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Predicting the response to preoperative radiation or chemoradiation by a microarray analysis of the gene expression profiles in rectal cancer

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Abstract

Preoperative radiotherapy or chemoradiotherapy (CRT) has become a standard treatment for patients with locally advanced rectal cancer. However, there is a wide spectrum of responses to preoperative CRT, ranging from none to complete. There has been intense interest in the identification of molecular biomarkers to predict the response to preoperative CRT, in order to spare potentially non-responsive patients from unnecessary treatment. However, no specific molecular biomarkers have yet been definitively proven to be predictive of the response to CRT. Instead of focusing on specific factors, microarray-based gene expression profiling technology enables the simultaneous analysis of large numbers of genes, and might therefore have immense potential for predicting the response to preoperative CRT. We herein review published studies using a microarray-based analysis to identify gene expression profiles associated with the response of rectal cancer to radiation or CRT. Although some studies have reported gene expression signatures capable of high predictive accuracy, the compositions of these signatures have differed considerably, with little gene overlap. However, considering the promising data regarding gene profiling in breast cancer, the microarray analysis could still have potential to improve the management of locally advanced rectal cancer. Increasing the number of patients analyzed for more accurate prediction and the extensive validation of predictive classifiers in prospective clinical trials are necessary before such profiling can be incorporated into future clinical practice.

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References

  1. Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351:1731–40.

    Article  PubMed  CAS  Google Scholar 

  2. Gerard JP, Conroy T, Bonnetain F, Bouche O, Chapet O, Closon-Dejardin MT, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3–4 rectal cancers: results of FFCD 9203. J Clin Oncol. 2006;24:4620–5.

    Article  PubMed  Google Scholar 

  3. Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006;355:1114–23.

    Article  PubMed  CAS  Google Scholar 

  4. Maas M, Nelemans PJ, Valentini V, Das P, Rodel C, Kuo LJ, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol. 2010;11:835–44.

    Article  PubMed  Google Scholar 

  5. Rodel C, Martus P, Papadoupolos T, Fuzesi L, Klimpfinger M, Fietkau R, et al. Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol. 2005;23:8688–96.

    Article  PubMed  Google Scholar 

  6. Chan AK, Wong A, Jenken D, Heine J, Buie D, Johnson D. Posttreatment TNM staging is a prognostic indicator of survival and recurrence in tethered or fixed rectal carcinoma after preoperative chemotherapy and radiotherapy. Int J Radiat Oncol Biol Phys. 2005;61:665–77.

    Article  PubMed  Google Scholar 

  7. Gavioli M, Luppi G, Losi L, Bertolini F, Santantonio M, Falchi AM, et al. Incidence and clinical impact of sterilized disease and minimal residual disease after preoperative radiochemotherapy for rectal cancer. Dis Colon Rectum. 2005;48:1851–7.

    Article  PubMed  Google Scholar 

  8. Capirci C, Valentini V, Cionini L, De Paoli A, Rodel C, Glynne-Jones R, et al. Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: long-term analysis of 566 ypCR patients. Int J Radiat Oncol Biol Phys. 2008;72:99–107.

    Article  PubMed  Google Scholar 

  9. Vecchio FM, Valentini V, Minsky BD, Padula GD, Venkatraman ES, Balducci M, et al. The relationship of pathologic tumor regression grade (TRG) and outcomes after preoperative therapy in rectal cancer. Int J Radiat Oncol Biol Phys. 2005;62:752–60.

    Article  PubMed  Google Scholar 

  10. Kuo LJ, Liu MC, Jian JJ, Horng CF, Cheng TI, Chen CM, et al. Is final TNM staging a predictor for survival in locally advanced rectal cancer after preoperative chemoradiation therapy? Ann Surg Oncol. 2007;14:2766–72.

    Article  PubMed  Google Scholar 

  11. Kuremsky JG, Tepper JE, McLeod HL. Biomarkers for response to neoadjuvant chemoradiation for rectal cancer. Int J Radiat Oncol Biol Phys. 2009;74:673–88.

    Article  PubMed  CAS  Google Scholar 

  12. Miura K, Fujibuchi W, Ishida K, Naitoh T, Ogawa H, Ando T, et al. Inhibitor of apoptosis protein family as diagnostic markers and therapeutic targets of colorectal cancer. Surg Today. 2011;41:175–82.

    Article  PubMed  CAS  Google Scholar 

  13. Luna-Perez P, Arriola EL, Cuadra Y, Alvarado I, Quintero A. p53 protein overexpression and response to induction chemoradiation therapy in patients with locally advanced rectal adenocarcinoma. Ann Surg Oncol. 1998;5:203–8.

    Article  PubMed  CAS  Google Scholar 

  14. Spitz FR, Giacco GG, Hess K, Larry L, Rich TA, Janjan N, et al. p53 immunohistochemical staining predicts residual disease after chemoradiation in patients with high-risk rectal cancer. Clin Cancer Res. 1997;3:1685–90.

    PubMed  CAS  Google Scholar 

  15. Esposito G, Pucciarelli S, Alaggio R, Giacomelli L, Marchiori E, Iaderosa GA, et al. P27kip1 expression is associated with tumor response to preoperative chemoradiotherapy in rectal cancer. Ann Surg Oncol. 2001;8:311–8.

    Article  PubMed  CAS  Google Scholar 

  16. Lin LC, Lee HH, Hwang WS, Li CF, Huang CT, Que J, et al. p53 and p27 as predictors of clinical outcome for rectal-cancer patients receiving neoadjuvant therapy. Surg Oncol. 2006;15:211–6.

    Article  PubMed  Google Scholar 

  17. Spindler KL, Nielsen JN, Lindebjerg J, Jakobsen A. Germline polymorphisms may act as predictors of response to preoperative chemoradiation in locally advanced T3 rectal tumors. Dis Colon Rectum. 2007;50:1363–9.

    Article  PubMed  Google Scholar 

  18. Giralt J, de las Heras M, Cerezo L, Eraso A, Hermosilla E, Velez D, et al. The expression of epidermal growth factor receptor results in a worse prognosis for patients with rectal cancer treated with preoperative radiotherapy: a multicenter, retrospective analysis. Radiother Oncol. 2005;74:101–8.

    Article  PubMed  CAS  Google Scholar 

  19. Kim JS, Kim JM, Li S, Yoon WH, Song KS, Kim KH, et al. Epidermal growth factor receptor as a predictor of tumor downstaging in locally advanced rectal cancer patients treated with preoperative chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2006;66:195–200.

    Article  PubMed  Google Scholar 

  20. Jakob C, Liersch T, Meyer W, Becker H, Baretton GB, Aust DE. Predictive value of Ki67 and p53 in locally advanced rectal cancer: correlation with thymidylate synthase and histopathological tumor regression after neoadjuvant 5-FU-based chemoradiotherapy. World J Gastroenterol. 2008;14:1060–6.

    Article  PubMed  CAS  Google Scholar 

  21. Negri FV, Campanini N, Camisa R, Pucci F, Bui S, Ceccon G, et al. Biological predictive factors in rectal cancer treated with preoperative radiotherapy or radiochemotherapy. Br J Cancer. 2008;98:143–7.

    Article  PubMed  CAS  Google Scholar 

  22. Saw RP, Morgan M, Koorey D, Painter D, Findlay M, Stevens G, et al. p53, deleted in colorectal cancer gene, and thymidylate synthase as predictors of histopathologic response and survival in low, locally advanced rectal cancer treated with preoperative adjuvant therapy. Dis Colon Rectum. 2003;46:192–202.

    Article  PubMed  Google Scholar 

  23. Villafranca E, Okruzhnov Y, Dominguez MA, Garcia-Foncillas J, Azinovic I, Martinez E, et al. Polymorphisms of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal cancer. J Clin Oncol. 2001;19:1779–86.

    PubMed  CAS  Google Scholar 

  24. Kim NK, Park JK, Lee KY, Yang WI, Yun SH, Sung J, et al. p53, BCL-2, and Ki-67 expression according to tumor response after concurrent chemoradiotherapy for advanced rectal cancer. Ann Surg Oncol. 2001;8:418–24.

    Article  PubMed  CAS  Google Scholar 

  25. Charara M, Edmonston TB, Burkholder S, Walters R, Anne P, Mitchell E, et al. Microsatellite status and cell cycle associated markers in rectal cancer patients undergoing a combined regimen of 5-FU and CPT-11 chemotherapy and radiotherapy. Anticancer Res. 2004;24:3161–7.

    PubMed  CAS  Google Scholar 

  26. Rau B, Sturm I, Lage H, Berger S, Schneider U, Hauptmann S, et al. Dynamic expression profile of p21WAF1/CIP1 and Ki-67 predicts survival in rectal carcinoma treated with preoperative radiochemotherapy. J Clin Oncol. 2003;21:3391–401.

    Article  PubMed  CAS  Google Scholar 

  27. Bertolini F, Bengala C, Losi L, Pagano M, Iachetta F, Dealis C, et al. Prognostic and predictive value of baseline and posttreatment molecular marker expression in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2007;68:1455–61.

    Article  PubMed  CAS  Google Scholar 

  28. Kudrimoti M, Lee EY, Kang Y, Ahmed M, Mohiuddin M. Genetic markers predictive of response to induction chemoradiotherapy for locally advanced rectal cancers. J Ky Med Assoc. 2007;105:18–22.

    PubMed  Google Scholar 

  29. Chang HJ, Jung KH, Kim DY, Jeong SY, Choi HS, Kim YH, et al. Bax, a predictive marker for therapeutic response to preoperative chemoradiotherapy in patients with rectal carcinoma. Hum Pathol. 2005;36:364–71.

    Article  PubMed  CAS  Google Scholar 

  30. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:2817–26.

    Article  PubMed  CAS  Google Scholar 

  31. Paik S, Tang G, Shak S, Kim C, Baker J, Kim W, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24:3726–34.

    Article  PubMed  CAS  Google Scholar 

  32. Sparano JA, Paik S. Development of the 21-gene assay and its application in clinical practice and clinical trials. J Clin Oncol. 2008;26:721–8.

    Article  PubMed  Google Scholar 

  33. van’t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415:530–6.

    Article  Google Scholar 

  34. van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347:1999–2009.

    Article  PubMed  Google Scholar 

  35. Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25:5287–312.

    Article  PubMed  CAS  Google Scholar 

  36. National Comprehensive Cancer Network Practice Guidelines in Oncology. http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf.

  37. Akiyoshi T, Kobunai T, Watanabe T. Recent approaches to identifying biomarkers for high-risk stage II colon cancer. Surg Today (in press).

  38. Ojima E, Inoue Y, Miki C, Mori M, Kusunoki M. Effectiveness of gene expression profiling for response prediction of rectal cancer to preoperative radiotherapy. J Gastroenterol. 2007;42:730–6.

    Article  PubMed  Google Scholar 

  39. Eschrich S, Zhang H, Zhao H, Boulware D, Lee JH, Bloom G, et al. Systems biology modeling of the radiation sensitivity network: a biomarker discovery platform. Int J Radiat Oncol Biol Phys. 2009;75:497–505.

    Article  PubMed  CAS  Google Scholar 

  40. Eschrich SA, Pramana J, Zhang H, Zhao H, Boulware D, Lee JH, et al. A gene expression model of intrinsic tumor radiosensitivity: prediction of response and prognosis after chemoradiation. Int J Radiat Oncol Biol Phys. 2009;75:489–96.

    Article  PubMed  CAS  Google Scholar 

  41. Spitzner M, Emons G, Kramer F, Gaedcke J, Rave-Frank M, Scharf JG, et al. A gene expression signature for chemoradiosensitivity of colorectal cancer cells. Int J Radiat Oncol Biol Phys. 2010;78:1184–92.

    Article  PubMed  CAS  Google Scholar 

  42. Torres-Roca JF, Eschrich S, Zhao H, Bloom G, Sung J, McCarthy S, et al. Prediction of radiation sensitivity using a gene expression classifier. Cancer Res. 2005;65:7169–76.

    Article  PubMed  CAS  Google Scholar 

  43. Watanabe T, Kobunai T, Yamamoto Y, Matsuda K, Ishihara S, Nozawa K, et al. Differential gene expression signatures between colorectal cancers with and without KRAS mutations: crosstalk between the KRAS pathway and other signalling pathways. Eur J Cancer. 2011;47:1946–54.

    Article  PubMed  CAS  Google Scholar 

  44. Nagtegaal ID, Gaspar CG, Peltenburg LT, Marijnen CA, Kapiteijn E, van de Velde CJ, et al. Radiation induces different changes in expression profiles of normal rectal tissue compared with rectal carcinoma. Virchows Arch. 2005;446:127–35.

    Article  PubMed  CAS  Google Scholar 

  45. Snipstad K, Fenton CG, Kjaeve J, Cui G, Anderssen E, Paulssen RH. New specific molecular targets for radio-chemotherapy of rectal cancer. Mol Oncol. 2009;4:52–64.

    Article  PubMed  Google Scholar 

  46. Ghadimi BM, Grade M, Difilippantonio MJ, Varma S, Simon R, Montagna C, et al. Effectiveness of gene expression profiling for response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. J Clin Oncol. 2005;23:1826–38.

    Article  PubMed  CAS  Google Scholar 

  47. Watanabe T, Komuro Y, Kiyomatsu T, Kanazawa T, Kazama Y, Tanaka J, et al. Prediction of sensitivity of rectal cancer cells in response to preoperative radiotherapy by DNA microarray analysis of gene expression profiles. Cancer Res. 2006;66:3370–4.

    Article  PubMed  CAS  Google Scholar 

  48. Japanese Society for Cancer of the Colon and Rectum. Japanese Classification of Colorectal Carcinoma. First English Edition. Tokyo: Kanehara & Co; 1997.

    Google Scholar 

  49. Kim IJ, Lim SB, Kang HC, Chang HJ, Ahn SA, Park HW, et al. Microarray gene expression profiling for predicting complete response to preoperative chemoradiotherapy in patients with advanced rectal cancer. Dis Colon Rectum. 2007;50:1342–53.

    Article  PubMed  Google Scholar 

  50. Rimkus C, Friederichs J, Boulesteix AL, Theisen J, Mages J, Becker K, et al. Microarray-based prediction of tumor response to neoadjuvant radiochemotherapy of patients with locally advanced rectal cancer. Clin Gastroenterol Hepatol. 2008;6:53–61.

    Article  PubMed  CAS  Google Scholar 

  51. Becker K, Mueller JD, Schulmacher C, Ott K, Fink U, Busch R, et al. Histomorphology and grading of regression in gastric carcinoma treated with neoadjuvant chemotherapy. Cancer. 2003;98:1521–30.

    Article  PubMed  Google Scholar 

  52. Nishioka M, Shimada M, Kurita N, Iwata T, Morimoto S, Yoshikawa K, et al. Gene expression profile can predict pathological response to preoperative chemoradiotherapy in rectal cancer. Cancer Genomics Proteomics. 2011;8:87–92.

    PubMed  CAS  Google Scholar 

  53. Daemen A, Gevaert O, De Bie T, Debucquoy A, Machiels JP, De Moor B, et al. Integrating microarray and proteomics data to predict the response on cetuximab in patients with rectal cancer. Pac Symp Biocomput. 2008:166–77.

  54. Debucquoy A, Haustermans K, Daemen A, Aydin S, Libbrecht L, Gevaert O, et al. Molecular response to cetuximab and efficacy of preoperative cetuximab-based chemoradiation in rectal cancer. J Clin Oncol. 2009;27:2751–7.

    Article  PubMed  CAS  Google Scholar 

  55. Machiels JP, Sempoux C, Scalliet P, Coche JC, Humblet Y, Van Cutsem E, et al. Phase I/II study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer. Ann Oncol. 2007;18:738–44.

    Article  PubMed  Google Scholar 

  56. Wheeler JM, Warren BF, Mortensen NJ, Ekanyaka N, Kulacoglu H, Jones AC, et al. Quantification of histologic regression of rectal cancer after irradiation: a proposal for a modified staging system. Dis Colon Rectum. 2002;45:1051–6.

    Article  PubMed  CAS  Google Scholar 

  57. Lossos IS, Czerwinski DK, Alizadeh AA, Wechser MA, Tibshirani R, Botstein D, et al. Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med. 2004;350:1828–37.

    Article  PubMed  CAS  Google Scholar 

  58. Chen HY, Yu SL, Chen CH, Chang GC, Chen CY, Yuan A, et al. A five-gene signature and clinical outcome in non-small-cell lung cancer. N Engl J Med. 2007;356:11–20.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Gastroenterological Center, Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan

    Takashi Akiyoshi

  2. Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan

    Takashi Kobunai & Toshiaki Watanabe

  3. Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Toshiaki Watanabe

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  1. Takashi Akiyoshi
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Correspondence to Toshiaki Watanabe.

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Akiyoshi, T., Kobunai, T. & Watanabe, T. Predicting the response to preoperative radiation or chemoradiation by a microarray analysis of the gene expression profiles in rectal cancer. Surg Today 42, 713–719 (2012). https://doi.org/10.1007/s00595-012-0223-8

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