Francesca Poggio

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.

Gonadotropin-Releasing Hormone Agonists During Chemotherapy for Preservation of Ovarian Function and Fertility in Premenopausal Patients With Early Breast Cancer: A Systematic Review and Meta-Analysis of Individual Patient–Level Data

Purpose The role of temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal women remains controversial. This systematic review and meta-analysis using individual patient-level data was conducted to better assess the efficacy and safety of this strategy in patients with early breast cancer. Methods The trials in which premenopausal women with early breast cancer were randomly assigned to receive (neo)adjuvant chemotherapy alone or with concurrent GnRHa were eligible for inclusion. Primary end points were premature ovarian insufficiency (POI) rate and post-treatment pregnancy rate. Disease-free survival and overall survival were secondary end points. Because each study represents a cluster, statistical analyses were performed using a random effects model. Results A total of 873 patients from five trials were included. POI rate was 14.1% in the GnRHa group and 30.9% in the control group (adjusted odds ratio, 0.38; 95% CI, 0.26 to 0.57; P < .001). A total of 37 (10.3%) patients had at least one post-treatment pregnancy in the GnRHa group and 20 (5.5%) in the control group (incidence rate ratio, 1.83; 95% CI, 1.06 to 3.15; P = .030). No significant differences in disease-free survival (adjusted hazard ratio, 1.01; 95% CI, 0.72 to 1.42; P = .999) and overall survival (adjusted hazard ratio, 0.67; 95% CI, 0.42 to 1.06; P = .083) were observed between groups. Conclusion Our findings provide evidence for the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy as an available option to reduce the likelihood of chemotherapy-induced POI and potentially improve future fertility in premenopausal patients with early breast cancer.

Patterns of Care and Clinical Outcomes of First-Line Trastuzumab-Based Therapy in HER2-Positive Metastatic Breast Cancer Patients Relapsing After (Neo)Adjuvant Trastuzumab: An Italian Multicenter Retrospective Cohort Study

BACKGROUND We evaluated the patterns of care and clinical outcomes of metastatic breast cancer patients treated with first-line trastuzumab-based therapy after previous (neo)adjuvant trastuzumab. MATERIALS AND METHODS A total of 416 consecutive, HER2-positive metastatic breast cancer patients who had received first-line trastuzumab-based therapy were identified at 14 Italian centers. A total of 113 patients had presented with de novo stage IV disease and were analyzed separately. Dichotomous clinical outcomes were analyzed using logistic regression and time-to-event outcomes using Cox proportional hazards models. RESULTS In the 202 trastuzumab-naïve patients and 101 patients with previous trastuzumab exposure, we observed the following outcomes, respectively: overall response rate, 69.9% versus 61.3% (adjusted odds ratio [OR], 0.62; p = .131), clinical benefit rate, 79.1% versus 72.5% (adjusted OR, 0.73; p = .370), median progression-free survival (PFS), 16.1 months versus 12.0 months (adjusted hazards ratio [HR], 1.33; p = .045), and median overall survival (OS), 52.2 months versus 48.2 months (adjusted HR, 1.18; p = .404). Patients with a trastuzumab-free interval (TFI) <6 months, visceral involvement, and hormone receptor-negative disease showed a worse OS compared with patients with a TFI of ≥6 months (29.5 vs. 48.3 months; p = .331), nonvisceral involvement (48.0 vs. 60.3 months; p = .270), and hormone receptor-positive disease (39.8 vs. 58.6 months; p = .003), respectively. CONCLUSION Despite the inferior median PFS, trastuzumab-based therapy was an effective first-line treatment for patients relapsing after (neo)adjuvant trastuzumab. Previous trastuzumab exposure and the respective TFI, type of first site of disease relapse, and hormone receptor status should be considered in the choice of the best first-line treatment option for HER2-positive metastatic breast cancer patients.

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.

New insights on the role of luteinizing hormone releasing hormone agonists in premenopausal early breast cancer patients

Luteinising hormone releasing hormone agonists (LH-RHa) are effective in the treatment of advanced endocrine-sensitive breast cancer in premenopausal patients, but their role in the adjuvant setting has remained controversial for a long time. Tamoxifen for 5 years has been traditionally considered the standard endocrine therapy for premenopausal patients and this is still valid for many patients. However, the recently reported SOFT trial has suggested that adding ovarian function suppression (OFS) to tamoxifen could improve DFS in women at sufficient risk to warrant adjuvant chemotherapy and who remained premenopausal after this therapy. The administration of an aromatase inhibitor plus OFS represents an additional therapeutic option for hormone-receptor positive premenopausal breast cancer patients, according to the combined analysis of the SOFT and TEXT trials. Temporary ovarian suppression induced by LH-RHa has been recognized as an effective strategy to preserve ovarian function from the toxic effects of chemotherapy and is now recommended in young breast cancer patients with endocrine-insensitive tumors. In this review, we discuss recent data on the role of LH-RHa in combination with tamoxifen or with an aromatase inhibitor, and we comment on its role as a strategy to preserve ovarian function in young patients candidates for adjuvant or neo-adjuvant chemotherapy.

The prognostic performance of Adjuvant! Online and Nottingham Prognostic Index in young breast cancer patients

Background:Limited data are available on the prognostic performance of Adjuvant! Online (AOL) and Nottingham Prognostic Index (NPI) in young breast cancer patients.Methods:This multicentre hospital-based retrospective cohort study included young (⩽40 years) and older (55–60 years) breast cancer patients treated from January 2000 to December 2004 at four large Belgian and Italian institutions. Predicted 10-year overall survival (OS) and disease-free survival (DFS) using AOL and 10-year OS using NPI were calculated for every patient. Tools ability to predict outcomes (i.e., calibration) and their discriminatory accuracy was assessed.Results:The study included 1283 patients, 376 young and 907 older women. Adjuvant! Online accurately predicted 10-year OS (absolute difference: 0.7%; P=0.37) in young cohort, but overestimated 10-year DFS by 7.7% (P=0.003). In older cohort, AOL significantly underestimated both 10-year OS and DFS by 7.2% (P<0.001) and 3.2% (P=0.04), respectively. Nottingham Prognostic Index significantly underestimated 10-year OS in both young (8.5%; P<0.001) and older (4.0%; P<0.001) cohorts. Adjuvant! Online and NPI had comparable discriminatory accuracy.Conclusions:In young breast cancer patients, AOL is a reliable tool in predicting OS at 10 years but not DFS, whereas the performance of NPI is sub-optimal.

News on the medical treatment of young women with early-stage HER2-negative breast cancer

ABSTRACT Introduction: Breast cancer in young women represents a public health problem with specific age-related issues to be faced by both patients and their treating physicians. Areas covered: This manuscript reviews the recent data on the medical management of young women with early-stage HER2-negative breast cancer. Expert opinion: For women candidates to receive (neo)adjuvant chemotherapy, anthracycline- and taxane-based regimens are standard of care. In high-risk patients, dose-dense regimens should be preferred; in women with triple-negative breast cancer and BRCA mutations, the addition of platinum compounds may also be considered. Several adjuvant endocrine therapy options have become available for the treatment of premenopausal women with early-stage luminal breast cancer. Specifically, young patients at low risk of relapse may be safely spared chemotherapy: endocrine therapy alone with tamoxifen for 5 years is the most appropriate treatment. In women at higher risk of relapse, ovarian function suppression is therapeutic: in this scenario, luteinizing hormone-releasing hormone agonists (LHRHa) should be considered in addition to tamoxifen or aromatase inhibitors. To women concerned about the possible risk of chemotherapy-induced premature ovarian failure, the use of temporary ovarian suppression with LHRHa should be proposed as a valid strategy to potentially preserve ovarian function and fertility.

Role of fulvestrant in the treatment of postmenopausal metastatic breast cancer patients

ABSTRACT Introduction: Endocrine therapy is considered the cornerstone treatment for postmenopausal women with hormone-receptor positive metastatic breast cancer. Fulvestrant is a selective estrogen receptor down-regulator (SERD) with demonstrated activity and efficacy in the treatment of these patients. Areas covered: The present manuscript aims to review the mechanism of action of fulvestrant, the clinical efficacy data with the use of different dosages and schedules, and finally its role in association with other medications. Expert commentary: Fulvestrant is an active compound with an excellent safety profile for the treatment of women with hormone receptor-positive metastatic breast cancer, The combination of fulvestrant with targeted agents showed increased efficacy and is expected to become a new standard treatment. Results of two clinical trials (i.e. the FALCON and FEVEX trials) are awaited to better clarify the place of fulvestrant in the armamentarium of the available therapies for the treatment of hormone receptor-positive metastatic breast cancer.

The burden of breast cancer from China to Italy.

Breast cancer is the second most common cancer in the world and the most frequent cancer among women, with an estimated 1.67 million new cancer cases diagnosed in 2012 (25% of all cancers) (1). In Europe the estimated age-adjusted annual incidence of breast cancer in 2012 was 94.2/100 thousand and the mortality 23.1/100 thousand (2). In USA, according to the SEER database [2006-2010], the age-adjusted annual incidence of breast cancer was 123.8/100 thousand and the mortality 22.6/100 thousand (3). The median age at breast cancer diagnosis is 61 years: about 10% of breast cancers occur among women aged younger than 50 years, while 65% occur among women aged 65 years or older (3). Overall, 60% of breast cancers are diagnosed at a localized stage, 32% at a regional stage and 5% at an advanced stage. The 5-year relative survival rate for women diagnosed with localized breast cancer is 98.6%; survival declines to 84.4% for regional stage and 24.3% for distant stage (3). In western countries, due to both early detection through screening programs and the improvement in the available treatment strategies, the percentage of women surviving at least 5 years after diagnosis and treatment has shifted from 74.8% in the early 1970s to 90.3% in the late 1990s (3). In Italy, it has been estimated that approximately 48,000 new cases of breast cancer has been diagnosed in 2013 (4). Excluding skin cancers, breast cancer is the most common cancer diagnosed in women: a total of 41% are diagnosed in the age group 0-49 years, 36% in patients aged 50-69 years and 21% in women older than 70 years (2,4,5). Breast cancer incidence and prevalence present a marked north-to-south gradient: the incidence rates are respectively 124.9, 100.3 and 95.6 per 100 thousand in the northern, central and southern areas (5). Regarding breast cancer prevalence, the proportion of prevalent cases in the northern area is remarkably higher (2,055-2,331 per 100 thousand) than in the central area (1,795 per 100 thousand) and about twice than in the southern area (1,151 per 100 thousand). In Italy, breast cancer mortality increased until the late 1980s reaching its maximum value at approximately 27 per 100 thousand, and started to decline thereafter (approximately –1.6%/year) (2). The mortality rate started to decline from the late 1980s in the northern central regions and from the mid-1990s in the southern regions. The 5-year relative survival increased from 78% in 1990-1992 to 87% in 2005-2007 (6,7); age standardized mortality rates are lower in the central area (20.6 per 100 thousand) than in the northern (24.7 per 100 thousand) and southern (25.2 per 100 thousand) areas (4). Breast cancer is a major burden also for Chinese women: Zeng and colleagues recently described the epidemiology of breast cancer in China in 2010, reporting breast cancer statistics by age and geographical area (8). Authors estimated the status of female breast cancer based on existing population-based cancer registries’ data available in 2010; these registries covered approximately 12.96% of the overall female population in China. The estimated number of female breast cancer cases was about 208 thousand; the overall crude incidence rate was 32.43 per 100 thousand, accounting for 16.2% of all cancer cases in Chinese women (first cause of cancer diagnosis). The rates standardized by World population and by China population were 24.20 per 100 thousand and 25.89 per 100 thousand respectively. The estimated number of female breast cancer death was about 55.5 thousand with an overall crude mortality rate of 8.65 per 100 thousand, accounting for 7.90% of all cancer deaths (fifth cause of cancer deaths in Chinese women). After age standardization by China population and World population, the standardized rates were 6.56 per 100 thousand and