, Volume 80, Issue 3, pp 245-255

Upregulation of HER-2/neu by Ovarian Ablation: Results of a Randomized Trial Comparing Leuprorelin to CMF as Adjuvant Therapy in Node-positive Breast Cancer Patients

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Abstract

Purpose. HER-2/neu oncogene expression is modulated by an estrogen-sensitive binding site in the HER-2/neu promoter. Utilizing the circulating antigen of HER-2/neu in serum (sHER-2/neu) as a surrogate marker we investigated whether ovarian ablation by adjuvant therapy leads to an upregulation of HER-2/neu in breast cancer patients.

Patients and methods. The analysis was done on sera from premenopausal, node-positive, hormone-receptor positive patients randomized in a multi-center trial. The study was designed with patients receiving either 11.25 mg of leuprorelin s.c. every 3 months over 2 years or CMF chemotherapy for 6 cycles. Sera, available from 80 patients in the leuprorelin arm and from 53 patients in the CMF arm, were collected at 0, 3, 6, 12, 18, 24 and 30 months. sHER-2/neu was measured using a standardized ELISA assay that has an upper limit of normal of 15 ng/ml. sHER-2/neu results were correlated to the levels of LH, FSH and estradiol as indicators of ovarian ablation and to the tumor marker, CA 27.29.

Results. During estradiol deprivation, sHER-2/neu levels increased significantly by more than one third from 8.1 ng/ml to 11.0 ng/ml (p < 0.0001) in both treatment arms. The most pronounced relative increase occurred within the first 3 months (p < 0.001). In only 2.7% (16/587) of sHER-2/neu measurements, the sHER-2/neu results were elevated above 15 ng/ml, confirming the upper limit of normal for breast cancer patients irrespective of their menopausal status. At month 30, the sHER-2/neu level started to decrease in the leuprorelin arm, reflecting reversible castration and estradiol reconstitution. Conversely, CA 27.29 levels did not show a trend over time, indicating that sHER-2/neu changes were of a regulatory nature and were not merely a reflection of increasing residual disease.

Conclusion. Our study demonstrates the upregulation of HER-2/neu during ovarian ablation. These results are consistent with data showing that the percentage of HER-2/neu positive tumors, evaluated by standardized immunohistochemistry on the primary tumor, is significantly increased during the follicular phase of the menstrual cycle (Balsari et al., Am J Pathol 155: 1543–1547, 1999). Regulatory processes at the HER-2/neu gene should be considered when prescribing specific therapy for breast cancer.