulative neurotoxicity were not conclusive
54;55. Therefore, our aim was to investigate these associations in our study of advanced colorectal cancer patients receiving oxaliplatin as part of second-line treatment.
In chapter 10, an explorative study is described that investigates associations of survival and toxicity in patients receiving oxaliplatin, using a SNP array. This commercially available array includes 100 SNPs located on 55 different genes that each play a role in DNA repair.
A relatively high number of tests need to be carried out when using an array of this size, taking into account the number of subjects. Therefore, the sole aim of our study was to select new candidate genes that may serve as a basis for further conformational studies in other, independent patient populations.
Finally, the theme of this thesis is summarized and the potential applications of pharmacogenetics in the chemotherapeutic treatment of advanced colorectal cancer are discussed in Chapter 11.
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