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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 6/2013

01-06-2013 | Original Article

Differential toxicity biomarkers for irinotecan- and oxaliplatin-containing chemotherapy in colorectal cancer

Authors: Lucía Cortejoso, María I. García, Pilar García-Alfonso, Eva González-Haba, Fernando Escolar, María Sanjurjo, Luis A. López-Fernández

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2013

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Abstract

Purpose

Oxaliplatin or irinotecan is usually administered jointly with fluoropyrimidines in colorectal cancer patients treated with chemotherapy. Both drugs have different toxicity patterns. Biomarkers for predicting high-risk severe adverse reactions can help select the best treatment.

Methods

A retrospective analysis of 106 colorectal cancer patients receiving an oxaliplatin-based treatment and 56 receiving an irinotecan-based treatment was performed. One copy number variant (GSTT1) and nine polymorphisms in irinotecan and oxaliplatin metabolism, transport or DNA repair genes (ABCB1, UGT1A1, XRCC1, ERCC1, ERCC2, GSTP1) were genotyped by SNaPshot, polymerase chain reactions’ length fragments, or copy number assays.

Results

In irinotecan-treated patients, C allele of ABCB1 C1236T SNP was associated with a lower risk of asthenia (OR = 0.043; 96 % CI = 0.004–0.444; P = 0.008) and C allele of ABCB1 C3435T SNP was associated with a lower risk of diarrhea (OR = 0.162; 95 % CI = 0.031–0.844; P = 0.031); and individuals with two copies of GSTT1 gene had a lower risk for asthenia (OR = 0.074; 95 % CI = 0.009–0.617; P = 0.016). In oxaliplatin-treated patients, carriers of two C variants of Asn118Asn ERCC1 SNP had a lower risk for neutropenia (OR = 0.203; 95 % CI = 0.060–0.683; P = 0.01).

Conclusions

These biomarkers could help oncologists select the best treatment by reducing toxicity associated with irinotecan or oxaliplatin in colorectal cancer patients, thus increasing their quality of life.
Literature
1.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90CrossRefPubMed
2.
Kelly H, Goldberg RM (2005) Systemic therapy for metastatic colorectal cancer: current options, current evidence. J Clin Oncol 23:4553–4560CrossRefPubMed
3.
Raymond E, Faivre S, Woynarowski JM, Chaney SG (1998) Oxaliplatin: mechanism of action and antineoplastic activity. Semin Oncol 25:4–12PubMed
4.
Iyer L, Ratain MJ (1998) Clinical pharmacology of camptothecins. Cancer Chemother Pharmacol 42(Suppl):S31–S43CrossRefPubMed
5.
Chua W, Kho PS, Moore MM, Charles KA, Clarke SJ (2011) Clinical, laboratory and molecular factors predicting chemotherapy efficacy and toxicity in colorectal cancer. Crit Rev Oncol Hematol 79:224–250CrossRefPubMed
6.
Fuchs CS, Moore MR, Harker G, Villa L, Rinaldi D, Hecht JR (2003) Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol 21:807–814CrossRefPubMed
7.
Cortejoso L, Lopez-Fernandez LA (2012) Pharmacogenetic markers of toxicity for chemotherapy in colorectal cancer patients. Pharmacogenomics 13:1173–1191CrossRefPubMed
8.
Taheri M, Mahjoubi F, Omranipour R (2010) Effect of MDR1 polymorphism on multidrug resistance expression in breast cancer patients. Genet Mol Res 9:34–40CrossRefPubMed
9.
Vaclavikova R, Nordgard SH, Alnaes GI, Hubackova M, Kubala E, Kodet R, Mrhalova M, Novotny J, Gut I, Kristensen VN, Soucek P (2008) Single nucleotide polymorphisms in the multidrug resistance gene 1 (ABCB1): effects on its expression and clinicopathological characteristics in breast cancer patients. Pharmacogenet Genomics 18:263–273CrossRefPubMed
10.
Glimelius B, Garmo H, Berglund A, Fredriksson LA, Berglund M, Kohnke H, Bystrom P, Sorbye H, Wadelius M (2011) Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer. Pharmacogenomics J 11:61–71CrossRefPubMed
11.
Shulman K, Cohen I, Barnett-Griness O, Kuten A, Gruber SB, Lejbkowicz F, Rennert G (2011) Clinical implications of UGT1A1*28 genotype testing in colorectal cancer patients. Cancer 117:3156–3162CrossRefPubMed
12.
Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ (2004) Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 22:1382–1388CrossRefPubMed
13.
Karam RA, Pasha HF, El-Shal AS, Rahman HM, Gad DM (2012) Impact of glutathione-S-transferase gene polymorphisms on enzyme activity, lung function and bronchial asthma susceptibility in Egyptian children. Gene 497:314–319CrossRefPubMed
14.
Inada M, Sato M, Morita S, Kitagawa K, Kawada K, Mitsuma A, Sawaki M, Fujita K, Ando Y (2010) Associations between oxaliplatin-induced peripheral neuropathy and polymorphisms of the ERCC1 and GSTP1 genes. Int J Clin Pharmacol Ther 48:729–734PubMed
15.
Boige V, Mendiboure J, Pignon JP, Loriot MA, Castaing M, Barrois M, Malka D, Tregouet DA, Bouche O, Le Corre D, Miran I, Mulot C, Ducreux M, Beaune P, Laurent-Puig P (2010) Pharmacogenetic assessment of toxicity and outcome in patients with metastatic colorectal cancer treated with LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000–05. J Clin Oncol 28:2556–2564CrossRefPubMed
16.
Goekkurt E, Al-Batran SE, Hartmann JT, Mogck U, Schuch G, Kramer M, Jaeger E, Bokemeyer C, Ehninger G, Stoehlmacher J (2009) Pharmacogenetic analyses of a phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil and leucovorin plus either oxaliplatin or cisplatin: a study of the arbeitsgemeinschaft internistische onkologie. J Clin Oncol 27:2863–2873CrossRefPubMed
17.
Zhang YW, Regairaz M, Seiler JA, Agama KK, Doroshow JH, Pommier Y (2011) Poly(ADP-ribose) polymerase and XPF-ERCC1 participate in distinct pathways for the repair of topoisomerase I-induced DNA damage in mammalian cells. Nucleic Acids Res 39:3607–3620CrossRefPubMed
18.
Stoehlmacher J, Ghaderi V, Iobal S, Groshen S, Tsao-Wei D, Park D, Lenz HJ (2001) A polymorphism of the XRCC1 gene predicts for response to platinum based treatment in advanced colorectal cancer. Anticancer Res 21:3075–3079PubMed
19.
Braun MS, Richman SD, Thompson L, Daly CL, Meade AM, Adlard JW, Allan JM, Parmar MK, Quirke P, Seymour MT (2009) Association of molecular markers with toxicity outcomes in a randomized trial of chemotherapy for advanced colorectal cancer: the FOCUS trial. J Clin Oncol 27:5519–5528CrossRefPubMed
20.
Gonzalez-Haba E, Garcia MI, Cortejoso L, Lopez-Lillo C, Barrueco N, Garcia-Alfonso P, Alvarez S, Jimenez JL, Martin ML, Munoz-Fernandez MA, Sanjurjo M, Lopez-Fernandez LA (2010) ABCB1 gene polymorphisms are associated with adverse reactions in fluoropyrimidine-treated colorectal cancer patients. Pharmacogenomics 11:1715–1723CrossRefPubMed
21.
Tan BR, Thomas F, Myerson RJ, Zehnbauer B, Trinkaus K, Malyapa RS, Mutch MG, Abbey EE, Alyasiry A, Fleshman JW, McLeod HL (2011) Thymidylate synthase genotype-directed neoadjuvant chemoradiation for patients with rectal adenocarcinoma. J Clin Oncol 29:875–883CrossRefPubMed
22.
Marcuello E, Paez D, Pare L, Salazar J, Sebio A, del Rio E, Baiget M (2011) A genotype-directed phase I–IV dose-finding study of irinotecan in combination with fluorouracil/leucovorin as first-line treatment in advanced colorectal cancer. Br J Cancer 105:53–57CrossRefPubMed
23.
Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22:229–237CrossRefPubMed
24.
Gordon MA, Zhang W, Yang D, Iqbal S, El-Khouiery A, Nagashima F, Lurje G, Labonte M, Wilson P, Sherrod A, Ladner RD, Lenz HJ (2011) Gender-specific genomic profiling in metastatic colorectal cancer patients treated with 5-fluorouracil and oxaliplatin. Pharmacogenomics 12:27–39CrossRefPubMed
25.
Sanoff HK, Sargent DJ, Campbell ME, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Goldberg RM (2008) Five-year data and prognostic factor analysis of oxaliplatin and irinotecan combinations for advanced colorectal cancer: N9741. J Clin Oncol 26:5721–5727CrossRefPubMed
26.
Sargent DJ, Kohne CH, Sanoff HK, Bot BM, Seymour MT, de Gramont A, Porschen R, Saltz LB, Rougier P, Tournigand C, Douillard JY, Stephens RJ, Grothey A, Goldberg RM (2009) Pooled safety and efficacy analysis examining the effect of performance status on outcomes in nine first-line treatment trials using individual data from patients with metastatic colorectal cancer. J Clin Oncol 27:1948–1955CrossRefPubMed
27.
Freyer G, Rougier P, Bugat R, Droz JP, Marty M, Bleiberg H, Mignard D, Awad L, Herait P, Culine S, Trillet-Lenoir V (2000) Prognostic factors for tumour response, progression-free survival and toxicity in metastatic colorectal cancer patients given irinotecan (CPT-11) as second-line chemotherapy after 5FU failure. CPT-11 F205, F220, F221 and V222 study groups. Br J Cancer 83:431–437CrossRefPubMed
28.
Jansen WJ, Hulscher TM, van Ark-Otte J, Giaccone G, Pinedo HM, Boven E (1998) CPT-11 sensitivity in relation to the expression of P170-glycoprotein and multidrug resistance-associated protein. Br J Cancer 77:359–365CrossRefPubMed
29.
Lin JH, Yamazaki M (2003) Role of P-glycoprotein in pharmacokinetics: clinical implications. Clin Pharmacokinet 42:59–98CrossRefPubMed
30.
Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, Cascorbi I, Gerloff T, Roots I, Eichelbaum M, Brinkmann U (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 97:3473–3478CrossRefPubMed
31.
Panczyk M, Balcerczak E, Piaskowski S, Jamroziak K, Pasz-Walczak G, Mirowski M (2009) ABCB1 gene polymorphisms and haplotype analysis in colorectal cancer. Int J Colorectal Dis 24:895–905CrossRefPubMed
32.
Rhodes KE, Zhang W, Yang D, Press OA, Gordon M, Vallbohmer D, Schultheis AM, Lurje G, Ladner RD, Fazzone W, Iqbal S, Lenz HJ (2007) ABCB1, SLCO1B1 and UGT1A1 gene polymorphisms are associated with toxicity in metastatic colorectal cancer patients treated with first-line irinotecan. Drug Metab Lett 1:23–30CrossRefPubMed
33.
Han JY, Lim HS, Yoo YK, Shin ES, Park YH, Lee SY, Lee JE, Lee DH, Kim HT, Lee JS (2007) Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecan-pharmacokinetics and clinical outcome in patients with advanced non-small cell lung cancer. Cancer 110:138–147CrossRefPubMed
34.
Hayes JD, Pulford DJ (1995) The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol 30:445–600CrossRefPubMed
35.
Romero RZ, Morales R, Garcia F, Huarriz M, Bandres E, De la Haba J, Gomez A, Aranda E, Garcia-Foncillas J (2006) Potential application of GSTT1-null genotype in predicting toxicity associated to 5-fluorouracil irinotecan and leucovorin regimen in advanced stage colorectal cancer patients. Oncol Rep 16:497–503PubMed
36.
Davies SM, Robison LL, Buckley JD, Tjoa T, Woods WG, Radloff GA, Ross JA, Perentesis JP (2001) Glutathione S-transferase polymorphisms and outcome of chemotherapy in childhood acute myeloid leukemia. J Clin Oncol 19:1279–1287PubMed
37.
Sweeney C, Nazar-Stewart V, Stapleton PL, Eaton DL, Vaughan TL (2003) Glutathione S-transferase M1, T1, and P1 polymorphisms and survival among lung cancer patients. Cancer Epidemiol Biomarkers Prev 12:527–533PubMed
38.
Koc E, Caner V, Buyukpinarbasili N, Tepeli E, Turk NS, Ozan Cetin G, Bagci G (2012) The determination of relationship between “excision repair cross-complementing group 1” (ERCC1) gene T19007C and C8092A single nucleotide polymorphisms and clinicopathological parameters in non-small cell lung cancer. Mol Biol Rep 39:375–380CrossRefPubMed
39.
Yu JJ, Lee KB, Mu C, Li Q, Abernathy TV, Bostick-Bruton F, Reed E (2000) Comparison of two human ovarian carcinoma cell lines (A2780/CP70 and MCAS) that are equally resistant to platinum, but differ at codon 118 of the ERCC1 gene. Int J Oncol 16:555–560PubMed
40.
Chen YC, Tzeng CH, Chen PM, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, Wang WS (2010) Influence of GSTP1 I105V polymorphism on cumulative neuropathy and outcome of FOLFOX-4 treatment in Asian patients with colorectal carcinoma. Cancer Sci 101:530–535CrossRefPubMed
41.
Chua W, Goldstein D, Lee CK, Dhillon H, Michael M, Mitchell P, Clarke SJ, Iacopetta B (2009) Molecular markers of response and toxicity to FOLFOX chemotherapy in metastatic colorectal cancer. Br J Cancer 101:998–1004CrossRefPubMed
42.
Sung P, Bailly V, Weber C, Thompson LH, Prakash L, Prakash S (1993) Human xeroderma pigmentosum group D gene encodes a DNA helicase. Nature 365:852–855CrossRefPubMed
43.
Wolfe KJ, Wickliffe JK, Hill CE, Paolini M, Ammenheuser MM, Abdel-Rahman SZ (2007) Single nucleotide polymorphisms of the DNA repair gene XPD/ERCC2 alter mRNA expression. Pharmacogenet Genomics 17:897–905CrossRefPubMed
44.
Hansen RD, Sorensen M, Tjonneland A, Overvad K, Wallin H, Raaschou-Nielsen O, Vogel U (2007) XPA A23G, XPC Lys939Gln, XPD Lys751Gln and XPD Asp312Asn polymorphisms, interactions with smoking, alcohol and dietary factors, and risk of colorectal cancer. Mutat Res 619:68–80CrossRefPubMed
45.
Artac M, Bozcuk H, Pehlivan S, Akcan S, Pehlivan M, Sever T, Ozdogan M, Savas B (2010) The value of XPD and XRCC1 genotype polymorphisms to predict clinical outcome in metastatic colorectal carcinoma patients with irinotecan-based regimens. J Cancer Res Clin Oncol 136:803–809CrossRefPubMed
46.
Ruzzo A, Graziano F, Loupakis F, Santini D, Catalano V, Bisonni R, Ficarelli R, Fontana A, Andreoni F, Falcone A, Canestrari E, Tonini G, Mari D, Lippe P, Pizzagalli F, Schiavon G, Alessandroni P, Giustini L, Maltese P, Testa E, Menichetti ET, Magnani M (2008) Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. Pharmacogenomics J 8:278–288CrossRefPubMed
47.
McLeod HL, Sargent DJ, Marsh S, Green EM, King CR, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Thibodeau SN, Grothey A, Morton RF, Goldberg RM (2010) Pharmacogenetic predictors of adverse events and response to chemotherapy in metastatic colorectal cancer: results from North American Gastrointestinal Intergroup Trial N9741. J Clin Oncol 28:3227–3233CrossRefPubMed
48.
Iyer L, Das S, Janisch L, Wen M, Ramirez J, Karrison T, Fleming GF, Vokes EE, Schilsky RL, Ratain MJ (2002) UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J 2:43–47CrossRefPubMed
49.
Marcuello E, Altes A, Menoyo A, Del Rio E, Gomez-Pardo M, Baiget M (2004) UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. Br J Cancer 91:678–682PubMed
50.
Martinez-Balibrea E, Abad A, Martinez-Cardus A, Gines A, Valladares M, Navarro M, Aranda E, Marcuello E, Benavides M, Massuti B, Carrato A, Layos L, Manzano JL, Moreno V (2010) UGT1A and TYMS genetic variants predict toxicity and response of colorectal cancer patients treated with first-line irinotecan and fluorouracil combination therapy. Br J Cancer 103:581–589CrossRefPubMed
51.
Massacesi C, Terrazzino S, Marcucci F, Rocchi MB, Lippe P, Bisonni R, Lombardo M, Pilone A, Mattioli R, Leon A (2006) Uridine diphosphate glucuronosyl transferase 1A1 promoter polymorphism predicts the risk of gastrointestinal toxicity and fatigue induced by irinotecan-based chemotherapy. Cancer 106:1007–1016CrossRefPubMed
52.
Rouits E, Charasson V, Petain A, Boisdron-Celle M, Delord JP, Fonck M, Laurand A, Poirier AL, Morel A, Chatelut E, Robert J, Gamelin E (2008) Pharmacokinetic and pharmacogenetic determinants of the activity and toxicity of irinotecan in metastatic colorectal cancer patients. Br J Cancer 99:1239–1245CrossRefPubMed
53.
Biason P, Masier S, Toffoli G (2008) UGT1A1*28 and other UGT1A polymorphisms as determinants of irinotecan toxicity. J Chemother 20:158–165PubMed
54.
Cecchin E, Innocenti F, D’Andrea M, Corona G, De Mattia E, Biason P, Buonadonna A, Toffoli G (2009) Predictive role of the UGT1A1, UGT1A7, and UGT1A9 genetic variants and their haplotypes on the outcome of metastatic colorectal cancer patients treated with fluorouracil, leucovorin, and irinotecan. J Clin Oncol 27:2457–2465CrossRefPubMed
55.
Cote JF, Kirzin S, Kramar A, Mosnier JF, Diebold MD, Soubeyran I, Thirouard AS, Selves J, Laurent-Puig P, Ychou M (2007) UGT1A1 polymorphism can predict hematologic toxicity in patients treated with irinotecan. Clin Cancer Res 13:3269–3275CrossRefPubMed
56.
Kweekel DM, Gelderblom H, Van der Straaten T, Antonini NF, Punt CJ, Guchelaar HJ (2008) UGT1A1*28 genotype and irinotecan dosage in patients with metastatic colorectal cancer: a Dutch Colorectal Cancer Group study. Br J Cancer 99:275–282CrossRefPubMed
57.
Liu CY, Chen PM, Chiou TJ, Liu JH, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, Wang WS (2008) UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities without affecting treatment outcome and survival in patients with metastatic colorectal carcinoma. Cancer 112:1932–1940CrossRefPubMed
58.
Innocenti F, Kroetz DL, Schuetz E, Dolan ME, Ramirez J, Relling M, Chen P, Das S, Rosner GL, Ratain MJ (2009) Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics. J Clin Oncol 27:2604–2614CrossRefPubMed
59.
Ferraldeschi R, Minchell LJ, Roberts SA, Tobi S, Hadfield KD, Blackhall FH, Mullamitha S, Wilson G, Valle J, Saunders M, Newman WG (2009) UGT1A1*28 genotype predicts gastrointestinal toxicity in patients treated with intermediate-dose irinotecan. Pharmacogenomics 10:733–739CrossRefPubMed
60.
Hoskins JM, Goldberg RM, Qu P, Ibrahim JG, McLeod HL (2007) UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters. J Natl Cancer Inst 99:1290–1295CrossRefPubMed
Metadata
Title
Differential toxicity biomarkers for irinotecan- and oxaliplatin-containing chemotherapy in colorectal cancer
Authors
Lucía Cortejoso
María I. García
Pilar García-Alfonso
Eva González-Haba
Fernando Escolar
María Sanjurjo
Luis A. López-Fernández
Publication date
01-06-2013
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 6/2013
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-013-2145-6

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