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The Combination of p53 Mutation and neu/erbB-2 Amplification Is Associated With Poor Survival in Node-Negative Breast Cancer

From the Samuel Lunenfeld Research Institute and Departments of Medicine, Pathology and Laboratory Medicine, and Surgery, Mount Sinai Hospital; Toronto-Sunnybrook and Women's Health Science Center; North York General Hospital; Toronto Hospital; Departments of Public Health Sciences, Laboratory Medicine and Pathobiology, Medicine and Anatomy, Medical Genetics, and Microbiology, University of Toronto, Toronto; and Credit Valley Hospital, Mississauga, Ontario, Canada

Address reprint requests to Irene L. Andrulis, PhD, Fred A. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Ave, Toronto, Ontario M5G 1X5, Canada; e-mail: Andrulis{at}mshri.on.ca

PURPOSE: Increases in neu/erbB-2 have been implicated in breast cancer prognosis, but do not predict all recurrences. On the basis of evidence that p53 mutation is involved in the development of human neoplasia, we examined the prognostic value of p53 alterations in combination with neu/erbB-2 amplification.

PATIENTS AND METHODS: A consecutive series of women were observed for recurrence and death (median follow-up of 85 months) and tumors from 543 individuals were analyzed for p53 mutation status and neu/erbB-2 amplification. Exons 4 through 10 of the p53 gene were analyzed by single-stranded conformational polymorphism and mutations were confirmed by DNA sequencing. The association of p53 mutation status and neu/erbB-2 amplification with risk of recurrence and death was examined in survival analyses with traditional and histologic markers as prognostic factors.

RESULTS: p53 mutations occurred in 24.5% of the axillary node-negative breast carcinomas. Mutations were more frequent in carcinomas with neu/erbB-2 amplification: 38.9% compared with only 20.9% in those without neu/erbB-2 amplification. We found elevated risks of disease recurrence and overall mortality in patients with both p53 mutation and neu/erbB-2 amplification in their tumor compared with patients with neither or only one of the alterations. This increase persisted with adjustment for other prognostic factors (relative risk, 2.32; P = .002 for recurrence; relative risk, 2.22; P = .004 for death).

CONCLUSION: Evaluation of tumors for p53 mutations may be beneficial to identify women at higher risk of disease recurrence and death when the tumor has neu/erbB-2 amplification, but in the absence of neu/erbB-2 amplification, the presence of p53 mutation may not provide additional independent prognostic information.

Supported by grants from the Canadian Breast Cancer Research Initiative and the Canadian Breast Cancer Foundation. S.B.B. is a Senior Investigator, Canadian Institutes for Health Research.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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