Top

Journal of Hepato-Biliary-Pancreatic Sciences

Published in:

01-02-2013 | Original article

Poor prognosis of KRAS or BRAF mutant colorectal liver metastasis without microsatellite instability

Authors: Yuzo Umeda, Takeshi Nagasaka, Yoshiko Mori, Hiroshi Sadamori, Dong-Sheng Sun, Susumu Shinoura, Ryuich Yoshida, Daisuke Satoh, Daisuke Nobuoka, Masashi Utsumi, Kazuhiro Yoshida, Takahito Yagi, Toshiyoshi Fujiwara

Published in: Journal of Hepato-Biliary-Pancreatic Sciences | Issue 2/2013

Abstract

Background

The discovery of practical biomarkers is important to realize personalized medicine for patients with malignant neoplasias, including colorectal cancer (CRC).

Purpose

The aim of this study was to determine reliable prognostic biomarkers by the analysis of patients with resectable colorectal liver metastases (CRLM).

Methods

Genomic DNA was obtained from the CRLM tissues of a cohort of 126 patients with CRLM with curative hepatic resection. The KRAS/BRAF mutation spectrum and microsatellite instability (MSI) status were successfully analyzed in 100 of the 126 CRLM tissues and these findings were examined in relation to the patients’ clinical outcomes.

Results

The cohort of 100 CRLM patients consisted of 46 with synchronous and 54 with metachronous liver metastasis. Overall survival and disease-free survival at 5 years were 57.4 and 24.9 %, respectively. MSI analysis revealed that none of the 100 CRLM specimens showed any evidence of MSI. By KRAS/BRAF mutation analysis, the analyzed CRLM patients were divided into 3 groups; KRAS-mutant (KRAS-Mt; n = 27), BRAF-mutant (BRAF-Mt; n = 3), and wild-types of both genes (Wild-type; n = 70). In the survival analysis, both KRAS-Mt and BRAF-Mt patients showed significantly poorer prognoses compared with Wild-type patients. Furthermore, although the population with the BRAF mutation was small, this mutation had a significant negative impact on disease-free survival.

Conclusions

In this study, all tumors in the cohort of CRLM patients were non-MSI tumors, suggesting MSI cancer in primary CRC would rarely reveal metastatic potential. KRAS and BRAF mutations are suggested to be poor prognostic factors in CRLM. Genetic information has an essential role as a prognostic marker and could contribute to the decisions on treatment strategy for CRLM.

Boyle P, Levin B. IARC: colorectal cancer. World Cancer report. Lyon: IARC; 2008. p. 374.

World Cancer Research Fund AlfCR. Food nutrition, physical activity and the prevention of cancer: a global perspective. Washington, DC: American institute for Cancer Research; 2007.

Adam R, Vinet E. Regional treatment of metastasis: surgery of colorectal liver metastases. Ann Oncol. 2004, 15 Suppl 4:iv103–6.

Jaffe BM, Donegan WL, Watson F, Spratt JS Jr. Factors influencing survival in patients with untreated hepatic metastases. Surg Gynecol Obstet. 1968;127(1):1–11.PubMed

Scheele J, Stangl R, Altendorf-Hofmann A. Hepatic metastases from colorectal carcinoma: impact of surgical resection on the natural history. Br J Surg. 1990;77(11):1241–6.PubMedCrossRef

Masi G, Loupakis F, Pollina L, Vasile E, Cupini S, Ricci S, et al. Long-term outcome of initially unresectable metastatic colorectal cancer patients treated with 5-fluorouracil/leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) followed by radical surgery of metastases. Ann Surg. 2009;249(3):420–5.PubMedCrossRef

Adam R, Aloia T, Levi F, Wicherts DA, de Haas RJ, Paule B, et al. Hepatic resection after rescue cetuximab treatment for colorectal liver metastases previously refractory to conventional systemic therapy. J Clin Oncol. 2007;25(29):4593–602.PubMedCrossRef

Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008;371(9617):1007–16.PubMedCrossRef

Kopetz S, Abbruzzese JL. Hidden biases in an observational study of bevacizumab beyond progression. J Clin Oncol. 2009;27(10):1732–3 (author reply 1733).

10.

Geiersbach KB, Samowitz WS. Microsatellite instability and colorectal cancer. Arch Pathol Lab Med. 2011;135(10):1269–77.PubMedCrossRef

11.

Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med. 2005;352(18):1851–60.PubMedCrossRef

12.

Abdel-Rahman WM, Peltomaki P. Lynch syndrome and related familial colorectal cancers. Crit Rev Oncog. 2008;14(1):1–22 (discussion 23–31).

13.

Muller A, Fishel R. Mismatch repair and the hereditary non-polyposis colorectal cancer syndrome (HNPCC). Cancer Invest. 2002;20(1):102–9.PubMedCrossRef

14.

Park JG, Kim DW, Hong CW, Nam BH, Shin YK, Hong SH, et al. Germ line mutations of mismatch repair genes in hereditary nonpolyposis colorectal cancer patients with small bowel cancer: International Society for Gastrointestinal Hereditary Tumours Collaborative Study. Clin Cancer Res. 2006;12(11 Pt 1):3389–93.PubMedCrossRef

15.

Goel A, Nagasaka T, Arnold CN, Inoue T, Hamilton C, Niedzwiecki D, et al. The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer. Gastroenterology. 2007;132(1):127–38.PubMedCrossRef

16.

Nagasaka T, Sasamoto H, Notohara K, Cullings HM, Takeda M, Kimura K, et al. Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes showing different patterns of DNA methylation. J Clin Oncol. 2004;22(22):4584–94.PubMedCrossRef

17.

Lengauer C, Kinzler KW, Vogelstein B. Genetic instability in colorectal cancers. Nature. 1997;386(6625):623–7.PubMedCrossRef

18.

Nagasaka T, Koi M, Kloor M, Gebert J, Vilkin A, Nishida N, et al. Mutations in both KRAS and BRAF may contribute to the methylator phenotype in colon cancer. Gastroenterology. 2008;134(7):1950–1960, 1960 e1951.

19.

Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010;138(6):2073–87 e2073.

20.

Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66(8):3992–5.PubMedCrossRef

21.

Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(10):1626–34.PubMedCrossRef

22.

Peeters M, Price T, Hotko Y, Cervantes A, Ducreux M, Andre T, et al. Randomized phase 3 study of panitumumab (PMAB) with FOLFIRI compared to FOLFIRI alone as second-line treatment (TX) for metastatic colorectal cancer (MCRC): secondary endpoint results. Ann Oncol. 2010;21:15.

23.

Peyssonnaux C, Eychene A. The Raf/MEK/ERK pathway: new concepts of activation. Biol Cell. 2001;93(1–2):53–62.PubMedCrossRef

24.

Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54.PubMedCrossRef

25.

Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature. 2002;418(6901):934.PubMedCrossRef

26.

Roth AD, Tejpar S, Delorenzi M, Yan P, Fiocca R, Klingbiel D, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol. 2010;28(3):466–74.PubMedCrossRef

27.

Japanese classification of colorectal carcinoma. 2nd English edition. Tokyo: Kanehara; 2009.

28.

Goel A, Nagasaka T, Hamelin R, Boland CR. An optimized pentaplex PCR for detecting DNA mismatch repair-deficient colorectal cancers. PLoS One. 2010;5(2):e9393.PubMedCrossRef

29.

Koopman M, Kortman GA, Mekenkamp L, Ligtenberg MJ, Hoogerbrugge N, Antonini NF, et al. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer. 2009;100(2):266–73.PubMedCrossRef

30.

Parc Y, Gueroult S, Mourra N, Serfaty L, Flejou JF, Tiret E, et al. Prognostic significance of microsatellite instability determined by immunohistochemical staining of MSH2 and MLH1 in sporadic T3N0M0 colon cancer. Gut. 2004;53(3):371–5.PubMedCrossRef

31.

Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349(3):247–57.PubMedCrossRef

32.

French AJ, Sargent DJ, Burgart LJ, Foster NR, Kabat BF, Goldberg R, et al. Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer. Clin Cancer Res. 2008;14(11):3408–15.PubMedCrossRef

33.

Etienne-Grimaldi MC, Formento JL, Francoual M, Francois E, Formento P, Renee N, et al. K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy. Clin Cancer Res. 2008;14(15):4830–5.PubMedCrossRef

34.

Heinemann V, Stintzing S, Kirchner T, Boeck S, Jung A. Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. Cancer Treat Rev. 2009;35(3):262–71.PubMedCrossRef

35.

Bleeker WA, Hayes VM, Karrenbeld A, Hofstra RM, Hermans J, Buys CC, et al. Impact of KRAS and TP53 mutations on survival in patients with left- and right-sided Dukes’ C colon cancer. Am J Gastroenterol. 2000;95(10):2953–7.PubMedCrossRef

36.

37.

Esteller M, Gonzalez S, Risques RA, Marcuello E, Mangues R, Germa JR, et al. K-ras and p16 aberrations confer poor prognosis in human colorectal cancer. J Clin Oncol. 2001;19(2):299–304.PubMed

38.

Tortola S, Marcuello E, Gonzalez I, Reyes G, Arribas R, Aiza G, et al. p53 and K-ras gene mutations correlate with tumor aggressiveness but are not of routine prognostic value in colorectal cancer. J Clin Oncol. 1999;17(5):1375–81.PubMed

39.

Westra JL, Schaapveld M, Hollema H, de Boer JP, Kraak MM, de Jong D, et al. Determination of TP53 mutation is more relevant than microsatellite instability status for the prediction of disease-free survival in adjuvant-treated stage III colon cancer patients. J Clin Oncol. 2005;23(24):5635–43.PubMedCrossRef

40.

Richman SD, Seymour MT, Chambers P, Elliott F, Daly CL, Meade AM, et al. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol. 2009;27(35):5931–7.PubMedCrossRef

41.

Andreyev HJ, Norman AR, Cunningham D, Oates J, Dix BR, Iacopetta BJ, et al. Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study. Br J Cancer. 2001;85(5):692–6.PubMedCrossRef

42.

Andreyev HJ, Norman AR, Cunningham D, Oates JR, Clarke PA. Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study. J Natl Cancer Inst. 1998;90(9):675–84.PubMedCrossRef

43.

Ogino S, Meyerhardt JA, Irahara N, Niedzwiecki D, Hollis D, Saltz LB, et al. KRAS mutation in stage III colon cancer and clinical outcome following intergroup trial CALGB 89803. Clin Cancer Res. 2009;15(23):7322–9.PubMedCrossRef

44.

Benatti P, Gafà R, Barana D, Marino M, Scarselli A, Pedroni M, et al. Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res. 2005;11:8332–40.PubMedCrossRef

45.

Raut C, Pawlik T, Rodriguez-Bigas MA. Clinicopathologic features in colorectal cancer patients with microsatellite instability. Mutat Res. 2004;568:275–82.PubMedCrossRef

46.

Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005;23:609–18.PubMedCrossRef

47.

Yuen ST, Davies H, Chan TL, Ho JW, Bignell GR, Cox C, et al. Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res. 2002;62(22):6451–5.PubMed

48.

Yokota T, Ura T, Shibata N, Takahari D, Shitara K, Nomura M, et al. BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer. Br J Cancer. 2011;104(5):856–62.PubMedCrossRef

49.

Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009;361(1):98–9.PubMedCrossRef

Title: Poor prognosis of KRAS or BRAF mutant colorectal liver metastasis without microsatellite instability
Authors: Yuzo Umeda
Takeshi Nagasaka
Yoshiko Mori
Hiroshi Sadamori
Dong-Sheng Sun
Susumu Shinoura
Ryuich Yoshida
Daisuke Satoh
Daisuke Nobuoka
Masashi Utsumi
Kazuhiro Yoshida
Takahito Yagi
Toshiyoshi Fujiwara
Publication date: 01-02-2013
Publisher: Springer Japan
Published in: Journal of Hepato-Biliary-Pancreatic Sciences / Issue 2/2013
Print ISSN: 1868-6974
Electronic ISSN: 1868-6982
DOI: https://doi.org/10.1007/s00534-012-0531-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Poor prognosis of KRAS or BRAF mutant colorectal liver metastasis without microsatellite instability

Abstract

Background

Purpose

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 2/2013

Metallic stents are more efficacious than plastic stents in unresectable malignant hilar biliary strictures: a randomized controlled trial

Impact of hybrid techniques on laparoscopic major hepatectomies

Newsletter, February 1, 2013

The learning curve in laparoscopic major liver resection

Contrast-enhanced intraoperative ultrasound for hepatocellular carcinoma: high sensitivity of diagnosis and therapeutic impact

Laparoscopic major liver resection in Korea: a multicenter study