International Journal of Radiation Oncology * Biology * Physics
Volume 74, Issue 3 , Pages 673-688 , 1 July 2009

Biomarkers for Response to Neoadjuvant Chemoradiation for Rectal Cancer

  • Jeffrey G. Kuremsky, B.A.

      Affiliations

    • University of North Carolina (UNC) Institute for Pharmacogenomics and Individualized Therapy, Chapel Hill, NC
    • UNC Doris Duke Clinical Research Fellowship Program, Chapel Hill, NC
    • ,
  • Joel E. Tepper, M.D.

      Affiliations

    • UNC Schools of Pharmacy and Medicine, Chapel Hill, NC
    • UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC
    • ,
  • Howard L. McLeod, Pharm.D.

      Affiliations

    • University of North Carolina (UNC) Institute for Pharmacogenomics and Individualized Therapy, Chapel Hill, NC
    • UNC Schools of Pharmacy and Medicine, Chapel Hill, NC
    • UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC
    • Corresponding Author InformationReprint requests to: Howard L. McLeod, Pharm.D., Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Kerr Hall, Campus Box 7360, Chapel Hill, NC 27599-7360. Tel: (919) 966-5242; Fax: (919) 966-5863

Received 16 December 2008 ,Revised 27 February 2009 ,Accepted 3 March 2009.

References 

  1. Jemal A, Siegel R, Ward E, et al. Cancer statistics. CA Cancer J Clin. 2008;2008(58):71–96
  2. Gunderson LL, Sargent DJ, Tepper JE, et al. Impact of T and N substage on survival and disease relapse in adjuvant rectal cancer: A pooled analysis. Int J Radiat Oncol Biol Phys. 2002;54:386–396
  3. Mohiuddin M, Marks J, Marks G. Management of rectal cancer: Short- vs. long-course preoperative radiation. Int J Radiat Oncol Biol Phys. 2008;72:636–643
  4. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351:1731–1740
  5. Nelson H, Sargent DJ. Refining multimodal therapy for rectal cancer. N Engl J Med. 2001;345:690–692
  6. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001;345:638–646
  7. Janjan NA, Khoo VS, Abbruzzese J, et al. Tumor downstaging and sphincter preservation with preoperative chemoradiation in locally advanced rectal cancer: The M.D. Anderson Cancer Center experience. Int J Radiat Oncol Biol Phys. 1999;44:1027–1038
  8. Kim JS, Kim JS, Cho MJ, et al. Preoperative chemoradiation using oral capecitabine in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2002;54:403–408
  9. Glynne-Jones R, Harrison M. Locally advanced rectal cancer: What is the evidence for induction chemoradiation?. Oncologist. 2007;12:1309–1318
  10. Crane CH, Skibber JM, Feig BW, et al. Response to preoperative chemoradiation increases the use of sphincter-preserving surgery in patients with locally advanced low rectal carcinoma. Cancer. 2003;97:517–524
  11. Rodel C, Martus P, Papadoupolos T, et al. Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol. 2005;23:8688–8696
  12. Valentini V, Coco C, Picciocchi A, et al. Does downstaging predict improved outcome after preoperative chemoradiation for extraperitoneal locally advanced rectal cancer? A long-term analysis of 165 patients. Int J Radiat Oncol Biol Phys. 2002;53:664–674
  13. Kuerbitz SJ, Plunkett BS, Walsh WV, et al. Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci U S A. 1992;89:7491–7495
  14. Lowe SW, Ruley HE, Jacks T, et al. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell. 1993;74:957–967
  15. Lowe SW, Schmitt EM, Smith SW, et al. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature. 1993;362:847–849
  16. McIlwrath AJ, Vasey PA, Ross GM, et al. Cell cycle arrests and radiosensitivity of human tumor cell lines: Dependence on wild-type p53 for radiosensitivity. Cancer Res. 1994;54:3718–3722
  17. Rau B, Sturm I, Lage H, et al. Dynamic expression profile of p21WAF1/CIP1 and Ki-67 predicts survival in rectal carcinoma treated with preoperative radiochemotherapy. J Clin Oncol. 2003;21:3391–3401
  18. Bertolini F, Bengala C, Losi L, 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;68:1455–1461
  19. Saw RP, Morgan M, Koorey D, 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
  20. Chang HJ, Jung KH, Kim DY, et al. Bax, a predictive marker for therapeutic response to preoperative chemoradiotherapy in patients with rectal carcinoma. Hum Pathol. 2005;36:364–371
  21. Terzi C, Canda AE, Sagol O, et al. Survivin, p53, and Ki-67 as predictors of histopathologic response in locally advanced rectal cancer treated with preoperative chemoradiotherapy. Int J Colorectal Dis. 2008;23:37–45
  22. Rodel F, Hoffmann J, Grabenbauer GG, et al. High survivin expression is associated with reduced apoptosis in rectal cancer and may predict disease-free survival after preoperative radiochemotherapy and surgical resection. Strahlenther Onkol. 2002;178:426–435
  23. Scott N, Hale A, Deakin M, et al. A histopathological assessment of the response of rectal adenocarcinoma to combination chemo-radiotherapy: Relationship to apoptotic activity, p53 and bcl-2 expression. Eur J Surg Oncol. 1998;24:169–173
  24. Tannapfel A, Nusslein S, Fietkau R, et al. Apoptosis, proliferation, bax, bcl-2 and p53 status prior to and after preoperative radiochemotherapy for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 1998;41:585–591
  25. Diez M, Ramos P, Medrano MJ, et al. Preoperatively irradiated rectal carcinoma: Analysis of the histopathologic response and predictive value of proliferating cell nuclear antigen immunostaining. Oncology. 2003;64:213–219
  26. Kim NK, Park JK, Lee KY, et al. p53, BCL-2, and Ki-67 expression according to tumor response after concurrent chemoradiotherapy for advanced rectal cancer. Ann Surg Oncol. 2001;8:418–424
  27. Elsaleh H, Robbins P, Joseph D, et al. Can p53 alterations be used to predict tumour response to pre-operative chemo-radiotherapy in locally advanced rectal cancer?. Radiother Oncol. 2000;56:239–244
  28. Charara M, Edmonston TB, Burkholder S, 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;24:3161–3167
  29. Okonkwo A, Musunuri S, Talamonti M, et al. Molecular markers and prediction of response to chemoradiation in rectal cancer. Oncol Rep. 2001;8:497–500
  30. Reerink O, Karrenbeld A, Plukker JT, et al. Molecular prognostic factors in locally irresectable rectal cancer treated preoperatively by chemo-radiotherapy. Anticancer Res. 2004;24:1217–1221
  31. Kudrimoti M, Lee EY, Kang Y, et al. Genetic markers predictive of response to induction chemoradiotherapy for locally advanced rectal cancers. J Ky Med Assoc. 2007;105:18–22
  32. Jakob C, Liersch T, Meyer W, et al. 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;14:1060–1066
  33. Negri FV, Campanini N, Camisa R, et al. Biological predictive factors in rectal cancer treated with preoperative radiotherapy or radiochemotherapy. Br J Cancer. 2008;98:143–147
  34. Lin LC, Lee HH, Hwang WS, et al. p53 and p27 as predictors of clinical outcome for rectal-cancer patients receiving neoadjuvant therapy. Surg Oncol. 2006;15:211–216
  35. Luna-Perez P, Arriola EL, Cuadra Y, et al. p53 protein overexpression and response to induction chemoradiation therapy in patients with locally advanced rectal adenocarcinoma. Ann Surg Oncol. 1998;5:203–208
  36. Spitz FR, Giacco GG, Hess K, et al. p53 immunohistochemical staining predicts residual disease after chemoradiation in patients with high-risk rectal cancer. Clin Cancer Res. 1997;3:1685–1690
  37. Esposito G, Pucciarelli S, Alaggio R, et al. P27kip1 expression is associated with tumor response to preoperative chemoradiotherapy in rectal cancer. Ann Surg Oncol. 2001;8:311–318
  38. Akimoto T, Hunter NR, Buchmiller L, et al. Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas. Clin Cancer Res. 1999;5:2884–2890
  39. Liang K, Ang KK, Milas L, et al. The epidermal growth factor receptor mediates radioresistance. Int J Radiat Oncol Biol Phys. 2003;57:246–254
  40. Goldstein NS, Armin M. Epidermal growth factor receptor immunohistochemical reactivity in patients with American Joint Committee on Cancer Stage IV colon adenocarcinoma: Implications for a standardized scoring system. Cancer. 2001;92:1331–1346
  41. Giralt J, de las Heras M, Cerezo L, 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;74:101–108
  42. Kim JS, Kim JM, Li S, 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
  43. Spindler KL, Nielsen JN, Lindebjerg J, et al. Prediction of response to chemoradiation in rectal cancer by a gene polymorphism in the epidermal growth factor receptor promoter region. Int J Radiat Oncol Biol Phys. 2006;66:500–504
  44. Spindler KL, Nielsen JN, Lindebjerg J, et al. Germline polymorphisms may act as predictors of response to preoperative chemoradiation in locally advanced T3 rectal tumors. Dis Colon Rectum. 2007;50:1363–1369
  45. Salonga D, Danenberg KD, Johnson M, et al. Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Cancer Res. 2000;6:1322–1327
  46. Lenz HJ, Danenberg KD, Leichman CG, et al. p53 and thymidylate synthase expression in untreated stage II colon cancer: Associations with recurrence, survival, and site. Clin Cancer Res. 1998;4:1227–1234
  47. Pullarkat ST, Stoehlmacher J, Ghaderi V, et al. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J. 2001;1:65–70
  48. Mandola MV, Stoehlmacher J, Zhang W, et al. A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels. Pharmacogenetics. 2004;14:319–327
  49. Mandola MV, Stoehlmacher J, Muller-Weeks S, et al. A novel single nucleotide polymorphism within the 5' tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res. 2003;63:2898–2904
  50. Marcuello E, Altes A, del Rio E, et al. Single nucleotide polymorphism in the 5' tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil-based chemotherapy in advanced colorectal cancer patients. Int J Cancer. 2004;112:733–737
  51. Villafranca E, Okruzhnov Y, Dominguez MA, 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;19:1779–1786
  52. Horie N, Aiba H, Oguro K, et al. Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5'-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct. 1995;20:191–197
  53. Kawakami K, Salonga D, Park JM, et al. Different lengths of a polymorphic repeat sequence in the thymidylate synthase gene affect translational efficiency but not its gene expression. Clin Cancer Res. 2001;7:4096–4101
  54. Scholzen T, Gerdes J. The Ki-67 protein: From the known and the unknown. J Cell Physiol. 2000;182:311–322
  55. Brown DC, Gatter KC. Ki67 protein: The immaculate deception?. Histopathology. 2002;40:2–11
  56. Rodel C, Grabenbauer GG, Papadopoulos T, et al. Apoptosis as a cellular predictor for histopathologic response to neoadjuvant radiochemotherapy in patients with rectal cancer. Int J Radiat Oncol Biol Phys. 2002;52:294–303
  57. el-Deiry WS, Harper JW, O'Connor PM, et al. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 1994;54:1169–1174
  58. Lu Y, Yamagishi N, Yagi T, et al. Mutated p21(WAF1/CIP1/SDI1) lacking CDK-inhibitory activity fails to prevent apoptosis in human colorectal carcinoma cells. Oncogene. 1998;16:705–712
  59. Waldman T, Lengauer C, Kinzler KW, et al. Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature. 1996;381:713–716
  60. Wouters BG, Giaccia AJ, Denko NC, et al. Loss of p21Waf1/Cip1 sensitizes tumors to radiation by an apoptosis-independent mechanism. Cancer Res. 1997;57:4703–4706
  61. Wang YA, Elson A, Leder P. Loss of p21 increases sensitivity to ionizing radiation and delays the onset of lymphoma in atm-deficient mice. Proc Natl Acad Sci U S A. 1997;94:14590–14595
  62. Tian H, Wittmack EK, Jorgensen TJ. p21WAF1/CIP1 antisense therapy radiosensitizes human colon cancer by converting growth arrest to apoptosis. Cancer Res. 2000;60:679–684
  63. Yamaguchi H, Bhalla K, Wang HG. Bax plays a pivotal role in thapsigargin-induced apoptosis of human colon cancer HCT116 cells by controlling Smac/Diablo and Omi/HtrA2 release from mitochondria. Cancer Res. 2003;63:1483–1489
  64. Wagener C, Bargou RC, Daniel PT, et al. Induction of the death-promoting gene bax-alpha sensitizes cultured breast-cancer cells to drug-induced apoptosis. Int J Cancer. 1996;67:138–141
  65. Zhang L, Yu J, Park BH, et al. Role of BAX in the apoptotic response to anticancer agents. Science. 2000;290:989–992
  66. Walton MI, Whysong D, O'Connor PM, et al. Constitutive expression of human Bcl-2 modulates nitrogen mustard and camptothecin induced apoptosis. Cancer Res. 1993;53:1853–1861
  67. Miyashita T, Reed JC. bcl-2 gene transfer increases relative resistance of S49.1 and WEHI7.2 lymphoid cells to cell death and DNA fragmentation induced by glucocorticoids and multiple chemotherapeutic drugs. Cancer Res. 1992;52:5407–5411
  68. Fukunaga-Johnson N, Ryan JJ, Wicha M, et al. Bcl-2 protects murine erythroleukemia cells from p53-dependent and -independent radiation-induced cell death. Carcinogenesis. 1995;16:1761–1767
  69. Ghadimi BM, Grade M, Difilippantonio MJ, et al. Effectiveness of gene expression profiling for response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. J Clin Oncol. 2005;23:1826–1838
  70. Rimkus C, Friederichs J, Boulesteix AL, 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
  71. Read TE, McNevin MS, Gross EK, et al. Neoadjuvant therapy for adenocarcinoma of the rectum: Tumor response and acute toxicity. Dis Colon Rectum. 2001;44:513–522
  72. Stoehlmacher J, Goekkurt E, Mogck U, et al. Thymidylate synthase genotypes and tumour regression in stage II/III rectal cancer patients after neoadjuvant fluorouracil-based chemoradiation. Cancer Lett. 2008;272:221–225
  73. Terrazzino S, Agostini M, Pucciarelli S, et al. A haplotype of the methylenetetrahydrofolate reductase gene predicts poor tumor response in rectal cancer patients receiving preoperative chemoradiation. Pharmacogenet Genomics. 2006;16:817–824
  74. Debucquoy A, Goethals L, Geboes K, et al. Molecular responses of rectal cancer to preoperative chemoradiation. Radiother Oncol. 2006;80:172–177
  75. Smith FM, Reynolds JV, Kay EW, et al. COX-2 overexpression in pretreatment biopsies predicts response of rectal cancers to neoadjuvant radiochemotherapy. Int J Radiat Oncol Biol Phys. 2006;64:466–472
  76. Debucquoy A, Libbrecht L, Roobrouck V, et al. Morphological features and molecular markers in rectal cancer from 95 patients included in the European Organisation for Research and Treatment of Cancer 22921 trial: Prognostic value and effects of preoperative radio (chemo) therapy. Eur J Cancer. 2008;44:791–797

 Conflict of interest: none.

PII: S0360-3016(09)00361-7

doi: 10.1016/j.ijrobp.2009.03.003

International Journal of Radiation Oncology * Biology * Physics
Volume 74, Issue 3 , Pages 673-688 , 1 July 2009

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