MDM2 amplification is an independent prognostic feature of node-negative, estrogen receptor-positive early-stage breast cancer

Article type: Research Article

Authors: Choschzick, Matthias^{a; *} | Heilenkötter, Uwe^b | Lebeau, Annette^a | Jaenicke, Fritz^c | Terracciano, Luigi^d | Bokemeyer, Carsten^e | Sauter, Guido^a | Simon, Ronald^a

Affiliations: [a] Institute of Pathology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany | [b] Department of Gynecology, Hospital Itzehoe, Itzehoe, Germany | [c] Department of Gynecology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany | [d] Institute of Pathology, University Hospital Basel, Basel, Switzerland | [e] Department of Oncology and Hematology, Bone Marrow Transplantation with Section Pneumology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

Correspondence: [*] Corresponding author: M. Choschzick, MD, Department of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. E-mail: mchoschz@uke.uni-hamburg.de.

Abstract: Background:MDM2 is overexpressed and amplified in a number of malignant tumors including breast carcinomas. Cell culture experiments showed a close connection between MDM2 expression and estrogen receptor status in breast cancer cell lines. Only little is known about the role of MDM2 amplifications in early-stage breast carcinomas with positive estrogen receptor status. Methods:661 highly characterized node-negative breast carcinomas with positive estrogen receptor status (ER+ early-stage breast carcinomas) were analyzed on a tissue microarray. Molecular (HER2, CCND1, MDM2, MYC, 8q21), as well as estrogen receptor expression data used in this analysis, was available from previously published studies. The primary endpoint of overall survival analysis was death after 10 years. Results:Gene amplifications were found in 194/661 (29%) ER+ early-stage breast carcinomas and 40 (7%) exhibited amplification of the MDM2 oncogene. MDM2 amplifications were significantly related to advanced tumor stage (p < 0.05) and high Ki67 expression levels (p < 0.05). There was no relationship between MDM2 copy number changes and tumor grade, estrogen receptor expression level and co-amplification of HER2, CCND1 and 8q. Tumor stage (pT1 vs pT2-pT4; HR 1.51; 95% CI 1.02–2.24; p=0.042), grading (G1-G2 vs G3; HR 2.27; 95% CI 1.51–3.43; p < 0.001), high Ki67 proliferation index (HR 2.03; 95% CI 1.31–3.15; p=0.0015), HER2 (HR 2.6; 95% CI 1.51 to 4.5; p < 0.001) and MDM2 amplification (HR 2.05, 95% CI 1.06–3.97, p =0.033) were statistically adverse prognostic risk factors in univariate Cox regression analysis. Patient age, estrogen receptor expression level, CCND1 and 8q amplification were not associated to overall survival. Multivariate Cox regression analysis of survival data included tumor stage, grading, Ki67 labeling index, HER2 and MDM2 amplification status. In this statistical model, only MDM2 amplification was an independent factor for overall patient survival in ER+ early- stage breast carcinomas (HR 2.64; 95% CI 1.32 to 5.28; p=0.006). Conclusion:The MDM2 oncogene is amplified in a substantial proportion of ER+ early-stage breast carcinomas and an independent parameter for poor patient outcome in this subgroup. The prognostic effect of MDM2 is closely connected to estrogen receptor expression of breast carcinomas.

Keywords: MDM2, amplification, breast cancer, prognosis

DOI: 10.3233/DMA-2011-0806

Journal: Cancer Biomarkers, vol. 8, no. 2, pp. 53-60, 2011