Breast Cancer Research and Treatment

, Volume 47, Issue 1, pp 47–55

Is p53 a protein that predicts the response to chemotherapy in node negative breast cancer?

  • Armelle Degeorges
  • Anne de Roquancourt
  • Jean Marc Extra
  • Marc Espie
  • Edwige Bourstyn
  • Patricia de Cremoux
  • Thierry Soussi
  • Michel Marty
Article

Abstract

The role of p53 in modulating apoptosis has suggested that it may affect efficacy of anti cancer agents. For this reason, we have evaluated p53 alterations in 282 consecutive patients with infiltrating node-negative breast cancer who underwent primary surgery and were randomized either to CMF (Cyclophosphamide 400 mg/m2, Fluorouracil 400 mg/m2, and Methotrexate 40 mg/m2) or control arm (no adjuvant therapy) from 1980 to 1989. p53 alterations were analyzed by immunohistochemistry using DO7 MoAb, revealed by immunoperoxidase technique, and quantitated in term of percentage of positive cells. We observed a positive staining in 24% of the tumors. Among them, 10% had a positive staining in more than 75% of the cells. There was a highly significant association between the proportion of positive cells and histologic grade of the infiltrating ductal carcinomas (p > 0.004). However, there was no association with age, tumor size, hormone receptor content, or vascular embolism. There was a trend but no significant relationship between positive staining and overall survival either in each arm of the trial or in the overall population. Interestingly, we observed a higher relative risk of local relapse after conservative therapy in the boosted area in the group of mutated p53 (RR = 4.41; p > 0.0005). We conclude that, in this node-negative breast tumor population, alteration of p53 cannot predict the response to the chemotherapy. However, it may represent a useful marker of risk of local relapse and of radio resistance.

breast carcinoma adjuvant chemotherapy immunohistochemistry p53 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Mansour G, Gray R, Shatila A, Osborne C, Tormey D, Gilchrist K, Cooper M, Falkson G: Efficacy of adjuvant chemotherapy in high-risk node-negative breast cancer: an inter group study. N Engl J Med 320: 485–478, 1989Google Scholar
  2. 2.
    Fisher B, Redmond C, Dimitrov N, Bowman D, Legaut-Poisson S, Wickerham L, Wolmark N, Fisher E, Margolese R, Sutherland C, Glass A, Foster R, Caplan R et al.: A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-negative tumors. N Engl J Med 320: 473–478, 1989Google Scholar
  3. 3.
    McGuire W, Clark G: Prognostic factors and treatment decisions in axillary-node-negative breast cancer. N Engl J Med 326: 1756–1761, 1992Google Scholar
  4. 4.
    Chang J, Kim DH, Lee SW, Choi KY, Sung YC: Transactivation ability of p53 transcriptional activation domain is directly related to the binding affinity to TATA-binding protein. J Biol Chem 270: 25014–25019, 1995Google Scholar
  5. 5.
    Soussi T, Legros Y, Lubin R, Ory K, Schlichtholz B: Multifactorial analysis of p53 alteration in human cancer - a review. Int J Cancer 57: 1–9, 1994Google Scholar
  6. 6.
    Lane DP, Benchimol S: p53: oncogene or anti-oncogene? Gen Devel 4: 1–8, 1990Google Scholar
  7. 7.
    Lane DP: On the expression of the p53 protein in human cancer. Mol Biol Rep 19: 23–29, 1994Google Scholar
  8. 8.
    Frebourg T, Friend H: The importance of p53 gene alterations in human cancer - is there more than circumstantial evidence? J Natl Cancer Inst 85: 1554–1557, 1993Google Scholar
  9. 9.
    Lowe SW, Ruley HE, Jacks T, Housman DE: p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74: 957–967, 1993Google Scholar
  10. 10.
    Bloom H, Richardson W: Histological grading and prognosis in breast cancer. Br J Cancer 11: 359–377, 1957Google Scholar
  11. 11.
    Jacobs T, Priolleau J, Stillman I, Schnitt S: Loss of tumor marker immunostaining intensity on stored paraffin slides of breast cancer. 88: 1054–1059, 1996Google Scholar
  12. 12.
    Martinazzi M: Expression of p53 oncoprotein in different histological types of breast carcinoma. Am J Pathol 144: 205, 1994Google Scholar
  13. 13.
    Barbareschi M, Leonardi E, Mauri FA, Serio G, Dalla Palma P: p53 and c-erbB-2 protein expression in breast carcinomas- an immunohistochemical study including correlations with receptor status, proliferation markers, and clinical stage in human breast cancer. Am J Clin Pathol 98: 408–418, 1992Google Scholar
  14. 14.
    Visscher DW, Sarkar FH, Wykes S, Kothari K, Macoska J, Crissman J: Clinicopathologic significance of p53 immunostaining in adenocarcinoma of the breast. Arch Pathol Lab Med 117: 973–976, 1993Google Scholar
  15. 15.
    Cattoretti G, Rilke F, Anderola S, Damato L, Delia D: p53 expression in breast cancer. Int J Cancer 41: 178–183, 1988Google Scholar
  16. 16.
    Horne GM, Anderson JJ, Tiniakos DG, McIntosh GG, Thomas MD, Angus B, Henry JA, Lennard TWJ, Horne CHW: p53 protein as a prognostic indicator in breast carcinoma: a comparison of four antibodies for immunohistochemistry. Br J Cancer 73: 29–35, 1996Google Scholar
  17. 17.
    Isola J, Visakorpi T, Holli K, Kallioniemi OP: Association of overexpression of tumor suppressor protein p53 with rapid cell proliferation and poor prognosis in node-negative breast cancer patients. J Natl Cancer Inst 84: 1109–1114, 1992Google Scholar
  18. 18.
    Silvestrini R, Benini E, Daidone MG, Veneroni S, Boracchi P, Cappelletti V, DiFronzo G, Veronesi U: p53 as an independent prognostic marker in lymph node-negative breast cancer patients. J Natl Cancer Inst 85: 965–970, 1993Google Scholar
  19. 19.
    Barnes DM, Dublin EA, Fisher CJ, Levison DA, Millis RR: Immunohistochemical detection of p53 protein in mammary carcinoma: an important new independent indicator of prognosis? Hum Pathol 24: 469–476, 1993Google Scholar
  20. 20.
    MacGrogan G, Bonichon F, Demascarel I, Trojani M, Durand M, Avril A, Coindre JM: Prognostic value of p53 in breast invasive ductal carcinoma: an immunohistochemical study on 942 cases. Breast Cancer Res Treat 36: 71–81, 1995Google Scholar
  21. 21.
    Ostrowski JL, Sawan A, Henry L, Wright C, Henry JA, Hennessy C, Lennard TJW, Angus B, Horne CHW: p53 expression in human breast cancer related to survival and prognostic factors - an immunohistochemical study. J Pathol 164: 75–81, 1991Google Scholar
  22. 22.
    Lipponen P, Ji H, Aaltomaa S, Syrjanen S, Syrjanen K: p53 protein expression in breast cancer as related to histopathological characteristics and prognosis. Int J Cancer 55: 51–56, 1993Google Scholar
  23. 23.
    Pietilainen T, Lipponen P, Aaltomaa S, Eskelinen M, Kosma VM, Syrjanen K: Expression of p53 protein has no independent prognostic value in breast cancer. J Pathol 177: 225–232, 1995Google Scholar
  24. 24.
    Rosen PP, Lesser ML, Arroyo CD, Cranor M, Borgen P, Norton L: p53 in node-negative breast carcinoma: an immunohistochemical study of epidemiologic risk factors, histologic features, and prognosis. J Clin Oncol 13: 821–830, 1995Google Scholar
  25. 25.
    Thor AD, Yandell DW: Prognostic significance of p53 overexpression in node-negative breast carcinoma - preliminary studies support cautious optimism. J Natl Cancer Inst 85: 176–177, 1993Google Scholar
  26. 26.
    Barbareschi M: Prognostic value of the immunohistochemical expression of p53 in breast carcinoma - a review of the literature involving over 9,000 patients. 4: 106–116, 1996Google Scholar
  27. 27.
    Fan SJ, El-Deiry WS, Bae I, Freeman J, Jondle D, Bhatia K, Fornace AJ, Magrath I, Kohn KW, O'Connor PM: p53 gene mutations are associated with decreased sensitivity of human lymphoma cells to DNA damaging agents. Cancer Res 54: 5824–5830, 1994Google Scholar
  28. 28.
    Lowe SW, Bodis S, McClatchey A, Remington L, Ruley HE, Fisher DE, Housman DE, Jacks T: p53 status and the efficacy of cancer therapy in vivo. Science 266: 807–810, 1994Google Scholar
  29. 29.
    Tsang NM, Nagasawa H, Li CY, Little JB: Abrogation of p53 function by transfection of HPV16 E6 gene enhances the resistance of human diploid fibroblasts to ionizing radiation. Oncogene 10: 2403–2408, 1995Google Scholar
  30. 30.
    Delia D, Mitzutani S, Lamorte G, Goi K, Iwata S, Pierotti M: p53 activity and chemotherapy. Nat Med 2: 724–725, 1996Google Scholar
  31. 31.
    Wahl AF, Donaldson KL, Fairchild C, Lee FYF, Foster SA, Demers GW, Galloway DA: Loss of normal p53 function confers sensitization to taxol by increasing G2/M arrest and apoptosis. Nat Med 2: 72–79, 1996Google Scholar
  32. 32.
    Hawkins D, Demers G, Galloway D: Inactivation of p53 enhances sensitivity to multiple chemotherapeutic agents. Cancer Res 56: 892–898, 1996Google Scholar
  33. 33.
    Wu GS, El-Deiry WS: P53 and chemosensitivity. Nat Med 2: 255–256, 1996Google Scholar
  34. 34.
    Aas T, Borensen A, Geisler S, Varhaug J, Akslen L, Lonning P: Specific p53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nat Med 2: 811–814, 1996Google Scholar
  35. 35.
    Stal O, Askmalm MS, Wingren S, Rutqvist LE, Skoog L, Ferraud L, Sullivan S, Carstensen J, Nordenskjold B: p53 expression and the result of adjuvant therapy of breast cancer. Acta Oncol 34: 767–770, 1995Google Scholar
  36. 36.
    Jansson T, Inganas M, Sjogren S, Norberg T, Lindgren A, Holmberg L, Bergh J: p53 status predicts survival in breast cancer patients treated with or without postoperative radiotherapy: a novel hypothesis based on clinical findings. J Clin Oncol 13: 2745–2751, 1995Google Scholar
  37. 37.
    O'Connor DJ, Lam EWF, Griffin S, Zhong S, Leighton LC, Burbidge SA, Lu X: Physical and functional interactions between p53 and cell cycle co-operating transcription factors, E2F1 and DP1.EMBO J 14: 6184–6192, 1995Google Scholar
  38. 38.
    Bergh J, Norberg T, Sjogren S, Lindgren A, Holmberg L: Complete sequencing of the p53 gene provides prognostic information in breast cancer patients, particularly in relation to adjuvant systemic therapy and radiotherapy. Nat Med 1: 1029–1034, 1995Google Scholar

Copyright information

© Kluwer Academic Publishers 1998

Authors and Affiliations

  • Armelle Degeorges
  • Anne de Roquancourt
  • Jean Marc Extra
  • Marc Espie
  • Edwige Bourstyn
  • Patricia de Cremoux
  • Thierry Soussi
  • Michel Marty

There are no affiliations available

Personalised recommendations