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Open Access 01-08-2006 | Research article

p53 protein accumulation predicts resistance to endocrine therapy and decreased post-relapse survival in metastatic breast cancer

Authors: Hiroko Yamashita, Tatsuya Toyama, Mariko Nishio, Yoshiaki Ando, Maho Hamaguchi, Zhenhuan Zhang, Shunzo Kobayashi, Yoshitaka Fujii, Hirotaka Iwase

Published in: Breast Cancer Research | Issue 4/2006

Abstract

Introduction

Endocrine therapy is the most important treatment option for women with hormone receptor-positive breast cancer. The potential mechanisms for endocrine resistance involve estrogen receptor (ER)-coregulatory proteins and cross-talk between ER and other growth factor-signaling networks. However, the factors and pathways responsible for endocrine resistance are still poorly identified.

Materials and methods

The expression of HER2, p53, and Ki67 was examined by immunohistochemistry in primary breast tumour specimens from 73 metastatic breast cancer patients who received first-line treatment with endocrine therapy on relapse, and analysed to determine whether expression of these molecular markers affected the response to endocrine therapy.

Results

Of the 73 invasive ductal carcinomas, 12.3%, 21.9%, and 35.6% were positive for HER2 overexpression, p53 protein accumulation, and Ki67 expression, respectively. All patients received endocrine therapy as first-line treatment for metastatic breast cancer; 34 patients (46.6%) responded. Patients with primary breast tumours that had p53 protein accumulation and Ki67 expression showed significantly more resistance to endocrine therapy (P = 0.0049 and P = 0.024, respectively). There were also tendencies for HER2 overexpression to correlate with resistance to endocrine therapy, but this did not reach significance. p53 protein accumulation and HER2 overexpression significantly reduced post-relapse survival (P < 0.0001 and P = 0.001, respectively), and these factors were also statistically significant in a multivariate analysis.

Conclusion

These data suggest that p53 protein accumulation is helpful in selecting patients who may benefit from endocrine therapy and is a prognostic marker in hormone receptor-positive metastatic breast cancer.

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Johnston SR, Head J, Pancholi S, Detre S, Martin LA, Smith IE, Dowsett M: Integration of signal transduction inhibitors with endocrine therapy: an approach to overcoming hormone resistance in breast cancer. Clin Cancer Res. 2003, 9: 524S-532S.PubMed

Schiff R, Massarweh S, Shou J, Osborne CK: Breast cancer endocrine resistance: how growth factor signaling and estrogen receptor coregulators modulate response. Clin Cancer Res. 2003, 9: 447S-454S.PubMed

Elledge RM, Green S, Ciocca D, Pugh R, Allred DC, Clark GM, Hill J, Ravdin P, O'Sullivan J, Martino S, et al: HER-2 expression and response to tamoxifen in estrogen receptor-positive breast cancer: a Southwest Oncology Group Study. Clin Cancer Res. 1998, 4: 7-12.PubMed

Yamauchi H, Stearns V, Hayes DF: When is a tumor marker ready for prime time? A case study of c-erbB-2 as a predictive factor in breast cancer. J Clin Oncol. 2001, 19: 2334-2356.PubMed

Stal O, Borg A, Ferno M, Kallstrom AC, Malmstrom P, Nordenskjold B: ErbB2 status and the benefit from two or five years of adjuvant tamoxifen in postmenopausal early stage breast cancer. Ann Oncol. 2000, 11: 1545-1550. 10.1023/A:1008313310474.CrossRefPubMed

De Laurentiis M, Arpino G, Massarelli E, Ruggiero A, Carlomagno C, Ciardiello F, Tortora G, D'Agostino D, Caputo F, Cancello G, et al: A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer. Clin Cancer Res. 2005, 11: 4741-4748. 10.1158/1078-0432.CCR-04-2569.CrossRefPubMed

Fitzgibbons PL, Page DL, Weaver D, Thor AD, Allred DC, Clark GM, Ruby SG, O'Malley F, Simpson JF, Connolly JL, et al: Prognostic factors in breast cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med. 2000, 124: 966-978.PubMed

Hurlimann J, Chaubert P, Benhattar J: p53 Gene alterations and p53 protein accumulation in infiltrating ductal breast carcinomas: correlation between immunohistochemical and molecular biology techniques. Mod Pathol. 1994, 7: 423-428.PubMed

Kerns BJ, Jordan PA, Moore MB, Humphrey PA, Berchuck A, Kohler MF, Bast RC, Iglehart JD, Marks JR: p53 overexpression in formalin-fixed, paraffin-embedded tissue detected by immunohistochemistry. J Histochem Cytochem. 1992, 40: 1047-1051.CrossRefPubMed

10.

Elledge RM, Allred DC: The p53 tumor suppressor gene in breast cancer. Breast Cancer Res Treat. 1994, 32: 39-47. 10.1007/BF00666204.CrossRefPubMed

11.

Yamashita H, Nishio M, Toyama T, Sugiura H, Zhang Z, Kobayashi S, Iwase H: Coexistence of HER2 over-expression and p53 protein accumulation is a strong prognostic molecular marker in breast cancer. Breast Cancer Res. 2004, 6: R24-30. 10.1186/bcr738.CrossRefPubMed

12.

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. 1994, 266: 807-810.CrossRefPubMed

13.

Kandioler-Eckersberger D, Ludwig C, Rudas M, Kappel S, Janschek E, Wenzel C, Schlagbauer-Wadl H, Mittlbock M, Gnant M, Steger G, et al: TP53 mutation and p53 overexpression for prediction of response to neoadjuvant treatment in breast cancer patients. Clin Cancer Res. 2000, 6: 50-56.PubMed

14.

Thor AD, Berry DA, Budman DR, Muss HB, Kute T, Henderson IC, Barcos M, Cirrincione C, Edgerton S, Allred C, et al: erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst. 1998, 90: 1346-1360. 10.1093/jnci/90.18.1346.CrossRefPubMed

15.

Geisler S, Lonning PE, Aas T, Johnsen H, Fluge O, Haugen DF, Lillehaug JR, Akslen LA, Borresen-Dale AL: Influence of TP53 gene alterations and c-erbB-2 expression on the response to treatment with doxorubicin in locally advanced breast cancer. Cancer Res. 2001, 61: 2505-2512.PubMed

16.

Aas T, Borresen AL, Geisler S, Smith-Sorensen B, Johnsen H, Varhaug JE, Akslen LA, Lonning PE: Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nat Med. 1996, 2: 811-814. 10.1038/nm0796-811.CrossRefPubMed

17.

Rahko E, Blanco G, Soini Y, Bloigu R, Jukkola A: A mutant TP53 gene status is associated with a poor prognosis and anthracycline-resistance in breast cancer patients. Eur J Cancer. 2003, 39: 447-453. 10.1016/S0959-8049(02)00499-9.CrossRefPubMed

18.

Clahsen PC, van de Velde CJ, Duval C, Pallud C, Mandard AM, Delobelle-Deroide A, van den Broek L, Sahmoud TM, van de Vijver MJ: p53 protein accumulation and response to adjuvant chemotherapy in premenopausal women with node-negative early breast cancer. J Clin Oncol. 1998, 16: 470-479.PubMed

19.

Bertheau P, Plassa F, Espie M, Turpin E, de Roquancourt A, Marty M, Lerebours F, Beuzard Y, Janin A, de The H: Effect of mutated TP53 on response of advanced breast cancers to high-dose chemotherapy. Lancet. 2002, 360: 852-854. 10.1016/S0140-6736(02)09969-5.CrossRefPubMed

20.

Askmalm MS, Carstensen J, Nordenskjold B, Olsson B, Rutqvist LE, Skoog L, Stal O: Mutation and accumulation of p53 related to results of adjuvant therapy of postmenopausal breast cancer patients. Acta Oncol. 2004, 43: 235-244. 10.1080/02841860410029474.CrossRefPubMed

21.

Andersson J, Larsson L, Klaar S, Holmberg L, Nilsson J, Inganas M, Carlsson G, Ohd J, Rudenstam CM, Gustavsson B, et al: Worse survival for TP53 (p53)-mutated breast cancer patients receiving adjuvant CMF. Ann Oncol. 2005, 16: 743-748. 10.1093/annonc/mdi150.CrossRefPubMed

22.

Geisler S, Borresen-Dale AL, Johnsen H, Aas T, Geisler J, Akslen LA, Anker G, Lonning PE: TP53 gene mutations predict the response to neoadjuvant treatment with 5-fluorouracil and mitomycin in locally advanced breast cancer. Clin Cancer Res. 2003, 9: 5582-5588.PubMed

23.

Knoop AS, Bentzen SM, Nielsen MM, Rasmussen BB, Rose C: Value of epidermal growth factor receptor, HER2, p53, and steroid receptors in predicting the efficacy of tamoxifen in high-risk postmenopausal breast cancer patients. J Clin Oncol. 2001, 19: 3376-3384.PubMed

24.

Berry DA, Muss HB, Thor AD, Dressler L, Liu ET, Broadwater G, Budman DR, Henderson IC, Barcos M, Hayes D, et al: HER-2/neu and p53 expression versus tamoxifen resistance in estrogen receptor-positive, node-positive breast cancer. J Clin Oncol. 2000, 18: 3471-3479.PubMed

25.

Elledge RM, Green S, Howes L, Clark GM, Berardo M, Allred DC, Pugh R, Ciocca D, Ravdin P, O'Sullivan J, et al: bcl-2, p53, and response to tamoxifen in estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group study. J Clin Oncol. 1997, 15: 1916-1922.PubMed

26.

Archer SG, Eliopoulos A, Spandidos D, Barnes D, Ellis IO, Blamey RW, Nicholson RI, Robertson JF: Expression of ras p21, p53 and c-erbB-2 in advanced breast cancer and response to first line hormonal therapy. Br J Cancer. 1995, 72: 1259-1266.CrossRefPubMedPubMedCentral

27.

Berns EM, Klijn JG, van Putten WL, de Witte HH, Look MP, Meijer-van Gelder ME, Willman K, Portengen H, Benraad TJ, Foekens JA: p53 protein accumulation predicts poor response to tamoxifen therapy of patients with recurrent breast cancer. J Clin Oncol. 1998, 16: 121-127.PubMed

28.

Yamashita H, Nishio M, Kobayashi S, Ando Y, Sugiura H, Zhang Z, Hamaguchi M, Mita K, Fujii Y, Iwase H: Phosphorylation of estrogen receptor alpha serine 167 is predictive of response to endocrine therapy and increases postrelapse survival in metastatic breast cancer. Breast Cancer Res. 2005, 7: R753-764. 10.1186/bcr1285.CrossRefPubMedPubMedCentral

29.

Allred DC, Harvey JM, Berardo M, Clark GM: Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol. 1998, 11: 155-168.PubMed

Title: p53 protein accumulation predicts resistance to endocrine therapy and decreased post-relapse survival in metastatic breast cancer
Authors: Hiroko Yamashita
Tatsuya Toyama
Mariko Nishio
Yoshiaki Ando
Maho Hamaguchi
Zhenhuan Zhang
Shunzo Kobayashi
Yoshitaka Fujii
Hirotaka Iwase
Publication date: 01-08-2006
Publisher: BioMed Central
Published in: Breast Cancer Research / Issue 4/2006
Electronic ISSN: 1465-542X
DOI: https://doi.org/10.1186/bcr1536

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