The PREgnancy and FERtility (PREFER) study: an Italian multicenter prospective cohort study on fertility preservation and pregnancy issues in young breast cancer patients.

BACKGROUND: Fertility and pregnancy issues are of key importance for young breast cancer patients. Despite several advances in the field, there are still multiple unmet needs and barriers in discussing and dealing with these concerns. To address the significant challenges related to fertility and pregnancy issues, the PREgnancy and FERtility (PREFER) study was developed as a national comprehensive program aiming to optimize care and improve knowledge around these topics. METHODS: The PREFER study is a prospective cohort study conducted across several Italian institution affiliated with the Gruppo Italiano Mammella (GIM) group evaluating patterns of care and clinical outcomes of young breast cancer patients dealing with fertility and pregnancy issues. It is composed of two distinctive studies: PREFER-FERTILITY and PREFER-PREGNANCY. The PREFER-FERTILITY study is enrolling premenopausal patients aged 18-45 years, diagnosed with non-metastatic breast cancer, who are candidates to (neo)adjuvant chemotherapy and not previously exposed to anticancer therapies. The primary objective is to obtain and centralize data about patients' preferences and choices towards the available fertility preserving procedures. The success and safety of these strategies and the hormonal changes during chemotherapy and study follow-up are secondary objectives. The PREFER-PREGNANCY study is enrolling survivors achieving a pregnancy after prior history of breast cancer and patients diagnosed with pregnancy-associated breast cancer (PABC). The primary objectives are to obtain and centralize data about the management and clinical outcomes of these women. Patients' survival outcomes, and the fetal, obstetrical and paediatric care of their children are secondary objectives. For both studies, the initial planned recruitment period is 5 years and patients will remain in active follow-up for up to 15 years. The PREFER-FERTILITY study was first activated in November 2012, and the PREFER-PREGNANCY study in May 2013. DISCUSSION: The PREFER study is expected to support and improve oncofertility counseling in Italy, to explore the real need of fertility preserving procedures, and to acquire prospectively more robust data on the efficacy and safety of the available strategies for fertility preservation, on the management of breast cancer survivors achieving a pregnancy and of women with PABC (including the possible short- and long-term complications in their children). TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT02895165 (Retrospectively registered in August 2016).

Treatment with aromatase inhibitors and markers of cardiovascular disease.

PURPOSE: The cardiovascular effects of estrogen deprivation induced by aromatase inhibitors are unknown. We carried out a cross-sectional study to evaluate the effect of estrogen deprivation induced by aromatase inhibitors on markers of cardiovascular risk. METHODS: We enrolled 410 postmenopausal women: 200 consecutive breast cancer patients treated with aromatase inhibitors for a median of 53 months (range 23-122) and 210 volunteer controls. Carotid intima-media thickness, presence of carotid stenosis, and presence of abdominal aortic aneurism were evaluated through an ultrasound examination. RESULTS: Average carotid intima-media thickness was 0.97 ± 0.02 mm and 1.08 ± 0.02 mm for breast cancer group and control group, respectively (p < 0.005). The incidence of carotid stenosis in the two groups was similar: 24.2 % in the breast cancer group and 28.6 % in the control group (OR 0.80; 95 % CI 0.51-1.25; p = 0.32). No aneurismatic dilatation of the aorta was recorded. Average abdominal aortic diameter was 14.9 ± 2.4 mm in the breast cancer group and 15.0 ± 2.4 mm in the control group. CONCLUSIONS: Our study showed no association between treatment with aromatase inhibitors for five or less years and increased carotid intima-media thickness and higher prevalence of carotid stenosis or abdominal aortic aneurism. The lack of impact on these markers suggests that cardiovascular risk is not increased by treatment with aromatase inhibitors.

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.

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.

Hormonal therapy followed by chemotherapy or the reverse sequence as first-line treatment of hormone-responsive, human epidermal growth factor receptor-2 negative metastatic breast cancer patients: results of an observational study.

Introduction Although hormonal-therapy is the preferred first-line treatment for hormone-responsive, HER2 negative metastatic breast cancer, no data from clinical trials support the choice between hormonal-therapy and chemotherapy.Methods Patients were divided into two groups according to the treatment: chemotherapy or hormonal-therapy. Outcomes in terms of clinical benefit and median overall survival (OS) were retrospectively evaluated in the two groups. To calculate the time spent in chemotherapy with respect to OS in the two groups, the proportion of patients in chemotherapy relative to those present in either group was computed at every day from the start of therapy.Results From 1999 to 2013, 119 patients received first-line hormonal-therapy (HT-first group) and 100 first-line chemotherapy (CT-first group). Patients in the CT-first group were younger and with poorer prognostic factors as compared to those in HT-first group. Clinical benefit (77 vs 81%) and median OS (50.7 vs 51.1 months) were similar in the two groups. Time spent in chemotherapy was significantly longer during the first 3 years in CT-first group (54-34%) as compared to the HT-first group (11-18%). This difference decreased after the third year and overall was 28% in the CT-first group and 18% in the HT-first group.Conclusions The sequence first-line chemotherapy followed by hormonal-therapy, as compared with the opposite sequence, is associated with a longer time of OS spent in chemotherapy. However, despite the poorer prognostic factors, patients in the CT-first group had a superimposable OS than those in the HT-first group.

Dose-dense adjuvant chemotherapy in premenopausal breast cancer patients: A pooled analysis of the MIG1 and GIM2 phase III studies.

BACKGROUND: No evidence exists to recommend a specific chemotherapy regimen in young breast cancer patients. We performed a pooled analysis of two randomised clinical trials to evaluate the efficacy of adjuvant dose-dense chemotherapy in premenopausal breast cancer patients and its impact on the risk of treatment-induced amenorrhoea. PATIENTS AND METHODS: In the MIG1 study, node-positive or high-risk node-negative patients were randomised to 6 cycles of fluorouracil/epirubicin/cyclophosphamide every 2 (dose-dense) or 3 (standard-interval) weeks. In the GIM2 study, node-positive patients were randomised to 4 cycles of dose-dense or standard-interval EC or FEC followed by 4 cycles of dose-dense or standard-interval paclitaxel. Using individual patient data, the hazard ratio (HR) for overall survival by means of a Cox proportional hazards model and the odds ratio for treatment-induced amenorrhoea through a logistic regression model were calculated for each study. A meta-analysis of the two studies was performed using the random effect model to compute the parameter estimates. RESULTS: A total of 1,549 patients were included. Dose-dense chemotherapy was associated with a significant improved overall survival as compared to standard-interval chemotherapy (HR, 0.71; 95% confidence intervals [CI], 0.54-0.95; p = 0.021). The pooled HRs were 0.78 (95% CI, 0.54-1.12) and 0.65 (95% CI, 0.40-1.06) for patients with hormone receptor-positive and -negative tumours, respectively (interaction p = 0.330). No increased risk of treatment-induced amenorrhoea was observed with dose-dense chemotherapy (odds ratio, 1.00; 95% CI, 0.80-1.25; p = 0.989). CONCLUSION: Dose-dense adjuvant chemotherapy may be considered the preferred treatment option in high-risk premenopausal breast cancer patients.

Progesterone receptor status and clinical outcome in breast cancer patients with estrogen receptor-positive locoregional recurrence.

AIMS AND BACKGROUND: The aim of this retrospective multicenter study was to evaluate the impact of progesterone receptor (PgR) loss on locoregional recurrence in patients with estrogen receptor (ER)-positive primary breast cancer and ER-positive locoregional recurrence. PATIENTS AND METHODS: Eight Italian oncology centers collected data from consecutive patients with ER-positive breast cancer and a subsequent ER-positive locoregional recurrence. RESULTS: Data were available for 265 patients diagnosed with breast cancer between 1990 and 2009. Median metastasis-free survival was 111 months in patients with PgR-positive primary tumors and locoregional recurrence (PgRpos), 38 months in patients with PgR-negative primary tumors and locoregional recurrence (PgRneg), and 63 months in patients with PgR-positive primary tumors and PgR-negative locoregional recurrence (PgRloss). In multivariate analysis, PgR status was independently associated with metastasis-free survival, with a hazard ratio of 2.84 (95% CI 1.34-6.00) for PgRneg compared with PgRpos, and 2.93 (95% CI: 1.51-5.70) for PgRloss compared with PgRpos. CONCLUSIONS: PgR absence was found to be a negative prognostic factor in breast cancer patients with ER-positive locoregional recurrence. Thus, PgR status could be a biological marker in ER-positive recurrent breast cancer.

Incidence of hepatitis in patients with evidence of past or current hepatitis B or C during chemotherapy for early breast cancer.

AIM/BACKGROUND: Few data are available about the prevalence of hepatitis B and C infections in early breast cancer patients and its impact on systemic treatments. The objectives of this study were to determine the incidence of positive serology for hepatitis B and C in women with early breast cancer and to assess the clinical course and its impact on liver function during adjuvant treatments. PATIENTS AND METHODS: we retrospectively reviewed hepatitis B and C serology [HBs antigen (HBsAg), HBc antibodies (HBcAb), HBs antibodies (HBsAb) and HC (HCV) antibodies] in 746 consecutive patients with early breast cancer treated at our Institution between 2009 and 2011. RESULTS: Among 375 evaluable patients, we identified 312 controls (83.2%) and 63 patients (16.8%) with positive serology (cases): 15 patients (4%) with HCV, 8 (2.1%) with resolved HBV without anti-HBs (HBsAg-negative, HBsAgAb-negative, HBcAgAb-positive), 36 (9.6%) with resolved HBV with anti-HBs (HBsAg-negative, HBsAgAb-positive, HBcAgAb-positive) and 4 (1%) with chronic HBV (HBsAg-positive, HBsAgAb-negative, HBcAgAb-positive). During systemic treatments, hepatitis (defined as at least a three-fold increase in serum alanine aminotransferase level) occurred in nine (20.4%) out of 44 evaluable cases and in 14 (5.9%) out of 234 evaluable controls. CONCLUSION: Approximately 20% of patients with early breast cancer with positive serology for viral hepatitis may develop hepatitis during systemic treatment. Pre-treatment serum detection of viral hepatitis B and C antigens and antibodies may be useful in the adjuvant therapy decision-making process and for adequate monitoring of liver function during antineoplastic therapy.

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.

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.

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 patient's 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.