Comparison of Methods of Measuring HER-2 in Metastatic Breast Cancer Patients Treated With High-Dose Chemotherapy

Authors

Lyndsay N. Harris

Lyndsay N. Harris, Vlayka Liotcheva, Gloria Broadwater, Michael J. Ramirez, Peter Maimonis, Steven Anderson, Tajuana Everett, David Harpole, Mary Beth Moore, Donald A. Berry, David Rizzeri, James J. Vredenburgh, Rex C. Bentley

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PURPOSE: HER-2 is overexpressed in 20% to 30% of human breast cancer and is associated with poor outcome. Studies suggest an association between HER-2 overexpression and resistance to alkylating agents. To further evaluate this relationship, we assessed the interaction of HER-2, measured by different methods, and outcome after dose intensification with alkylating agents in metastatic breast cancer.

PATIENTS AND METHODS: From 1988 to 1995 at Duke University, 425 patients with metastatic breast cancer were enrolled in a study of high-dose alkylating agents (HDC) with autologous cellular support after doxorubicin-based therapy (AFM). HER-2 was measured in serum for shed extracellular domain (ECD) and in tissue by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH).

RESULTS: HER-2 ECD was positive in 29% (19 of 65) of patients pre-AFM and in 11.7% (34 of 290) pre-HDC. Higher pre-AFM and higher pre-HDC HER-2 ECD predicted worse overall survival (P = .045 and P = .0096, respectively). HER-2 overexpression by IHC and FISH showed no correlation with worse disease-free survival or overall survival. FISH and ECD were highly specific for IHC (97.3% and 97.7% respectively). However, ECD had a low sensitivity for IHC—only 22% of patients with HER-2 in the primary tumor shed ECD into the serum.

CONCLUSION: These data suggest that the method of measuring HER-2 is important in predicting clinical outcome. HER2 ECD may identify a poor prognosis subgroup of HER-2–positive tumors. Lack of association of HER2 by IHC/FISH with worse outcome suggests that therapy with AFM and/or HDC therapy may be able to overcome the effect of this prognostic factor or it may not be a prognostic factor in this setting.