Skip to main content
Log in

The results of colorectal cancer treatment by p53 status

Treatment-specific overview

  • Original Contributions
  • Published:
Diseases of the Colon & Rectum

Abstract

PURPOSE: Both negative and positive influences of mutant p53 on treatment outcome have been reported, and we present here a meta-analysis of published studies where outcome was reported for defined treatment groups. METHODS: We identified articles on the effect of p53 status by treatment modality, excluding those not stratified by method of treatment. A common hazard ratio was estimated from studies that reported a multivariate analysis. We also estimated the numbers of patients expressing the endpoint at the mean or median follow-up time and calculated a pooled odds ratio. RESULTS: Twenty-eight articles were evaluable (23 using immunohistochemistry to detect over-expression of p53 and 8 using DNA sequencing), for a total of 4,416 patients. For patients treated with surgery only, the immunohistochemistry studies showed a significant influence of p53 status on disease-free survival and a marginally significant influence on overall survival. In the studies using DNA sequencing, by contrast, there was a significant influence of p53 mutations on overall survival, but not disease-free survival. For patients treated with surgery and radio-therapy, the influence of p53 status on disease-free survival was either insignificant or marginally significant, depending on test used; there was no influence on overall survival. CONCLUSIONS: Although this pooled analysis of published studies where treatment was accounted for shows that there is a borderline significant hazard associated with p53 overexpression or mutationvs. p53 wild-type, it is unlikely that p53 can be applied in a routine clinical setting along-side factors such as T stage, nodal status, and residual tumor, whose prognostic value is much stronger.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Hermanek P, Guggenmoos-Holzmann I, Gall FP. Prognostic factors in rectal carcinoma: a contribution to the further development of tumor classification. Dis Colon Rectum 1989;32:593–9.

    Google Scholar 

  2. Fielding LP, Arsenault PA, Chapuis PH,et al. Clinicopathological staging for colorectal cancer: an International Documentation System (IDS) and an International Comprehensive Anatomical Terminology (ICAT). J Gastroenterol Hepatol 1991;6:325–44.

    Google Scholar 

  3. Nathanson SD. Is there a role for clinical prognostic factors in staging patients with colorectal cancer? Semin Surg Oncol 1994;10:176–82.

    Google Scholar 

  4. Broll R, Schauer V, Schimmelpenning H,et al. Prognostic relevance of occult tumor cells in lymph nodes of colorectal carcinomas: an immunohistochemical study. Dis Colon Rectum 1997;40:1465–71.

    Google Scholar 

  5. Cunningham C, Dunlop MG. Molecular genetic basis of colorectal cancer susceptibility. Br J Surg 1996;83:321–9.

    Google Scholar 

  6. Cohen AM, Minsky BD, Schilsky RL. Cancer of the Colon. In: DeVita VT, Hellman S, Rosenberg SA, eds. Principles and practice in oncology. 5th ed. Vol. 1. Philadelphia: Lippincott-Raven, 1997:1154–62

    Google Scholar 

  7. Moran MR, Rothenberger DA, Gallo RA,et al. Multifactorial analysis of local recurrences in rectal cancer, including DNA ploidy studies: a predictive model. World J Surg 1993;17:801–5.

    Google Scholar 

  8. Ratto C, Sofo L, Ippoliti M,et al. Prognostic factors in colorectal cancer. Literature review for clinical application. Dis Colon Rectum 1998;41:1033–49.

    Google Scholar 

  9. Bosari S, Viale G. The clinical significance of p53 aberrations in human tumours. Virchows Arch 1995;427:229–41.

    Google Scholar 

  10. Tomlinson I, Ilyas M, Novelli M. Molecular genetics of colon cancer. Cancer Metastasis Rev 1997;16:67–79.

    Google Scholar 

  11. Muto T, Watanabe T. Colorectal carcinoma: recent advances in its biology and treatment. J Cancer Res Clin Oncol 1999;125:245–53.

    Google Scholar 

  12. Oren M, Rotter V. Introduction: p53—the first twenty years. Cell Mol Life Sci 1999;55:9–11.

    Google Scholar 

  13. Hermanek P (International Union Against Cancer (UICC)), ed. TNM atlas: illustrated guide to the TNM/pTNM classification of malignant tumours. 4th ed. Berlin: Springer, 1997.

    Google Scholar 

  14. Demets DL. Methods for combining randomized clinical trials: strengths and limitations. Stat Med 1987;6:341–50.

    Google Scholar 

  15. Sacks HS, Berrier J, Reitman D,et al. Meta-analyses of randomized controlled trials. N Engl J Med 1987;316:450–5.

    Google Scholar 

  16. Breslow NE, Day NE. Statistical methods in cancer research. Lyon: International Agency for Research on Cancer, 1980.

    Google Scholar 

  17. Pharoah PD, Day NE, Caldas C. Somatic mutations in the p53 gene and prognosis in breast cancer: a meta-analysis. Br J Cancer 1999;80:1968–73.

    Google Scholar 

  18. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719–48.

    Google Scholar 

  19. Yusuf S, Collins R, Peto R,et al. Intravenous and intracoronary fibrinolytic therapy in acute myocardial infarction: overview of results on mortality, reinfarction and side-effects from 33 randomized controlled trials. Eur Heart J 1985;6:556–85.

    Google Scholar 

  20. Houbiers JG, van der Burg SH, van de Watering LM,et al. Antibodies against p53 are associated with poor prognosis of colorectal cancer. Br J Cancer 1995;72:637–41

    Google Scholar 

  21. Auvinen A, Isola J, Visakorpi T,et al. Overexpression of p53 and long-term survival in colon carcinoma. Br J Cancer 1994;70:293–6.

    Google Scholar 

  22. Caldes T, Iniesta P, Vega FJ,et al. Comparative survival analysis of p53 gene mutations and protein accumulation in colorectal cancer. Oncology 1998;55:249–57.

    Google Scholar 

  23. Goh HS, Yao J, Smith DR. p53 point mutation and survival in colorectal cancer patients. Cancer Res 1995;55:5217–21.

    Google Scholar 

  24. Manne U, Myers RB, Moron C,et al. Prognostic significance of Bcl-2 expression and p53 nuclear accumulation in colorectal adenocarcinoma. Int J Cancer 1997;74:346–58.

    Google Scholar 

  25. Mulder JW, Baas IO, Polak MM,et al. Evaluation of p53 protein expression as a marker for long-term prognosis in colorectal carcinoma. Br J Cancer 1995;71:1257–62.

    Google Scholar 

  26. Tanaka M, Omura K, Watanabe Y,et al. Prognostic factors of colorectal cancer: K-ras mutation, overexpression of the p53 protein, and cell proliferative activity. J Surg Oncol 1994;57:57–64.

    Google Scholar 

  27. Hirvikoski P, Auvinen A, Servomaa K,et al. K-ras and p53 mutations and overexpressions as prognostic factors in female rectal carcinoma. Anticancer Res 1999;19:685–91.

    Google Scholar 

  28. Feeley KM, Fullard JF, Heneghan MA,et al. Microsatellite instability in sporadic colorectal carcinoma is not an indicator of prognosis. J Pathol 1999;188:14–7.

    Google Scholar 

  29. Desai GR, Myerson RJ, Higashikubo R,et al. Carcinoma of the rectum. Possible cellular predictors of metastatic potential and response to radiation therapy. Dis Colon Rectum 1996;39:1090–6.

    Google Scholar 

  30. Bhatavdekar JM, Patel DD, Ghosh N,et al. Coexpression of Bcl-2, c-Myc, and p53 oncoproteins as prognostic discriminants in patients with colorectal carcinoma. Dis Colon Rectum 1997;40:785–90.

    Google Scholar 

  31. Borresen-Dale AL, Lothe RA, Meling GI,et al. TP53 and long-term prognosis in colorectal cancer: mutations in the L3 zinc-binding domain predict poor survival. Clin Cancer Res 1998;4:203–10.

    Google Scholar 

  32. Kressner U, Inganas M, Byding S,et al. Prognostic value of p53 genetic changes in colorectal cancer. J Clin Oncol 1999;17:593–9.

    Google Scholar 

  33. Lanza G, Jr, Maestri I, Dubini A,et al. p53 expression in colorectal cancer: relation to tumor type, DNA ploidy pattern and short-term survival. Am J Clin Pathol 1996;105:604–12.

    Google Scholar 

  34. Sory A, Minamoto T, Ohta T,et al. Does p53 overexpression cause metastases in early invasive colorectal adenocarcinoma? Eur J Surg 1997;163:685–92.

    Google Scholar 

  35. Vermeulen PB, Van den Eynden GG, Huget P,et al. Prospective study of intraumoral microvessel density, p53 expression and survival in colorectal cancer. Br J Cancer 1999;79:316–22.

    Google Scholar 

  36. 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;5:203–8.

    Google Scholar 

  37. Benhattar J, Cerottini JP, Saraga E,et al. p53 mutations as a possible predictor of response to chemotherapy in metastatic colorectal carcinomas. Int J Cancer 1996;69:190–2.

    Google Scholar 

  38. Iniesta P, Vega FJ, Caldes T,et al. p53 exon 7 mutations as a predictor of poor prognosis in patients with colorectal cancer. Cancer Lett 1998;130:153–60.

    Google Scholar 

  39. Paradiso A, Rabinovich M, Vallejo C,et al. p53 and PCNA expression in advanced colorectal cancer: response to chemotherapy and long-term prognosis. Int J Cancer 1996;69:437–41.

    Google Scholar 

  40. Sinicrope FA, Hart J, Michelassi F,et al. Prognostic value of bcl-2 oncoprotein expression in stage II colon carcinoma. Clin Cancer Res 1995;1:1103–10.

    Google Scholar 

  41. 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;3:1685–90.

    Google Scholar 

  42. Tomoda H, Kakeji Y. Immunohistochemical analysis of p53 in colorectal cancer regarding clinicopathological correlation and prognostic significance. J Surg Oncol 1995;58:125–8.

    Google Scholar 

  43. Sun XF, Carstensen JM, Nordenskjold B. Expression of c-erbB-2 and p53 in colorectal adenocarcinoma. Anal Cell Pathol 1995;8:203–11.

    Google Scholar 

  44. Sun XF, Carstensen JM, Zhang H,et al. Prognostic significance of p53 nuclear and cytoplasmic overexpression in right and left colorectal adenocarcinomas. Eur J Cancer 1996;32A:1963–7.

    Google Scholar 

  45. Ahnen DJ, Feigl P, Quan G,et al. Ki-ras mutation and p53 overexpression predict the clinical behavior of colorectal cancer: a Southwest Oncology Group study. Cancer Res 1998;58:1149–58.

    Google Scholar 

  46. Diez M, Enriquez JM, Camunas J,et al. Prediction of recurrence in B-C stages of colorectal cancer by p53 nuclear overexpression in comparison with standard pathological features. Eur J Surg Oncol 1995;21:635–9.

    Google Scholar 

  47. Flamini G, Curigliano G, Ratto C,et al. Prognostic significance of cytoplasmic p53 overexpression in colorectal cancer. An immunohistochemical analysis. Eur J Cancer 1996;32A:802–6.

    Google Scholar 

  48. Ilyas M, Hao XP, Wilkinson K,et al. Loss of Bcl-2 expression correlates with tumour recurrence in colorectal cancer. Gut 1998;43:383–7.

    Google Scholar 

  49. Leahy DT, Salman R, Mulcahy H, Sheahan K, O'Donoghue DP, Parfrey NA. Prognostic significance of p53 abnormalities in colorectal carcinoma detected by PCR-SSCP and immunohistochemical analysis. J Pathol 1996;180:364–70.

    Google Scholar 

  50. Maeda K, Chung YS, Kang SM,et al. Overexpression of cyclin D1 and p53 associated with disease recurrence in colorectal adenocarcinoma. Int J Cancer 1997;74:310–5.

    Google Scholar 

  51. Nathanson SD, Linden MD, Tender P,et al. Relationship among p53, stage, and prognosis of large bowel cancer. Dis Colon Rectum 1994;37:527–34.

    Google Scholar 

  52. Pereira H, Silva S, Juliao R,et al. Prognostic markers for colorectal cancer: expression of P53 and BCL2. World J Surg 1997;21:210–3.

    Google Scholar 

  53. Poller DN, Baxter KJ, Shepherd NA. p53, and Rb1 protein expression: are they prognostically useful in colorectal cancer? Br J Cancer 1997; 75:87–93.

    Google Scholar 

  54. Smith DR, Ji CY, Goh HS. Prognostic significance of p53 overexpression and mutation in colorectal adenocarcinomas. Br J Cancer 1996;74:216–23.

    Google Scholar 

  55. Soong R, Grieu F, Robbins P,et al. p53 alterations are associated with improved prognosis in distal colonic carcinomas. Clin Cancer Res 1997;3:1405–11.

    Google Scholar 

  56. Sun XF, Carstensen JM, Stal O,et al. Prognostic significance of p53 expression in relation to DNA ploidy in colorectal adenocarcinoma. Virchows Arch A Pathol Anat Histopathol 1993;423:443–8.

    Google Scholar 

  57. Tollenaar RA, van Krieken JH, van Slooten HJ,et al. Immunohistochemical detection of p53 and Bcl-2 in colorectal carcinoma: no evidence for prognostic significance. Br J Cancer 1998;77:1842–7.

    Google Scholar 

  58. Yamamura T, Matsuzaki H, Suda T,et al. Clinicopathological variables and p53 overexpression as a combined prognosticator for hematogenic recurrence in colorectal cancer. J Surg Oncol 1999;70:1–5.

    Google Scholar 

  59. Zeng ZS, Sarkis AS, Zhang ZF,et al. p53 nuclear overexpression: an independent predictor of survival in lymph node-positive colorectal cancer patients. J Clin Oncol 1994;12:2043–50.

    Google Scholar 

  60. Hardingham JE, Butler WJ, Roder D,et al. Somatic mutations, acetylator status, and prognosis in colorectal cancer. Gut 1998;42:669–72.

    Google Scholar 

  61. Tortola S, Marcuello E, Gonzalez I,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;17:1375–81.

    Google Scholar 

  62. Kressner U, Lindmark G, Gerdin B,et al. Immunohistological p53 staining is of limited value in the staging and prognostic prediction of colorectal cancer. Anticancer Res 1996;16:951–7.

    Google Scholar 

  63. Kim YW, Lee S, Park JH,et al. An immunohistochemical study of the expression of p53 protein in colon cancer. J Korean Med Sci 1995;10:176–82.

    Google Scholar 

  64. Bosari S, Viale G, Bossi P,et al. Cytoplasmic accumulation of p53 protein: an independent prognostic indicator in colorectal adenocarcinomas. J Natl Cancer Inst 1994;86:681–7.

    Google Scholar 

  65. Grewal H, Guillem JG, Klimstra DS,et al. p53 nuclear overexpression may not be an independent prognostic marker in early colorectal cancer. Dis Colon Rectum 1995;38:1176–81.

    Google Scholar 

  66. Pricolo VE, Finkelstein SD, Hansen K,et al. Mutated p53 gene is an independent adverse predictor of survival in colon carcinoma. Arch Surg 1997;132:371–4.

    Google Scholar 

  67. Baretton GB, Diebold J, Christoforis G,et al. Apoptosis and immunohistochemical bcl-2 expression in colorectal adenomas and carcinomas. Aspects of carcinogenesis and prognostic significance. Cancer 1996;77:255–64.

    Google Scholar 

  68. Wiggenraad R, Tamminga R, Blok P,et al. The prognostic significance of p53 expression for survival and local control in rectal carcinoma treated with surgery and postoperative radiotherapy. Int J Radiat Oncol Biol Phys 1998;41:29–35.

    Google Scholar 

  69. Adell G, Sun XF, Stal O,et al. p53 status: an indicator for the effect of preoperative radiotherapy of rectal cancer. Radiother Oncol 1999;51:169–74.

    Google Scholar 

  70. Nehls O, Klump B, Holzmann K,et al. Influence of p53 status on prognosis in preoperatively irradiated rectal carcinoma. Cancer 1999;85:2541–8.

    Google Scholar 

  71. Hamelin R, Laurent-Puig P, Olschwang S,et al. Association of p53 mutations with short survival in colorectal cancer. Gastroenterology 1994;106:42–8.

    Google Scholar 

  72. Hayashi N, Ito I, Yanagisawa A,et al. Genetic diagnosis of lymph-node metastasis in colorectal cancer. Lancet 1995;345:1257–9.

    Google Scholar 

  73. Gelber RD, Goldhirsch A. Meta-analysis: the fashion of summing-up evidence. Part I. Rationale and conduct. Ann Oncol 1991;2:461–8.

    Google Scholar 

  74. Gelber RD, Coates AS, Goldhirsch A. Meta-analysis: the fashion of summing-up evidence. Part II: Interpretations and uses. Ann Oncol 1992:3:683–91.

    Google Scholar 

  75. Amundson SA, Myers TG, Fornace AJ Jr. Roles for p53 in growth arrest and apopotosis: putting on the brakes after genotoxic stress. Oncogene 1998;17:3287–99.

    Google Scholar 

  76. Kirsch DG, Kastan MB. Tumor-suppressor p53: implications for tumor development and prognosis. J Clin Oncol 1998;16:3158–68.

    Google Scholar 

  77. Wallace-Brodeur RR, Lowe SW. Clinical implications of p53 mutations. Cell Mol Life Sci 1999;55:64–75.

    Google Scholar 

  78. Hartmann A, Blaszyk H, McGovern RM,et al. p53 gene mutations inside and outside of exons 5–8: the patterns differ in breast and other cancers. Oncogene 1995;10:681–8.

    Google Scholar 

  79. Hermanek P. Impact of surgeon's technique on outcome after treatment of rectal carcinoma. Dis Colon Rectum 1999;42:559–62.

    Google Scholar 

  80. Petersen S, Freitag M, Hellmich G,et al. Anastomotic leakage: impact on local recurrence and survival in surgery of colorectal cancer. Int J Colorectal Dis 1998;13:160–3.

    Google Scholar 

  81. Runkel NS, Schlag P, Schwarz V,et al. Outcome after emergency surgery for cancer of the large intestine. Br J Surg 1991;78:183–8.

    Google Scholar 

  82. Bruch HP, Schwandner O, Schiedeck TH,et al. Actual standards and controversies on operative technique and lymph-node dissection in colorectal cancer. Langenbecks Arch Surg 1999;384:167–75.

    Google Scholar 

  83. Abulafi AM, Williams NS. Local recurrence of colorectal cancer: the problem, mechanisms, management and adjuvant therapy. Br J Surg 1994;81:7–19.

    Google Scholar 

  84. Viale G. Prognostic and predictive value of p53 aberrations in tumours of the gastrointestinal tract and pancreas. In: Klijn JG, ed. Prognostic and predictive value of p53. Vol. 1. Amsterdam: Elsevier Science, 1997; 131–41

    Google Scholar 

  85. Bristow RG, Benchimol S, Hill RP. The p53 gene as a modifier of intrinsic radiosensitivity: implications for radiotherapy. Radiother Oncol 1996;40:197–223.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

About this article

Cite this article

Petersen, S., Thames, H.D., Nieder, C. et al. The results of colorectal cancer treatment by p53 status. Dis Colon Rectum 44, 322–333 (2001). https://doi.org/10.1007/BF02234727

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02234727

Key words

Navigation