Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 5/2019

01-05-2019 | Gastric Cancer | Original Article

CDA and MTHFR polymorphisms are associated with clinical outcomes in gastroenteric cancer patients treated with capecitabine-based chemotherapy

Authors: Duo Liu, Xiang Li, Xuehua Li, Mingyan Zhang, Juan Zhang, Dan Hou, Zhiqiang Tong, Mei Dong

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2019

Login to get access

Abstract

Purpose

The impact of pharmacogenetics on predicting survival in gastroenteric cancer remains unclear.

Methods

We tested 322 consecutive patients treated with capecitabine-based chemotherapy for CDA and MTHFR polymorphisms.

Results

Patients who carried the CDA 79 A>C (rs2072671) CC genotype showed significantly shorter progression-free survival (PFS) comparing with A-allele (P = 0.008). A significant better PFS was found in the patients with 451 A>G (rs532545) G-allele (P = 0.002) and 92 C>T (rs602950) T-allele (P = 0.002). In addition, a shorter PFS was also observed in patients with MTHFR 1298 A>C (rs1801131) CC genotype than the patients with AC or AA genotype after capecitabine-based chemotherapy (P = 0.002). Furthermore, the colon, female, or elder (> 65 years old) patients with MTHFR 1298 A>C CC genotype had poorer PFS than A-allele. Moreover, CDA 451 A>G was independent predictors of chemotherapy-induced toxicity in colon patients. Multivariate Cox regression analysis demonstrated that the CDA 79 A>C CC, 451 A>G AA, 92 C>T CC, and MTHFR 1298 A>C CC were predictive of shorter PFS in gastroenteric cancer patients.

Conclusions

The results reminded us those gastroenteric cancer patients with CDA 79 A>C CC, 451 A>G AA, 92 C>T CC, or MTHFR 1298 A>C CC genotype are not likely to benefit from the therapy of capecitabine-based chemotherapy.
Literature
1.
Beets GL, Beets-Tan RG (2012) Capecitabine in the treatment of rectal cancer. Lancet Oncol 13(6):560–561CrossRefPubMed
2.
3.
Silvestris N, Maiello E, De Vita F, Cinieri S, Santini D, Russo A, Tommasi S, Azzariti A, Numico G, Pisconti S, Petriella D, Lorusso V, Millaku A, Colucci G (2010) Update on capecitabine alone and in combination regimens in colorectal cancer patients. Cancer Treat Rev 36(10):S46–S55CrossRefPubMed
4.
Rosmarin D, Palles C, Church D, Domingo E, Jones A, Johnstone E, Wang H, Love S, Julier P, Scudder C, Nicholson G, Gonzalez-Neira A, Martin M, Sargent D, Green E, McLeod H, Zanger UM, Schwab M, Braun M, Seymour M, Thompson L, Lacas B, Boige V, Ribelles N, Afzal S, Enghusen H, Jensen SA, Etienne-Grimaldi MC, Milano G, Wadelius M, Glimelius B, Garmo H, Gusella M, Lecomte T, Laurent-Puig P, Martinez-Balibrea E, Sharma R, Garcia-Foncillas J, Kleibl Z, Morel A, Pignon JP, Midgley R, Kerr D, Tomlinson I (2014) Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens: investigation in the QUASAR2 study, systematic review, and meta-analysis. J Clin Oncol 32(10):1031–1039CrossRefPubMedPubMedCentral
5.
Thorn CF, Marsh S, Carrillo MW, McLeod HL, Klein TE, Altman RB (2011) PharmGKB summary: fluoropyrimidine pathways. Pharmacogenet Genomics 21(4):237–242PubMedPubMedCentral
6.
Lam SW, Guchelaar HJ, Boven E (2016) The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treat Rev 50:9–22CrossRefPubMed
7.
Amstutz U, Froehlich TK, Largiadèr CR (2011) Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity. Pharmacogenomics 12(9):1321–1336CrossRefPubMed
8.
Mercier C, Ciccolini J (2007) Profiling dihydropyrimidine dehydrogenase deficiency in patients with cancer undergoing 5-fluorouracil/capecitabine therapy. Clinical Colorectal Cancer 6(4):288–296CrossRef
9.
Morita T, Matsuzaki A, Kurokawa S, Tokue A (2003) Forced expression of cytidine deaminase confers sensitivity to capecitabine. Oncology 65(3):267–274CrossRefPubMed
10.
Serdjebi C, Milano G, Ciccolini J (2015) Role of cytidine deaminase in toxicity and efficacy of nucleoside analogs. Expert Opin Drug Metab Toxicol 11(5):665–672CrossRefPubMed
11.
Mercier C, Dupuis C, Blesius A, Fanciullino R, Yang CG, Padovani L, Giacometti S, Frances N, Iliadis A, Duffaud F, Ciccolini J (2009) Early severe toxicities after capecitabine intake: possible implication of a cytidine deaminase extensive metabolizer profile. Cancer Chemother Pharmacol 63(6):1177–1180CrossRefPubMed
12.
Longley DB, Harkin DP, Johnston PG (2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3(5):330–338CrossRefPubMed
13.
Nazki FH, Sameer AS, Ganaie BA (2014) Folate: metabolism, genes, polymorphisms and the associated diseases. Gene 533(1):11–20CrossRefPubMed
14.
Rodriguez J, Boni V, Hernández A, Bitarte N, Zarate R, Ponz-Sarvisé M, Chopitea A, Bandres E, Garcia-Foncillas J (2011) Association of RRM1 -37A>C polymorphism with clinical outcome in colorectal cancer patients treated with gemcitabine-based chemotherapy. Eur J Cancer 47(6):839–847CrossRefPubMed
15.
Meulendijks D, Rozeman EA, Cats A, Sikorska K, Joerger M, Deenen MJ, Beijnen JH, Schellens JHM (2017) Pharmacogenetic variants associated with outcome in patients with advanced gastric cancer treated with fluoropyrimidine and platinum-based triplet combinations: a pooled analysis of three prospective studies. Pharmacogenomics J 17(5):441–451CrossRefPubMed
16.
Pellicer M, García-González X, García MI, Robles L, Grávalos C, García-Alfonso P, Pachón V, Longo F, Martínez V, Blanco C, Iglesias I, Sanjurjo M, López-Fernández LA (2017) Identification of new SNPs associated with severe toxicity to capecitabine. Pharmacol Res 120:133–137CrossRefPubMed
17.
García-González X, Cortejoso L, García MI, García-Alfonso P, Robles L, Grávalos C, González-Haba E, Marta P, Sanjurjo M, López-Fernández LA (2015) Variants in CDA and ABCB1 are predictors of capecitabine-related adverse reactions in colorectal cancer. Oncotarget 6(8):6422–6430CrossRefPubMedPubMedCentral
18.
Caronia D, Martin M, Sastre J, de la Torre J, García-Sáenz JA, Alonso MR, Moreno LT, Pita G, Díaz-Rubio E, Benítez J, González-Neira A (2011) A polymorphism in the cytidine deaminase promoter predicts severe capecitabine-induced hand-foot syndrome. Clin Cancer Res 17(7):2006–2013CrossRefPubMed
19.
Hamzic S, Kummer D, Milesi S, Mueller D, Joerger M, Aebi S, Amstutz U, Largiader CR (2017) Novel genetic variants in carboxylesterase 1 predict severe early-onset capecitabine-related toxicity. Clin Pharmacol Ther 102(5):796–804CrossRefPubMed
20.
Loganayagam A, Arenas Hernandez M, Corrigan A, Fairbanks L, Lewis CM, Harper P, Maisey N, Ross P, Sanderson JD, Marinaki AM (2013) Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity. Br J Cancer 108(12):2505–2515CrossRefPubMedPubMedCentral
21.
Ribelles N, López-Siles J, Sánchez A, González E, Sánchez MJ, Carabantes F, Sánchez-Rovira P, Márquez A, Dueñas R, Sevilla I, Alba E (2008) A carboxylesterase 2 gene polymorphism as predictor of capecitabine on response and time to progression. Curr Drug Metab 9(4):336–343CrossRefPubMed
22.
Deenen MJ, Meulendijks D, Boot H, Legdeur MC, Beijnen JH, Schellens JH, Cats A (2015) Phase 1a/1b and pharmacogenetic study of docetaxel, oxaliplatin and capecitabine in patients with advanced cancer of the stomach or the gastroesophageal junction. Cancer Chemother Pharmacol 76(6):1285–1295CrossRefPubMed
23.
Zhong L, He X, Zhang Y, Chuan JL, Chen M, Zhu SM, Peng Q (2018) Relevance of methylenetetrahydrofolate reductase gene variants C677T and A1298C with response to fluoropyrimidine-based chemotherapy in colorectal cancer: a systematic review and meta-analysis. Oncotarget 9(58):31291–31301CrossRefPubMedPubMedCentral
24.
Suh KW, Kim JH, Kim DY, Kim YB, Lee C, Choi S (2006) Which gene is a dominant predictor of response during FOLFOX chemotherapy for the treatment of metastatic colorectal cancer, the MTHFR or XRCC1 gene? Ann Surg Oncol 13:1379–1385CrossRefPubMed
25.
Huang MY, Fang WY, Lee SC, Cheng TL, Wang JY, Lin SR (2008) ERCC2 2251A>C genetic polymorphism was highly correlated with early relapse in high-risk stage II and stage III colorectal cancer patients: a preliminary study. BMC Cancer 8:50CrossRefPubMedPubMedCentral
26.
Chai H, Pan J, Zhang X, Zhang X, Shen X, Li H, Zhang K, Yang C, Sheng H, Gao H (2012) ERCC1 C118T associates with response to FOLFOX4 chemotherapy in colorectal cancer patients in Han Chinese. Int J Clin Exp Med 5:186–194PubMedPubMedCentral
27.
Kumamoto K, Ishibashi K, Okada N, Tajima Y, Kuwabara K, Kumagai Y, Baba H, Haga N, Ishida H (2013) Polymorphisms of GSTP1ERCC2 and TS-3′UTR are associated with the clinical outcome of mFOLFOX6 in colorectal cancer patients. Oncol Lett 6:648–654CrossRefPubMedPubMedCentral
28.
Zhao J, Zhang W, Li WH, Zhang Z, Zhu D, Yu QH, Guo WJ, Li J (2012) Predictive role of single nucleotide polymorphisms of MTHFR and ABCG2 genes in the response to first-Line chemotherapy in advanced colorectal cancer. Tumor 32:709–716
29.
Tang C, Yu S, Jiang H, Li W, Xu X, Cheng X, Peng K, Chen E, Cui Y, Liu T (2018) A meta-analysis: methylenetetrahydrofolate reductase C677T polymorphism in gastric cancer patients treated with 5-Fu based chemotherapy predicts serious hematologic toxicity but not prognosis. J Cancer 9(6):1057–1066CrossRefPubMedPubMedCentral
30.
Liu R, Zhao X, Liu X, Chen Z, Qiu L, Geng R, Guo W, He G, Yin J, Li J, Zhu X (2016) Influences of ERCC1, ERCC2, XRCC1, GSTP1, GSTT1, and MTHFR polymorphisms on clinical outcomes in gastric cancer patients treated with EOF chemotherapy. Tumour Biol 37(2):1753–1762CrossRefPubMed
31.
Chen JS, Chao Y, Bang YJ, Roca E, Chung HC, Palazzo F, Kim YH, Myrand SP, Mullaney BP, Shen LJ, Linn C (2010) A phase I/II and pharmacogenomic study of pemetrexed and cisplatin in patients with unresectable, advanced gastric carcinoma. Anticancer Drugs 21:777–784CrossRefPubMed
32.
Huang ZH, Hua D, Li LH (2009) The polymorphisms of TS and MTHFR predict survival of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in Chinese population. Cancer Chemother Pharmacol 63:911–918CrossRefPubMed
33.
Zhao T, Gu D, Xu Z, Huo X, Shen L, Wang C, Tang Y, Wu P, He J, Gong W, He ML, Chen J (2015) Polymorphism in one-carbon metabolism pathway affects survival of gastric cancer patients: large and comprehensive study. Oncotarget 6(11):9564–9576PubMedPubMedCentral
34.
Morishita T, Hishida A, Okugawa Y, Morimoto Y, Shirai Y, Okamoto K, Momokita S, Ogawa A, Tanaka K, Nishikawa R, Toiyama Y, Inoue Y, Sakurai H, Urata H, Tanaka M, Miki C (2018) Polymorphisms in folic acid metabolism genes do not associate with cancer cachexia in Japanese gastrointestinal patients. Nagoya J Med Sci 80(4):529–539PubMedPubMedCentral
35.
Leicher LW, de Graaf JC, Coers W, Tascilar M, de Groot JW (2017) Tolerability of capecitabine monotherapy in metastatic colorectal cancer: a real-world study. Drugs R D 17(1):117–124CrossRefPubMed
36.
Saif MW, Katirtzoglou NA, Syrigos KN (2018) Capecitabine: an overview of the side effects and their management. Anticancer Drugs 19(5):447–464
37.
Beijers AJ, Jongen JL, Vreugdenhil G (2012) Chemotherapy-induced neurotoxicity: the value of neuroprotective strategies. Neth J Med 70(1):18–25PubMed
38.
39.
Marse H, Van Cutsem E, Grothey A, Valverde S (2004) Management of adverse events and other practical considerations in patients receiving capecitabine (Xeloda). Eur J Oncol Nurs 8(Suppl 1):S16–S30CrossRefPubMed
40.
Huang XZ, Chen Y, Chen WJ, Zhang X, Wu CC, Wang ZN, Wu J (2018) Clinical evidence of prevention strategies for capecitabine-induced hand-foot syndrome. Int J Cancer 142(12):2567–2577CrossRefPubMed
Metadata
Title
CDA and MTHFR polymorphisms are associated with clinical outcomes in gastroenteric cancer patients treated with capecitabine-based chemotherapy
Authors
Duo Liu
Xiang Li
Xuehua Li
Mingyan Zhang
Juan Zhang
Dan Hou
Zhiqiang Tong
Mei Dong
Publication date
01-05-2019
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 5/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-019-03809-2

Other articles of this Issue 5/2019

Cancer Chemotherapy and Pharmacology 5/2019 Go to the issue

Original Article

Gefitinib exposure and occurrence of interstitial lung disease in Japanese patients with non-small-cell lung cancer

Original Article

Classification and regression tree-based prediction of 6-mercaptopurine-induced leucopenia grades in children with acute lymphoblastic leukemia

Original Article

TGFβ receptor inhibitor galunisertib is linked to inflammation- and remodeling-related proteins in patients with pancreatic cancer

Original Article

A study of second-line irinotecan plus cisplatin vs. irinotecan alone in platinum-naïve patients with early relapse of gastric cancer refractory to adjuvant S-1 monotherapy: exploratory subgroup analysis of the randomized phase III TRICS trial

Original Article

Regorafenib regressed a doxorubicin-resistant Ewing’s sarcoma in a patient-derived orthotopic xenograft (PDOX) nude mouse model

Original Article

The impact of genetic polymorphism on CYP19A1 in androgen-deprivation therapy among Japanese men
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits