Clinical Implications of Genetic Polymorphisms on Stomach Cancer

6 bp-del) or high- (two VNTR repeats, Clinical implications of genetic (G) in the third VNTR repeat, 30UTR- 6 bp-ins) expressing alleles can dis- polymorphisms on stomach cancer criminate between patients with different clinical outcomes. The pa- drug therapy tients presenting a combination of high-expressing alleles had a higher risk of relapse (P ¼ 0.003, by w2 test), G Toffoli and E Cecchin lower OS (hazard ratio (HR) ¼ 2.9, 95% confidence interval (CI): 1.7–4.1) and Experimental and Clinical Pharmacology, CRO-National Cancer Institute, Aviano, Italy lower disease-free survival (DFS) (HR ¼ 3.5, 95% CI: 2.1–4.9).3 A further study, considering the 30UTR TYMS The Pharmacogenomics Journal (2007) 7, ration before translation to the treat- polymorphism in a population of 106 76–80. doi:10.1038/sj.tpj.6500405; ment of GC. In this review, we discuss advanced GC patients, demonstrated a published online 27 June 2006 recent data concerning possible roles significantly higher response rate for genetic polymorphisms in GC among patients with the 6-bp deletion treatment. in at least one allele (P ¼ 0.045).4 The Gastric cancer (GC) is the second 5-fluorouracil (5-FU) is the basis for role of the TYMS polymorphisms on leading cause of cancer-related death several combinatory regimens or sin- 5-FU sensitivity has been explored also worldwide, although its incidence in gle-agent chemotherapy in GC. Two for other tumors. In colorectal cancer many Western countries declined dur- enzymes are known to affect therapy (CRC) patients, the combination of ing the last decade. Chemotherapy is outcome: thymidilate synthase (TYMS; 50UTR and 30UTR TYMS polymor- widely used to treat GC, and a number the major intracellular 5-FU target) phisms could discriminate between of randomized studies have recently and dihydropyrimidine dehydrogen- high and low responders in terms of demonstrated that systemic treatment ase (DPYD; involved in 5-FU catabolic improved DFS, with better survival in can improve overall survival (OS) or inactivation). Many studies indicate individuals carrying the low-expres- quality of life. However, expected that low levels of DPYD or TYMS sing alleles.5,6 However, an opposite survival for the advanced disease is mRNA expression increase the toxic trend has been reported by Jakobsen generally poor (less than 1 year). A effect of 5-FU. Some polymorphisms in et al.7 Differences reported among number of newer chemotherapeutic TYMS lead to modulation of TYMS studies could be due to several factors compounds have been studied inten- mRNA expression, including a 30UTR including genotyped tissues (healthy sively. These include taxanes, topoi- 6-bp deletion, a variable number of a or tumor), which employed a different somerase I inhibitors and oral 28-bp repeats (VNTR) in the promoter method of drug administration and a fluoropyrimidines, as well as new region (X3 instead of 2) and a G4C different treatment setting (metastatic biological agents aiming to inhibit or nucleotide change in the third repeat disease vs adjuvant therapy). In any modulate different targets of signal- of the VNTR polymorphism.1 Ishida case, it is likely that a single poly- transduction pathways or angiogen- et al.2 reported a trend between the morphism of TYMS is not sufficient to esis. However, no active second-line VNTR polymorphism of TYMS and the explain changes in the clinical benefit therapy has demonstrated definitive OS in GC patients with a nonsignifi- of 5-FU, and complex combinations of clinical benefit in patients with ad- cantly higher survival among patients variants should be considered. vanced GC, and in some patients carrying at least one allele with two The DPYD polymorphism located in therapy results solely in severe, unpre- 28-bp repeats (low expressing), com- intron 14 of the DPYD gene (IV14 þ dictable toxicity without any tumor pared to those with both alleles with 1G4A) has been associated with response. It is therefore crucial to three 28-bp repeats (high expressing). reduced enzymatic activity. Patients individualize GC chemotherapy to In subsequent studies, a com- carrying this polymorphism were allow the discernment of patients in bination of polymorphisms in more prone to develop G3–4 toxicity whom a particular therapy will exert a the 50UTR and 30UTR of the TYMS after 5-FU treatment.8 However, the real benefit. gene was considered instead of the IV14 þ 1G4A is a quite rare poly- Pharmacogenetics has emerged as a single 28-bp VNTR variant. Data from morphism (variant allele o1%) and is promising new tool for better therapy 187 GC patients indicate that a com- therefore insufficient for explaining design. However, despite encouraging bination of the TYMS polymorphisms the severe 5-FU toxic effect expected prospects, data reported so far are resulting in low- (two VNTR repeats, in a more substantial percentage of conflicting and need critical conside- (C) in the third VNTR repeat, 30UTR- patients. Nevertheless, the IV14 þ 1G4A Pharmacogenetics in gastric cancer G Toffoli and E Cecchin 77

allele has been associated with 5-FU increase the toxicity and response to survival time (15 months vs 6) toxic death in some studies8 and thus MTX by enhancing hyperhomocystei- (P ¼ 0.037).17 The same polymorphism should be included in the pharmaco- nemia subsequent to drug administra- has also been associated with more genetic analysis of 5-FU. tion.13,14 Consistent with reports for severe oxaliplatin-induced neuropathy Recently, the oral fluoropyrimidine rheumatoid arthritis, our group in 299 CRC patients treated with 5-FU/ capecitabine has been proposed for GC demonstrated in 43 ovarian cancer leucovorin/oxaliplatin (P ¼ 0.03).18 treatment. It is converted to 5-FU by patients treated with MTX that the Polymorphisms of other GST isoforms, thymidine phosphorylase. Although a homozygous 677TT carriers had a in particular the GSTM1, null geno- number of mutations correlated with greater risks of hyperhomocysteinemia type, characterized by a lack of enzy- thymidine phosphorylase activity de- and G3–4 toxicity.15 In our study, as in matic activity, have been linked to ficiency have been characterized,9 no the rheumatoid arthritis therapy, MTX longer OS and progression-free inter- common polymorphisms with clear was administered chronically for sev- val in other neoplasms.19 However, clinical meaning have been described eral days, and this could exacerbate critical considerations must be made for the encoding gene. the effect of deficiencies in folate regarding the impact of GST poly- Impaired activity of methylenetetra- metabolism. Nonetheless, the effect morphisms on OS of patients treated hydrofolate reductase (MTHFR) in- of MTHFR polymorphisms, when with platinum derivatives for GC. creases intracellular levels of 5, MTX was administered in pulse dose, Notably, GST polymorphisms might 10-methylentetrahydrofolate, leading as in the FAMTX regimen, remains to result in increased tumor response to an increased cytotoxic effect of be elucidated further. and better survival after platinum 5-FU. Two common MTHFR poly- Other polymorphisms of genes in- derivative chemotherapy, but at the morphisms, 677C4T and 1298G4A, volved in MTX transport (e.g., reduced same time they could be associated have been associated with reduced folate carrier and the ATP-binding with increased risk of developing MTHFR activity. Preliminary in vitro cassette C2) or of genes encoding GC.20 data supported a major role of the MTX target proteins (e.g., dihydro- Among the DNA repair genes, the MTHFR 677C4T polymorphism in 5- folate reductase, TYMS, AICARF nucleotide excision repair system is FU cytotoxicity,10 which was con- and GAR transformylases) are under considered to play a pivotal role in firmed in clinical trials. Gao et al.11 investigation, but only sparse, incon- developing DNA repair-associated reported, in 75 advanced GC patients, clusive data have been reported thus resistance to platinum therapy. a 6.57-fold (95% CI: 2.8–15.6) higher far.16 Although no data for GC have been sensitivity to 5-FU among patients Platinum derivatives, mainly cispla- reported so far, different studies agreed carrying a 677TT and a 1298AA geno- tin but more recently oxaliplatin, have on a detrimental role of the ERCC2 types compared to the others, demon- been used in several chemotherapeutic 35931A4C (Lys751Gln) polymorph- strating a strong predictive ability of regimens for treating GC. The phar- ism in response and survival in some these polymorphisms in response to 5- macogenetics of platinum derivatives tumors.21,22 Recently, data have also FU-based chemotherapy in GC.11 is a topic of increased interest. In emerged regarding ERCC1. In particu- Furthermore, in a population of 98 particular, genes that antagonize drug lar, the 8092C4A polymorphism has CRC patients, those carrying the var- action, including those responsible for been associated with increased toxicity iant T allele were more likely to platinum detoxification (such as glu- in non-small-cell lung cancer (NSCLC) respond to treatment (OR ¼ 1.88, 95% tathione S-transferase (GST) genes) patients treated with cisplatin/carbo- CI: 0.66–5.62).12 More recently, Jakob- and DNA repair, have been investi- platin-based therapy,23 but data on the sen et al.7 reported a better prognosis gated. Data on GST isoforms (in parti- role of ERCC1 polymorphisms in for MTHFR 677TT patients (higher cular GSTT1, M1 and P1) involved in response and survival need further response rate, 66% for 677TT vs 33% platinum derivative conjugation with clarification.24–26 for 677CT or 21% for 677CC, P ¼ 0.04) glutathione seem to agree on a pro- Regarding the base excision repair in a study of 88 CRC patients. tective role against platinum-related system, the XRCC1 28152G4A Methotrexate (MTX) is used in the toxicity and a detrimental role in (Arg399Gln) polymorphism was linked FAMTX (5-FU, doxorubicin and MTX) chemotherapeutic response of high- to a shorter survival in patients affected regimen for treating GC. Pharmacoge- activity GST alleles. The GSTP1 by NSCLC22 or CRC27 and treated with netic implications of genes involved in 313G4A polymorphism results in re- platinum therapy. This XRCC1 poly- folate metabolism, such as MTHFR, duced enzymatic activity and has been morphism is located in the PARP- have been investigated extensively for associated with improved survival and binding domain.28 The PARP proteins MTX therapy. Many published studies response after cisplatin/5-FU treat- exert complex regulatory and auto- concern the use of the drug in rheu- ment in a population of 52 advanced regulatory functions to transmit sig- matoid arthritis, where MTHFRÀ GC patients. Patients with a 313AA nals for DNA repair or apoptosis. Thus, 677C4T and MTHFRÀ1298G4A poly- genotype had a response rate of 67 vs a defect in this cellular pathway could morphisms appear to be associated 21% in patients with at least one lead to failure in apoptotic initiation with more severe toxicity of the treat- 313G allele (P ¼ 0.038). Those patients in response to platinum-induced DNA ment. MTHFR polymorphisms likely also presented a significantly superior damage.29

The Pharmacogenomics Journal Pharmacogenetics in gastric cancer G Toffoli and E Cecchin 78

Anthracyclines (doxorubicin or epir- and severe neutropenia.35,36 However, development. New target-oriented ubicin) are used as single agents or in this variant could also be associated agents are under evaluation for treat- combination therapy for GC. Pharma- with an increased response rate, so a ment of GC, including tyrosine kinase- cogenetics studies indicate a major dose reduction appears questionable targeting drugs (epidermal growth effect of cellular transporters (ABCB1) in patients having the UGT1A1*28 factor receptor (EGFR) inhibitors such and phase II metabolism enzymes polymorphism.37 Carlini et al.38 inves- as cetuximab or gefitinib), anti-angio- (GSTT1, M1 and P1) on anthracycline tigated polymorphisms in UGT1A7 genetic agents (anti-vascular endothe- pharmacology. The ABCB1 encoded and UGT1A9 genes, also involved in lial growth factor (VEGF) antibodies protein mediates the cellular extrusion CPT11 glucuronidation, highlighting such as bevacizumab), proteasome in- of platinum derivatives, whereas the that they may be predictors of re- hibitors (bortezomib) and anti-metas- GST family of enzymes detoxifies sponse and toxicity to CPT11 therapy. tasis agents (matrix metalloproteinase products of oxidative DNA damage, Mathijssen et al.39 extended the ana- inhibitors such as marimastat).42 such as those generated by anthracy- lysis to polymorphisms of genes in- Pharmacogenetics is still an open clines, through conjugation to glu- volved in metabolic and transport field in targeted therapy. Moreover, tathione. Data on GC, with regard to steps, such as ABCB1 and ABCC2 considering that constitutive poly- this topic, are still lacking; however, (CPT11 cell detoxification), CYP3A4 morphisms in genes such as EGFR or some studies on other neoplasms and CYP3A5 (CPT11 oxidative meta- VEGF could be biased by the presence suggested a role of ABCB1À3435C4T bolism) and CES1 and CES2. A signifi- of extensive genetic aberrations, it is a polymorphism in improving the out- cant association with CPT11 challenge to identify polymorphisms come of therapies with anthracy- pharmacokinetic parameters was strictly involved in tumor progression clines,30,31 whereas the GSTM1- and found only for the ABCB1À1236C4T and to determine the impact of any GSTT1-null genotypes seemed to im- polymorphism, whereas no associa- single polymorphism. Typically, com- prove the chance of disease recurrence tion was reported for UGT1A1*28. plex patterns of somatic mutations and the OS.32 However, the authors noted the low have been considered to predict clin- Recently, data on 64 cases of locally prevalence of the UGT1A1*28 poly- ical responses to these classes of advanced GC treated with a docetaxel- morphism in the Asian population drugs.43 Nonetheless, some interesting containing regimen (docetaxel, 5-FU used in the study. The correlation data have emerged regarding a poly- and carboplatin) indicated better OS between CES2 polymorphisms and morphism present in intron 1 of EGFR. (12.4 vs 8.7 months, P ¼ 0.0005) com- CPT11 toxicity and pharmacokinetics The number of repeats of a CA micro- pared to a conventional ECF scheme has not been fully explored. None- satellite (ranging from 9 to 21) influ- (epirubicin, cisplatin and 5-FU).33 Lit- theless, recent studies evidenced enced the expression level of the gene tle data are available regarding genetic a significant relationship between and was associated in vitro with polymorphisms that influence doce- CES2 mRNA expression levels in response to EGFR tyrosine kinase taxel pharmacodynamics. CYP3A4 and lymphocytes and pharmacokinetics inhibitors such as erlotinib.44 Genetic CYP3A5 isoforms contribute to doce- (P ¼ 0013), and a trend association of polymorphisms with a functional im- taxel oxidative metabolism, but a CES2 mRNA expression levels with pact on the protein have also been clinical trial on 31 docetaxel-treated drug toxicity, in 45 CRC patients observed in other target genes such solid cancer patients failed to correlate treated with the FOLFIRI regimen.40 as VEGF,45 but further studies are pharmacokinetic and pharmacody- These data encourage further studies warranted. namic profiles with CYP3A4*1B or on possible genetic markers of protein In conclusion, current data on the CYP3A5*3 genotypes.34 expression. pharmacogenetics of GC do not allow Among the topoisomerase I inhibi- NADPH-quinone oxidoreductase final conclusions, but some sugges- tors, irinotecan (CPT11) is under in- (NQO1) catalyzes the reduction reac- tions can be derived from studies vestigation for treatment of GC. tion activating mitomycin C, em- investigating the impact of poly- CPT11 is activated to SN38 by human ployed in some association schemes morphisms potentially affecting drugs carboxylesterases (CES1 and CES2). for GC treatment, to its cytotoxic used in GC on different pathologies. The pharmacogenetics of this drug semiquinone derivative. NQO1 poly- On these grounds, toxicity data, has been investigated extensively, in morphism 609C4T has been asso- derived from any area of oncology, CRC, especially concerning the uridi- ciated with diminished catalytic are likely to be relevant also to GC nediphosphoglucuronosil transferase efficacy of the enzyme and, in 117 patients. Conversely, concerning effi- 1A1 (UGT1A1) polymorphism. gastrointestinal cancer patients, longer cacy, data from other tumors could UGT1A1 mediates the glucuronidation survival in wild-type genotype pa- only give suggestions of the real effect of SN38, thus inactivating it. The tients was reported (more than 43.6 of genetic polymorphisms on GC variant allele UGT1A1*28 is associated vs 23 months, P ¼ 0.037).41 sensitivity to chemotherapy. Nonethe- with reduced expression of the gene The lack of an effective second-line less, emerging data, recently produced and was linked to higher plasmatic chemotherapy in GC patients allows on GC patients, especially about the levels of SN38, a lower glucuronida- rapid regulatory approval of new impact of genetic polymorphisms tion ratio (SN38 glucuronide/SN38) active drugs, even at early stages of on sensitivity to 5-FU and platinum

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