Sara Giraudi

Effect of the Gonadotropin-Releasing Hormone Analogue Triptorelin on the Occurrence of Chemotherapy-Induced Early Menopause in Premenopausal Women With Breast Cancer: A Randomized Trial

CONTEXT 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. OBJECTIVE 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. DESIGN, SETTING, AND PATIENTS 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. INTERVENTIONS 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. MAIN OUTCOME MEASURE 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). RESULTS 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). CONCLUSION 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. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00311636.

Gonadotropin-releasing hormone analogues for the prevention of chemotherapy-induced premature ovarian failure in cancer women: systematic review and meta-analysis of randomized trials.

BACKGROUND The role of temporary ovarian suppression with gonadotropin-releasing hormone analogues (GnRHa) in the prevention of chemotherapy-induced premature ovarian failure (POF) is still controversial. We conducted a systematic review and meta-analysis of randomized trials evaluating the efficacy of GnRHa, given before and during chemotherapy, in the prevention of POF in premenopausal cancer patients. METHODS Studies were retrieved by searching PubMed, Web of Knowledge database and the proceedings of major conferences. We calculated Odds Ratios (OR) and 95% confidence intervals (CIs) for POF from each trial and obtained pooled estimates through the random effects model as suggested by DerSimonian and Laird. RESULTS Nine studies were included in the meta-analysis with 225 events of POF occurring in 765 analyzed patients. The pooled OR estimate indicates a highly significant reduction in the risk of POF (OR=0.43; 95% CI: 0.22-0.84; p=0.013) in patients receiving GnRHa. There was statistically significant heterogeneity among studies (I(2)=55.8%; p=0.012). There was no evidence of publication bias. Subgroups analyses showed that the protective effect of GnRHa against POF was similar in subgroups of patients defined by age and timing of POF assessment, while it was present in breast cancer but unclear in ovarian cancer and lymphoma patients. CONCLUSIONS Our pooled analysis of randomized studies shows that the temporary ovarian suppression induced by GnRHa significantly reduces the risk of chemotherapy-induced POF in young cancer patients.

Ovarian Suppression With Triptorelin During Adjuvant Breast Cancer Chemotherapy and Long-term Ovarian Function, Pregnancies, and Disease-Free Survival: A Randomized Clinical Trial.

IMPORTANCE Whether the administration of luteinizing hormone-releasing hormone analogues (LHRHa) during chemotherapy is a reliable strategy to preserve ovarian function is controversial owing to both the lack of data on long-term ovarian function and pregnancies and the safety concerns about the potential negative interactions between endocrine therapy and chemotherapy. OBJECTIVE To evaluate long-term results of LHRHa-induced ovarian suppression during breast cancer chemotherapy. DESIGN, SETTING, AND PARTICIPANTS Parallel, randomized, open-label, phase 3 superiority trial conducted at 16 Italian sites. Between October 2003 and January 2008, 281 premenopausal women with stage I to III hormone receptor-positive or hormone receptor-negative breast cancer were enrolled. Last annual follow-up was June 3, 2014. INTERVENTIONS Patients were randomized to receive adjuvant or neoadjuvant chemotherapy alone (control group) or chemotherapy plus triptorelin (LHRHa group). MAIN OUTCOMES AND MEASURES The primary planned end point was incidence of chemotherapy-induced early menopause. Post hoc end points were long-term ovarian function (evaluated by yearly assessment of menstrual activity and defined as resumed by the occurrence of at least 1 menstrual cycle), pregnancies, and disease-free survival (DFS). RESULTS A total of 281 women (median age, 39 [range, 24-45] years) were randomized. Median follow-up was 7.3 years (interquartile range, 6.3-8.2 years). The 5-year cumulative incidence estimate of menstrual resumption was 72.6% (95% CI, 65.7%-80.3%) among the 148 patients in the LHRHa group and 64.0% (95% CI, 56.2%-72.8%) among the 133 patients in the control group (hazard ratio [HR], 1.28 [95% CI, 0.98-1.68]; P = .07; age-adjusted HR, 1.48 [95% CI, 1.12-1.95]; P = .006). Eight pregnancies (5-year cumulative incidence estimate of pregnancy, 2.1% [95% CI, 0.7%-6.3%]) occurred in the LHRHa group and 3 (5-year cumulative incidence estimate of pregnancy, 1.6% [95% CI, 0.4%-6.2%]) in the control group (HR, 2.56 [95% CI, 0.68-9.60]; P = .14; age-adjusted HR, 2.40 [95% CI, 0.62-9.22]; P = .20). Five-year DFS was 80.5% (95% CI, 73.1%-86.1%) in the LHRHa group and 83.7% (95% CI, 76.1%-89.1%) in the control group (LHRHa vs control: HR, 1.17 [95% CI, 0.72-1.92]; P = .52). CONCLUSIONS AND RELEVANCE Among premenopausal women with either hormone receptor-positive or hormone receptor-negative breast cancer, concurrent administration of triptorelin and chemotherapy, compared with chemotherapy alone, was associated with higher long-term probability of ovarian function recovery, without a statistically significant difference in pregnancy rate. There was no statistically significant difference in DFS for women assigned to triptorelin and those assigned to chemotherapy alone, although study power was limited. TRIAL REGISTRATION clinicaltrials.gov Identifier:NCT00311636.

Medical approaches to preservation of fertility in female cancer patients

Introduction: The loss or impairment of ovarian function is an irreversible side effect that can occur in young cancer patients undergoing anticancer treatments. Its incidence varies according to the type of chemotherapy and the patients age. Areas covered: The review includes studies or data available in literature from 1987 to 2010, examining current strategies to protect ovarian function and/or fertility in patients undergoing chemotherapy, which include oocyte, embryo or ovarian tissue cryopreservation, and temporary ovarian suppression during chemotherapy obtained by the administration of gonadotropin-releasing hormone analogues (GnRHa). The reader will gain an understanding of the incidence of premature ovarian function loss associated with chemotherapy; the advantages and disadvantages of the different strategies in protecting ovarian function; and the magnitude of the effect of GnRHa strategy in preserving ovarian function during chemotherapy. Expert opinion: The administration of GnRHa before and during chemotherapy is associated with an absolute reduction in the incidence of early menopause of nearly 20%. Such a strategy may be offered to young cancer patients who are candidates for chemotherapy. The capability of such an approach in inducing long-term preservation of ovarian function including fertility is still unknown.

Luteinising hormone releasing hormone agonists (LH-RHa) in premenopausal early breast cancer patients: Current role and future perspectives

Luteinising hormone releasing hormone agonists (LH-RHa) induce ovarian suppression in premenopausal women that is usually reversible on cessation of therapy. They act by binding to pituitary LH-RH receptors, resulting in down regulation of receptors and subsequent suppression of luteinising hormone and estradiol. LH-RHa are effective in the treatment of advanced breast cancer in premenopausal women but their role as adjuvant treatment of early breast cancer is still controversial. Approximately 60% of tumors in premenopausal women are hormone sensitive and these patients are candidates for hormonal treatment. Tamoxifen for 5 years is considered the standard endocrine therapy for all premenopausal women with hormone sensitive breast cancer. There is no definitive evidence of additional benefit associated with the use of LH-RHa administered as an alternative or in addition to tamoxifen. In this review we discuss available data on the role of LH-RHa alone or in combination with tamoxifen; on the role of LH-RHa in combination with aromatase inhibitors; and on the potential role of LH-RHa as a strategy to preserve ovarian function during adjuvant chemotherapy.

Estrone Sulphate, FSH, and Testosterone Levels in Two Male Breast Cancer Patients Treated with Aromatase Inhibitors

Estrone sulphate, follicle-stimulating hormone, and testosterone levels in male breast cancer patients treated with aromatase inhibitors are examined.

Trastuzumab as first-line therapy in HER2-positive metastatic breast cancer patients

Trastuzumab is a humanized monoclonal antibody against the extracellular domain of hEGF receptor-2 (HER2). Trastuzumab in combination with chemotherapy has proven efficacy in treating both early and metastatic HER2-positive breast cancer. In the metastatic setting, the addition of trastuzumab to chemotherapy is associated with a statistically significant longer time to disease progression, higher rate of objective response and improvement in overall survival. Trastuzumab efficacy is not influenced by hormone receptor status, but differences in median overall survival exist between HER2-positive and HER2-negative states. Reassessment of the benefit of re-exposing patients with metastatic breast cancer to trastuzumab following relapse in the adjuvant setting is necessary. Ongoing research into new HER2-targeted therapies and trials involving combination anti-HER2 drug therapy without chemotherapy show promise. This review is focused on the available results obtained with the use of trastuzumab in the subset of HER2-positive breast cancer patients with metastatic disease.

Long-term outcome results of the phase III PROMISE-GIM6 study evaluating the role of LHRH analog (LHRHa) during chemotherapy (CT) as a strategy to reduce ovarian failure in early breast cancer (BC) patients.

105 Background: The PROMISE-GIM6 phase III randomized study showed that the use of triptorelin-induced temporary ovarian suppression during CT in premenopausal patients with early-stage BC reduced the occurrence of CT-induced early menopause (Del Mastro L, JAMA 2011). The 2013 ASCO and ESMO guidelines on fertility preservation in cancer patients consider this strategy still experimental due to the absence of data on long-term ovarian function and pregnancy rates, and some concerns exist on the safety of this procedure particularly for hormone-receptor positive BC patients. The present analysis reports long-term outcome results of the study. METHODS From October 2003 to January 2008, 281 premenopausal women with stage I through III BC who were candidates for adjuvant or neoadjuvant CT were randomized to receive CT alone or combined with triptorelin. The primary objective was to compare the incidence of CT-induced early menopause in patients treated with CT alone or combined with triptorelin. The present analysis considers data on recurrences, pregnancies and long-term ovarian function. RESULTS A total of 133 pts were enrolled in the CT alone arm and 148 in the CT + LHRHa arm; 82% and 79% of pts had hormone receptor positive-disease, respectively. The median follow-up at the time of the analysis was 7.3 years (interquartile range: 6.3-8.2 years). No differences in the 5-year disease-free survival (DFS) between treatment arms were observed (83.7% in CT alone arm vs 80.5% in CT plus LHRHa: HR=1.17; 95% CI 0.72-1.92, p=0.519). After the end of adjuvant treatments, 4 pregnancies (3.0%; incidence rate per 100 person-year=0.4) occurred in the CT-alone group and 8 pregnancies (5.4%; incidence rate per 100 person-year=0.8) occurred in the CT plus triptorelin group (CT + LHRHa arm vs CT alone: OR=1.84; 95% CI 0.54-6.27, p=0.39). CONCLUSIONS The administration of LHRHa with CT was associated with the occurrence of more pregnancies; no differences in DFS were observed. The analysis on long-term ovarian function is still ongoing and will be presented at the meeting. CLINICAL TRIAL INFORMATION NCT00311636.

Body mass index and circulating oestrone sulphate in women treated with adjuvant letrozole

Background:Obesity is an independent adverse prognostic factor in early breast cancer patients, but it is still controversial whether obesity may affect adjuvant endocrine therapy efficacy. The aim of our study (ancillary to the two clinical trials Gruppo Italiano Mammella (GIM)4 and GIM5) was to investigate whether the circulating oestrogen levels during treatment with the aromatase inhibitor letrozole are related to body mass index (BMI) in postmenopausal women with breast cancer.Methods:Plasma concentration of oestrone sulphate (ES) was evaluated by radioimmunoassay in 370 patients. Plasma samples were obtained after at least 6 weeks of letrozole therapy (steady-state time). Patients were divided into four groups according to BMI. Differences among the geometric means (by ANOVA and ANCOVA) and correlation (by Spearman’s rho) between the ES levels and BMI were assessed.Results:Picomolar geometric mean values (95% confidence interval, n=patients) of circulating ES during letrozole were 58.6 (51.0–67.2, n=150) when BMI was <25.0 kg m−2; 65.6 (57.8–74.6, n=154) when 25.0–29.9 kg m−2; 59.3 (47.1–74.6, n=50) when 30.0–34.9 kg m−2; and 43.3 (23.0–81.7, n=16) when ⩾35.0 kg m−2. No statistically significant difference in terms of ES levels among groups and no correlation with BMI were observed.Conclusions:Body mass index does not seem to affect circulating oestrogen levels in letrozole-treated patients.

Use in current clinical practice of 70-gene signature in early breast cancer

on 21 early breast cancer patients. All patients gavewritten informed consent approved by the Ethic Committee.After the breast tumor was removed, a tumor sample wasstored by pathologist and sent to Agendia for MammaPrint test.Nine patients had a MammaPrint result which is not use-ful for clinical decision about adjuvant chemotherapy because3 were ductal carcinoma in situ, 4 (22%) had quality of sam-ples not sufficient to perform the MammaPrint assay and 2had both oestrogen- and progesterone-receptors negative andthen patients were candidates for chemotherapy regardlessthe MammaPrint results.In the remaining 12 cases (67%) both clinical risk (definedby clinical-pathological parameters) and MammaPrint riskwere considered for decision-making about adjuvant treat-ment. All cases were discussed in the Breast Disease Manage-ment Team with the presence of medical oncologists, sur-geons and pathologists. Characteristics of the 12 patients areshowed in Table 1.In five (42%) cases (2, 4, 5, 6, 11) clinical risk was dis-cordant with the risk estimated by MammaPrint. In thesecases decision about chemotherapy was based on clinical-pathological factors and disagreed with MammaPrint risk. Infact, in our Institute we recommend chemotherapy in endo-crine-responsive patients with node-positive (2 and 5) or T2tumor or G3 or age 35 years. Conversely, we do not recom-mend usually chemotherapy in endocrine-responsive patientswith age 70 years (4 and 6). Patient 11 had a lobular inva-sive carcinoma and, although she had a T2, we did not rec-ommend chemotherapy because lobular invasive carcinomaappeared to be less responsive to chemotherapy.