0. 00 0. 25 0. 50 0. 75 1. 00 P ro b ab ili ty 0 1 2 3 4 5 Time (years) 0. 00 0. 25 0. 50 0. 75 1. 00 P ro b ab ili ty 0 1 2 3 4 5 Time (years) p53 < 10% p53 >/= 10% p53 < 10% p53 >/= 10%
p53 expression is a significant predictor of response and prognosis
in stage II-III breast cancer patients treated with neoadjuvant chemotherapy
Methods
Methods
Introduction and Aims
Introduction and Aims
Results
Results
• The p53 protein is a transcriptional regulator involved in the cellular response to DNA damage.
• Mutation in p53 genes is frequently observed in breast cancer, and has been studied as a marker of tumor cell sensitivity to
cytotoxic agents.
• Aim of this analysis is to identify thel predictive and/or prognostic role of p53 in a series of patients with stage II-III breast cancer
treated with anthracycline +/- taxane based preoperative chemotherapy
• The expression of p53 was evaluated on the diagnostic core biopsy, by using IHC (D07Ab). The presence or absence of
immunoreaction (diffuse or focal), and percentage of immunostained cells have been recorded. The cut off for considering p53
overexpression was 10%.
• Pathologic complete response (pCR) was defined as complete absence of invasive tumor in both breast and axillary nodes.
•The association between biomarkers expression and pCR was assessed by logistic regression; survival curves were estimated with
the Kaplan-Meier method and the log rank test was used to test for differences between groups.
IMPAKT Breast Cancer Conference, Brussels, 7-9 May 2009 Supported in part by a Ministry of Health Research grant (Progetti Integrati Oncologia # 04/07)
Summary and Conclusions
Summary and Conclusions
Valentina Guarneri, Federico Piacentini, Elena Barbieri, Guido Ficarra, Roberto D’Amico, PierFranco Conte
Department of Oncology, Hematology and Respiratory Diseases, and Department of Pathology, University Hospital, Modena, Italy
OR for pCR 95%CI p value p53 < 10%
p53 10%
ref
10.03 1.2;83.66 0.0077 Hormone receptors positive, HER2 negative
Triple negative HER2 positive ref 10.8 12.41 1.07;108.381.33;115.5 0.0430.027 Grading 1,2
Grading 3 7.258ref 1.08; not est. 0.0389
EGFR <1% EGFR >/= 1% 1.37ref 0.26;7.09 0.6933 Ki67<15% Ki67 15% ref 2.14 0.25;18.04 0.4443
5yr DFS (95% CI) p value 5yr OS (95% CI) p value
All patients 71% (61;79) - 86% (77;92)
-p53 < 10% p53 10%
82%(71;90)
56% (40;70) 0.0043 99% (91;99)69% (51;82) 0.0002 Hormone receptors positive, HER2 negative
Triple negative HER2 positive 78% (66;86) 67% (45;82) 62% (38;80) 0.3380.314 90% (77;96) 79% (57;91) 81% (60;92) 0.0400.040 Ki67<15% Ki67>/= 15% 84% (66;93)65% (52;76) 0.0449 91% (69;98)85% (74;91) 0.1438 Nodal negativity Nodal positivity 87% (73;94) 64% (52;74) 0.0145 93% (79;98) 84% (72;91) 0.3234
Prediction of pathologic complete response
Patients and tumor characteristics
•
p53expression was significantly associated with triple negative tumor phenotype, high proliferation, and poor differentiation
• The probability of pCR was significantly higher in case of p53positive tumors, and in case of triple negative and HER2 positive molecular subtypes
• In the univariate analysis, the expression of p53 was a predictor of a worse DFS, together with high proliferation and lymph-nodal involvement after preoperative chemotherapy; patients with p53 positivity have also a worse OS
• When grouping patients according to molecular subtypes, the probability of relapse was not significantly different among the three groups; however, both triple negative and HER2 positive subgroups have a significantly worse OS as compared to hormone receptor
positive-HER2 negative group
• In the multivariate analysis, as adjusted for molecular subtypes and proliferation, both p53 expression and nodal status after preoperative chemotherapy were significant predictors of DFS and OS
Patients 154
Median Age at Diagnosis (range) 51 (28-76) Clinical Stage IIA 38.5% IIB 40.5% III 21% Molecular classification Triple negative 18.4%
Hormone receptors positive, HER2 negative 59.9%
HER2 positive 21.7% Nuclear Grade 1 1.9% 2 33.8% 3 58.4% Not evaluable 5.8% P53 expression (IHC) Patients with p53>/= 10% 43.5% Patients with p53<10% 56.5%
Mean p53 expression (range) 24.5% (0-99) Proliferation (Ki-67)
Patients with low proliferation (<15%) 23% Patients with high proliferation (>/= 15%) 77% Preoperative Chemotherapy
Anthracycline-taxane combinations
Anthracycline containing regimens 71%
Other 26%
Type of Surgery
Breast Conserving Surgery
Mastectomy 44.2%
Pathologic complete response
Yes 5.2%
No 94.8%
Association between p53 expression and tumor biology
OR for p53 expression 95%CI p value Hormone receptors positive, HER2 negative
Triple negative HER2 positive ref 2.45 2.21 1.03;5.820.98;4.96 0.0410.054 Grading 1,2 Grading 3 2.67ref 1.31;5.41 0.006 EGFR <1% EGFR >/= 1% 1.01ref 0.51;2.01 0.967 Ki67<15% Ki67 15% ref 2.79 1.20;6.46 0.017
5-year Disease Free and Overall Survival (univariate analysis)
Log rank test p=0.0043
Kaplan Meier plot of Disease Free and Overall Survival by p53 expression
Log rank test p=0.0002
Disease free Survival Overall Survival
HR 95%CI p value HR 95%CI p value
p53 < 10% p53 10% ref 2.29 1.17;4.5 0.015 ref 7.74 2.13;28.0 0.002 Hormone receptors positive, HER2 negative
Triple negative HER2 positive ref 1.32 1.80 0.78;4.160.55;3.2 0.5300.164 ref 2.65 4.23 1.22;14.660.71;9.89 0.1450.023 Ki67<15% Ki67 15% ref 1.76 0.71;4.3 0.217 1.14ref 0.29;4.50 0.841 Nodal negativity
Nodal positivity 3.63ref 1.54;8.58 0.003 3.64ref 1.05;12.54 0.041
