goserelin and formestane

Aromatase inhibition in postmenopausal women causes a marked fall in the plasma levels of oestrogens and is an effective treatment for breast cancer, however, trials with aminoglutethimide found that this aromatase inhibitor was ineffective in suppressing plasma oestrogen levels in premenopausal breast cancer patients. We found that the more potent inhibitor, 4-hydroxyandrostenedione (4-OHA), which can suppress oestrogen synthesis in rodents and non-human primates with intact ovarian function, was also unsuccessful as an oestrogen suppressant in premenopausal women at its maximum tolerated dose (500 mg/week i.m.). GnRH agonists are effective suppressants of ovarian oestrogen synthesis but oestrogen production from peripheral sites is unaffected. Our studies of a combination of the GnRH agonist goserelin and 4-OHA demonstrated that the combination caused greater oestrogen suppression than goserelin alone and led to objective clinical response in 4/6 breast cancer patients after their relapse from treatment with goserelin as a single agent. The combination of a GnRH agonist and an aromatase inhibitor should be subjected to clinical trials.

Topics: Androstenedione; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Buserelin; Estrogens; Female; Goserelin; Humans; Menopause

Topics: Androstenedione; Breast Neoplasms; Buserelin; Female; Goserelin; Humans; Receptors, Estrogen; Receptors, Progesterone; Tamoxifen

We wanted to determine whether neoadjuvant systemic chemoendocrine therapy guided by the estrogen receptor (ER) status of the primary breast cancer, followed by conventional surgery and/or radiotherapy, reduces local and distant recurrence and improves survival compared with adjuvant treatment given conventionally postoperatively.. Two hundred ten patients with primary breast cancer (T1-T4, N0, N1-2) were randomised to receive treatment with neoadjuvant chemoendocrine therapy or conventional post-operative chemoendocrine therapy. Systemic therapy was based on the estrogen receptor (ER) status of the primary tumour obtained by trucut core biopsy. ER-negative patients received MMM chemotherapy (methotrexate (30 mg/m2), mitozantrone (7 mg/m2) and mitomycin (7 mg/m2) three-weekly for three months and ER-positive patients who were premenopausal received goserelin (3.75 mg monthly), and post menopausal women formestane (250 mg every two weeks) over three months.. With a minimum of five years follow-up, there is no evidence of any survival benefit from the pretreatment neoadjuvant therapy regimen, with five year overall survival being 79% +/- 4.7% (neoadjuvant) and 87% +/- 3.4% (adjuvant). Similarly, there was no apparent benefit in terms of disease-free survival. There was, however, a significant reduction in the incidence of distant metastases in responders (4 of 51; 8%) compared with non-responders (17 of 49; 35%) (P < 0.01). There was a reduction in the need for surgery in responding patients with T1 and T2 tumours, since 10 of 74 (14%) had no detectable residual tumour, without any apparent increase in the risk of local or distant recurrence.. In this study neoadjuvant treatment with endocrine or chemotherapy provided no obvious survival benefit to women with breast cancer. However, it does allow avoidance of surgery in some cases. Also, the patients whose tumours respond to neoadjuvant systemic therapy have a lower incidence of distant metastases after five year follow-up compared to those whose tumours fail to respond.

Topics: Adult; Aged; Androstenedione; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Goserelin; Humans; Methotrexate; Middle Aged; Mitomycin; Mitoxantrone; Neoadjuvant Therapy; Neoplasm Metastasis; Postmenopause; Premenopause; Prognosis; Receptors, Estrogen; Survival Analysis

The high potency and selectivity of new aromatase inhibitors has translated to greater efficacy and improved tolerability in comparison with established second-line hormonal agents for advanced breast cancer in phase III clinical trials. Two pharmacological studies are reported which assess the use of one of these inhibitors, vorozole, in combination or comparison with well-established methods of oestrogen deprivation in pre and postmenopausal patients. When combined with the gonadotrophin-releasing hormone agonist (GnRHa) goserelin in 10 premenopausal patients, vorozole markedly enhanced the suppression of serum levels of oestrone, oestradiol and, oestrone sulphate beyond that achieved by goserelin alone (by a mean 74%, 83%, and 89%, respectively). The combination was well-tolerated and had no significant effects on androgen levels. Vorozole was compared with formestane in 13 postmenopausal women and serum oestrone, oestradiol, and oestrone sulphate levels were suppressed by 47%, 30%, and 70%, respectively, more by vorozole than by the steroidal aromatase inhibitor. Again the tolerability was excellent. The plasma oestrogen levels in the postmenopausal patients on vorozole were lower than in the premenopausal patients on goserelin plus vorozole, indicating that ovarian oestrogen synthesis may be relatively resistant to aromatase inhibition, even during GnRHa treatment. Thus, in both pre and postmenopausal patients substantially greater suppression of oestrogen can be achieved by vorozole compared with alternative approaches. Existing clinical-pharmacological correlates suggest that these increases in pharmacological effectiveness may result in enhanced clinical effectiveness.

Topics: Adult; Androstenedione; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Breast Neoplasms; Estradiol; Female; Goserelin; Humans; Middle Aged; Ovary; Postmenopause; Premenopause; Triazoles

Between 1984 and 1990, 94 women presenting to the Edinburgh Breast Unit with operable breast cancer of 4 cm or greater in diameter (T2, T3, N0, N1, M0) were given preoperative systemic therapy. Initially, all women received hormone therapy, with CHOP (cyclophosphamide 1 g m(-2), doxorubicin 50 mg m(-2), vincristine 1.4 mg m(-2) to a maximum of 2 mg and prednisolone 40 mg per day orally for 5 days) chemotherapy being administered to those who failed to respond by 3 months. After April 1987, first-line hormone therapy was only offered to women with oestrogen receptor (ER)-moderate/-rich (> 20 fmol mg(-1) protein) tumours, and CHOP was reserved for those women whose tumours failed to respond to hormone therapy and for those with ER-negative/-poor tumours. Response data have been published previously (Anderson et al, 1991). After a median follow-up of 7.5 years, there is no difference in survival between those women given initial hormone therapy and those given chemotherapy, with neither group having yet reached its median survival. The two key factors that predicted for a poor survival were the number of involved axillary nodes after preoperative systemic therapy (P < 0.00001) and a lack of response to preoperative therapy (P < 0.05). These data suggest that many women with ER-moderate/-rich tumours will have a good prognosis after preoperative hormone therapy alone. However, it is possible to identify, by their post-systemic therapy axillary node status, a group of women who still have an appalling prognosis after preoperative chemotherapy or hormone therapy.

Topics: Adult; Aged; Aminoglutethimide; Androstenedione; Antineoplastic Combined Chemotherapy Protocols; Axilla; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Follow-Up Studies; Goserelin; Humans; Hydrocortisone; Lymphatic Metastasis; Middle Aged; Neoplasms, Hormone-Dependent; Ovariectomy; Prednisone; Preoperative Care; Tamoxifen; Treatment Outcome; Vincristine

Sixty patients with locally advanced breast cancer, but with no evidence of distant metastases were randomised to receive primary endocrine therapy or chemotherapy after assessment and 'Trucut' biopsy of the primary tumour. After 12 weeks all patients were assessed. Eight out of 30 (27%) of the patients who received chemotherapy showed complete clinical regression of the primary cancer, eight patients' tumours had regressed by more than 50%, and ten showed a 25-50% reduction in bi-dimensional diameter. Only four (13%) patients' tumours failed to reduce in size. Seven patients were judged to require mastectomy at the end of the 12 week period of treatment with chemotherapy. In contrast, only three out of 30 (10%) patients receiving endocrine therapy showed a greater than 50% reduction in tumour size, and four patients had a 25-50% reduction at 12 weeks. The remaining patients' tumours either stabilised (12 patients) or enlarged (11 patients). We conclude that primary chemotherapy in patients with primary breast cancer is more effective in rapidly reducing the size of the primary breast cancer than endocrine therapy (P = 0.001) and alters significantly the future management of these patients. However, at 65 weeks on completion of the follow-up, there is no significant difference in the number of patients' disease-free, locally or distant recurrent, or dead.

Topics: Adult; Aged; Androstenedione; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Buserelin; Female; Goserelin; Humans; Immunohistochemistry; Middle Aged; Neoplasm Staging; Pilot Projects; Receptors, Estrogen

Eighty-eight patients presenting with operable breast cancer of 4 cm or greater in diameter (T2, T3, N0, N1, M0) have received primary systemic therapy. Response was assessed following 12 weeks of systemic therapy by linear regression analysis of changes in tumour volume. Definitive locoregional surgery (mastectomy n = 82, wide local excision n = 6) was performed on completion of systemic therapy (3-6 months). Response was observed in 24 (39%) of the 61 patients who received endocrine therapy; all 24 had tumours with an oestrogen receptor (ER) concentration of greater than or equal to 20 fmol mb-1 cytosol protein. Cytotoxic therapy was reserved for patients with tumours of ER concentration less than 20 fmol mg-1 cytosol protein (n = 27) or when endocrine therapy had failed (n = 20). Response was observed in 34 patients (72%). The overall survival rate at 3 years was 86%, with 81% remaining free from local relapse. We propose that the treatment policy outlined in this paper should now be tested against orthodox management by controlled randomised trial.

Topics: Adult; Aged; Aminoglutethimide; Androstenedione; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Buserelin; Combined Modality Therapy; Female; Goserelin; Humans; Lymphatic Metastasis; Middle Aged; Ovariectomy; Tamoxifen

The aromatase inhibitor, 4-hydroxyandrostenedione (4OHA) is an effective treatment for advanced post-menopausal breast cancer. The clinical and endocrine effects of 4OHA treatment were studied in five pre- and perimenopausal women with metastatic breast cancer. Serum oestradiol levels were not significantly reduced as a result of treatment with 500 mg of 4OHA by weekly i.m. injections and no patient had a tumour response. Four patients were subsequently treated with the luteinising hormone releasing hormone (LHRH) analogue, gosereline, and three had objective responses. The endocrine effects of combined treatment with goserelin (Zoladex), and 4OHA were studied in a further five premenopausal women. Serum oestradiol levels after treatment with goserelin alone were typical of post-menopausal women. Addition of 4OHA led to a further suppression of oestradiol to within the range observed in post-menopausal patients treated with further suppression of oestradiol to within the range observed in post-menopausal patients treated with 4OHA. Six patients whose tumours had regressed as a result of goserelin treatment and who subsequently relapsed were then given combined treatment. Four of the six experienced a second remission. We conclude that while 4OHA alone is unlikely to be a satisfactory treatment for premenopausal patients with advanced breast cancer, 4OHA in conjunction with goserelin leads to profound suppression of oestradiol. The combination of LHRH analogue and aromatase inhibitor may prove to be a superior treatment to LHRH analogue alone in these patients.

Topics: Adult; Androstenedione; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Buserelin; Female; Goserelin; Humans; Menopause; Middle Aged; Ovariectomy

Topics: Androstenedione; Breast Neoplasms; Buserelin; Female; Goserelin; Humans; Receptors, Estrogen; Receptors, Progesterone; Tamoxifen

Patients with invasive cancer of the breast (T1-4, N0-2, M0) were assigned to pretreatment based on oestrogen receptor (ER) status; patients with ER-negative tumours received chemotherapy [mitozantrone, methotrexate and mitomycin C (MMM)] for 3 months, patients with ER-positive tumours underwent endocrine therapy [luteinising hormone releasing hormone (LHRH) agonist goserelin (leuprolide-premenopausal) or 4-hydroxyandrostenedione (formestane-post-menopausal)] for 3 months. Of the first 100 patients assessed at 3 months, 47 with ER-positive tumours had a 40.4% response (premenopausal 53.8%; post-menopausal 35%) and 53 with ER-negative tumours had a 60% response (premenopausal 57%; post-menopausal 63%). Patients with early breast cancer (T1/T2) had a complete clinical resolution in 41% (16/39) of cases after MMM and in 20% (7/35) of cases following endocrine therapy compared with 14% (2/14) advanced tumours (T3/T4) following MMM and (0/12) following endocrine therapy. However, in those patients achieving a complete clinical response, subsequent appropriate surgery showed that 16 of 19 patients (84%) had evidence of residual viable tumour on histological examination.

Topics: Adult; Aged; Androstenedione; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Combined Modality Therapy; Female; Goserelin; Humans; Immunohistochemistry; Methotrexate; Middle Aged; Mitomycin; Mitoxantrone; Neoplasms, Hormone-Dependent; Receptors, Estrogen

Topics: Aminoglutethimide; Androstenedione; Aromatase Inhibitors; Breast Neoplasms; Buserelin; Female; Goserelin; Humans; Neoplasms, Hormone-Dependent; Tamoxifen

Forty-three patients with large (greater than or equal to 4 cm) but operable carcinoma of the breast have been treated by endocrine manipulation before definitive local surgery. This has allowed the study of the relationship between response to therapy and pretreatment oestrogen receptor (ER) concentration, as measured by a dextran-coated charcoal adsorption method. Premenopausal patients (17) were treated by surgical (4) or medical (13) oophorectomy. Post-menopausal patients (26) received either tamoxifen (10) or an aromatase inhibitor (16). Response was assessed from statistical analysis of the changes in tumour size. On completion of 12 weeks of endocrine therapy, there was significant regression of tumour size in 18 of the 43 patients. All 18 patients had tumours with ER concentrations of greater than or equal to 20 fmol mg-1 cytosol protein. Conversely all patients except one progressing on treatment had tumours with ER concentrations of less than 20 fmol mg-1 cytosol protein. This relationship applied for both premenopausal and post-menopausal patients. The overall response rate of patients with tumours of ER concentration greater than or equal to 20 fmol mg-1 cytosol protein was 60%.

Topics: Aminoglutethimide; Androstenedione; Breast Neoplasms; Buserelin; Female; Goserelin; Humans; Menopause; Receptors, Estrogen; Tamoxifen