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.
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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.
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.
Nathanson SD. Is there a role for clinical prognostic factors in staging patients with colorectal cancer? Semin Surg Oncol 1994;10:176–82.
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.
Cunningham C, Dunlop MG. Molecular genetic basis of colorectal cancer susceptibility. Br J Surg 1996;83:321–9.
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
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.
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.
Bosari S, Viale G. The clinical significance of p53 aberrations in human tumours. Virchows Arch 1995;427:229–41.
Tomlinson I, Ilyas M, Novelli M. Molecular genetics of colon cancer. Cancer Metastasis Rev 1997;16:67–79.
Muto T, Watanabe T. Colorectal carcinoma: recent advances in its biology and treatment. J Cancer Res Clin Oncol 1999;125:245–53.
Oren M, Rotter V. Introduction: p53—the first twenty years. Cell Mol Life Sci 1999;55:9–11.
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.
Demets DL. Methods for combining randomized clinical trials: strengths and limitations. Stat Med 1987;6:341–50.
Sacks HS, Berrier J, Reitman D,et al. Meta-analyses of randomized controlled trials. N Engl J Med 1987;316:450–5.
Breslow NE, Day NE. Statistical methods in cancer research. Lyon: International Agency for Research on Cancer, 1980.
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.
Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719–48.
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.
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
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.
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.
Goh HS, Yao J, Smith DR. p53 point mutation and survival in colorectal cancer patients. Cancer Res 1995;55:5217–21.
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.
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.
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.
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.
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.
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.
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.
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.
Kressner U, Inganas M, Byding S,et al. Prognostic value of p53 genetic changes in colorectal cancer. J Clin Oncol 1999;17:593–9.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Tomoda H, Kakeji Y. Immunohistochemical analysis of p53 in colorectal cancer regarding clinicopathological correlation and prognostic significance. J Surg Oncol 1995;58:125–8.
Sun XF, Carstensen JM, Nordenskjold B. Expression of c-erbB-2 and p53 in colorectal adenocarcinoma. Anal Cell Pathol 1995;8:203–11.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Smith DR, Ji CY, Goh HS. Prognostic significance of p53 overexpression and mutation in colorectal adenocarcinomas. Br J Cancer 1996;74:216–23.
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.
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.
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.
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.
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.
Hardingham JE, Butler WJ, Roder D,et al. Somatic mutations, acetylator status, and prognosis in colorectal cancer. Gut 1998;42:669–72.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Nehls O, Klump B, Holzmann K,et al. Influence of p53 status on prognosis in preoperatively irradiated rectal carcinoma. Cancer 1999;85:2541–8.
Hamelin R, Laurent-Puig P, Olschwang S,et al. Association of p53 mutations with short survival in colorectal cancer. Gastroenterology 1994;106:42–8.
Hayashi N, Ito I, Yanagisawa A,et al. Genetic diagnosis of lymph-node metastasis in colorectal cancer. Lancet 1995;345:1257–9.
Gelber RD, Goldhirsch A. Meta-analysis: the fashion of summing-up evidence. Part I. Rationale and conduct. Ann Oncol 1991;2:461–8.
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.
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.
Kirsch DG, Kastan MB. Tumor-suppressor p53: implications for tumor development and prognosis. J Clin Oncol 1998;16:3158–68.
Wallace-Brodeur RR, Lowe SW. Clinical implications of p53 mutations. Cell Mol Life Sci 1999;55:64–75.
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.
Hermanek P. Impact of surgeon's technique on outcome after treatment of rectal carcinoma. Dis Colon Rectum 1999;42:559–62.
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.
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.
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.
Abulafi AM, Williams NS. Local recurrence of colorectal cancer: the problem, mechanisms, management and adjuvant therapy. Br J Surg 1994;81:7–19.
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
Bristow RG, Benchimol S, Hill RP. The p53 gene as a modifier of intrinsic radiosensitivity: implications for radiotherapy. Radiother Oncol 1996;40:197–223.
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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
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DOI: https://doi.org/10.1007/BF02234727