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Prognostic interaction between expression of p53 and estrogen receptor in patients with node-negative breast cancer: results from IBCSG Trials VIII and IX

Alan S Coates123*, Ewan KA Millar1456, Sandra A O'Toole1789, Timothy J Molloy1, Giuseppe Viale10113, Aron Goldhirsch123, Meredith M Regan133, Richard D Gelber133, Zhuoxin Sun133, Monica Castiglione-Gertsch3, Barry Gusterson3, Elizabeth A Musgrove17 and Robert L Sutherland137

Author Affiliations

1 The Kinghorn Cancer Centre & Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia

2 School of Public Health, University of Sydney, New South Wales 2006, Australia

3 International Breast Cancer Study Group, Bern, Switzerland

4 Department of Anatomical Pathology, South Eastern Area Laboratory Service, St George Hospital, Kogarah, New South Wales 2217, Australia

5 School of Medicine and Health Sciences, University of Western Sydney, Campbelltown, New South Wales 2560, Australia

6 School of Medical Sciences, Faculty of Medicine, University of NSW, Kensington, New South Wales 2052, Australia

7 St Vincent's Clinical School, Faculty of Medicine, University of NSW, Kensington, New South Wales 2052, Australia

8 Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia

9 Central Clinical School, University of Sydney, New South Wales 2006, Australia

10 International Breast Cancer Study Group Central Pathology Office, Division of Pathology and Laboratory Medicine and European Institute of Oncology, Milan 20141, Italy

11 University of Milan, Milan 20122, Italy

12 Division of Medical Oncology, Department of Medicine, European Institute of Oncology, Milan 20141, Italy

13 IBCSG Statistical Center, Dana Farber Cancer Institute, Harvard Medical School, Harvard School of Public Health Boston, MA 02215, USA

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Breast Cancer Research 2012, 14:R143  doi:10.1186/bcr3348

Published: 5 November 2012



The prognostic significance of p53 protein expression in early breast cancer remains uncertain, with some but not all studies finding an association with poorer outcomes. Estrogen receptor (ER) expression is both a positive prognostic marker and predictive of response to endocrine therapies. The relationship between these biomarkers is unknown.


We constructed tissue microarrays (TMAs) from available pathological material from 1113 patients participating in two randomized clinical trials comparing endocrine therapy alone versus chemo-endocrine therapy in node-negative breast cancer. Expression of p53 defined as >10% positive nuclei was analyzed together with prior immunohistochemical assays of ER performed at central pathological review of whole tumor sections.


ER was present (i.e. >1% positive tumor cell nuclei) in 80.1% (880/1092). p53 expression was significantly more frequent when ER was absent, 125/212 (59%) than when ER was present, 171/880 (19%), p <0.0001. A significant qualitative interaction was observed such that p53 expression was associated with better disease-free survival (DFS) and overall survival (OS) among patients whose tumors did not express ER, but worse DFS and OS among patients whose tumors expressed ER. The interaction remained significant after allowance for pathologic variables, and treatment. Similar effects were seen when luminal and non-luminal intrinsic subtypes were compared.


Interpretation of the prognostic significance of p53 expression requires knowledge of concurrent expression of ER. The reason for the interaction between p53 and ER is unknown but may reflect qualitatively different p53 mutations underlying the p53 expression in tumors with or without ER expression.

Trial registration

Current Controlled Trials ACTRN12607000037404 (Trial VIII) and ACTRN12607000029493 (Trial IX).