Prospective Randomized Trial Concerning Hyper- and Normoprolactinemia and the Use of Bromoergocryptine in Patients with Metastatic Breast Cancer

Abstract

This prospective trial was designed to help in selecting therapy for patients with elevated and normal plasma prolactin. Ninety-two patients entered this trial, of whom 86 were evaluable for final analysis. Hyperprolactinemic patients (n = 31) were randomized to receive VAC/FMC chemotherapy with or without bromoergocryptine. Normoprolactinemic patients with ‘low risk’ metastatic disease (disease-free interval > 30 months, ER/PR positive or unknown) were treated with medroxyprogesterone acetate or VAC/FMC chemotherapy. Normoprolactinemic ‘high risk’ patients (n = 42) (disease-free interval < 30 months, ER/PR negative) received VAC/ FMC chemotherapy with or without medroxyprogesterone acetate (MAP). The results show that bromoergocryptine does not improve response rate, duration of response and survival. Median survival of patients with elevated basal plasma prolactin ( > 15 ng/ml) is reduced to 9 months compared to patients with normal basal plasma prolactin (17 months, log-rank p = 0.005). Unexpectedly, TRH stimulation proved inappropriate to separate normo- and hyperprolactinemic patients in terms of survival. Normoprolactinemic ‘low risks’ (tamoxi-fen failures) were observed to qualify for further hormone therapy (median survival 21+ months). Normoprolactinemic ‘high risks’ showed median survival of about 12 months with no apparent benefit . for those receiving MAP, additionally. The results suggest that basal hyperprolactinemia, disease free interval, ER/PR receptor status, and liver metastasis are important prognostic variables. Endocrine and cytotoxic chemotherapy should be selected according to these risk factors.

Development and Potential Clinical Uses of Human Prolactin Receptor Antagonists

“…At the therapeutic level, only a few trials have been reported, and the results obtained from the treatment of breast or prostate cancer patients with dopamine agonists are disappointing. Although bromocriptine was shown to normalize PRL levels in metastatic breast cancer and prostate carcinoma patients, it was not found to provide significant benefit to breast cancer (70,71) or prostate cancer (72) patients. One report indicated that lowering PRL levels using bromocriptine improved the antitumor actions of chemotherapeutic agents such as Taxotere (73), which is an interesting issue that requires confirmation.…”

Human relevance of rodent prolactin-induced non-genotoxic mammary carcinogenesis: prolactin involvement in human breast cancer and significance for toxicology risk assessments

“…This had particular weight in view of the extensive and long history of use of antipsychotic dopamine antagonists known pharmacologically to elevate prolactin. Additionally, prolactin-suppressing dopamine agonist drugs such as bromocriptine were shown to be ineffective in breast cancer treatment (Fritze et al, 1986;Bonneterre et al, 1988;Holtcamp and Nagel, 1988), which strengthened the view that prolactin had no clinical relevance to breast cancer despite early evidence that hyperprolactinaemia was correlated with poor breast cancer prognosis (Holtkamp et al, 1984;Wang et al, 1986). Thus, there was little evidence of an effect of prolactin in human breast cancer (as assessed by centrally acting dopaminemodulating drugs) versus a wealth of experience of prolactin and mammary carcinogenesis in rodents, because the rat had been used as a model of mammary carcinogenesis in cancer research.…”

Hypothesis Prolactin is tumorigenic to human breast: dispelling the myth that prolactin‐induced mammary tumors are rodent‐specific

“…Mershon et al , ; Ben‐Jonathan et al , ; Liby et al , ; and see Bhatavdekar et al , on prolactin as a local growth promoter in breast cancer patients). It has been noted (Clevenger et al , ; Harvey et al , ) that it was probably the lack of control of local autocrine/paracrine prolactin secretion from tumors/breast epithelium that prevented efficacy of dopamine agonist prolactin‐lowering drugs in early patient trials (see Fritze et al , ; Holtkamp and Nagel, ), although some success in improving breast cancer treatment has been achieved by lowering systemic prolactin (Lissoni et al , ; Frontini et al , ).…”