Top

Cancer Chemotherapy and Pharmacology

Published in:

Open Access 01-06-2017 | Original Article

Gene expression levels of gamma-glutamyl hydrolase in tumor tissues may be a useful biomarker for the proper use of S-1 and tegafur-uracil/leucovorin in preoperative chemoradiotherapy for patients with rectal cancer

Authors: Sotaro Sadahiro, T. Suzuki, A. Tanaka, K. Okada, G. Saito, H. Miyakita, T. Ogimi, H. Nagase

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2017

Abstract

Purpose

Preoperative chemoradiotherapy (CRT) using 5-fluorouracil (5-FU)-based chemotherapy is the standard of care for rectal cancer. The effect of additional chemotherapy during the period between the completion of radiotherapy and surgery remains unclear. Predictive factors for CRT may differ between combination chemotherapy with S-1 and with tegafur-uracil/leucovorin (UFT/LV).

Methods

The subjects were 54 patients with locally advanced rectal cancer who received preoperative CRT with S-1 or UFT/LV. The pathological tumor response was assessed according to the tumor regression grade (TRG). The expression levels of 18 CRT-related genes were determined using RT-PCR assay.

Results

A pathological response (TRG 1-2) was observed in 23 patients (42.6%). In a multivariate logistic regression analysis for pathological response, the overall expression levels of four genes, HIF1A, MTHFD1, GGH and TYMS, were significant, and the accuracy rate of the predictive model was 83.3%. The effects of the gene expression levels of GGH on the response differed significantly according to the treatment regimen. The total pathological response rate of both high-GGH patients in the S-1 group and low-GGH patients in the UFT/LV group was 58.3%.

Conclusion

Additional treatment with 5-FU-based chemotherapy during the interval between radiotherapy and surgery is not beneficial in patients who have received 5-FU-based CRT. The expression levels of four genes, HIF1A, MTHFD1, GGH and TYMS, in tumor tissues can predict the response to preoperative CRT including either S-1 or UFT/LV. In particular, the gene expression level of GGH in tumor tissues may be a useful biomarker for the appropriate use of S-1 and UFT/LV in CRT.

Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, Bardet E, Beny A, Ollier JC (2006) Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 355(11):1114–1123. doi:10.1056/NEJMoa060829 CrossRefPubMed

Gerard JP, Conroy T, Bonnetain F, Bouche O, Chapet O, Closon-Dejardin MT, Untereiner M, Leduc B, Francois E, Maurel J, Seitz JF, Buecher B, Mackiewicz R, Ducreux M, Bedenne L (2006) Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 24(28):4620–4625. doi:10.1200/JCO.2006.06.7629 CrossRefPubMed

Peeters KC, Marijnen CA, Nagtegaal ID, Kranenbarg EK, Putter H, Wiggers T, Rutten H, Pahlman L, Glimelius B, Leer JW, van de Velde CJ (2007) The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg 246(5):693–701. doi:10.1097/01.sla.0000257358.56863.ce CrossRefPubMed

Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, Becker H, Raab HR, Villanueva MT, Witzigmann H, Wittekind C, Beissbarth T, Rodel C (2012) Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol 30(16):1926–1933. doi:10.1200/JCO.2011.40.1836 CrossRefPubMed

de Campos-Lobato LF, Stocchi L, da Luz Moreira A, Kalady MF, Geisler D, Dietz D, Lavery IC, Remzi FH, Fazio VW (2010) Downstaging without complete pathologic response after neoadjuvant treatment improves cancer outcomes for cIII but not cII rectal cancers. Ann Surg Oncol 17(7):1758–1766. doi:10.1245/s10434-010-0924-4 CrossRefPubMed

Maas M, Nelemans PJ, Valentini V, Das P, Rodel C, Kuo LJ, Calvo FA, Garcia-Aguilar J, Glynne-Jones R, Haustermans K, Mohiuddin M, Pucciarelli S, Small W Jr, Suarez J, Theodoropoulos G, Biondo S, Beets-Tan RG, Beets GL (2010) Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 11(9):835–844. doi:10.1016/S1470-2045(10)70172-8 CrossRefPubMed

Mohiuddin M, Hayne M, Regine WF, Hanna N, Hagihara PF, McGrath P, Marks GM (2000) Prognostic significance of postchemoradiation stage following preoperative chemotherapy and radiation for advanced/recurrent rectal cancers. Int J Radiat Oncol Biol Phys 48(4):1075–1080CrossRefPubMed

Sadahiro S, Suzuki T, Tanaka A, Okada K, Saito G, Kamijo A, Nagase H (2016) Increase in gene expression of TYMP, DPYD and HIF1A are associated with response to preoperative chemoradiotherapy including S-1 or UFT for rectal cancer. Anticancer Res 36(5):2433–2440PubMed

Wolthuis AM, Penninckx F, Haustermans K, Ectors N, Van Cutsem E, D’Hoore A (2011) Outcome standards for an organ preservation strategy in stage II and III rectal adenocarcinoma after neoadjuvant chemoradiation. Ann Surg Oncol 18(3):684–690. doi:10.1245/s10434-010-1324-5 CrossRefPubMed

10.

Garcia-Aguilar J, Chow OS, Smith DD, Marcet JE, Cataldo PA, Varma MG, Kumar AS, Oommen S, Coutsoftides T, Hunt SR, Stamos MJ, Ternent CA, Herzig DO, Fichera A, Polite BN, Dietz DW, Patil S, Avila K (2015) Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial. Lancet Oncol 16(8):957–966. doi:10.1016/S1470-2045(15)00004-2 CrossRefPubMedPubMedCentral

11.

Berger SH, Hakala MT (1984) Relationship of dUMP and free FdUMP pools to inhibition of thymidylate synthase by 5-fluorouracil. Mol Pharmacol 25(2):303–309PubMed

12.

Houghton JA, Williams LG, Radparvar S, Houghton PJ (1988) Characterization of the pools of 5,10-methylenetetrahydrofolates and tetrahydrofolates in xenografts of human colon adenocarcinoma. Cancer Res 48(11):3062–3069PubMed

13.

Morgan RG (1989) Leucovorin enhancement of the effects of the fluoropyrimidines on thymidylate synthase. Cancer 63(6 Suppl):1008–1012CrossRefPubMed

14.

Carmichael J, Popiela T, Radstone D, Falk S, Borner M, Oza A, Skovsgaard T, Munier S, Martin C (2002) Randomized comparative study of tegafur/uracil and oral leucovorin versus parenteral fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 20(17):3617–3627. doi:10.1200/JCO.2002.10.129 CrossRefPubMed

15.

Douillard JY, Hoff PM, Skillings JR, Eisenberg P, Davidson N, Harper P, Vincent MD, Lembersky BC, Thompson S, Maniero A, Benner SE (2002) Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 20(17):3605–3616. doi:10.1200/JCO.2002.04.123 CrossRefPubMed

16.

Sadahiro S, Tsuchiya T, Sasaki K, Kondo K, Katsumata K, Nishimura G, Kakeji Y, Baba H, Sato S, Koda K, Yamaguchi Y, Morita T, Matsuoka J, Usuki H, Hamada C, Kodaira S (2015) Randomized phase III trial of treatment duration for oral uracil and tegafur plus leucovorin as adjuvant chemotherapy for patients with stage IIB/III colon cancer: final results of JFMC33-0502. Ann Oncol 26(11):2274–2280. doi:10.1093/annonc/mdv358 CrossRefPubMedPubMedCentral

17.

Sadahiro S, Suzuki T, Tanaka A, Okada K, Saito G, Kamijo A, Akiba T, Kawada S (2015) Phase II study of preoperative concurrent chemoradiotherapy with S-1 plus bevacizumab for locally advanced resectable rectal adenocarcinoma. Oncology 88(1):49–56. doi:10.1159/000367972 CrossRefPubMed

18.

Sadahiro S, Suzuki T, Tanaka A, Okada K, Kamijo A, Murayama C, Akiba T, Nakayama Y (2011) Phase I/II study of preoperative concurrent chemoradiotherapy with S-1 for locally advanced, resectable rectal adenocarcinoma. Oncology 81(5–6):306–311. doi:10.1159/000334580 CrossRefPubMed

19.

Suzuki T, Sadahiro S, Tanaka A, Okada K, Saito G, Kamijo A, Akiba T, Kawada S (2014) Relationship between histologic response and the degree of tumor shrinkage after chemoradiotherapy in patients with locally advanced rectal cancer. J Surg Oncol 109(7):659–664. doi:10.1002/jso.23550 CrossRefPubMed

20.

Suzuki T, Sadahiro S, Tanaka A, Okada K, Kamata H, Kamijo A, Murayama C, Akiba T, Kawada S (2013) Biopsy specimens obtained 7 days after starting chemoradiotherapy (CRT) provide reliable predictors of response to CRT for rectal cancer. Int J Radiat Oncol Biol Phys 85(5):1232–1238. doi:10.1016/j.ijrobp.2012.09.031 CrossRefPubMed

21.

Sadahiro S, Suzuki T, Ishikawa K, Fukasawa M, Saguchi T, Yasuda S, Makuuchi H, Murayama C, Ohizumi Y (2004) Preoperative radio/chemo-radiotherapy in combination with intraoperative radiotherapy for T3-4Nx rectal cancer. Eur J Surg Oncol 30(7):750–758. doi:10.1016/j.ejso.2004.04.012 CrossRefPubMed

22.

Sadahiro S, Suzuki T, Tanaka A, Okada K, Nagase H, Uchida J (2012) Association of right-sided tumors with high thymidine phosphorylase gene expression levels and the response to oral uracil and tegafur/leucovorin chemotherapy among patients with colorectal cancer. Cancer Chemother Pharmacol 70(2):285–291. doi:10.1007/s00280-012-1909-8 CrossRefPubMed

23.

Sadahiro S, Suzuki T, Maeda Y, Tanaka A, Ogoshi K, Kamijo A, Murayama C, Tsukioka S, Sakamoto E, Fukui Y, Oka T (2010) Molecular determinants of folate levels after leucovorin administration in colorectal cancer. Cancer Chemother Pharmacol 65(4):735–742. doi:10.1007/s00280-009-1079-5 CrossRefPubMed

24.

Sadahiro S, Suzuki T, Tanaka A, Okada K, Kamijo A, Nagase H, Uchida J (2013) Reduction in gamma-glutamyl hydrolase expression is associated with response to uracil and tegafur/leucovorin chemotherapy in patients with colorectal cancer. Anticancer Res 33(8):3431–3438PubMed

25.

Mandard AM, Dalibard F, Mandard JC, Marnay J, Henry-Amar M, Petiot JF, Roussel A, Jacob JH, Segol P, Samama G et al (1994) Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer 73(11):2680–2686CrossRefPubMed

26.

Suzuki T, Sadahiro S, Fukasawa M, Ishikawa K, Kamijo A, Yasuda S, Makuuchi H, Ohizumi Y, Murayama C (2004) Predictive factors of tumor shrinkage and histological regression in patients who received preoperative radiotherapy for rectal cancer. Jpn J Clin Oncol 34(12):740–746. doi:10.1093/jjco/hyh140 CrossRefPubMed

27.

Yeo SG, Kim DY, Kim TH, Jung KH, Hong YS, Chang HJ, Park JW, Lim SB, Choi HS, Jeong SY (2010) Tumor volume reduction rate measured by magnetic resonance volumetry correlated with pathologic tumor response of preoperative chemoradiotherapy for rectal cancer. Int J Radiat Oncol Biol Phys 78(1):164–171. doi:10.1016/j.ijrobp.2009.07.1682 CrossRefPubMed

28.

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247. doi:10.1016/j.ejca.2008.10.026 CrossRefPubMed

29.

Mori R, Wang Q, Danenberg KD, Pinski JK, Danenberg PV (2008) Both beta-actin and GAPDH are useful reference genes for normalization of quantitative RT-PCR in human FFPE tissue samples of prostate cancer. Prostate 68(14):1555–1560. doi:10.1002/pros.20815 CrossRefPubMed

30.

Kreuzer KA, Lass U, Landt O, Nitsche A, Laser J, Ellerbrok H, Pauli G, Huhn D, Schmidt CA (1999) Highly sensitive and specific fluorescence reverse transcription-PCR assay for the pseudogene-free detection of beta-actin transcripts as quantitative reference. Clin Chem 45(2):297–300PubMed

31.

Huntington CR, Boselli D, Symanowski J, Hill JS, Crimaldi A, Salo JC (2016) Optimal timing of surgical resection after radiation in locally advanced rectal adenocarcinoma: an analysis of the national cancer database. Ann Surg Oncol 23(3):877–887. doi:10.1245/s10434-015-4927-z CrossRefPubMed

32.

Rombouts AJ, Hugen N, Elferink MA, Nagtegaal ID, de Wilt JH (2016) Treatment interval between neoadjuvant chemoradiotherapy and surgery in rectal cancer patients: a population-based study. Ann Surg Oncol 23(11):3593–3601. doi:10.1245/s10434-016-5294-0 CrossRefPubMedPubMedCentral

33.

Sun Z, Adam MA, Kim J, Shenoi M, Migaly J, Mantyh CR (2016) Optimal timing to surgery after neoadjuvant chemoradiotherapy for locally advanced rectal cancer. J Am Coll Surg 222(4):367–374. doi:10.1016/j.jamcollsurg.2015.12.017 CrossRefPubMed

34.

Lefevre JH, Mineur L, Kotti S, Rullier E, Rouanet P, de Chaisemartin C, Meunier B, Mehrdad J, Cotte E, Desrame J, Karoui M, Benoist S, Kirzin S, Berger A, Panis Y, Piessen G, Saudemont A, Prudhomme M, Peschaud F, Dubois A, Loriau J, Tuech JJ, Meurette G, Lupinacci R, Goasgen N, Parc Y, Simon T, Tiret E (2016) Effect of interval (7 or 11 weeks) between neoadjuvant radiochemotherapy and surgery on complete pathologic response in rectal cancer: a multicenter, randomized, controlled trial (GRECCAR-6). J Clin Oncol. doi:10.1200/JCO.2016.67.6049 PubMed

35.

Suh JR, Herbig AK, Stover PJ (2001) New perspectives on folate catabolism. Annu Rev Nutr 21:255–282. doi:10.1146/annurev.nutr.21.1.255 CrossRefPubMed

36.

Schneider E, Ryan TJ (2006) Gamma-glutamyl hydrolase and drug resistance. Clin Chim Acta Int J Clin Chem 374(1–2):25–32. doi:10.1016/j.cca.2006.05.044

37.

Sakamoto E, Tsukioka S, Oie S, Kobunai T, Tsujimoto H, Sakamoto K, Okayama Y, Sugimoto Y, Oka T, Fukushima M (2008) Folylpolyglutamate synthase and gamma-glutamyl hydrolase regulate leucovorin-enhanced 5-fluorouracil anticancer activity. Biochem Biophys Res Commun 365(4):801–807. doi:10.1016/j.bbrc.2007.11.043 CrossRefPubMed

38.

Fox JT, Stover PJ (2008) Folate-mediated one-carbon metabolism. Vitam Horm 79:1–44. doi:10.1016/S0083-6729(08)00401-9 CrossRefPubMed

39.

Tsukihara H, Tsunekuni K, Takechi T (2016) Folic acid-metabolizing enzymes regulate the antitumor effect of 5-fluoro-2′-deoxyuridine in colorectal cancer cell lines. PloS one 11(9):e0163961. doi:10.1371/journal.pone.0163961 CrossRefPubMedPubMedCentral

40.

Rahman L, Voeller D, Rahman M, Lipkowitz S, Allegra C, Barrett JC, Kaye FJ, Zajac-Kaye M (2004) Thymidylate synthase as an oncogene: a novel role for an essential DNA synthesis enzyme. Cancer cell 5(4):341–351CrossRefPubMed

41.

Davis ST, Berger SH (1993) Variation in human thymidylate synthase is associated with resistance to 5-fluoro-2′-deoxyuridine. Mol Pharmacol 43(5):702–708PubMed

42.

Johnston PG, Lenz HJ, Leichman CG, Danenberg KD, Allegra CJ, Danenberg PV, Leichman L (1995) Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res 55(7):1407–1412PubMed

43.

Peters GJ, van der Wilt CL, van Groeningen CJ, Smid K, Meijer S, Pinedo HM (1994) Thymidylate synthase inhibition after administration of fluorouracil with or without leucovorin in colon cancer patients: implications for treatment with fluorouracil. J Clin Oncol 12(10):2035–2042. doi:10.1200/jco.1994.12.10.2035 CrossRefPubMed

44.

Moeller BJ, Dewhirst MW (2006) HIF-1 and tumour radiosensitivity. Br J Cancer 95(1):1–5. doi:10.1038/sj.bjc.6603201 CrossRefPubMedPubMedCentral

45.

Toiyama Y, Inoue Y, Saigusa S, Okugawa Y, Yokoe T, Tanaka K, Miki C, Kusunoki M (2010) Gene expression profiles of epidermal growth factor receptor, vascular endothelial growth factor and hypoxia-inducible factor-1 with special reference to local responsiveness to neoadjuvant chemoradiotherapy and disease recurrence after rectal cancer surgery. Clin Oncol (R Coll Radiol) 22(4):272–280. doi:10.1016/j.clon.2010.01.001 CrossRef

Title: Gene expression levels of gamma-glutamyl hydrolase in tumor tissues may be a useful biomarker for the proper use of S-1 and tegafur-uracil/leucovorin in preoperative chemoradiotherapy for patients with rectal cancer
Authors: Sotaro Sadahiro
T. Suzuki
A. Tanaka
K. Okada
G. Saito
H. Miyakita
T. Ogimi
H. Nagase
Publication date: 01-06-2017
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 6/2017
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-017-3295-8

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

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 6/2017

Accelerating drug development by efficiently using emerging PK/PD data from an adaptable entry-into-human trial: example of lumretuzumab

UGT1A1 polymorphisms with irinotecan-induced toxicities and treatment outcome in Asians with Lung Cancer: a meta-analysis

CYT-Rx20 inhibits ovarian cancer cells in vitro and in vivo through oxidative stress-induced DNA damage and cell apoptosis

Phase II study of S-1 plus bevacizumab combination therapy for patients previously treated for non-squamous non-small cell lung cancer

Neurotoxicity after high-dose methotrexate (MTX) is adequately explained by insufficient folinic acid rescue

Enhancing the therapeutic range of a targeted small-molecule tubulysin conjugate for folate receptor-based cancer therapy

Keynote webinar | Spotlight on antibody–drug conjugates in cancer