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p95HER-2 Predicts Worse Outcome in Patients with HER-2-Positive Breast Cancer

Authors' Affiliations:¹ Cell Biology Department, Faculty of Biological Sciences, University of Valencia, Burjasot; ² Hematology and Medical Oncology Service, Hospital Clínico Universitario, Valencia; ³ Laboratory of Oncology Research, Medical Oncology Service, Vall d'Hebron Hospital, Barcelona, Spain; and Departments of ⁴ Physiology and Pharmacology and ⁵ Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon

Requests for reprints: Gail M. Clinton, Department of Biochemistry and Molecular Biology, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97239. Phone: 503-494-2543; Fax: 503-494-8393; E-mail: clinton{at}ohsu.edu.

Background: The HER-2 receptor undergoes a proteolytic cleavage generating an NH₂-terminally truncated fragment, p95HER-2, that is membrane-associated and tyrosine-phosphorylated. We have reported that p95HER-2, but not the full-length receptor, p185HER-2, correlated with the extent of lymph node involvement in patients with breast cancer and its expression was significantly enhanced in nodal metastatic tissue. These facts suggested an important role for p95HER-2 either as a marker or cause of metastasis and poor outcome in breast cancer. In this work, we have studied the prognostic value of p95HER-2 in breast cancer.

Methods: Primary breast tumor tissues (n = 483) were from surgical resections conducted in hospitals in two different countries: the U.S. (n = 334) and Spain (n = 149). HER-2 protein forms, including p185HER-2 and p95HER-2, were examined in extracts of primary breast tumors by Western blot analysis. The levels of the two forms (high or low) were tested for association with other clinicopathologic factors and for correlation with disease-free survival.

Results: The median follow-up was 46 months. A high level of p95HER-2 in primary tumor tissue correlated with reduced 5-year disease-free survival (hazard ratio, 2.55; 95% confidence interval, 2.13-8.01; P < 0.0001). The median time for disease-free survival was 32 versus 139 months in patients with low levels of p95HER-2. In comparison, high levels of the full-length p185HER-2 did not significantly correlate with poor outcome (P > 0.1). Multivariate analysis revealed that high p95HER-2 was an independent predictor of disease-free survival (hazard ratio, 1.59; 95% confidence interval, 1.246-1.990; P = 0.0004).

Conclusions: p95HER-2 expression is an independent prognostic factor in breast cancer and defines a group of patients with HER-2-positive breast cancer with significantly worse outcome.

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