M. Lambertini

Ovarian suppression using luteinizing hormone-releasing hormone agonists during chemotherapy to preserve ovarian function and fertility of breast cancer patients: a meta-analysis of randomized studies

BACKGROUNDnThe role of temporary ovarian suppression with luteinizing hormone-releasing hormone agonists (LHRHa) in the prevention of chemotherapy-induced premature ovarian failure (POF) is still controversial. Our meta-analysis of randomized, controlled trials (RCTs) investigates whether the use of LHRHa during chemotherapy in premenopausal breast cancer patients reduces treatment-related POF rate, increases pregnancy rate, and impacts disease-free survival (DFS).nnnMETHODSnA literature search using PubMed, Embase, and the Cochrane Library, and the proceedings of major conferences, was conducted up to 30 April 2015. Odds ratios (ORs) and 95% confidence intervals (CIs) for POF (i.e. POF by study definition, and POF defined as amenorrhea 1 year after chemotherapy completion) and for patients with pregnancy, as well hazard ratios (HRs) and 95% CI for DFS, were calculated for each trial. Pooled analysis was carried out using the fixed- and random-effects models.nnnRESULTSnA total of 12 RCTs were eligible including 1231 breast cancer patients. The use of LHRHa was associated with a significant reduced risk of POF (OR 0.36, 95% CI 0.23-0.57; P < 0.001), yet with significant heterogeneity (I(2) = 47.1%, Pheterogeneity = 0.026). In eight studies reporting amenorrhea rates 1 year after chemotherapy completion, the addition of LHRHa reduced the risk of POF (OR 0.55, 95% CI 0.41-0.73, P < 0.001) without heterogeneity (I(2) = 0.0%, Pheterogeneity = 0.936). In five studies reporting pregnancies, more patients treated with LHRHa achieved pregnancy (33 versus 19 women; OR 1.83, 95% CI 1.02-3.28, P = 0.041; I(2) = 0.0%, Pheterogeneity = 0.629). In three studies reporting DFS, no difference was observed (HR 1.00, 95% CI 0.49-2.04, P = 0.939; I(2) = 68.0%, Pheterogeneity = 0.044).nnnCONCLUSIONnTemporary ovarian suppression with LHRHa in young breast cancer patients is associated with a reduced risk of chemotherapy-induced POF and seems to increase the pregnancy rate, without an apparent negative consequence on prognosis.

Twenty years of anti-HER2 therapy-associated cardiotoxicity.

Over the past 20u2005years, the prognosis of HER2-positive breast cancer has been transformed by the development of anti-HER2 targeted therapies. In early clinical trials of trastuzumab (ie, the first anti-HER2 agent to be developed) cardiotoxicity became a major concern. In the first published phase 3 trial of trastuzumab, 27% of patients receiving anthracyclines and trastuzumab experienced cardiac events and 16% suffered from severe congestive heart failure. In subsequent trials conducted in advanced and early settings, the incidence of cardiac events was reduced through changes in chemotherapy regimens, more strict patient selection and close cardiac assessment. However, cardiotoxicity remains a significant problem in clinical practice that is likely to increase as new agents are approved and exposure times increase through improved patients survival. Though numerous trials have led to improved understanding of many aspects of anti-HER2 therapy-related cardiotoxicity, its underlying physiopathology mechanisms are not well understood. The purpose of this article is to provide an in-depth review on anti-HER2 therapy-related cardiotoxicity, including data on both trastuzumab and the recently developed anti-HER2 targeted agents.

Chemotherapy-induced premature ovarian failure and its prevention in premenopausal breast cancer patients

Breast cancer accounts for more than one quarter of all malignant tumors diagnosed in women of reproductive age: every year, more than 25,000 new cases of invasive breast carcinoma are diagnosed in patients under the age of 45 years in the United States [1]. This is a relatively small proportion (approximately 11%) of all new cases of breast tumors; however, breast cancer in young women represents a public health problem due to both medical and psychosocial challenges unique to or accentuated by their age [2]. Due to the fact that young women with breast cancer have an increased risk of presenting with biologically aggressive types of tumors, the majority are candidates to receive antineoplastic treatments that include the use of chemotherapy [3]. A possible side effect of chemotherapy in premenopausal patients is the occurrence of premature ovarian failure (POF), resulting in temporary or permanent amenorrhea. Even in the presence or resumed regular menses after chemotherapy, patients are still at risk of developing early menopause due to the damage of cytotoxic therapy to their ovarian reserve [4]. The effects of chemotherapy on ovarian function are variable and are strongly affected by patients’ age at the time of treatment, type, and dose of chemotherapy [4]. The most common chemotherapy regimens used in the adjuvant or neoadjuvant treatment of breast cancer are associated with an intermediate risk of developing POF (40–60%) in patients aged 30–39 years; however, the same regimens are associated with a high risk of developing POF (more than 80%) in women older than 40 and a low risk (less than 20%) in those under the age of 30 [4]. The development of chemotherapy-induced POF is associated with improved survival outcomes in premenopausal breast cancer patients [5]. However, the loss of ovarian function negatively impacts on global health of young breast cancer survivors being associated with several side effects, such as hot flashes, sweats, breast pain or sensitivity, vaginal dryness, vaginal discharge, lack of sexual desire, and weight gain [6]. Moreover, strongly associated with the loss of ovarian function is the risk of infertility: fertility issues represent a major concern for young breast cancer patients and can also influence their treatment decisions [7]. Recent data from the Suppression of Ovarian Function Trial (SOFT) study demonstrated excellent survival outcomes in premenopausal breast cancer patients who resumed their ovarian function after chemotherapy and were treated with ovarian suppression for 5 years as part of adjuvant endocrine therapy [8]. Moreover, it has been recently shown that having a pregnancy after prior breast cancer diagnosis and treatment should be considered safe, also in patients with endocrine sensitive disease [9]. These findings highlight the importance of maintaining ovarian function and fertility of young breast cancer patients who are candidates to receive chemotherapy during their reproductive age. Embryo and oocyte cryopreservation are considered standard procedure for fertility preservation, but no proven methods for preservation of ovarian function are yet available [10,11]. According to the American Society of Clinical Oncology and European Society for Medical Oncology guidelines, the two available strategies with the potential to preserve gonadal function of breast cancer patients undergoing chemotherapy, i.e. ovarian tissue cryopreservation and pharmacological protection of the ovaries with the use of gonadotropin releasing hormone analogues (GnRHa) during cytotoxic therapy, are still considered experimental techniques [10,11]. Unlike cryopreservation of embryos or oocytes, ovarian tissue cryopreservation can save not only fertility but also hormonal gonadal function. Moreover, ovarian tissue cryopreservation has other potential advantages: it can be performed at any time during the menstrual cycle and no hormonal stimulation is required, thus no delay EXPERT REVIEW OF QUALITY OF LIFE IN CANCER CARE, 2016 VOL. 1, NO. 1, 5–7 http://dx.doi.org/10.1080/23809000.2016.1139458

Imprint of parity and age at first birth on the genomic landscape of subsequent breast cancer

Background Although parity and age at first birth are among the most known extrinsic factors that modulates breast cancer risk, their impact on the biology of subsequent breast cancer has never been explored in depth. In this study, we investigate the imprint of parity and age at first birth on the pattern of somatic mutations, somatic copy number alterations (SCNAs), transcriptomic profiles, and tumor infiltrating lymphocytes (TILs) levels of subsequent breast cancer. Methods A total of 313 patients with primary breast cancer with available whole genome and RNA sequencing data were included in this study. We used a multivariate analysis adjusted for age at diagnosis, pathological stage, molecular subtypes and histological subtypes. We compared nulliparous vs. parous, late parous vs. early parous, and nulliparous vs. pregnancy associated breast cancer (PABC) patients. Late and early parous patients were grouped by using the median age at first birth as a cut-off value. PABC was defined as patients diagnosed up to 10 years postpartum. Results Genomic alterations of breast cancer are associated with age at first birth but not parity status alone. Independently of clinicopathological features, early parous patients developed tumors characterized by a higher number of Indels (Padj = 0.002), a lower frequency of CDH1 mutations (1.2% vs. 12.7% Padj = 0.013), a higher frequency of TP53 mutations (50% vs. 22.5%; Padj = 0.010) and MYC amplification (28% vs. 7% Padj = 0.008), and a lower prevalence of mutational signature 2. PABC were associated with increased TILs infiltration (Padj = 0.0495). Conclusions These findings highlight an unprecedented link between reproductive history and the genomic landscape of subsequent breast cancer. With the rapid development of precision oncology, this work advocates that reproductive history should not be underestimated in future clinical studies of breast cancer.

Breast Cancer in Special Groups: Breast Cancer in Pregnancy

Breast cancer is one of the most frequently diagnosed malignancies among pregnant women. Breast cancer diagnosed during pregnancy (BCP) remains a feared and challenging situation facing both patients and their treating physicians. Since abortion does not improve patients’ prognosis, correct management of this critical clinical situation is crucial. Specific guidelines have been developed to help physicians in managing patients with BCP. The present chapter aims to review the management of women with BCP, focusing on diagnosis and staging, local and systemic treatments, obstetric care and long-term follow-up of children with prenatal exposure to anticancer treatments.

HM35 Role of temporary ovarian suppression obtained with GnRH analogue in reducing premature ovarian failure induced by chemotherapy in premenopausal cancer patients: a meta-analysis of randomized studies

OR34 Sexual functioning in young women with breast cancer S. Rosenberg *, R. Tamimi, S. Gelber, K. Ruddy, S. Kereakoglow, V. Borges, S. Come, L. Schapira, E. Winer, A. Partridge. Harvard School of Public Health, Department of Epidemiology, Boston, USA, Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, USA, University of Colorado-Denver, Department of Medical Oncology, Denver, USA, Beth Israel Deaconess Medical Center, Department of Medical Oncology, Boston, USA, Massachusetts General Hospital, Department of Medical Oncology, Boston, USA