Annals of Surgical Oncology

, Volume 22, Issue 8, pp 2640–2648 | Cite as

Association of MicroRNA-31-5p with Clinical Efficacy of Anti-EGFR Therapy in Patients with Metastatic Colorectal Cancer

  • Hisayoshi Igarashi
  • Hiroyoshi Kurihara
  • Kei Mitsuhashi
  • Miki Ito
  • Hiroyuki Okuda
  • Shinichi Kanno
  • Takafumi Naito
  • Shinji Yoshii
  • Hiroaki Takahashi
  • Takaya Kusumi
  • Tadashi Hasegawa
  • Yasutaka Sukawa
  • Yasushi Adachi
  • Kenji Okita
  • Koichi Hirata
  • Yu Imamura
  • Yoshifumi Baba
  • Kohzoh Imai
  • Hiromu Suzuki
  • Hiroyuki Yamamoto
  • Katsuhiko Nosho
  • Yasuhisa Shinomura
Colorectal Cancer

Abstract

Background

Gene mutations in the pathway downstream of epidermal growth factor receptor (EGFR) are considered to induce resistance to anti-EGFR therapy in colorectal cancer (CRC). We recently reported that microRNA-31 (miR-31)-5p may regulate BRAF activation and play a role in the signaling pathway downstream of EGFR in CRC. Therefore, we hypothesized that miR-31-5p can be a useful biomarker for anti-EGFR therapy in CRC.

Methods

We evaluated miR-31-5p expression and gene mutations [KRAS (codon 61 or 146), NRAS (codon 12, 13, or 61), and BRAF (V600E)] in the EGFR downstream pathway in 102 CRC patients harboring KRAS (codon 12 or 13) wild-type who were treated with anti-EGFR therapeutics. Progression-free survival (PFS) and overall survival (OS) were evaluated.

Results

KRAS (codon 61 or 146), NRAS, and BRAF mutations were detected in 6.9, 6.9, and 5.9 % patients, respectively. Compared with CRCs with at least one mutation (n = 20), significantly better PFS (P = 0.0003) but insignificantly better OS were observed in CRCs harboring all wild-type genes (KRAS, NRAS, and BRAF). High miR-31-5p expression was identified in 11 % (n = 11) patients and was significantly associated with shorter PFS (P = 0.003). In CRCs carrying all wild-type genes, high miR-31-5p was associated with shorter PFS (P = 0.027).

Conclusions

High miR-31-5p expression was associated with shorter PFS in patients with CRC treated with anti-EGFR therapeutics. Moreover, in CRCs carrying all wild-type genes, high miR-31-5p was associated with shorter PFS, suggesting that it may be a useful and additional prognostic biomarker for anti-EGFR therapy.

Keywords

Overall Survival Epidermal Growth Factor Receptor BRAF Mutation Colon Cancer Cell Line Epidermal Growth Factor Receptor Pathway 

Notes

Acknowledgment

The authors thank the pathology departments of Sapporo Medical University Hospital and Keiyukai Sapporo Hospital for providing the tissue specimens. The authors also thank Enago (www.enago.jp) for English language review. This work was supported by the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research [Grant Numbers: 23790800 (to K.N.) and 23390200 (to Y.S.)], A-STEP (Adaptable & Seamless, Technology Transfer Program through Target-driven R&D) (to K.N.), Sapporo Jikeikai Tomoiki Foundation (to K.N.), Takeda Science Foundation (to K.N.), and Daiwa Securities Health Foundation (to H.I.).

Disclosure

None.

Supplementary material

10434_2014_4264_MOESM1_ESM.docx (50 kb)
Supplementary material 1 Supplementary Method (DOCX 49 kb)
10434_2014_4264_MOESM2_ESM.tif (78 kb)
Supplementary material 2 Supplementary Figure 1 The scatter diagram of relative expression levels of micorRNA-31-5p and -3p of 102 colorectal cancer (CRC) patients who received anti-EGFR therapy (TIFF 78 kb)
10434_2014_4264_MOESM3_ESM.tif (118 kb)
Supplementary material 3 Supplementary Figure 2. Kaplan–Meier survival curves of patients treated with anti-EGFR therapy according to the mutational status in KRAS, NRAS, and BRAF genes. (a) Overall survival (OS) of patients with at least one mutation in KRAS (codon 61 or 146) or NRAS (codon 12, 13, or 61) versus patients with all wild-type copies of the 2 genes. (b) OS of patients with mutation in BRAF versus patients with wild-type copies of BRAF. (c) OS of patients with at least one mutation in KRAS, NRAS, and BRAF versus all wild-type copies of the 3 genes. (TIFF 117 kb)
10434_2014_4264_MOESM4_ESM.tif (61 kb)
Supplementary material Supplementary Figure 3. Kaplan–Meier survival curves of patients treated with anti-EGFR therapy according to microRNA-31-5p expression. Overall survival of the high-expression group versus the low-expression group 4 (TIFF 60 kb)
10434_2014_4264_MOESM5_ESM.tif (89 kb)
Supplementary material Supplementary Figure 4. Kaplan–Meier survival curves of patients treated with anti-EGFR therapy according to microRNA-31-3p expression. (a) Progression-free survival and (b) overall survival of the high-expression group versus the low-expression group 5 (TIFF 88 kb)
10434_2014_4264_MOESM6_ESM.tif (44 kb)
Supplementary material 6 Supplementary Figure 5. The distribution of relative expression levels of miR-31-5p or -3p of colon cancer cell lines. (TIFF 44 kb)

References

  1. 1.
    Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337–45.PubMedCrossRefGoogle Scholar
  2. 2.
    Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010;28:4697–705.PubMedCrossRefGoogle Scholar
  3. 3.
    Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28:4706–13.PubMedCrossRefGoogle Scholar
  4. 4.
    Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757–65.PubMedCrossRefGoogle Scholar
  5. 5.
    Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–17.PubMedCrossRefGoogle Scholar
  6. 6.
    Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626–34.PubMedCrossRefGoogle Scholar
  7. 7.
    Loupakis F, Ruzzo A, Cremolini C, et al. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer. 2009;101:715–21.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010;11:753–62.PubMedCrossRefGoogle Scholar
  9. 9.
    De Roock W, Piessevaux H, De Schutter J, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol. 2008;19:508–15.PubMedCrossRefGoogle Scholar
  10. 10.
    Blanke CD, Goldberg RM, Grothey A, et al. KRAS and colorectal cancer: ethical and pragmatic issues in effecting real-time change in oncology clinical trials and practice. Oncologist. 2011;16:1061–8.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;26:5705–12.PubMedCrossRefGoogle Scholar
  12. 12.
    Loupakis F, Pollina L, Stasi I, et al. PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J Clin Oncol. 2009;27:2622–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Laurent-Puig P, Cayre A, Manceau G, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009;27:5924–30.PubMedCrossRefGoogle Scholar
  14. 14.
    Bardelli A, Siena S. Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J Clin Oncol. 2010;28:1254–61.PubMedCrossRefGoogle Scholar
  15. 15.
    De Roock W, Lambrechts D, Tejpar S. K-ras mutations and cetuximab in colorectal cancer. N Engl J Med. 2009;360:834; author reply 5–6.Google Scholar
  16. 16.
    Saridaki Z, Tzardi M, Papadaki C, et al. Impact of KRAS, BRAF, PIK3CA mutations, PTEN, AREG, EREG expression and skin rash in ≥2 line cetuximab-based therapy of colorectal cancer patients. PLoS One. 2011;6:e15980.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Sood A, McClain D, Maitra R, et al. PTEN gene expression and mutations in the PIK3CA gene as predictors of clinical benefit to anti-epidermal growth factor receptor antibody therapy in patients with KRAS wild-type metastatic colorectal cancer. Clin Colorectal Cancer. 2012;11:143–50.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Prenen H, De Schutter J, Jacobs B, et al. PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin Cancer Res. 2009;15:3184–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Pentheroudakis G, Kotoula V, De Roock W, et al. Biomarkers of benefit from cetuximab-based therapy in metastatic colorectal cancer: interaction of EGFR ligand expression with RAS/RAF, PIK3CA genotypes. BMC Cancer. 2013;13:49.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023–34.PubMedCrossRefGoogle Scholar
  21. 21.
    Devun F, Bousquet G, Biau J, et al. Preclinical study of the DNA repair inhibitor Dbait in combination with chemotherapy in colorectal cancer. J Gastroenterol. 2012;47:266–75.PubMedCrossRefGoogle Scholar
  22. 22.
    Wu KL, Huang EY, Jhu EW, et al. Overexpression of galectin-3 enhances migration of colon cancer cells related to activation of the K-Ras-Raf-Erk1/2 pathway. J Gastroenterol. 2013;48:350–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Van Cutsem E, Kohne CH, Lang I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29:2011–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Zhang Y, Guo J, Li D, et al. Down-regulation of miR-31 expression in gastric cancer tissues and its clinical significance. Med Oncol. 2010;27:685–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Bartley AN, Yao H, Barkoh BA, et al. Complex patterns of altered MicroRNA expression during the adenoma-adenocarcinoma sequence for microsatellite-stable colorectal cancer. Clin Cancer Res. 2011;17:7283–93.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Balaguer F, Moreira L, Lozano JJ, et al. Colorectal cancers with microsatellite instability display unique miRNA profiles. Clin Cancer Res. 2011;17:6239–49.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Chen X, Guo X, Zhang H, et al. Role of miR-143 targeting KRAS in colorectal tumorigenesis. Oncogene. 2009;28:1385–92.PubMedCrossRefGoogle Scholar
  28. 28.
    Pagliuca A, Valvo C, Fabrizi E, et al. Analysis of the combined action of miR-143 and miR-145 on oncogenic pathways in colorectal cancer cells reveals a coordinate program of gene repression. Oncogene. 2013;32:4806–13.PubMedCrossRefGoogle Scholar
  29. 29.
    Arcaroli JJ, Quackenbush KS, Powell RW, et al. Common PIK3CA mutants and a novel 3’ UTR mutation are associated with increased sensitivity to saracatinib. Clin Cancer Res. 2012;18:2704–14.PubMedCrossRefGoogle Scholar
  30. 30.
    Valastyan S, Reinhardt F, Benaich N, et al. A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis. Cell. 2009;137:1032–46.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Creighton CJ, Fountain MD, Yu Z, et al. Molecular profiling uncovers a p53-associated role for microRNA-31 in inhibiting the proliferation of serous ovarian carcinomas and other cancers. Cancer Res. 2010;70:1906–15.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Leidner RS, Ravi L, Leahy P, et al. The microRNAs, MiR-31 and MiR-375, as candidate markers in Barrett’s esophageal carcinogenesis. Genes Chromosom Cancer. 2012;51:473–9.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Wang CJ, Zhou ZG, Wang L, et al. Clinicopathological significance of microRNA-31, -143 and -145 expression in colorectal cancer. Dis Markers. 2009;26:27–34.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Chang KH, Miller N, Kheirelseid EA, et al. MicroRNA signature analysis in colorectal cancer: identification of expression profiles in stage II tumors associated with aggressive disease. Int J Colorectal Dis. 2011;26:1415–22.PubMedCrossRefGoogle Scholar
  35. 35.
    Schee K, Boye K, Abrahamsen TW, et al. Clinical relevance of microRNA miR-21, miR-31, miR-92a, miR-101, miR-106a and miR-145 in colorectal cancer. BMC Cancer. 2012;12:505.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Cekaite L, Rantala JK, Bruun J, et al. MiR-9, -31, and -182 deregulation promote proliferation and tumor cell survival in colon cancer. Neoplasia. 2012;14:868–79.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Slaby O, Svoboda M, Fabian P, et al. Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer. Oncology. 2007;72:397–402.PubMedCrossRefGoogle Scholar
  38. 38.
    Cottonham CL, Kaneko S, Xu L. miR-21 and miR-31 converge on TIAM1 to regulate migration and invasion of colon carcinoma cells. J Biol Chem. 2010;285:35293–302.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Pichler M, Winter E, Stotz M, et al. Down-regulation of KRAS-interacting miRNA-143 predicts poor prognosis but not response to EGFR-targeted agents in colorectal cancer. Br J Cancer. 2012;106:1826–32.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Zhang W, Winder T, Ning Y, et al. A let-7 microRNA-binding site polymorphism in 3’-untranslated region of KRAS gene predicts response in wild-type KRAS patients with metastatic colorectal cancer treated with cetuximab monotherapy. Ann Oncol. 2011;22:104–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Kurokawa K, Tanahashi T, Iima T, et al. Role of miR-19b and its target mRNAs in 5-fluorouracil resistance in colon cancer cells. J Gastroenterol. 2012;47:883–95.PubMedCrossRefGoogle Scholar
  42. 42.
    Kalimutho M, Del Vecchio Blanco G, Di Cecilia S, et al. (2011) Differential expression of miR-144* as a novel fecal-based diagnostic marker for colorectal cancer. J Gastroenterol. 46:1391–402.PubMedCrossRefGoogle Scholar
  43. 43.
    Iino I, Kikuchi H, Miyazaki S, et al. Effect of miR-122 and its target gene cationic amino acid transporter 1 on colorectal liver metastasis. Cancer Sci. 2013;104:624–30.PubMedCrossRefGoogle Scholar
  44. 44.
    Tsuchida A, Ohno S, Wu W, et al. miR-92 is a key oncogenic component of the miR-17-92 cluster in colon cancer. Cancer Sci. 2011;102:2264–71.PubMedCrossRefGoogle Scholar
  45. 45.
    Nosho K, Igarashi H, Nojima M, et al. Association of microRNA-31 with BRAF mutation, colorectal cancer survival and serrated pathway. Carcinogenesis. 2014;35:776–83.PubMedCrossRefGoogle Scholar
  46. 46.
    Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.PubMedCrossRefGoogle Scholar
  47. 47.
    Irahara N, Baba Y, Nosho K, et al. NRAS mutations are rare in colorectal cancer. Diagn Mol Pathol. 2010;19:157–63.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Vaughn CP, Zobell SD, Furtado LV, et al. Frequency of KRAS, BRAF, and NRAS mutations in colorectal cancer. Genes Chromosom Cancer. 2011;50:307–12.PubMedCrossRefGoogle Scholar
  49. 49.
    Seymour MT, Brown SR, Middleton G, et al. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol. 2013;14:749–59.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009;361:98–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Manceau G, Imbeaud S, Thiebaut R, et al. Hsa-miR-31-3p expression is linked to progression-free survival in patients with KRAS wild-type metastatic colorectal cancer treated with anti-EGFR therapy. Clin Cancer Res. 2014;20:3338–47.Google Scholar

Copyright information

© Society of Surgical Oncology 2014

Authors and Affiliations

  • Hisayoshi Igarashi
    • 1
  • Hiroyoshi Kurihara
    • 1
  • Kei Mitsuhashi
    • 1
  • Miki Ito
    • 1
  • Hiroyuki Okuda
    • 2
  • Shinichi Kanno
    • 1
  • Takafumi Naito
    • 1
  • Shinji Yoshii
    • 3
    • 4
  • Hiroaki Takahashi
    • 3
  • Takaya Kusumi
    • 5
  • Tadashi Hasegawa
    • 6
  • Yasutaka Sukawa
    • 1
    • 7
  • Yasushi Adachi
    • 1
  • Kenji Okita
    • 8
  • Koichi Hirata
    • 8
  • Yu Imamura
    • 9
  • Yoshifumi Baba
    • 9
  • Kohzoh Imai
    • 10
  • Hiromu Suzuki
    • 11
  • Hiroyuki Yamamoto
    • 12
  • Katsuhiko Nosho
    • 1
  • Yasuhisa Shinomura
    • 1
  1. 1.Department of Gastroenterology, Rheumatology and Clinical ImmunologySapporo Medical University School of MedicineSapporoJapan
  2. 2.Department of OncologyKeiyukai Sapporo HospitalSapporoJapan
  3. 3.Department of GastroenterologyKeiyukai Sapporo HospitalSapporoJapan
  4. 4.Department of GastroenterologyNTT East Sapporo HospitalSapporoJapan
  5. 5.Department of SurgeryKeiyukai Sapporo HospitalSapporoJapan
  6. 6.Department of PathologySapporo Medical University School of MedicineSapporoJapan
  7. 7.Department of Medical OncologyDana-Farber Cancer InstituteBostonUSA
  8. 8.Department of Surgery, Surgical Oncology and ScienceSapporo Medical University School of MedicineSapporoJapan
  9. 9.Department of Gastroenterological Surgery, Graduate School of Medical ScienceKumamoto UniversityKumamotoJapan
  10. 10.Division of Cancer Research, The Institute of Medical ScienceThe University of TokyoTokyoJapan
  11. 11.Department of Molecular BiologySapporo Medical University School of MedicineSapporoJapan
  12. 12.Division of Gastroenterology and Hepatology, Department of Internal MedicineSt. Marianna University School of MedicineKawasakiJapan

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