trelstar and Breast-Neoplasms

For young patients with hormone receptor-positive early breast cancer, tamoxifen for at least 5 years is the standard endocrine treatment. Prolonged endocrine treatment over 5 years is recommended for patients with high risk of late relapse. When adjuvant chemotherapy is indicated, prolonged iatrogenic amenorrhea is a strong pronostic factor. WIthout persistant amenorrhea after chemotherapy, it is indicated to associate ovarian suppression to the endocrine treatment. Optimal duration of this induced amenorrhea is unknown.

Topics: Adult; Amenorrhea; Anastrozole; Androstadienes; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Goserelin; Humans; Luteolytic Agents; Neoplasm Recurrence, Local; Randomized Controlled Trials as Topic; Selective Estrogen Receptor Modulators; Tamoxifen; Time Factors; Triptorelin Pamoate

A 1-month formulation of the gonadotrophin-releasing hormone agonist (GnRHa) triptorelin (Decapeptyl

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Drug Approval; Europe; Female; Humans; Neoplasm Recurrence, Local; Premenopause; Quality of Life; Tamoxifen; Triptorelin Pamoate

Between 20-25% of all breast cancers are diagnosed in patients younger than 50 years of age, most of whom are still premenopausal. Currently, tamoxifen is considered the standard of care for adjuvant treatment in these cases. However, in postmenopausal women, aromatase inhibitors (AIs) are a better choice. Given the superiority of AIs over tamoxifen in postmenopausal women, multiple investigators explored the potential role of AIs in premenopausal patients receiving ovarian suppression. Until very recently, available data derived from the ABCSG-12 clinical trial argued against the combination of AIs and ovarian suppression. This idea, however, may have changed with the release of the combined analysis of two clinical trials: SOFT and TEXT which evaluated the use of ovarian suppression in combination therapy. Clinicians will soon reconsider the possibility of using this strategy for premenopausal patients. Given the availability of this new data this review will analyze the consequences derived from this study, contextualize this new information within the vast available literature of anti-hormonal therapy, and discuss potential arguments in favor of and against the use of this approach.

Topics: Androstadienes; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Drug Therapy, Combination; Estrogen Antagonists; Female; Humans; Multicenter Studies as Topic; Ovary; Premenopause; Randomized Controlled Trials as Topic; Tamoxifen; Triptorelin Pamoate

Topics: Androgen Antagonists; Animals; Aromatase Inhibitors; Breast Neoplasms; Buserelin; Estrogen Antagonists; Female; Gonadotropin-Releasing Hormone; Goserelin; Humans; Luteolytic Agents; Progestins; Rats; Somatostatin; Triptorelin Pamoate

Topics: Antineoplastic Agents; Breast Neoplasms; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Ovarian Neoplasms; Prostatic Neoplasms; Triptorelin Pamoate

To evaluate endocrine activity in terms of ovarian function suppression (OFS) of degarelix (a gonadotropin-releasing hormone [GnRH] antagonist) versus triptorelin (a GnRH agonist) in premenopausal patients receiving letrozole as neoadjuvant endocrine therapy for breast cancer.. Premenopausal women with stage cT2 to 4b, any N, M0; estrogen receptor and progesterone receptor greater than 50%; human epidermal growth factor receptor 2-negative breast cancer were randomly assigned to triptorelin 3.75 mg administered intramuscularly on day 1 of every cycle or degarelix 240 mg administered subcutaneously (SC) on day 1 of cycle 1 then 80 mg SC on day 1 of cycles 2 through 6, both with letrozole 2.5 mg/day for six 28-day cycles. Surgery was performed 2 to 3 weeks after the last injection. Serum was collected at baseline, after 24 and 72 hours, at 7 and 14 days, and then before injections on cycles 2 through 6. The primary end point was time to optimal OFS (time from the first injection to first assessment of centrally assessed estradiol level ≤ 2.72 pg/mL [≤ 10 pmol/L] during neoadjuvant therapy). The trial had 90% power to detect a difference using a log-rank test with a two-sided α of .05. Secondary end points included response, tolerability, and patient-reported endocrine symptoms.. Between February 2014 and January 2017, 51 patients were enrolled (n = 26 received triptorelin plus letrozole; n = 25 received degarelix plus letrozole). Time to optimal OFS was three times faster for patients assigned to degarelix and letrozole than to triptorelin and letrozole (median, 3 v 14 days; hazard ratio, 3.05; 95% CI, 1.65 to 5.65; P < .001). Furthermore, OFS was maintained during subsequent cycles for all patients assigned to receive degarelix and letrozole, whereas 15.4% of patients assigned to receive triptorelin and letrozole had suboptimal OFS after cycle 1 (six events during 127 measurements). Adverse events as a result of both degarelix plus letrozole and triptorelin plus letrozole were as expected.. In premenopausal women receiving letrozole for neoadjuvant endocrine therapy, OFS was achieved more quickly and maintained more effectively with degarelix than with triptorelin.

Topics: Adult; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Estradiol; Female; Gonadotropin-Releasing Hormone; Humans; Letrozole; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Neoplasms, Hormone-Dependent; Oligopeptides; Ovary; Premenopause; Receptors, Estrogen; Receptors, Progesterone; Triptorelin Pamoate

The aim of the study is to analyse whether letrozole (L) and zoledronic acid plus L (ZL) are more effective than tamoxifen (T) as adjuvant endocrine treatment of premenopausal patients with breast cancer with hormone receptor-positive (HR+) tumours.. In a phase 3 trial, 1065 premenopausal patients with HR + early breast cancer received triptorelin to suppress ovarian function and were randomly assigned (1:1:1) to adjuvant T, L or ZL for 5 years. Cancer recurrence, second breast or non-breast cancer and death were considered events for the intention-to-treat disease-free survival (DFS) analysis.. With a 64-month median follow-up and 134 reported events, the disease-free rate at 5 years was 85.4%, 93.2% and 93.3% with T, L and ZL, respectively (overall P = 0.008). The hazard ratio for a DFS event was 0.52 (95% confidence interval [CI], 0.34 to 0.80; P = 0.003) with ZL vs T, 0.72 (95% CI, 0.48 to 1.07; P = 0.06) with L vs T and 0.70 (95% CI, 0.44 to 1.12; P = 0.22) with ZL vs L. With 36 deaths, there was no significant difference in overall survival (P = 0.14). Treatment was stopped for toxicity or refusal in 7.3%, 7.3% and 16.6% patients, and in the safety population, grade 3-4 side-effects were reported in 4.2%, 6.9% and 9.1% patients treated with T, L or ZL, respectively.. HOBOE study shows that in premenopausal patients with early breast cancer undergoing ovarian function suppression with triptorelin, ZL significantly improves DFS, while worsening compliance and toxicity, as compared with T. (NCT00412022).

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Bone Density Conservation Agents; Breast Neoplasms; Chemotherapy, Adjuvant; Disease Progression; Disease-Free Survival; Estrogen Antagonists; Female; Humans; Italy; Letrozole; Middle Aged; Ovary; Premenopause; Tamoxifen; Time Factors; Triptorelin Pamoate; Zoledronic Acid

To describe estradiol (E2), estrone (E1), and estrone sulfate (E1S) levels during the first year of monthly triptorelin plus exemestane or tamoxifen and to assess possible suboptimal suppression while receiving exemestane plus triptorelin.. Premenopausal patients with early breast cancer on the Suppression of Ovarian Function Trial who selected triptorelin as the ovarian suppression method and were randomly assigned to exemestane plus triptorelin or tamoxifen plus triptorelin were enrolled until the target population of 120 patients was reached. Blood sampling time points were 0, 3, 6, 12, 18, 24, 36, and 48 months. Serum estrogens were measured with a highly sensitive and specific assay. This preplanned 12-month analysis evaluated E2, E1, E1S, follicle-stimulating hormone, and luteinizing hormone levels in all patients and the proportion of patients with E2 levels greater than 2.72 pg/mL at any time point during treatment with exemestane plus triptorelin.. One hundred sixteen patients (exemestane, n = 86; tamoxifen, n = 30; median age, 44 years; median E2, 51 pg/mL; 55% prior chemotherapy) started triptorelin and had one or more samples drawn. With exemestane plus triptorelin, median reductions from baseline E2, E1, and E1S levels were consistently ≥ 95%, resulting in significantly lower levels than with tamoxifen plus triptorelin at all time points. Among patients on exemestane plus triptorelin, 25%, 24%, and 17% had an E2 level greater than 2.72 pg/mL at 3, 6, and 12 months, respectively. Baseline factors related to on-treatment E2 level greater than 2.72 pg/mL were no prior chemotherapy (P = .06), higher body mass index (P = .05), and lower follicle-stimulating hormone and luteinizing hormone (each P < .01).. During the first year, most patients on exemestane plus triptorelin had E2 levels below the defined threshold of 2.72 pg/mL, consistent with levels reported in postmenopausal patients on aromatase inhibitors, but at each time point, at least 17% of patients had levels greater than the threshold.

Topics: Adult; Androstadienes; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Estradiol; Estrogens; Estrone; Female; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Ovary; Tamoxifen; Triptorelin Pamoate

The Suppression of Ovarian Function trial showed improved disease control for tamoxifen plus ovarian function suppression (OFS) compared with tamoxifen alone for the cohort of premenopausal patients who received prior chemotherapy. We present the patient-reported outcomes.. The quality-of-life (QoL) analysis includes 1,722 of 2,045 premenopausal patients with hormone receptor-positive breast cancer randomly assigned to receive adjuvant treatment with 5 years of tamoxifen plus OFS or tamoxifen alone. Chemotherapy use before enrollment was optional. Patients completed a QoL form consisting of global and symptom indicators at baseline, every 6 months for 24 months, and annually during years 3 to 6. Differences in the change of QoL from baseline between the two treatments were tested at 6, 24, and 60 months with mixed models for repeated measures with and without chemotherapy and overall.. Patients on tamoxifen plus OFS were more affected than patients on tamoxifen alone by hot flushes at 6 and 24 months, by loss of sexual interest and sleep disturbance at 6 months, and by vaginal dryness up to 60 months. Without prior chemotherapy, patients on tamoxifen alone reported more vaginal discharge over the 5 years than patients on tamoxifen plus OFS. Symptom-specific treatment differences at 6 months were less pronounced in patients with prior chemotherapy. Changes in global QoL indicators from baseline were small and similar between treatments over the whole treatment period.. Overall, OFS added to tamoxifen resulted in worse endocrine symptoms and sexual functioning during the first 2 years of treatment, with variable magnitudes of treatment differences. Short-term differences in symptom-specific QoL, treatment burden, and coping effort between treatment groups were less pronounced for patients with prior chemotherapy, the cohort that benefited most from OFS in terms of disease control.

Topics: Adult; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Humans; Lymphatic Metastasis; Ovary; Premenopause; Quality of Life; Self Report; Tamoxifen; Triptorelin Pamoate

Twenty-five percent of breast cancer cases are detected during premenopausal period and the number of young women suffering from breast cancer is increasing in the world, especially in Iran. Preservation of fertility and ovarian function leads to improved quality of life of these patients. The aim of this study was to evaluate the effect of gonadotropin releasing hormone (GnRH) agonist on menstrual reverse in breast cancer cases treated with cyclophosphamide regimen.. This randomized clinical trial (RCT) was conducted on 42 adenocarcinoma cases. Mean age of patients was 37 +/- 5 years (range 25 to 45). Primary stages to Stage II (T2N1M0) whose histology reports were negative ER/PR were enrolled in this study. All the enrolled patients were candidates for cyclophosphamide (600 mg/m2), adriamycin (60 mg/m2), and taxoter (75 mg/m2) chemotherapy regimens.. Spontaneous menstrual reverse occurred in 90.5% of patients receiving diphereline at three to six months after treatment which occurred in 33.3% of control cases. In control group, 14.3% (three cases) had oligomenorrhea and hypomenorrhea during chemotherapy and 19%(four cases) had spontaneous menstrual reverse at three to six months. It should be noted that there was a significant difference between controls and cases (p < 0.001). This difference was insignificant in cases younger than 35 years (p < 0.594). In 100% of patients older than 35 years who received diphereline, spontaneous menstrual reverse occurred during six months after chemotherapy, but this occurred in only 20% of controls (p < 0.001). Mean serum level of follicle stimulating hormone (FSH) and luteinizing hormone (LH) during and at three months after therapy was significantly lower in cases in comparison with controls, but serum level of estradiol was significantly more in cases three months after chemotherapy (p < 0.001).. GnRH agonists significantly improve ovarian function andfertility. They also lead to spontaneous menstrual reverse in negative ER/PR breast cancer cases.

Topics: Adult; Antineoplastic Agents, Hormonal; Breast Neoplasms; Cyclophosphamide; Estradiol; Female; Fertility Preservation; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Menstrual Cycle; Middle Aged; Organ Sparing Treatments; Triptorelin Pamoate

Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor-positive breast cancer.. In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor-positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials.. After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane-ovarian suppression group and 87.3% in the tamoxifen-ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P<0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane-ovarian suppression group, as compared with 88.8% in the tamoxifen-ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane-ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P=0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane-ovarian suppression group and 29.4% of those in the tamoxifen-ovarian suppression group, with profiles similar to those for postmenopausal women.. In premenopausal women with hormone-receptor-positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. (Funded by Pfizer and others; TEXT and SOFT ClinicalTrials.gov numbers, NCT00066703 and NCT00066690, respectively.).

Topics: Adult; Androstadienes; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Chemotherapy, Adjuvant; Disease-Free Survival; Estradiol; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Mastectomy; Middle Aged; Osteoporosis; Premenopause; Quality of Life; Tamoxifen; Triptorelin Pamoate

In 2003 the International Breast Cancer Study Group (IBCSG) initiated the TEXT and SOFT randomized phase III trials to answer two questions concerning adjuvant treatment for premenopausal women with endocrine-responsive early breast cancer: 1-What is the role of aromatase inhibitors (AI) for women treated with ovarian function suppression (OFS)? 2-What is the role of OFS for women who remain premenopausal and are treated with tamoxifen?. TEXT randomized patients to receive exemestane or tamoxifen with OFS. SOFT randomized patients to receive exemestane with OFS, tamoxifen with OFS, or tamoxifen alone. Treatment was for 5 years from randomization.. TEXT and SOFT successfully met their enrollment goals in 2011. The 5738 enrolled women had lower-risk disease and lower observed disease-free survival (DFS) event rates than anticipated. Consequently, 7 and 13 additional years of follow-up for TEXT and SOFT, respectively, were required to reach the targeted DFS events (median follow-up about 10.5 and 15 years). To provide timely answers, protocol amendments in 2011 specified analyses based on chronological time and median follow-up. To assess the AI question, exemestane + OFS versus tamoxifen + OFS, a combined analysis of TEXT and SOFT became the primary analysis (n = 4717). The OFS question became the primary analysis from SOFT, assessing the unique comparison of tamoxifen + OFS versus tamoxifen alone (n = 2045). The first reports are anticipated in mid- and late-2014.. We present the original designs of TEXT and SOFT and adaptations to ensure timely answers to two questions concerning optimal adjuvant endocrine treatment for premenopausal women with endocrine-responsive breast cancer. Trial Registration TEXT: Clinicaltrials.govNCT00066703 SOFT: Clinicaltrials.govNCT00066690.

Topics: Androstadienes; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Humans; Ovariectomy; Ovary; Premenopause; Research Design; Statistics as Topic; Tamoxifen; Triptorelin Pamoate

To estimate the effectiveness of gonadotropin-releasing hormone (GnRH) analogues cotreatment in preventing chemotherapy-induced amenorrhea in young breast cancer patients undergoing cyclophosphamide-based chemotherapy.. One hundred hormone-insensitive breast cancer participants (aged 18-40 years) were recruited from two university-affiliated oncology centers in Egypt. Opting for type of cotreatment was based on available timeframe until start of chemotherapy. Fifty women ready for early chemotherapy were randomized to receive either chemotherapy alone (arm I) or chemotherapy after downregulation (estradiol less than 50 pg/mL) by GnRH antagonist and agonist (arm II). Then, GnRH antagonist was discontinued and agonist was continued until the end of chemotherapy. When chemotherapy was to start later than 10 days after study inclusion, 50 women were randomized to receive either chemotherapy alone (arm III) or chemotherapy after downregulation with GnRH agonist (arm IV). Resumption of menstruation at 12 months after end of chemotherapy was the primary outcome. Postchemotherapy hormonal and ultrasound changes were secondary outcomes.. Twelve months after termination of chemotherapy, there were no differences in menstruation resumption rates between GnRH-treated patients and control group individuals in either early (80% in arms I and II, risk ratio 1, 95% confidence interval 0.7-.32; P=1.00) or delayed chemotherapy groups (80% and 84% in arms III and IV, risk ratio 0.95, 95% confidence interval 0.73-1.235; P=.71). There were no differences in hormonal and ultrasound markers between GnRH analogue users and control group individuals. The use of GnRH analogue cotreatment did not predict independently the odds of menstruating at 12 months.. GnRH analogue cotreatment does not offer a significant protective effect on ovarian function in patients treated by cyclophosphamide-based chemotherapy.. Australian New Zealand Clinical Trials Registry. www.anzctr.org.au, ACTRN12609001059257.. I.

Topics: Adolescent; Adult; Amenorrhea; Antineoplastic Agents; Breast Neoplasms; Cyclophosphamide; Egypt; Female; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Menstruation; Ovary; Treatment Outcome; Triptorelin Pamoate; Ultrasonography; Young Adult

Chemotherapy-induced amenorrhea is a serious concern for women undergoing cancer therapy. This prospective randomized trial evaluated the use of gonadotropin-releasing hormone (GnRH) analog triptorelin to preserve ovarian function in women treated with chemotherapy for early-stage breast cancer.. Premenopausal women age 44 years or younger were randomly assigned to receive either triptorelin or no triptorelin during (neo)adjuvant chemotherapy and were further stratified by age (< 35, 35 to 39, > 39 years), estrogen receptor status, and chemotherapy regimen. Objectives included the resumption of menses and serial monitoring of follicle-stimulating hormone (FSH) and inhibin A and B levels.. Targeted for 124 patients with a planned 5-year follow-up, the trial was stopped for futility after 49 patients were enrolled (median age, 39 years; range, 21 to 43 years); 47 patients were treated according to assigned groups with four cycles of adriamycin plus cyclophosphamide alone or followed by four cycles of paclitaxel or six cycles of fluorouracil, epirubicin, and cyclophosphamide. Menstruation resumed in 19 (90%) of 21 patients in the control group and in 23 (88%) of 26 in the triptorelin group (P= .36). Menses returned after a median of 5.8 months (range, 1 to 19 months) after completion of chemotherapy in the triptorelin versus 5.0 months (range, 0 to 28 months) in the control arm (P= .58). Two patients (age 26 and 35 years at random assignment) in the control group had spontaneous pregnancies with term deliveries. FSH and inhibin B levels correlated with menstrual status.. When stratified for age, estrogen receptor status, and treatment regimen, amenorrhea rates on triptorelin were comparable to those seen in the control group.

Topics: Adult; Amenorrhea; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Breast Neoplasms; Chemotherapy, Adjuvant; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Epirubicin; Female; Fertility; Fluorouracil; Follicle Stimulating Hormone; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Inhibins; Menstruation; Neoadjuvant Therapy; Neoplasm Staging; Ovary; Paclitaxel; Tamoxifen; Time Factors; Treatment Outcome; Triptorelin Pamoate

Premenopausal patients with breast cancer are at high risk of premature ovarian failure induced by systemic treatments, but no standard strategies for preventing this adverse effect are yet available.. To determine the effect of the temporary ovarian suppression obtained by administering the gonadotropin-releasing hormone analogue triptorelin during chemotherapy on the incidence of early menopause in young patients with breast cancer undergoing adjuvant or neoadjuvant chemotherapy.. The PROMISE-GIM6 (Prevention of Menopause Induced by Chemotherapy: A Study in Early Breast Cancer Patients-Gruppo Italiano Mammella 6) study, a parallel, randomized, open-label, phase 3 superiority trial, was conducted at 16 sites in Italy and enrolled 281 patients between October 2003 and January 2008. The patients were premenopausal women with stage I through III breast cancer who were candidates for adjuvant or neoadjuvant chemotherapy. Assuming a 60% rate of early menopause in the group treated with chemotherapy alone, it was estimated that 280 patients had to be enrolled to detect a 20% absolute reduction in early menopause in the group treated with chemotherapy plus triptorelin. The intention-to-treat analysis was performed by including all randomized patients and using imputed values for missing data.. Before beginning chemotherapy, patients were randomly allocated to receive chemotherapy alone or combined with triptorelin. Triptorelin was administered intramuscularly at a dose of 3.75 mg at least 1 week before the start of chemotherapy and then every 4 weeks for the duration of chemotherapy.. Incidence of early menopause (defined as no resumption of menstrual activity and postmenopausal levels of follicle-stimulating hormone and estradiol 1 year after the last cycle of chemotherapy).. The clinical and tumor characteristics of the 133 patients randomized to chemotherapy alone and the 148 patients randomized to chemotherapy plus triptorelin were similar. Twelve months after the last cycle of chemotherapy (last follow-up, August 18, 2009), the rate of early menopause was 25.9% in the chemotherapy-alone group and 8.9% in the chemotherapy plus triptorelin group, an absolute difference of -17% (95% confidence interval, -26% to -7.9%; P < .001). The odds ratio for treatment-related early menopause was 0.28 (95% confidence interval, 0.14 to 0.59; P < .001).. The use of triptorelin-induced temporary ovarian suppression during chemotherapy in premenopausal patients with early-stage breast cancer reduced the occurrence of chemotherapy-induced early menopause.. clinicaltrials.gov Identifier: NCT00311636.

Topics: Adult; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Cisplatin; Female; Fluorouracil; Goserelin; Humans; Infertility, Female; Injections, Intramuscular; Luteolytic Agents; Menopause; Methotrexate; Middle Aged; Neoadjuvant Therapy; Premenopause; Primary Ovarian Insufficiency; Tamoxifen; Triptorelin Pamoate

Luteinizing hormone-releasing hormone (LHRH) agonists (e.g., triptorelin) reduce ovarian estrogen production in premenopausal women with hormone-sensitive breast cancer. Aromatase inhibitors (e.g., exemestane) inhibit extraovarian production of estrogen and may further reduce circulating estrogens when combined with an LHRH agonist.. Healthy premenopausal women were randomized to receive 3.75 mg triptorelin (T) on days 1 and 29 with 25 mg exemestane (EX) or matched placebo once daily for 8 weeks, from day 1 to day 56. The primary objective was to evaluate the effect of T +/- EX on estradiol (E(2)) suppression by comparing the AUC(day 36-57 )for the 2 treatments. Secondary objectives included evaluation of estrone (E(1)), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) suppression; effects of EX on the T-induced gonadotrophin and estrogen flare; pharmacokinetics (PK); and safety.. Twenty-eight (14 in each arm) were evaluable for efficacy and PK. Mean plasma estrogen levels (AUC(day 36-57)) were significantly lower for subjects who received T + EX than for subjects who received T alone (20.6 vs. 54.0 pg d/ml [-62%; P < 0.05], and 38.9 vs. 198.0 pg d/ml [-80%; P < 0.01] for E(2) and E(1), respectively). Coadministration of EX did not affect the initial flare or subsequent suppression of LH and FSH following the first dose of T, or the PK of T. Both treatments were well tolerated.. Coadministration of T and EX resulted in greater estrogen suppression than when T was given alone. These findings could translate into improved clinical outcomes for premenopausal breast cancer patients receiving LHRH agonists.

Topics: Adult; Androstadienes; Antineoplastic Agents; Breast Neoplasms; Double-Blind Method; Estradiol; Estrone; Female; Gonadotropins; Humans; Ovary; Premenopause; Triptorelin Pamoate; Young Adult

To compare the endocrine effects of 6 months of adjuvant treatment with letrozole + triptorelin or tamoxifen + triptorelin in premenopausal patients with early breast cancer within an ongoing phase 3 trial (Hormonal Adjuvant Treatment Bone Effects study).. Prospectively collected hormonal data were available for 81 premenopausal women, of whom 30 were assigned to receive tamoxifen + triptorelin and 51 were assigned letrozole + triptorelin +/- zoledronate. Serum 17-beta-estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), Delta4-androstenedione, testosterone, dehydroepiandrosterone-sulfate, progesterone, adrenocorticotropic hormone (ACTH), and cortisol were measured at baseline and after 6 months of treatment. For each hormone, 6-month values were compared between treatment groups by the Wilcoxon-Mann-Whitney exact test.. Median age was 44 years for both groups of patients. Letrozole + triptorelin (+/- zoledronate) induced a stronger suppression of median E2 serum levels (P = .0008), LH levels (P = .0005), and cortisol serum levels (P < .0001) compared with tamoxifen + triptorelin. Median FSH serum levels were suppressed in both groups, but such suppression was lower among patients receiving letrozole, who showed significantly higher median FSH serum levels (P < .0001). No significant differences were observed for testosterone, progesterone, ACTH, androstenedione, and dehydroepiandrosterone between the two groups of patients.. Letrozole in combination with triptorelin induces a more intense estrogen suppression than tamoxifen + triptorelin in premenopausal patients with early breast cancer.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Gonadal Hormones; Humans; Letrozole; Middle Aged; Nitriles; Premenopause; Prospective Studies; Statistics, Nonparametric; Tamoxifen; Treatment Outcome; Triazoles; Triptorelin Pamoate

The purpose of this study was to determine optimal adjuvant therapy between complete hormonal blockade in premenopausal patients with hormone receptor positive breast cancer and one to three positive nodes.. We randomised 333 patients to receive either LHRH agonist (triptorelin 3.75 mg i.m., monthly) plus tamoxifen 30 mg/day for 3 years (TAM-LHRHa, n=164), or fluorouracil 500 mg/m2, epirubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 21 days for six cycles, without any hormonal treatment (FEC50, n=169).. The 7-year disease-free survival (DFS) was 76% with TAM-LHRHa, and 72% with FEC50 (P=0.13). The 7-year overall survival (OS) was 91% and 88%, respectively (P=0.20). The multivariate analysis confirmed that both treatments were not different for DFS and OS (P=0.83 and P=0.41, respectively). Amenorrhoea occurred in 64% of patients treated with FEC50; it was temporary in 58% of cases after hormonotherapy and in 31% after chemotherapy.. In intermediate-risk breast cancer, complete hormonal blockade and chemotherapy provided similar outcomes. Hormonal treatment is an alternative to chemotherapy in hormone-sensitive patients, considering the preference of patients in terms of quality of life.

Topics: Adult; Amenorrhea; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Cyclophosphamide; Disease-Free Survival; Epirubicin; Estrogen Antagonists; Female; Fluorouracil; Gonadotropin-Releasing Hormone; Heart Diseases; Humans; Lymph Node Excision; Middle Aged; Neoplasms; Premenopause; Receptors, Steroid; Tamoxifen; Triptorelin Pamoate

The aim of this multicenter trial was to evaluate the role of ovarian suppression in patients with early breast cancer previously treated with local surgery and adjuvant chemotherapy.. Nine hundred and twenty-six premenopausal patients with completely resected breast cancer and either axillary node involvement or histological grade 2 or 3 tumors were randomized after surgery to adjuvant chemotherapy alone (control arm) or adjuvant chemotherapy plus ovarian suppression (ovarian suppression arm). Ovarian suppression was obtained by either radiation-induced ovarian ablation or triptorelin for 3 years. The analyses were performed with Cox models stratified by center.. Median follow-up was 9.5 years. Mean age was 43 years. Ninety per cent of patients had histologically proven positive axillary nodes, 63% positive hormonal receptors and 77% had received an anthracycline-based chemotherapy regimen. Ovarian suppression was by radiation-induced ovarian ablation (45% of patients) or with triptorelin (48%). At the time of randomization, all patients had regular menses or their follicle-stimulating hormone and estradiol levels indicated a premenopausal status. The 10-year disease-free survival rates were 49% [95% confidence interval (CI) 44% to 54%] in both arms (P = 0.51). The 10-year overall survival rates were 66% (95% CI 61% to 70%) for the ovarian suppression arm and 68% (95% CI 63% to 73%) for the control arm (P = 0.19). There were no variations in the treatment effect according to age, hormonal receptor status or ovarian suppression modality. However, in patients <40 years of age and with estrogen receptor-positive tumors, ovarian suppression significantly decreased the risk of recurrence (P = 0.01).. The results of this trial, after at least 10 years of follow-up, do not favor the use of ovarian suppression after adjuvant chemotherapy. The potential beneficial effect in younger women with hormono-dependent tumors should be further assessed.

Topics: Adult; Age Factors; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Chemotherapy, Adjuvant; Estradiol; Female; Follicle Stimulating Hormone; Humans; Luteolytic Agents; Lymphatic Metastasis; Middle Aged; Neoplasm Recurrence, Local; Ovary; Premenopause; Receptors, Estrogen; Risk Factors; Survival Analysis; Treatment Outcome; Triptorelin Pamoate

The present randomized phase III trial was designed to detect a 15% benefit in relapse-free survival (RFS) or overall survival (OS) from the incorporation of adjuvant tamoxifen to the combination of CNF [cyclophosphamide, 500 mg/m2; mitoxantrone (Novantrone), 10 mg/m2; fluorouracil, 500 mg/m2 chemotherapy and ovarian ablation in premenopausal patients with node-positive breast cancer and conversely from the incorporation of CNF chemotherapy to adjuvant tamoxifen in node-positive postmenopausal patients. From April 1992 until March 1998, 456 patients with operable breast cancer and one to nine infiltrated axillary nodes entered the study. Premenopausal patients were treated with six cycles of CNF chemotherapy followed by ovarian ablation with monthly injections of triptoreline 3.75 mg for 1 year (Group A, 84 patients) or the same treatment followed by 5 years of tamoxifen (Group B, 92 patients). Postmenopausal patients received 5 years of tamoxifen (Group C, 145 patients) or 6 cycles of CNF followed by 5 years of tamoxifen (Group D, 135 patients). Adjuvant radiation was administered to all patients with partial mastectomy. After a median follow-up period of 5 years, 125 patients (27%) relapsed and 79 (17%) died. The 5-year actuarial RFS for premenopausal patients was 65% in Group A and 68% in Group B (p = 0.86) and for postmenopausal patients 70% in Group C and 67% in Group D (p = 0.36). Also, the respective OS rates were 77% and 80% (p = 0.68) for premenopausal and 84% and 78% (p = 0.10) for postmenopausal patients. Severe toxicities were infrequently seen, with the exception of leukopenia (18%), among the 311 patients treated with CNF. In conclusion, the present study failed to demonstrate a 15% difference in RFS in favor of node-positive premenopausal patients treated with an additional 5 years of tamoxifen after CNF adjuvant chemotherapy and ovarian ablation. Similarly, six cycles of CNF preceding 5 years of tamoxifen did not translate to a 15% RFS benefit in node-positive postmenopausal patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Female; Fluorouracil; Humans; Lymphatic Metastasis; Middle Aged; Mitoxantrone; Neoplasms, Hormone-Dependent; Postmenopause; Premenopause; Survival Analysis; Tamoxifen; Triptorelin Pamoate

the combination of a luteinising hormone-releasing hormone (LH-RH) analogue and an aromatase inhibitor (AI) induces greater oestrogen suppression than the analogue alone in premenopausal breast cancer. However, very few data on the biological effects of such a combination are currently available.. the short-term effects of treatment with the LH-RH analogue triptorelin alone or in association with the AI formestane on bone metabolism were investigated in premenopausal breast cancer. Circulating levels of the bone formation markers carboxy-terminal and amino-terminal propeptides of type I procollagen (PICP and PINP) and the bone resorption marker cross-linked carboxy-terminal telopeptide of type I collagen (ICTP) were assessed. In addition, serum levels of insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3 and interleukin 6 (IL-6) were evaluated.. twenty-one patients with advanced breast cancer were randomly given triptorelin monthly alone (n=10, arm A) or in combination with formestane fortnightly (n=11, arm B). Blood samples were collected over a 3-month period.. serum PICP and PINP levels increased significantly over time (P=0.0065 and 0.0197 in arm A and B, respectively); no change in ICTP levels was observed. A rise in IGF-I and IGFBP-3 levels was seen in each treatment group, but only the increase in IGF-I was significant (P=0.0138, always). The on-treatment levels of the bone turnover markers and IGF-system components were inversely correlated with serum oestrogens. Neither treatment modalities significantly affected serum IL-6 levels over time. No difference in the behaviour of any of the assessed biomarkers was observed between patients with or without skeletal metastases.. it is worth noting that complete oestrogen depletion, at least in our case series, seems to increase only osteoblastic activity markers. The observed modifications appear to be related to oestrogen depletion per se rather than the degree of oestrogen suppression or the different therapeutic regimen administered.

Topics: Adult; Androstenedione; Aromatase Inhibitors; Biomarkers; Bone and Bones; Breast Neoplasms; Estradiol; Female; Gonadotropin-Releasing Hormone; Growth Substances; Humans; Interleukin-6; Middle Aged; Premenopause; Statistics, Nonparametric; Triptorelin Pamoate

Decapeptyl (D-TRP-6), a potent luteinizing hormone-releasing hormone analogue, was administered to 27 premenopausal women with advanced breast cancer; patients were known to have hormone receptor-positive tumors. An overall response rate of 70% was achieved (complete response = 18%, partial response = 52%), with a median time to progression for the whole patient population of 12 months. Toxicity of the schedule was restricted to hot flushes, and the use of a 4-week initial covering period of tamoxifen prevented any flare-up of disease activity from occurring.

Topics: Adult; Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Humans; Middle Aged; Receptors, Estrogen; Receptors, Progesterone; Triptorelin Pamoate

The Tamoxifen and Exemestane Trial (TEXT)/Suppression of Ovarian Function Trial (SOFT) showed superior outcomes for premenopausal women with hormone receptor (HR)-positive breast cancer treated with adjuvant exemestane plus ovarian function suppression (OFS) or tamoxifen plus OFS versus tamoxifen alone. We previously reported the magnitude of absolute improvements in freedom from any recurrence across a continuous, composite measure of recurrence risk to tailor decision making. With longer follow-up, we now focus on distant recurrence.. The TEXT/SOFT HR-positive/human epidermal growth factor receptor 2 (HER2)-negative analysis population included 4,891 women stratified by predetermined chemotherapy use. Kaplan-Meier estimates of 8-year freedom from distant recurrence were analyzed using subpopulation treatment effect pattern plot (STEPP) methodology across subpopulations defined by the continuous composite measure of recurrence risk. For each patient, the composite risk value was obtained from a Cox model that incorporated age; nodal status; tumor size; grade; and estrogen receptor, progesterone receptor, and Ki-67 labeling index expression levels.. The overall rate of 8-year freedom from distant recurrence was 91.1% and ranged from approximately 100% to 63% across lowest to highest composite risks. TEXT patients who received chemotherapy had an average absolute improvement with exemestane plus OFS versus tamoxifen plus OFS of 5.1%, and STEPP analysis showed improvements from less than 1% to more than 15% from lowest to highest composite risks. SOFT patients who remained premenopausal after chemotherapy had an average 5.2% absolute improvement with exemestane plus OFS versus tamoxifen and reached 10% across composite risks; for tamoxifen plus OFS versus tamoxifen, the maximum improvement was approximately 3.5%. Women who did not receive chemotherapy had a more than 97% rate of 8-year freedom from distant recurrence, and improvements with exemestane plus OFS ranged from 1% to 4%.. Premenopausal women with HR-positive/HER2-negative breast cancer and high recurrence risk, as defined by clinicopathologic characteristics, may experience a 10% to 15% absolute improvement in 8-year freedom from distant recurrence with exemestane plus OFS versus tamoxifen plus OFS or tamoxifen alone. The potential benefit of escalating endocrine therapy versus tamoxifen alone is minimal for those at low recurrence risk.

Topics: Androstadienes; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Female; Humans; Neoplasm Recurrence, Local; Ovariectomy; Ovary; Premenopause; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Tamoxifen; Triptorelin Pamoate

An altered consistency of tumor microenvironment facilitates the progression of the tumor towards metastasis. Here we combine data from secretome and proteome analysis using mass spectrometry with microarray data from mesenchymal transformed breast cancer cells (MCF-7-EMT) to elucidate the drivers of epithelial-mesenchymal transition (EMT) and cell invasion. Suppression of connective tissue growth factor (CTGF) reduced invasion in 2D and 3D invasion assays and expression of transforming growth factor-beta-induced protein ig-h3 (TGFBI), Zinc finger E-box-binding homeobox 1 (ZEB1) and lysyl oxidase (LOX), while the adhesion of cell-extracellular matrix (ECM) in mesenchymal transformed breast cancer cells is increased. In contrast, an enhanced expression of CTGF leads to an increased 3D invasion, expression of fibronectin 1 (FN1), secreted protein acidic and cysteine rich (SPARC) and CD44 and a reduced cell ECM adhesion. Gonadotropin-releasing hormone (GnRH) agonist Triptorelin reduces CTGF expression in a Ras homolog family member A (RhoA)-dependent manner. Our results suggest that CTGF drives breast cancer cell invasion in vitro and therefore could be an attractive therapeutic target for drug development to prevent the spread of breast cancer.

Topics: Breast Neoplasms; Connective Tissue Growth Factor; Epithelial-Mesenchymal Transition; Extracellular Matrix; Extracellular Matrix Proteins; Female; Fibronectins; Gene Expression; Humans; Hyaluronan Receptors; MCF-7 Cells; Neoplasm Invasiveness; Osteonectin; Protein-Lysine 6-Oxidase; rhoA GTP-Binding Protein; Signal Transduction; Transforming Growth Factor beta; Triptorelin Pamoate; Zinc Finger E-box-Binding Homeobox 1

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Triptorelin Pamoate

The understanding of adhesive interaction at the nanoscale between functionalized nanoparticles and biological cells is of great importance to develop effective theranostic nanocarriers for targeted cancer therapy. Here, we report a combination of experimental and computational approaches to evaluate the adhesion between Triptorelin (a Luteinizing Hormone-Releasing Hormone (LHRH) agonist)-conjugated poly-(ethylene glycol) (PEG)-coated magnetite nanoparticles (Triptorelin-MNPs) and breast cells. The adhesion forces between Triptorelin-MNPs and normal/cancerous breast cells are obtained using atomic force microscopy. The corresponding work of adhesion is then estimated using Johnson-Kendall-Roberts model. Our results demonstrate that Triptorelin-MNPs have a fourteen-fold greater work of adhesion to breast cancer cells than to normal breast cells. In addition, the work of adhesion between Triptorelin-MNPs and breast cancer cells is found to be three times more than that between unmodified MNPs and breast cancer cells. Hence, the experimental observation indicates that Triptorelin ligands facilitate the specific targeting of breast cancer cells. Furthermore, molecular dynamics simulations are performed to investigate the molecular origins of the adhesive interactions. The simulations reveal that the interactions between molecules (e.g. Triptorelin and PEG) and LHRH receptors are dominated by van der Waals energies, while the interactions of these molecules with cell membrane are dominated by electrostatic interactions. Moreover, both experimental and computational results reveal that PEG serves as an effective coating that enhances adhesive interactions to breast cancer cells that over-express LHRH receptors, while reduces the adhesion to normal breast cells. Our results highlight the potential to develop Triptorelin-MNPs into tumor-specific MRI contrast agents and drug carriers.. Systematic investigation of adhesive interactions between functionalized nanoparticles and cancer cells is of great importance in developing effective theranostic nanocarriers for targeted cancer therapy. Herein, we use a combination of atomic force microscopy technique and molecular dynamics simulations approach to explore the adhesive interactions at the nanoscale between Triptorelin-conjugated polyethylene glycol (PEG)-coated magnetite nanoparticles and normal/cancerous breast cells. This study characterizes and quantifies the work of adhesion, as well as adhesion forces, at the nanocarrier/cell interfaces, unravels the molecular origins of adhesive interactions and highlights the effectiveness of PEG coatings and Triptorelin ligands in the specific targeting of breast cancer cells. Our findings expand the fundamental understanding of nanoparticle/cell adhesion and provide guidelines for the design of more rational nanocarriers.

Topics: Breast Neoplasms; Coated Materials, Biocompatible; Drug Delivery Systems; Female; Humans; Magnetite Nanoparticles; Polyethylene Glycols; Triptorelin Pamoate

This study analyzes our single-center, retrospective experience on 63 premenopausal breast cancer patients treated with monthly triptorelin and concomitant chemotherapy.. Concomitant chemotherapy and triptorelin were adopted as part of premature ovarian failure prevention strategy.. Age at diagnosis was the main factor influencing fertility preservation (p = 0.002). Compared with patients aged 41-45 years, the probability of menses resumption was almost threefold than for women aged 35-40 years, and significantly higher for women aged <35 years (hazard ratio: 9.0; p = 0.0001). The cumulative proportion among patients who resumed menses was 33.3% at 6 months, 75% at 12 months and 87.5% at 24 months. Seven patients attempted pregnancy, and five (71%) obtained healthy deliveries.. We observed an acceptable rate of fertility preservation. Age at diagnosis influences fertility preservation.

Topics: Adult; Age Factors; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Female; Fertility Preservation; Follow-Up Studies; Humans; Middle Aged; Pregnancy; Premenopause; Primary Ovarian Insufficiency; Retrospective Studies; Treatment Outcome; Triptorelin Pamoate

Triple negative breast cancers express receptors for gonadotropin-releasing hormone (GnRH) in more than 50% of the cases, which can be targeted with peptidic analogs of GnRH, such as triptorelin. The current study investigates cytotoxic activity of triptorelin as a monotherapy and in treatment combinations with chemotherapeutic agents and inhibitors of the PI3K and the ERK pathways in in vitro models of triple negative breast cancers (TNBC). GnRH receptor expression of TNBC cell lines MDA-MB-231 and HCC1806 was investigated. Cells were treated with triptorelin, chemotherapeutic agents (cisplatin, docetaxel, AEZS-112), PI3K/AKT inhibitors (perifosine, AEZS-129), an ERK inhibitor (AEZS-134), and dual PI3K/ERK inhibitor AEZS-136 applied as single agent therapies and in combinations. MDA-MB-231 and HCC1806 TNBC cells both expressed receptors for GnRH on messenger (m)RNA and protein level and were found sensitive to triptorelin with a respective median effective concentration (EC50) of 31.21 ± 0.21 and 58.50 ± 19.50. Synergistic effects occurred when triptorelin was combined with cisplatin. In HCC1806 cells, synergy occurred when triptorelin was applied with PI3K/AKT inhibitors perifosine and AEZS-129. In MDA-MB-231 cells, synergy was observed after co-treatment with triptorelin and ERK inhibitor AEZS-134 and dual PI3K/ERK inhibitor AEZS-136. GnRH receptors on TNBC cells can be used for targeted therapy of these cancers with GnRH agonist triptorelin. Treatment combinations based on triptorelin and PI3K and ERK inhibitors and chemotherapeutic agent cisplatin have synergistic effects in in vitro models of TNBC. If confirmed in vivo, clinical trials based on triptorelin and cisplatin could be quickly carried out, as triptorelin is FDA approved for other indications and known to be well tolerated.

Topics: Aniline Compounds; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cisplatin; DNA Mutational Analysis; Dose-Response Relationship, Drug; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Gonadotropin-Releasing Hormone; Humans; Phosphatidylinositol 3-Kinases; Phosphorylcholine; Receptors, LHRH; Triple Negative Breast Neoplasms; Triptorelin Pamoate

Topics: Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Female; Humans; Tamoxifen; Triptorelin Pamoate

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Gonadotropin-Releasing Hormone; Humans; Neoplasm Staging; Premenopause; Receptors, Estrogen; Receptors, Progesterone; Treatment Outcome; Triptorelin Pamoate

Topics: Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Tamoxifen; Triptorelin Pamoate

Topics: Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Tamoxifen; Triptorelin Pamoate

Topics: Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Tamoxifen; Triptorelin Pamoate

Topics: Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Tamoxifen; Triptorelin Pamoate

Topics: Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Tamoxifen; Triptorelin Pamoate

Topics: Adult; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Buserelin; Female; Goserelin; Humans; Leuprolide; Middle Aged; Ovary; Perimenopause; Premenopause; Survival Analysis; Treatment Outcome; Triptorelin Pamoate

Topics: Amenorrhea; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Fertility; Gonadotropin-Releasing Hormone; Goserelin; Humans; Neoadjuvant Therapy; Ovary; Triptorelin Pamoate

Topics: Amenorrhea; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Fertility; Gonadotropin-Releasing Hormone; Humans; Neoadjuvant Therapy; Ovary; Triptorelin Pamoate

Topics: Amenorrhea; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Fertility; Gonadotropin-Releasing Hormone; Humans; Neoadjuvant Therapy; Ovary; Triptorelin Pamoate

Topics: Amenorrhea; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Fertility; Gonadotropin-Releasing Hormone; Humans; Neoadjuvant Therapy; Ovary; Triptorelin Pamoate

This report describes the case of a 27-year-old woman with breast cancer who underwent ovarian stimulation for fertility preservation with recombinant FSH in conjunction with a gonadotrophin-releasing hormone (GnRH) antagonist and an aromatase inhibitor from the beginning of the treatment. A 3.75-mg triptorelin depot formulation was given intramuscularly when the follicular diameter of three follicles reached ≥ 20 mm and a total of 13 follicles reached ≥ 15 mm. Oocyte retrieval was scheduled for 36 h later and 10 mature oocytes were collected and vitrified. This case report demonstrates that a depot GnRH-agonist trigger effectively leads to mature oocyte retrieval, with the advantage of initiating ovarian suppression for the purpose of fertility preservation during adjuvant chemotherapy in breast-cancer patients.

Topics: Adult; Antineoplastic Agents; Aromatase Inhibitors; Breast Neoplasms; Cryopreservation; Delayed-Action Preparations; Female; Gonadotropin-Releasing Hormone; Humans; Infertility, Female; Oocyte Retrieval; Oocytes; Ovulation Induction; Treatment Outcome; Triptorelin Pamoate

Topics: Adult; Antineoplastic Agents; Breast Neoplasms; Female; Humans; Infertility, Female; Luteolytic Agents; Middle Aged; Premenopause; Primary Ovarian Insufficiency; Triptorelin Pamoate

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Humans; Menstrual Cycle; Ovary; Randomized Controlled Trials as Topic; Triptorelin Pamoate

Topics: Antineoplastic Agents; Breast Neoplasms; Female; Humans; Infertility, Female; Luteolytic Agents; Menopause; Primary Ovarian Insufficiency; Triptorelin Pamoate

Gonadotrophin releasing hormone (GnRH) analogs lower estrogen levels in pre-menopausal breast cancer patients. GnRH receptor (GnRH-R) activation also directly inhibits the growth of certain cells. The applicability of GnRH anti-proliferation to breast cancer was therefore analyzed.. GnRH-R expression in 298 primary breast cancer samples was measured by quantitative immunofluorescence. Levels of functional GnRH-R in breast-derived cell lines were assessed using 125I-ligand binding and stimulation of 3H-inositol phosphate production. Elevated levels of GnRH-R were stably expressed in cells by transfection. Effects of receptor activation on in vitro cell growth were investigated in comparison with IGF-I and EGF receptor inhibition, and correlated with intracellular signaling using western blotting.. GnRH-R immunoscoring was highest in hormone receptor (triple) negative and grade 3 breast tumors. However prior to transfection, functional endogenous GnRH-R were undetectable in four commonly studied breast cancer cell lines (MCF-7, ZR-75-1, T47D and MDA-MB-231). After transfection with GnRH-R, high levels of cell surface GnRH-R were detected in SVCT and MDA-MB-231 clones while low-moderate levels of GnRH-R occurred in MCF-7 clones and ZR-75-1 clones. MCF-7 sub-clones with high levels of GnRH-R were isolated following hygromycin phosphotransferase transfection. High level cell surface GnRH-R enabled induction of high levels of 3H-inositol phosphate and modest growth-inhibition in SVCT cells. In contrast, growth of MCF-7, ZR-75-1 or MDA-MB-231 clones was unaffected by GnRH-R activation. Cell growth was inhibited by IGF-I or EGF receptor inhibitors. IGF-I receptor inhibitor lowered levels of p-ERK1/2 in MCF-7 clones. Washout of IGF-I receptor inhibitor resulted in transient hyper-elevation of p-ERK1/2, but co-addition of GnRH-R agonist did not alter the dynamics of ERK1/2 re-phosphorylation.. Breast cancers exhibit a range of GnRH-R immunostaining, with higher levels of expression found in triple-negative and grade 3 cancers. However, functional cell surface receptors are rare in cultured cells. Intense GnRH-R signaling in transfected breast cancer cells did not markedly inhibit growth, in contrast to transfected HEK 293 cells indicating the importance of intracellular context. GnRH-R signaling could not counteract IGF-I receptor-tyrosine kinase addiction in MCF-7 cells. These results suggest that combinatorial strategies with growth factor inhibitors will be needed to enhance GnRH anti-proliferative effects in breast cancer.

Topics: Analysis of Variance; Antineoplastic Agents, Hormonal; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Fluorescent Antibody Technique; Humans; Inositol Phosphates; MAP Kinase Signaling System; Microarray Analysis; Polymerase Chain Reaction; Receptors, LHRH; Transfection; Triptorelin Pamoate

Gonadotropin releasing hormone (GnRH) has a pivotal role in the biology of reproduction processes. In extrapituitary compartments GnRH and its receptor act as a part of the autocrin regulatory system of cell proliferation, resulting in its anticancer activity. Here the anticancer activity of a new analogue of GnRH has been investigated. Results indicate that proliferation of human breast and ovarian cancer cell lines is dose-dependently inhibited. The inhibitory efficiency of this new analogue is proved to be higher than the original triptorelin. In addition to its antimitogenic activity, evidence was found for the involvement of the apoptotic mechanism in the action of the new analogue. Furthermore the presence of chemical groups in the peptide sequence is thought to increase the protease stability of the new analogue in comparison with triptorelin. Consequently our new analogue can be considered as a good pharmaceutical candidate.

Topics: Amino Acid Sequence; Antineoplastic Agents, Hormonal; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Gonadotropin-Releasing Hormone; Humans; Molecular Structure; Ovarian Neoplasms; Triptorelin Pamoate

Topics: Adult; Androstadienes; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Chemical and Drug Induced Liver Injury; Diphenhydramine; Drug Synergism; Estrogen Receptor Modulators; Fatal Outcome; Female; Hepatitis, Alcoholic; Humans; Hypnotics and Sedatives; Liver Failure, Acute; Middle Aged; Premenopause; Self Medication; Tamoxifen; Triptorelin Pamoate

The majority of human breast cancers and in addition most breast-cancer cell lines express gonadotropin-releasing hormone (GnRH) receptors. Their proliferation and in addition their bone-directed invasion is time- and dose-dependently reduced by GnRH. Osteolytic metastases are characteristic for breast cancer-derived metastasis. Since the osteolytic activity depends on the receptor activator of nuclear factor-kappaB (NFkappaB) ligand (RANKL)/osteoprotegerin (OPG) ratio, we analyzed RANKL and OPG expression in different breast-cancer cell lines.. Different human breast-cancer cell lines were tested for expression of GnRH receptor, OPG and RANKL. Using a co-culture system of breast-cancer cell lines and human primary osteoblasts (hOB), we analyzed the expression of OPG and RANKL in the GnRH receptor-positive breast-cancer cell line HCC70 co-cultured with or without hOB. In addition, we assessed the effects of GnRH analog treatment on OPG and RANKL mRNA and protein levels.. All tested breast-cancer cell lines were GnRH receptor-positive. The majority of these cell lines expressed OPG but not RANKL. The HCC70 breast-cancer cell line derived from an invasive ductal carcinoma with metastases was positive for both OPG and RANKL. The expression of RANKL by HCC70 cells was increased when co-cultured with hOB. Treatment with GnRH analogs reduced the expression of RANKL by HCC70 cells co-cultured with hOB. No effects were observed on breast cancer OPG expression.. These data show that the majority of human breast-cancer cell lines express OPG but not RANKL. The HCC70 breast-cancer cell line is RANKL-positive. Co-culture of HCC70 breast cancer cells with hOB increases RANKL expression. Activation of tumor GnRH receptors reduces RANKL expression. These experiments demonstrate that HCC70 breast cancer cells are able to activate osteoclasts directly via RANKL. The interaction between HCC70 breast cancer cells and osteoblasts induces osteoclastogenesis through an increase of RANKL expression. GnRH seems to play an important role by modulating the RANKL expression in HCC70 breast cancer cells.

Topics: Antineoplastic Agents, Hormonal; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Coculture Techniques; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Osteoblasts; Osteoprotegerin; RANK Ligand; Receptors, LHRH; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Triptorelin Pamoate

The majority of human endometrial, ovarian and breast cancers express receptors for gonadotropin-releasing hormone (GnRH). Their proliferation is time- and dose-dependently reduced by GnRH and its agonistic analogs. GnRH agonists inhibit the mitogenic signal transduction of growth factor receptors via activation of a phosphotyrosine phosphatase, resulting in downregulation of cancer cell proliferation. Induction of apoptosis is not involved. Recently we showed that the GnRH agonist triptorelin induces activation of nuclear factor-kappaB (NFkappaB) and thus reduces the apoptosis induced by the cytotoxic agent doxorubicin in human endometrial and ovarian cancer cells. The triptorelin-induced reduction of doxorubicin-induced apoptosis was blocked by inhibition of NFkappaB translocation into the nucleus. The present study was conducted to investigate whether knock-down of GnRH receptor expression reduces GnRH agonist-induced anti-apoptotic action. We show that knock-down of GnRH receptor expression results in an increase of doxorubicin-induced apoptosis in human endometrial and ovarian cancers and in the human breast cancer cell line MCF-7. These data further demonstrate that GnRH agonists suppress chemotherapeutic drug-induced apoptosis via activation of the GnRH receptor in these cancers. The situation is different with T-47-D breast cancer cells. After knock-down of GnRH receptor expression doxorubicin-induced apoptosis was decreased, indicating that GnRH agonists do not suppress chemotherapeutic drug-induced apoptosis in T-47-D breast cancer cells.

Topics: Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Doxorubicin; Drug Antagonism; Endometrial Neoplasms; Female; Gonadotropin-Releasing Hormone; Humans; Ovarian Neoplasms; Receptors, LHRH; Triptorelin Pamoate

We present the case of 48-year-old woman suffering from migraine with aura (MA) since menarche. During her life the patient frequently presented catamenial MA attacks with an increasing frequency during pregnancy in particular in the second and third trimesters, and then during breast-feeding. Treatment with oral contraceptive (OC) for endometriosis and later with cyclophosphamide, methotrexate, fluorouracil (CMF) for breast cancer produced a higher number of attacks. Instead, she referred an improvement with gonadotropin releasing hormone agonist (GnRH-a) for the treatment of endometriosis and then with tamoxifen as hormonal therapy after mastectomy and chemotherapy for breast cancer. We highlight the importance of physiological hormonal modification and hormonal therapies on the course of MA.

Topics: Amitriptyline; Analgesics; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Contraceptives, Oral, Hormonal; Cyclophosphamide; Endometriosis; Female; Flunarizine; Fluorouracil; Gonadotropin-Releasing Hormone; Humans; Methotrexate; Middle Aged; Migraine with Aura; Pregnancy; Selective Estrogen Receptor Modulators; Tamoxifen; Triptorelin Pamoate

Breast cancer remains the most common cancer among women, with an estimated 212,920 new cases and 40,970 deaths in the United States in 2006. The present work extends the studies of nanoparticles targeted to the luteinizing hormone-releasing hormone (LHRH) receptor which is overexpressed in breast, ovarian, endometrial and prostate cancer cells. In contrast, LHRH receptors are not expressed, or expressed at a low level in most visceral organs. In our studies, we conjugated Fe3O4 nanoparticles (20-30 nm) with [D-Trp6]LHRH (Triptorelin), a decapeptide analog of LHRH currently used for treatment of sex-hormone-dependent tumors. Conjugation of [D-Trp6]LHRH to Fe3O4 particles retained its binding affinity and biological activity for the LHRH receptor. Treatment of two separate breast tumor cell lines (MCF-7 and MDA-MB231) with these conjugated nanoparticles resulted in 95-98% cell death and loss of viability within 24 h whereas no change in cell proliferation or cell apoptosis was observed in cells treated with equal amounts of either [D-Trp6]LHRH or unconjugated Fe3O4 nanoparticles. These studies provide critical and important information regarding use of LHRH receptor targeted therapy for breast cancer.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Cell Death; Cell Line, Tumor; Cell Survival; Female; Ferric Compounds; Humans; Hydrogen-Ion Concentration; Metal Nanoparticles; Models, Chemical; Receptors, LHRH; Triptorelin Pamoate

About 50-64% of human breast cancers express receptors for GnRH-I. Direct antiproliferative effects of analogs of GnRH-I on human breast cancer cell lines have been shown. They are at least in part mediated by antagonizing growth promoting effects of estradiol, epidermal growth factor (EGF) or insulin-like growth factor. Recently, expression of a putative receptor for GnRH-II in human tissues was demonstrated. Antiproliferative effects of GnRH-II in human endometrial and ovarian cancer cells were shown not to be mediated through the GnRH-I receptor. Now we demonstrate direct anti-proliferative effects of the GnRH-I analog Triptorelin and the GnRH-II analog [d-Lys(6)]GnRH-II in MCF-7 and T47D human breast cancer cells expressing GnRH-I receptors and putative GnRH-II receptors. Pretreatment with Triptorelin or [d-Lys(6)]GnRH-II blocked EGF-induced autophosphoryla-tion of EGF receptor and activation of mitogen-activated protein kinase (extracellular-signal-regulated kinase 1/2 (ERK1/2)) in these cells. In sublines of MCF-7 and T47D cells, which were developed to be resistant to 4OH-tamoxifen, HER-2/p185 was overexpressed. Pretreatment of these cell lines with Triptorelin or [d-Lys(6)]GnRH-II completely abolished resistance to 4OH-tamoxifen, assessed by 4OH-tamoxifen-induced apoptosis. Analogs of GnRH-I and GnRH-II counteract EGF-dependent signal transduction in human breast cancer cells with expression of receptors for GnRH-I and GnRH-II. Through this mechanism, they probably reverse acquired resistance to 4OH-tamoxifen mediated through overexpression or activation of receptors of the c-erbB family.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Enzyme Activation; Epidermal Growth Factor; ErbB Receptors; Estrogen Antagonists; Extracellular Signal-Regulated MAP Kinases; Female; Gefitinib; Gonadotropin-Releasing Hormone; Humans; Phosphorylation; Quinazolines; Signal Transduction; Tamoxifen; Triptorelin Pamoate

The majority of human endometrial (>80%), ovarian (>80%) and breast (>50%) cancers express GnRH receptors. Their spontaneous and epidermal growth-factor-induced proliferation is dose- and time-dependently reduced by treatment with GnRH and its agonists. In this study, we demonstrate that the GnRH agonist triptorelin inhibits estradiol (E2)-induced cancer cell proliferation.. The proliferation of quiescent estrogen receptor alpha (ER alpha)-/ER beta-positive, but not of ER alpha-negative/ER beta-positive endometrial, ovarian and breast cancer cell lines, was significantly stimulated (P<0.001) (ANOVA) after treatment with E2 (10(-8) M). This effect was time- and dose-dependently antagonized by simultaneous treatment with triptorelin. The inhibitory effect was maximal at 10(-5) M concentration of triptorelin (P<0.001). In addition, we could show that, in ER alpha-/ER beta-positive cell lines, E2 induces activation of serum response element (SRE) and expression of the immediate early-response gene c-fos. These effects were blocked by triptorelin (P<0.001). E2-induced activation of estrogen-response element (ERE) was not affected by triptorelin.. The transcriptional activation of SRE by E2 is due to ER alpha activation of the mitogen-activated protein kinase (MAPK) pathway. This pathway is impeded by GnRH, resulting in a reduction of E2-induced SRE activation and, in consequence, a reduction of E2-induced c-fos expression. This causes downregulation of E2-induced cancer cell proliferation.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Cell Division; Cell Line, Tumor; Dose-Response Relationship, Drug; Endometrial Neoplasms; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Female; Gene Expression; Genes, fos; Genital Neoplasms, Female; Gonadotropin-Releasing Hormone; Humans; Ovarian Neoplasms; Proto-Oncogene Proteins c-fos; Response Elements; Serum Response Element; Triptorelin Pamoate

Topics: Adult; Alopecia; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Hormones; Humans; Letrozole; Nitriles; Premenopause; Triazoles; Triptorelin Pamoate

The present study evaluates the potential beneficial effect of co-treatment with LHRH-agonist in resolving premenopausal tamoxifen's induced supraphysiological serum 17beta estradiol levels and persistent ovarian cysts. Ultrasonographic and serum hormonal evaluations were performed before, during, and following three consecutive injections of long acting LHRH-agonist administered to 14 premenopausal breast cancer patients treated with tamoxifen, who had supraphysiological serum 17beta estradiol levels and simultaneous persistent ovarian cysts. Within 3 weeks of the first LHRH-agonist injection, all patients had menopausal serum estradiol levels. Ovarian cysts completely disappeared within 2 months following the first injection. Following the discontinuation of LHRH-agonist co-treatment, serum estradiol levels remained in physiological levels and the ovaries remained a normal size in 64.3% of the patients for 13.3 +/- 11.5 months. 28.6% of the patients had a gradual reappearance of high serum estradiol levels and of ovarian cysts, and were, therefore, treated with a second course of LHRH-agonist. Following the second course, serum estradiol levels remained in physiological levels and the ovaries remained a normal size for 8-15 months. It is concluded that short duration of co-treatment with long acting LHRH-agonist administered to premenopausal breast cancer patients treated with tamoxifen, successfully resolved the tamoxifen-induced supraphysiological serum 17beta estradiol levels and the ovarian cysts.

Topics: Adult; Antineoplastic Agents, Hormonal; Breast Neoplasms; Drug Evaluation; Estradiol; Female; Follicle Stimulating Hormone; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Middle Aged; Ovarian Cysts; Ovarian Hyperstimulation Syndrome; Premenopause; Progesterone; Tamoxifen; Triptorelin Pamoate; Ultrasonography

To present our clinical experience with gonadotropin-releasing hormone agonist (GnRHa) treatment of tamoxifen-treated women who had developed ovarian cysts, and to discuss the diagnostic and therapeutic options in such cases.. The study included six tamoxifen-treated premenopausal women with breast cancer who developed ovarian cysts and were followed up by our outpatient clinic. Tamoxifen was administered orally (20 mg/day). All patients underwent a pelvic examination and vaginal ultrasound using a 5-MHz vaginal probe. Blood samples for serum gonadotropins, estradiol (E2) and CA 125 levels were collected at the time of the ovarian cyst detection and every month thereafter. After detection of an ovarian cyst, the women were treated by monthly injections of GnRHa.. The patients' mean age was 44 years (range 37-51 years) and all had stage-II or -III breast cancer. The mean duration of tamoxifen administration at the time of ovarian cyst detection was 15 months (range 3-40 months). All six ovarian cysts were found to be simple cysts, measuring more than 30 x 30 mm. Serum E2 levels of the six patients at the time of ovarian cyst detection were between 939 and 1796 pg/ml and were suppressed to less than 25 pg/ml after GnRHa therapy. After between three and six monthly injections of GnRHa all six ovarian cysts disappeared. On follow-up 6 months later, all patients had a normal pelvic examination.. The findings of this preliminary report suggest that GnRHa might be an appropriate treatment for tamoxifen-treated women who develop ovarian cysts. It was demonstrated that the GnRHa caused regression of the ovarian cysts and enabled continuation with the adjuvant tamoxifen treatment.

Topics: Adult; Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Humans; Middle Aged; Ovarian Cysts; Tamoxifen; Treatment Outcome; Triptorelin Pamoate

The effects of the polypeptide Decapeptyl (a gonadotropin-releasing hormone (GnRH) agonist analogue) and of transforming growth factor-alpha (TGF-alpha), on estrone sulfate-sulfatase activities in the homogenates of various breast cancer cell lines were studied in the presence of heparin. In hormone-dependent MCF-7 breast cancer cells, Decapeptyl can inhibit sulfatase activity, and this effect is significantly augmented in the presence of heparin. In the other hormone-dependent T-47D breast cancer cell line, the decrease of sulfatase activity was only significant when Decapeptyl was associated with heparin. No significant effect on sulfatase activity elicited by heparin, Decapeptyl or a mixture of both was found in the hormone-independent MDA-MB-231 breast cancer cells. TGF-alpha stimulates sulfatase activity in the MDA-MB-231 cells but has no effect in the MCF-7 cells; in contrast, TGF-alpha combined with heparin provokes a decrease of the sulfatase activity in both cell lines. It is concluded that the sulfatase activity in some types of breast cancer cell can be inhibited by heparin combined with the polypeptides Decapeptyl or TGF-alpha.

Topics: Arylsulfatases; Breast Neoplasms; Dose-Response Relationship, Drug; Drug Interactions; Heparin; Humans; Steryl-Sulfatase; Transforming Growth Factor alpha; Triptorelin Pamoate; Tumor Cells, Cultured

Topics: Adenocarcinoma; Aged; Breast Neoplasms; Female; Humans; Lung Neoplasms; Menopause; Radiography; Triptorelin Pamoate

Pre-menopausal tamoxifen treatment causes hyperoestrogen production and ovarian cyst formation. Two pre-menopausal breast cancer patients who were treated with tamoxifen developed both permanent supraphysiological oestrogen concentration and ovarian cysts. Serum oestrogen decreased to post-menopausal concentrations and ovarian cysts completely resolved during and following simultaneous treatment with tamoxifen and gonadotrophin-releasing hormone agonist (GnRHa). In pre-menopausal breast cancer patients, GnRHa may prevent possible side-effects of tamoxifen, such as ovarian cysts and supraphysiological oestrogen production.

Topics: Adult; Breast Neoplasms; Estradiol; Female; Humans; Ovarian Cysts; Premenopause; Tamoxifen; Triptorelin Pamoate

In literature there have been only 8 cases of unavoidable laparotomy due to uterine leiomyomas performed in patients with breast cancer on Tamoxifen (TAM). Our article describes two cases of rapidly growing leiomyomas in patients treated with TAM: one of these underwent abdominal hysterectomy while the second stopped taking TAM and began therapy with Triptorelin. This therapeutical alternative could be a useful choice.

Topics: Adult; Breast Neoplasms; Female; Humans; Leiomyoma; Middle Aged; Tamoxifen; Triptorelin Pamoate; Uterine Neoplasms

The effects of triptorelin (Decapeptyl) and heparin, alone or in combination, on the intracellular concentration of estradiol (E2) after incubation of estrone sulfate (E1S) with the MCF-7 mammary cancer cells was investigated. Although heparin (10 mg/l culture medium) or Decapeptyl (5 x 10(-7) or 5 x 10(-5) mol/l) did not affect the levels of radioactive E2 after incubation with [3H]E1S, the combination of Decapeptyl and heparin significantly decreased the radioactive uptake and the intracellular concentrations of [3H]E2. In the absence of Decapeptyl and heparin incubations with E1S, the resulting E2 concentration (in nmol/kg DNA +/- SD) was 558 +/- 44; after heparin (10 mg/l) plus Decapeptyl (5 x 10(-7) or 5 x 10(-5) mol/l) the values were 389 +/- 55 and 165 +/- 18, respectively. It is concluded that Decapeptyl with heparin can decrease very significantly the conversion of E1S to E2 in MCF-7 cells, an observation that suggests new possibilities for the control of E2 in hormone-dependent breast cancer.

Topics: Breast Neoplasms; Estradiol; Estrone; Heparin; Humans; Triptorelin Pamoate; Tumor Cells, Cultured

The binding characteristics of several cytotoxic analogs of luteinizing hormone-releasing hormone (LH-RH) developed in our laboratory were examined in membranes from human breast cancer and estrogen independent MXT mammary cancer. Specific binding of [125I]D-Trp6-LH-RH and the cytotoxic LH-RH analog [125I]T-98 ([D-Lys6]LH-RH coupled to glutaryl-2-(hydroxymethyl)anthraquinone) (HMAQG) was demonstrated in membrane preparations from human breast and MXT mammary tumor cells. Ligand binding of T-98 was specific, saturable, and dependent on temperature, time, and plasma membrane concentration. Analysis of the binding data showed that in human breast cancer, interaction of [125I]T-98 was consistent with the presence of two classes of LH-RH receptors, one class showing high affinity and low capacity, and the other class showing low affinity and high capacity binding. In membranes from MXT mammary cancer, T-98 bound to one class of saturable, specific, noncooperative binding sites with high affinity and low capacity. The rates of association and dissociation for [125I]T-98 were calculated to be 4.757 x 10(8) M-1 min-1 and 0.016 min-1 (t1/2 = 38.7) in membranes from MXT mammary cancer. In human breast cancer, association rate constants (K1a and K1b) were 2.3 x 10(6) M-1 min-1 for binding to high affinity and 1.8 x 10(4) M-1 min-1 for binding to low affinity binding sites. Dissociation rate constants were K-1a = 0.0801 min-1 (t1/2a = 63.4 min) and K-1b = 0.0467 min-1 (t1/2b = 23.5 min), respectively. [125I]T-98 was not displaced by either unlabeled somatostatin or epidermal growth factor, but was displaced completely by unlabeled T-98 or [D-Trp6]LH-RH. The analysis of displacement curves of [D-Trp6]LH-RH by cytotoxic agonists and antagonists of LH-RH synthesized in our laboratory showed that T-121, AJ-11, T-120, T-133, and T-98 were the most potent in displacing [125I]D-Trp6-LH-RH from breast and MXT cancer membranes. Binding kinetics and analyses of displacement curves of [125I]D-Trp6-LH-RH and [125I]T-98 in membranes of human breast cancer and estrogen independent MXT mouse mammary cancer suggest that binding of the cytotoxic analog T-98 to the LH-RH receptor proceeds reversibly like that of its congeners without cytotoxic radicals. Our findings may provide a stimulus for further studies with LH-RH analogs carrying cytotoxic radicals.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adult; Aged; Aged, 80 and over; Animals; Breast Neoplasms; Female; Gonadotropin-Releasing Hormone; Humans; Mammary Neoplasms, Animal; Mice; Middle Aged; Neoplasms, Hormone-Dependent; Temperature; Time Factors; Triptorelin Pamoate; Tumor Cells, Cultured

The binding of luteinizing hormone-releasing hormone (LH-RH) analogues to the human mammary tumor cell line MCF-7 and their effect on the cell proliferation was studied to elucidate their direct action on estrogen-dependent mammary tumors. The growth rate of these cells was doubled by the addition of 1 nM estradiol to cells maintained in an estrogen-deficient medium. Although the basal growth rate was only slightly inhibited by the LH-RH antagonist [Ac-D-Nal(2)1,D-Phe(pCl)2,D-Pal(3)3,D-Cit6,D-Ala10]LH-RH (SB-75), the estrogen-stimulated growth was completely abolished by the antagonist. In contrast, the LH-RH agonist buserelin stimulated cell growth in estrogen-deficient medium, whereas it had no effect in the presence of estrogen. 125I-labeled buserelin was used for the measurement of LH-RH receptors on MCF-7 cells. A Scatchard plot analysis of buserelin-specific binding revealed a nonlinear plot, which suggested the presence of one high-affinity binding site with a Kd of 1.4 +/- 1.0 nM and the remaining sites with low affinity (Kd = 1.3 +/- 1.0 microM). The binding of 125I-labeled buserelin was displaced equally well by unlabeled buserelin and by the LH-RH antagonist SB-75, suggesting that both analogues are bound to the same receptor. When parallel experiments were performed with 125I-labeled SB-75, the binding was displaced by unlabeled SB-75 and other antagonists, but only partially displaced by unlabeled buserelin. The results suggest that in these mammary tumor cells there is a LH-RH antagonist binding site that is not recognizable by LH-RH agonists. This hypothesis was tested by measuring cell growth in the presence of both agonists and antagonists. It was found that SB-75 inhibited the stimulation of growth by buserelin, but buserelin did not prevent the inhibition by the antagonist of the estrogen-dependent growth. These results suggest that antagonists directly inhibit mammary tumor growth, not only by competing with LH-RH high-affinity receptors, but also by other mechanisms mediated by low-affinity antagonist binding sites.

Topics: Antineoplastic Agents; Breast Neoplasms; Buserelin; Cell Division; Dose-Response Relationship, Drug; Estradiol; Female; Gonadotropin-Releasing Hormone; Humans; Kinetics; Receptors, LHRH; Triptorelin Pamoate

We have been interested in the possible direct effects of luteinizing hormone releasing hormone (LHRH) and somatostatin (SS) analogs on the growth of human mammary tumor cells. Four recently synthesized peptide hormones including the LHRH agonists D-Trp6-LHRH and zoladex, LHRH antagonists SB30 and SB75, and the somatostatin analog RC 160 were analyzed for their effects on DNA synthesis of MCF-7 breast cancer cells in culture. At 48 hr, D-Trp6-LHRH and SB30 did not show significant effects (dose range, 10(-12)-10(-6) M). However, the combination of these two peptides at 10(-10) M produced significant inhibition of 3[H]thymidine incorporation (50% control). At 72 hr in the absence of estradiol-stimulated growth, D-Trp6-LHRH showed inhibition at 10(-12) and 10(-10) M (P less than 0.005 and 0.001). At higher concentrations, no significant inhibition was noted. In contrast to D-Trp6, SB30 (antagonist) showed no inhibition but significant stimulation of DNA synthesis at 10(-6) and 10(-4) M. In the presence of added estradiol (10(-9) M), complete reversal of D-Trp6-LHRH analog inhibition is noted. In contrast, there is persistent stimulation by SB30 (P less than 0.001). At 96 hr, D-Trp6-LHRH continued to show maximal inhibition of 70% in the absence of estradiol. SB30 stimulated DNA synthesis 100% at 10(-6) M. At 72 hr, the SS analog RC 160 demonstrated significant inhibition (53%) that was similar to D-Trp6 and SB75 peptides.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antineoplastic Agents; Breast Neoplasms; Buserelin; Carcinoma; Cell Division; Estrogens; Gonadotropin-Releasing Hormone; Goserelin; Hormones; Humans; In Vitro Techniques; Somatostatin; Triptorelin Pamoate; Tumor Cells, Cultured

Human breast carcinoma (MCF-7 MIII), which exhibits an estrogen-independent but estrogen-responsive phenotype, was xenografted in 8-9-week-old intact female athymic nude mice without estrogen supplementation. In this model, we investigated inhibitory effects of the modern luteinizing hormone-releasing hormone (LH-RH) antagonist SB-75 and the agonist D-Trp6-LH-RH. The analogs were administered in the form of sustained delivery systems (microcapsules and microgranules). In the first experiment, treatment lasted 10 weeks. After 9 weeks of treatment, a significant inhibition of tumor volume was first found only in the group treated with SB-75, but the final tumor volume was significantly suppressed both by D-Trp6-LH-RH and SB-75. In the second experiment, treatment was started 70 days after tumor transplantation and was continued for 6 weeks. Chronic treatment with SB-75 or D-Trp6-LH-RH appeared to completely arrest tumor growth as measured by tumor volume, percentage change in tumor volume, and tumor weight. Serum estradiol was suppressed to undetectable levels and LH levels were also diminished. Histologically, the regressive changes in the treated tumors were due to the enhancement of apoptosis (programmed cell death) of tumor cells. Membrane receptor assays showed that LH-RH binding sites were down-regulated in tumor cells after treatment with SB-75 or D-Trp6-LH-RH. The results indicate that the antagonist SB-75, released from sustained delivery systems, can inhibit the growth of MCF-7 MIII tumors as effectively as the agonist D-Trp6-LH-RH, but more rapidly. In view of its immediate blockade of the pituitary-gonadal axis and the absence of side effects, the LH-RH antagonist SB-75 might be considered as a possible new hormonal agent for the treatment of breast cancer.

Topics: Adenocarcinoma; Animals; Breast Neoplasms; Estrogens; Female; Gonadotropin-Releasing Hormone; Humans; Incidence; Injections, Subcutaneous; Insulin-Like Growth Factor I; Luteinizing Hormone; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Hormone-Dependent; Ovariectomy; Transplantation, Heterologous; Triptorelin Pamoate; Tumor Cells, Cultured

Analogues of somatostatin (SS) and luteinizing hormone-releasing hormone (LH-RH) activate tyrosine phosphatases in MIA PaCa-2 human pancreatic cancer cell line membranes and inhibit growth. We compared the substrates phosphorylated by epidermal growth factor (EGF) to those dephosphorylated by the SS analogue RC-160 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2) and [D-Trp6]LH-RH in cancer cell lines such as MIA PaCa-2 (human pancreatic cancer), HCPC (hamster cheek pouch carcinoma), A-549 (human lung cancer), HT-29 (human colon cancer), and R3230AC (breast cancer). EGF phosphorylated proteins of 170, 65, and 60 kDa and analogues of SS and LH-RH promoted the dephosphorylation of these proteins in MIA PaCa-2 and HCPC cell lines. The EGF receptor is 170 kDa. pp60src (60 kDa) is known to be a substrate for EGF receptor. The LH-RH receptor is also 60 kDa. The effects of RC-160 and [D-Trp6]LH-RH were quantitatively different. Examinations of HT-29, A-549, and R3230AC cancer cell lines revealed no phosphorylation by EGF or dephosphorylation by RC-160 and [D-Trp6]LH-RH. In addition to the 170-, 65-, and 60-kDa proteins, 35-kDa proteins were also phosphorylated in some cancer cell lines. This work demonstrates that analogues of SS and LH-RH can reverse the effects of EGF biochemically as well as functionally.

Topics: Amino Acid Sequence; Animals; Antineoplastic Agents; Autoradiography; Breast Neoplasms; Cell Line; Colonic Neoplasms; Epidermal Growth Factor; Gonadotropin-Releasing Hormone; Humans; Kinetics; Lung Neoplasms; Membrane Proteins; Molecular Sequence Data; Pancreatic Neoplasms; Phosphorus Radioisotopes; Phosphorylation; Protein Kinases; Protein-Tyrosine Kinases; Somatostatin; Triptorelin Pamoate; Tyrosine

Topics: Breast Neoplasms; Contraceptives, Oral; Delayed-Action Preparations; Estrogen Replacement Therapy; Female; Gonadotropin-Releasing Hormone; Humans; Ovulation; Pilot Projects; Risk Factors; Triptorelin Pamoate

Antiestrogens, such as tamoxifen, have a direct antitumor action and are widely used in cancer therapy. The direct antitumor action of GnRH analogs has been documented in both in vitro and clinical studies. GnRH analog direct action could therefore provide an alternative approach in postmenopausal patients developing antiestrogen resistance, a frequent cause of relapse during hormonal treatment of breast cancer. This study was carried out to compare the effects of two GnRH analogs (the agonist Decapeptyl and the antagonist BIM 21009C) and the antiestrogen 4-hydroxy-tamoxifen (OH-TAM) on proliferation in antiestrogen-responsive or antiestrogen-resistant human breast cancer cell lines (MCF-7, MCF-7 LY2). Ineffective when used without estrogen stimulation, both of the GnRH analogs and OH-TAM inhibit the 17 beta-estradiol-stimulated growth of the estrogen-responsive cell line MCF-7. Compared with parental MCF-7 cell line responsiveness, the antiestrogen-resistant variant MCF-7 LY2 appears to be resistant to GnRH analogs. These findings indicate similarities between the two types of compounds with regard to their antiestrogenic effects on growth observed in vitro. However, since unlike OH-TAM, Decapeptyl displays no effect on steroid receptor levels of sensitive MCF-7 cells, the intracellular inhibitory mechanisms of these drugs are probably in part different. This study suggests that the direct effect of the studied GnRH analogs would not be a potent tool for treating antiestrogen-resistant breast tumors.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Division; Drug Screening Assays, Antitumor; Estradiol; Estrogen Antagonists; Estrogens; Gonadotropin-Releasing Hormone; Humans; Receptors, Steroid; Stimulation, Chemical; Tamoxifen; Triptorelin Pamoate; Tumor Cells, Cultured

Topics: Adenocarcinoma; Adult; Breast Neoplasms; Buserelin; Combined Modality Therapy; Cyproterone; Cyproterone Acetate; Femoral Neoplasms; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Male; Tamoxifen; Triptorelin Pamoate

Binding capacities and apparent dissociation constants of receptors for [D-Trp6]-luteinizing hormone-releasing hormone [( D-Trp6]-LH-RH), somatostatin (SS-14), epidermal growth factor (EGF), and estrogen and progesterone were determined in 500 breast cancer specimens using multipoint assays. Specific binding sites greater than 10 fmol/mg cytosol protein for estrogen were found in 408 carcinomas (81.6%), and for progesterone in 340 specimens (68%). High affinity EGF receptors were present in membrane preparations from 335 samples (67%). In 260 of 500 samples (52%), two classes of [D-Trp6]-LH-RH membrane receptor sites were also detected, one class showing high affinity and low capacity, and the other class showing low affinity and high capacity; 178 biopsy samples (35.6%) exhibited binding sites for SS-14. Statistically significant inverse correlations were found between the binding capacities of estrogen and EGF receptors as well as between Bmax of progesterone and EGF receptors. Significant positive correlations were demonstrated between binding capacities of estrogen and progesterone and between Bmax of high affinity and low affinity binding sites of [D-Trp6]-LH-RH receptors. However, no correlation was found between the dissociation constants of different receptor sites in human breast cancer specimens. These results demonstrate that numerous human breast cancers, in addition to receptors for estrogen and progesterone, also show binding sites for EGF, [D-Trp6]-LH-RH and SS-14. The methods described herein permit a routine quantification of receptor sites for [D-Trp6]-LH-RH, SS-14, and EGF in membrane preparations of biopsy samples of breast cancer and can be used in conjunction with the determination of estrogen and progesterone receptors in nuclear-cytosolic extracts. The simultaneous measurements using a microanalytic approach allow the determination of peptide and steroid hormone receptors that might be involved in the response mechanisms of human breast cancer. It should be possible to correlate the levels of these receptors with clinical parameters to better identify endocrine-responsive neoplasms. This approach might be useful to guide a rational hormonal therapy in women with breast cancer.

Topics: Adult; Aged; Aged, 80 and over; Animals; Biopsy; Breast Neoplasms; ErbB Receptors; Female; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Receptors, LHRH; Receptors, Neurotransmitter; Receptors, Somatostatin; Receptors, Steroid; Somatostatin; Triptorelin Pamoate

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Capsules; Gonadotropin-Releasing Hormone; Humans; Injections, Intramuscular; Male; Mammary Neoplasms, Experimental; Neoplasms, Hormone-Dependent; Octreotide; Pancreatic Neoplasms; Prostatic Neoplasms; Rats; Somatostatin; Triptorelin Pamoate

We report two cases of metastatic breast cancer occurring in two postmenopausal women. Treatment with a luteinizing hormone-releasing hormone (LHRH) analogue, D-TRP6-LHRH, induced partial remission. The blood levels of the follicle stimulating hormone (FSH) and luteinizing hormone (LH) fell sharply under treatment, but the levels of estradiol, estriol, and estrone did not change significantly. We also described the putative mechanisms of action of the LHRH analog.

Topics: Aged; Aged, 80 and over; Breast Neoplasms; Estradiol; Estriol; Estrone; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Menopause; Triptorelin Pamoate