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.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
D000328:Adult; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018734:Genes, erbB-2; D006801:Humans; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D016729:Leuprolide / Q000008:administration & dosage / Q000494:pharmacology*; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D010053:Ovary / Q000187:drug effects / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000096:biosynthesis*; D016896:Treatment Outcome; D015854:Up-Regulation
D018931:Antineoplastic Agents, Hormonal; D003520:Cyclophosphamide; D005472:Fluorouracil; D016729:Leuprolide; D008727:Methotrexate; D018719:Erb-b2 Receptor Tyrosine Kinases