A. Levaggi

Fertility counseling of young breast cancer patients

Approximately 6% of women with breast cancer are diagnosed before the age of 40. Young age is an independent predictor of adverse outcome and most young breast cancer patients receive systemic treatment with chemotherapy, hormonal therapy or both. The loss or impairment of fertility is a potential side effect of antineoplastic treatments. Due to the rising trend to delaying pregnancy in life, an increasing proportion of young cancer patients who are yet to have a pregnancy will face the problem of iatrogenic menopause in the future. The incidence of anticancer-treatment-related ovarian failure depends on the type of chemotherapy regimen administered, the use of tamoxifen and the age of patients. It rises with increasing age, in the range of 22-61% and 61-97% in women aged <40 years and >40 years respectively. Although there is a clear trend to increasing incidence of ovarian failure with the rise in aging, there may be a small proportion of patients who became amenorrhoeic despite the very young age, thus indicating that also individual factors still unknown may affect the probability of treatment-related ovarian failure. A prompt referral of patients to reproductive counseling and a multidisciplinary team including Oncology and Reproductive Units are essential to face the management of fertility issues in cancer patients. Fertility counseling should include a detailed description of all the available techniques to preserve fertility. The main available fertility preservation techniques, standard and experimental, for young breast cancer patients include: temporary ovarian suppression during chemotherapy with gonadotropin-releasing hormone analogues, embryo cryopreservation, cryopreservation of oocytes and cryopreservation of ovarian tissue. Research efforts are still necessary to improve the efficacy and safety of the available fertility preservation strategies as well as an efficient collaboration between oncologists and gynecologists is necessary to improve patients access to the strategies themselves.

Pathological and molecular characteristics distinguishing contralateral metastatic from new primary breast cancer

BACKGROUNDnBreast cancer patients have a cumulative lifetime risk of 2%-15% of developing a contralateral metastatic or ex novo primary cancer. From prognostic and therapeutic viewpoints, it is important to differentiate metastatic from second primary. To distinguish these entities, we investigated whether the pattern of X chromosome inactivation could determine whether the two tumors derived from different progenitor cells.nnnMATERIALS AND METHODSnThe clonality of bilateral breast cancer was evaluated through the X-inactivation analysis using the human androgen receptor gene (HUMARA) polymorphism and the histopathologic and molecular results were compared. A different or an identical pattern of X inactivation was considered as indicator of a second primary cancer or not informative, respectively. We considered morphological indicators of a new primary cancer the absence of concordance in the histological type or a better histological differentiation.nnnRESULTSnTen patients with bilateral breast cancer were evaluated. Morphological criteria indicated that eight were second primary, a conclusion confirmed by the X-inactivation analysis. Two cases classified as recurrence according to morphological criteria were classified as second tumor by molecular analysis.nnnCONCLUSIONnOur results show that the HUMARA clonality assay can improve the histological parameters in differentiating metastatic cancer from second primary cancer.

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

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 <25.0u2009kgu2009m−2; 65.6 (57.8–74.6, n=154) when 25.0–29.9u2009kgu2009m−2; 59.3 (47.1–74.6, n=50) when 30.0–34.9u2009kgu2009m−2; and 43.3 (23.0–81.7, n=16) when ⩾35.0u2009kgu2009m−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.

Abstract P1-11-20: Open-Label Phase II Study of Neoadjuvant Bevacizumab Combined with FEC→Paclitaxel in Patients with Inflammatory or Locally Advanced Breast Cancer

Background: There is strong evidence that VEGF plays an important role in the pathogenesis and progression of human breast cancer. Bevacizumab, a monoclonal antibody, specifically inhibits VEGF. The combination of first-line bevacizumab with chemotherapy significantly improved the activity in comparison to chemotherapy alone in three randomized phase III trials in metastatic breast cancer patients (pts). In early breast cancer, the FEC→Paclitaxel regimen is a highly active standard therapy. Therefore we initiated a trial to evaluate the combination of bevacizumab with this efficacious chemotherapy regimen for the treatment of stage III or inflammatory early breast cancer (LABC). Patients and Methods: The study is designed to evaluate a sequential regimen of FEC90 followed by the combination of paclitaxel and bevacizumab as neoadjuvant therapy in patients with HER2-negative locally advanced (stage III or inflammatory) breast cancer. Patients are treated with neoadjuvant FEC 600/90/600 mg/m2 q21d x 4, followed by paclitaxel 80 mg/m2 weekly x 12 combined with bevacizumab 10 mg/kg q2w x 6. Patients undergo surgery 4 weeks after completing chemotherapy. Pathologic complete response (pCR), the primary endpoint, is defined as no evidence of invasive tumor in the final surgical sample both in the breast and axilla. Secondary endpoints include objective clinical response rate (RR), disease-free interval, overall survival, rate of breast-conserving surgery, and the safety of the regimen. Results: Between Feb 2008 and Dec 2009, 54 pts (mean age of 51±7.5 years) were enrolled into the study. To date, 32 pts have completed neoadjuvant treatment and surgery and are evaluable for response. Baseline characteristics in these 32 patients were as follows: cT3/cT4b: 20 (63%) and/or cN2/cN3: 14 (43%); estrogen receptor (ER) positive: 24 (75%) and 8 (25%) triple-negative (TN), defined as ER negative, progesterone receptor-(PgR-) negative, and HER2 negative. Histological type was ductal carcinoma in 24 patients (75%), lobular carcinoma in 4 (13%), inflammatory breast cancer in 1 (3%), and other in 3 (9%). Mastectomy was performed in 22 patients (69%) and breast-conserving surgery in 10 patients (31%). After neoadjuvant treatment, 8/32 patients (25%) achieved a pCR. Conclusions: This open-label, multicenter, phase II study demonstrated that the FEC→Paclitaxel plus bevacizumab combination is a highly active neoadjuvant treatment for HER2-negative locally advanced breast cancer. A 25% of pCR in this group of pts with high tumor burden, i.e. the LABC, is oneof the most promising chemotherapeutic regimen if confirmed in the final analyis. Results for all 54 pts enrolled will be presented at the meeting. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-20.

Trastuzumab before breast surgery: is concurrent administration with anthracycline-containing chemotherapy necessary?

Two randomized studies showed that the addition of trastuzumab to standard chemotherapy before surgery substantially increases the rate of pathological complete response (pCR) and the event-free survival in women with human epidermal growth factor receptor 2 (HER2)-positive locally advanced breast cancer [1, 2]. In both studies, trastuzumab was given concurrently with an anthracycline-containing chemotherapy regimen. In the study of Buzdar et al. [1], the pCR rate was 25% and 66.7% in chemotherapy and chemotherapy plus trastuzumab arms, respectively. In the study of Gianni et al. [2], the pCR rate was 38% among patients receiving trastuzumab plus chemotherapy and 19% among patients treated with chemotherapy alone. These results strongly support the use of trastuzumab concurrently with chemotherapy as neoadjuvant treatment. However, a major concern for clinicians is the concurrent use of trastuzumab and anthracyclines. In fact, the low cardiotoxicity of such a combination reported in the neoadjuvant setting does contrast with the data in the metastatic setting where this combination was associated with a 27% rate of cardiac events [3]. Starting from 2007, at the National Cancer Research Institute of Genoa, Italy, patients with histologically invasive HER2positive (3+ overexpression by immunohistochemistry or positive by FISH) breast cancer with stage II to III disease not candidates for conservative surgery are treated with a neoadjuvant regimen, chosen taking into account both the data of the literature on the treatment of early breast cancer patients and the local laws not allowing the concurrent administration of trastuzumab and anthracyclines. The chemotherapy regimen was the following: FEC (Fluorouracil 600 mg/m, epirubicin 90 mg/ m and cyclophosphamide 600 mg/m) every 3 weeks for four cycles followed by weekly paclitaxel (P) (Taxol) (80 mg/m) given concurrently with trastuzumab 2 mg/kg/weekly (loading dose: 4 mg/kg). Trastuzumab was continued after surgery for a total of 52 weeks. Because of the nonexperimental nature of the neoadjuvant regimen administered, patients were treated according to the standard practice of our Institute and not within a research protocol. Before beginning of chemotherapy, all patients gave written informed consent. After two cycles of chemotherapy, the tumor site was marked by the injection of a carbon suspension under ultrasound guidance. This procedure was omitted in the cases (multicenter disease and/or a large tumor involving the central quadrant of the breast at initial diagnosis) candidates to radical surgery, regardless the clinical response obtained. Cardiac evaluation included an echocardiogram or a cardiac scan performed at baseline and at the end of chemotherapy. The clinical response was assessed by physical examination and by echography, mammography or nuclear magnetic resonance (NMR). Pathological complete response was defined by the absence of invasive cancer both in breast and axilla. Breast surgery and axillary lymph node dissection were performed after the completion of neoadjuvant therapy. In cases with complete clinical response, breast resection was guided by the carbon placed under ultrasound guidance after two cycles of chemotherapy. Surgical specimen was sectioned into 3to 5-mm slices. For cases with clinical complete response, at least 15–20 blocks were examined to assess the

Erratum to: Analysis of in vitro ADCC and clinical response to trastuzumab: Possible relevance of FcγRIIIA/FcγRIIA gene polymorphisms and HER-2 expression levels on breast cancer cell lines [J Transl Med (2015) 13:324] DOI: 10.1186/s12967-015-0680-0

© 2016 Boero et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Erratum to: J Transl Med (2015) 13:324 DOI 10.1186/s12967‐015‐0680‐0 It has come the publisher’s attention that the original version of this article [1] unfortunately contained an error. In Table 3, first column, the FcγRIIA 131 H>R genotypes were incorrectly labelled. In particular, V/V should have read H/H, V/F should have read H/R and F/F should have read R/R. Please note that this correction does not change the genotype numerical values of FcγRIIA polymorphism. The correct Table 3 has been published as Table 1 in this Erratum. Open Access Journal of Translational Medicine

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