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Abstract: Survivorship has become a crucial component in breast cancer care. For women who have not completed their family planning, conceiving at the end of anticancer treatments should not be discouraged but might be challenging. Oncofertility counseling should be offered at the time of diagnosis to all patients, in order to inform them about the potential treatment-induced gonadotoxicity as well as the available strategies for fertility preservation, thus allowing to increase the chances of a future pregnancy. This article reports an updated overview on the current state of the art on pregnancy in women with prior breast cancer diagnosis and treatment, with a main focus on the issues faced by patients with history of hormone receptor-positive disease and BRCA carriers., Competing Interests: Conflicts of Interest and Source of Funding: F.P. received honoraria from Eli Lilly, Novartis, and Pfizer. M.L. had advisory role for Roche, Lilly, Novartis, Astrazeneca, MSD, Exact Sciences, Seagen, Gilead, and Pfizer and received speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, Knight, and Takeda outside the submitted work. M.L. acknowledges the Italian Association for Cancer Research (“Associazione Italiana per la Ricerca sul Cancro,” AIRC; MFAG 2020 ID 24698) and the Italian Ministry of Health (5 × 1000 funds 2017) for supporting his research in the field of breast cancer in young women and oncofertility. For the remaining authors, none were declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Although use of gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy is an established strategy to protect ovarian function in premenopausal breast cancer patients, no long-term safety data are available, raising some concerns in women with hormone receptor-positive disease. There are controversial data on its fertility preservation potential., Methods: The Prevention of Menopause Induced by Chemotherapy: a Study in Early Breast Cancer Patients-Gruppo Italiano Mammella 6 (PROMISE-GIM6) trial is a multicenter, randomized, open-label, phase III superiority trial conducted at 16 Italian centers from October 2003 to January 2008. Eligible patients were randomly assigned to (neo)adjuvant chemotherapy alone (control arm) or combined with the GnRHa triptorelin (GnRHa arm). The primary planned endpoint was incidence of chemotherapy-induced premature ovarian insufficiency. Post hoc endpoints were disease-free survival (DFS), overall survival (OS), and post-treatment pregnancies. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated., Results: Of 281 randomly assigned patients, 80.4% had hormone receptor-positive breast cancer. Median follow-up was 12.4 years (interquartile range = 11.3-13.2 years). No differences in 12-year DFS (65.7% [95% CI = 57.0% to 73.1%] in the GnRHa arm vs 69.2% [95% CI = 60.3% to 76.5%] in the control arm; HR = 1.16, 95% CI = 0.76 to 1.77) or in 12-year OS (81.2% [95% CI = 73.6% to 86.8%] in the GnRHa arm vs 81.3% [95% CI = 73.1% to 87.2%] in the control arm; HR = 1.17, 95% CI = 0.67 to 2.03) were observed. In patients with hormone receptor-positive disease, the hazard ratio was 1.02 (95% CI = 0.63 to 1.63) for DFS and 1.12 (95% CI = 0.59 to 2.11) for OS. In the GnRHa and control arms, 9 and 4 patients had a posttreatment pregnancy, respectively (HR = 2.14, 95% CI = 0.66 to 6.92)., Conclusions: Final analysis of the PROMISE-GIM6 trial provides reassuring results on the safety of GnRHa use during chemotherapy as a strategy to preserve ovarian function in premenopausal patients with early breast cancer, including those with hormone receptor-positive disease., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Symptoms of treatment-induced menopause negatively affect quality of life and adherence to endocrine therapy of breast cancer (BC) survivors. Nevertheless, the use of systemic hormone replacement therapy (HRT) to mitigate these symptoms may be associated with an increased risk of disease recurrence in these patients. This systematic review and meta-analysis aimed to assess the safety of systemic HRT on risk of disease recurrence in BC survivors., Methods: A systematic search of PubMed up to April 20, 2021 was conducted to identify randomized controlled trials (RCTs) that investigated the risk of disease recurrence with the use of HRT in BC survivors. A random-effect model was applied to calculate the risk of recurrence, reported as pooled hazard ratio (HR) with 95% confidence intervals (CI). A subgroup analysis was performed to estimate the risk of recurrence according to hormone receptor status., Results: Four RCTs were included in the meta-analysis (n = 4050 patients). Overall, 2022 patients were randomized to receive HRT (estrogen/progestogen combination or tibolone) and 2023 to the control group with placebo or no HRT. HRT significantly increased the risk of BC recurrence compared to placebo (HR 1.46, 95% CI 1.12-1.91, p = 0.006). At the subgroup analysis, the risk of BC recurrence with the use of HRT was significantly increased in patients with hormone receptor-positive disease (HR 1.8, 95% CI 1.15-2.82, p = 0.010) but not in those with hormone receptor-negative tumors (HR 1.19, 95% CI 0.80-1.77, p = 0.390)., Conclusion: Use of HRT was associated with a detrimental prognostic effect in BC survivors, particularly in those with hormone receptor-positive disease. Alternative interventions to mitigate menopause-related symptoms should be proposed., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The benefit of extending aromatase inhibitor therapy beyond 5 years in the context of previous aromatase inhibitors remains controversial. We aimed to compare extended therapy with letrozole for 5 years versus the standard duration of 2-3 years of letrozole in postmenopausal patients with breast cancer who have already received 2-3 years of tamoxifen., Methods: This multicentre, open-label, randomised, phase 3 trial was done at 69 hospitals in Italy. Women were eligible if they were postmenopausal at the time of study entry, had stage I-III histologically proven and operable invasive hormone receptor-positive breast cancer, had received adjuvant tamoxifen therapy for at least 2 years but no longer than 3 years and 3 months, had no signs of disease recurrence, and had an Eastern Cooperative Oncology Group performance status of 2 or lower. Patients were randomly assigned (1:1) to receive 2-3 years (control group) or 5 years (extended group) of letrozole (2·5 mg orally once a day). Randomisation, with stratification by centre, with permuted blocks of size 12, was done with a centralised, interactive, internet-based system that randomly generated the treatment allocation. Participants and investigators were not masked to treatment assignment. The primary endpoint was invasive disease-free survival in the intention-to-treat population. Safety analysis was done for patients who received at least 1 month of study treatment. This trial was registered with EudraCT, 2005-001212-44, and ClinicalTrials.gov, NCT01064635., Findings: Between Aug 1, 2005, and Oct 24, 2010, 2056 patients were enrolled and randomly assigned to receive letrozole for 2-3 years (n=1030; control group) or for 5 years (n=1026; extended group). After a median follow-up of 11·7 years (IQR 9·5-13·1), disease-free survival events occurred in 262 (25·4%) of 1030 patients in the control group and 212 (20·7%) of 1026 in the extended group. 12-year disease-free survival was 62% (95% CI 57-66) in the control group and 67% (62-71) in the extended group (hazard ratio 0·78, 95% CI 0·65-0·93; p=0·0064). The most common grade 3 and 4 adverse events were arthralgia (22 [2·2%] of 983 patients in the control group vs 29 [3·0%] of 977 in the extended group) and myalgia (seven [0·7%] vs nine [0·9%]). There were three (0·3%) serious treatment-related adverse events in the control group and eight (0·8%) in the extended group. No deaths related to toxic effects were observed., Interpretation: In postmenopausal patients with breast cancer who received 2-3 years of tamoxifen, extended treatment with 5 years of letrozole resulted in a significant improvement in disease-free survival compared with the standard 2-3 years of letrozole. Sequential endocrine therapy with tamoxifen for 2-3 years followed by letrozole for 5 years should be considered as one of the optimal standard endocrine treatments for postmenopausal patients with hormone receptor-positive breast cancer., Funding: Novartis and the Italian Ministry of Health., Translation: For the Italian translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests LDM receives honoraria and non-financial support from Roche, Novartis, Pfizer, MSD, Genomic Health, Takeda, Ipsen, Eisai, Eli Lilly, Celgene, Pierre Fabre, Seagen, Daiichi Sankyo, Exact Sciences, and Amgen. MM receives honoraria from Novartis, Pfizer, AstraZeneca, Roche, Eisai, Eli Lilly, and MSD. AF receives honoraria from Roche, Novartis, Eli Lilly, Daiichi Sankyo, Seagen, AstraZeneca, and Pfizer. SDP receives honoraria from Roche, Novartis, Pfizer, Celgene, Eli Lilly, AstraZeneca, Clovis, Seagen, Daichii Sankyo, and MSD. OG receives honoraria and non-financial support from Eisai, Novartis, MSD, Amgen, Eli Lilly, Pfizer, and Roche. CB receives honoraria from Novartis, Roche, and Eli Lilly. FPu receives honoraria from Eisai, Novartis, Astra Zeneca, Celgene, Roche, MSD, Daichii Sankyo, and Eli Lilly. GA receives honoraria from Roche, Amgen, AstraZeneca, Pfizer, Eli Lilly, Novartis, and MDS. FPo receives honoraria and non-financial support from MSD, Eli Lilly, and Novartis. ML acted as adviser for Roche, AstraZeneca, Eli Lilly, and Novartis; and receives honoraria from Takeda, Roche, AstraZeneca, Eli Lilly, Pfizer, Novartis, and Sandoz. FM receives honoraria from Roche, Novartis, Eli Lilly, Pierre Fabre, Novartis, Daichii Sankyo, Pfizer, AstraZeneca, Seagen, and Pierre Fabre. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: A systematic review and meta-analysis was performed to estimate mortality in adult patients with solid or hematological malignancies and SARS-CoV-2 infection., Methods: A systematic search of PubMed, up to 31 January 2021, identified publications reporting the case-fatality rate (CFR) among adult patients with solid or hematological malignancies and SARS-CoV-2 infection. The CFR, defined as the rate of death in this population, was assessed with a random effect model; 95% confidence intervals (CI) were calculated., Results: Among 135 selected studies (N = 33,879 patients), the CFR was 25.4% (95% CI 22.9%-28.2%). At a sensitivity analysis including studies with at least 100 patients, the CFR was 21.9% (95% CI 19.1%-25.1%). Among COVID-19 patients with lung (N = 1,135) and breast (N = 1,296) cancers, CFR were 32.4% (95% CI 26.5%-39.6%) and 14.2% (95% CI 9.3%-21.8%), respectively., Conclusions: Patients with solid or hematological malignancies and SARS-CoV-2 infection have a high probability of mortality, with comparatively higher and lower CFRs in patients with lung and breast cancers, respectively., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Offering ovarian function and/or fertility preservation strategies in premenopausal women with newly diagnosed breast cancer candidates to undergo chemotherapy is standard of care. However, few data are available on uptake and main reasons for refusing these options., Methods: The PREFER study (NCT02895165) is an observational, prospective study enrolling premenopausal women with early breast cancer, aged between 18 and 45 years, candidates to receive (neo)adjuvant chemotherapy. Primary objective is to collect information on acceptance rates and reasons for refusal of the proposed strategies for ovarian function and/or fertility preservation available in Italy., Results: At the study coordinating center, 223 patients were recruited between November 2012 and December 2020. Median age was 38 years (range 24 - 45 years) with 159 patients (71.3%) diagnosed at ≤40 years. Temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) was accepted by 58 out of 64 (90.6%) patients aged 41-45 years and by 151 out of 159 (95.0%) of those aged ≤40 years. Among patients aged ≤40 years, 57 (35.8%) accepted to access the fertility unit to receive a complete oncofertility counseling and 29 (18.2%) accepted to undergo a cryopreservation technique. Main reasons for refusal were fear of delaying the initiation of antineoplastic treatments and contraindications to the procedure or lack of interest in future childbearing. Patients with hormone-receptor positive breast cancer had a tendency for a higher acceptance rates of ovarian function and/or fertility preservation strategies than those with hormone-receptor negative disease., Conclusions: More than 90% of premenopausal women with early breast cancer, and particularly those with hormone receptor-positive disease, were concerned about the potential risk of chemotherapy-induced premature ovarian insufficiency and/or infertility and accepted GnRHa administration. Less than 1 out of 5 women aged ≤40 years accepted to undergo cryopreservation strategies., Competing Interests: FP reports consulting or advisory role from Merck Sharp and Dohme; speakers’ bureau from Eli Lilly, Novartis; travel, accommodations, expenses from Eli Lilly, Takeda. CB reports advisory board, clinical trials and lecture fee from Novartis, Roche, Lilly and Pfizer, outside the submitted work. ML acted as a consultant for Roche, AstraZeneca, Novartis and Lilly, and received honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, and Takeda outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Blondeaux, Massarotti, Fontana, Poggio, Arecco, Fregatti, Bighin, Giannubilo, Ruelle, Razeti, Boni, Anserini, Del Mastro and Lambertini.)

Introduction : The prognosis of patients with HER2-positive early breast cancer has radically improved after the introduction of (neo)adjuvant anti-HER2 targeted therapy. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate combining the anticancer properties of the anti-HER2 agent trastuzumab and the antineoplastic cytotoxic drug DM1. After demonstrating to be an effective and safe treatment for patients with HER2-positive advanced breast cancer, the development of T-DM1 has moved to the early setting. Areas covered : The aim of this review is to explore the current role of T-DM1 in the treatment landscape of HER2-positive early breast cancer, focusing specifically on the efficacy and safety data available in the adjuvant setting. Expert opinion : T-DM1 is an effective and safe treatment option in the adjuvant setting for patients with HER2-positive breast cancer without pathologic complete response after standard neoadjuvant chemotherapy plus anti-HER2 targeted therapy. With the availability of more effective anti-HER2 targeted agents, including T-DM1, there is an urgent need for more chemotherapy de-escalation research efforts in the early setting.

The diagnosis of breast cancer during pregnancy represents a challenging situation for the patient, her caregivers and physicians. Pregnancy adds complexity to oncological treatment planning, as many therapies can be potentially dangerous to the fetus. Therefore, a multidisciplinary approach is needed to offer a proper care for obtaining the best possible outcomes for the mother and the future child. Breast surgery is feasible throughout the pregnancy while radiotherapy should be postponed after delivery. Administration of chemotherapy is considered safe and can be given during the second and third trimesters, while it is contraindicated in the first trimester due to the high risk of fetal malformations. Endocrine therapy and targeted agents are not recommended during the whole pregnancy period; however, limited data are available on the use of the majority of new anticancer drugs in this context. The aim of the current review is to provide an update on the current state of art about the management of women diagnosed with breast cancer during pregnancy.

Purpose: To investigate the impact of the COVID-19 outbreak on the attitudes and practice of Italian oncologists toward breast cancer care and related research activities., Methods: A 29-question anonymous online survey was sent by e-mail to members of the Italian Association of Medical Oncology and the Italian Breast Cancer Study Group on April 3, 2020. Only medical oncologists (both those in training and specialists) were invited to complete the questionnaire., Results: Out of 165 responding oncologists, 121 (73.3.%) worked in breast units. In the (neo)adjuvant setting, compared with before the emergency, fewer oncologists adopted weekly paclitaxel (68.5% v 93.9%) and a dose-dense schedule for anthracycline-based chemotherapy (43% v 58.8%) during the COVID-19 outbreak. In the metastatic setting, compared with before the emergency, fewer oncologists adopted first-line weekly paclitaxel for HER2-positive disease (41.8% v 53.9%) or CDK4/6 inhibitors for luminal tumors with less-aggressive characteristics (55.8% v 80.0%) during the COVID-19 outbreak. A significant change was also observed in delaying the timing for monitoring therapy with CDK4/6 inhibitors, assessing treatment response with imaging tests, and flushing central venous devices. Clinical research and scientific activities were reduced in 80.3% and 80.1% of respondents previously implicated in these activities, respectively., Conclusion: Medical oncologists face many challenges in providing cancer care during the COVID-19 outbreak. Although most of the changes in their attitudes and practice were reasonable responses to the current health care emergency without expected major negative impact on patient outcomes, some potentially alarming signals of undertreatment were observed.

Background: In HER2-positive breast cancer, time elapsed between completion of (neo)adjuvant trastuzumab and diagnosis of metastatic disease ('trastuzumab-free interval', TFI) is crucial to choose the optimal first-line treatment. Nevertheless, there is no clear evidence to support its possible prognostic role., Methods: In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial, patients with HER2-positive early breast cancer were randomised to 1 year of either trastuzumab alone, lapatinib alone, their sequence or their combination. This exploratory analysis included only patients in the trastuzumab alone or trastuzumab plus lapatinib arms who developed a distant disease-free survival (DDFS) event. Overall survival (OS) was defined as time between date of DDFS event and death; age at diagnosis, tumour size and hormone receptor status were the variables included in the multivariate models., Results: Out of 8381 patients included in ALTTO, 404 patients in the trastuzumab alone and trastuzumab plus lapatinib arms developed a DDFS event, of which 201 occurred < 12 months (group A) and 203 >12 months (group B) after completion of adjuvant trastuzumab. No significant difference in location of first DDFS event was observed (p=0.073); a numerically higher number of patients in group A than in group B developed brain metastasis (26% vs 15%). Choice of first-line therapy differed between the two groups (p=0.022): in group A, more patients received lapatinib (25% vs 11%) and less pertuzumab (8% vs 17%). Median OS was 29.3 and 18.4 months in groups B and A, respectively (adjusted HR 0.69; 95% CI 0.54-0.89; p=0.004). The longer OS for patients in group B was observed across the analysed subgroups without interaction according to hormone receptor status (p=0.814) nor type of administered adjuvant anti-HER2 treatment (p=0.233)., Conclusions: TFI has prognostic value in patients with HER2-positive early breast cancer treated with adjuvant trastuzumab-based therapy. TFI is a valid tool to better individualise clinical recommendations and to design future first-line treatment trials for metastatic patients., Competing Interests: Competing interests: ML acted as a consultant for Roche and Novartis, and received speaker honoraria from Theramex, Roche, Takeda, Novartis, Pfizer and Lilly outside the submitted work. NFP acted as a consultant for Lilly; received speaker honoraria from AstraZeneca, Novartis, Lilly and Roche-Genentech, travel support from Novartis and research grants from Daiichi Sankyo, MSD and BMS outside the submitted work. OW reports employment at Novartis. LDM acted as a consultant for Roche, Novartis, MSD, Pfizer, Ipsen, AstraZeneca, Genomic Health, Lilly, Seattle Genetics, Eisai, Pierre Fabre, Daiichi Sankyo; received speaker honoraria from Roche, Novartis, Lilly and MSD, and travel grants from Roche, Pfizer and Celgene outside the submitted work. RC received speaker fees from Boehringer-Ingelheim, AstraZeneca and Janssen, and travel support from AstraZeneca and Pfizer, outside the submitted work. AM-A received research grants from GSK/Novartis (to the institution) outside the submitted work. MJP served as board member of Oncolytics; received honoraria from AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Roche-Genentech, Huya, Immunomedics, Lilly, Menarini, MSD, Novartis, Odone, Periphagen, Pfizer, Roche, Seattle Genetics, research grants from AstraZeneca, Lilly, MEDSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier and Synthon (to the institution) outside the submitted work. EdA received honoraria and/or advisory board from Roche/GNE, Novartis, Seattle Genetics and Zodiac, travel grants from Roche/GNE and GSK/Novartis, research grants to his institution from Roche/GNE, Astra-Zeneca, GSK/Novartis and Servier outside the submitted work; his institution has received research grants for the conduct of ALTTO., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Background: During COVID-19 outbreak, oncological care has been reorganized. Patients with cancer have been reported to experience a more severe COVID-19 syndrome; moreover, there are concerns of a potential interference between immune checkpoint inhibitors (ICIs) and SARS-CoV-2 pathogenesis., Materials and Methods: Between 6 and 16 May 2020, a 22-item survey was sent to Italian physicians involved in administering ICIs. It aimed at exploring the perception about SARS-CoV-2-related risks in cancer patients receiving ICIs, and the attitudes towards their management., Results: The 104 respondents had a median age of 35.5 years, 58.7% were females and 71.2% worked in Northern Italy. 47.1% of respondents argued a synergism between ICIs and SARS-CoV-2 pathogenesis leading to worse outcomes, but 97.1% would not deny an ICI only for the risk of infection. During COVID-19 outbreak, to reduce hospital visits, 55.8% and 30.8% opted for the highest labelled dose of each ICI and/or, among different ICIs for the same indication, for the one with the longer interval between cycles, respectively. 53.8% of respondents suggested testing for SARS-CoV-2 every cancer patient candidate to ICIs. 71.2% declared to manage patients with onset of dyspnoea and cough as infected by SARS-CoV-2 until otherwise proven; however, 96.2% did not reduce the use of steroids to manage immune-related toxicities. The administration of ICIs in specific situations for different cancer types has not been drastically conditioned., Conclusions: These results highlight the uncertainties around the perception of a potential interference between ICIs and COVID-19, supporting the need of focused studies on this topic., (© 2020 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Luminal A-like and luminal B-like subtypes have different sensitivity to (neo)adjuvant chemotherapy, but their role in predicting dose-dense (DD) efficacy in the high-risk setting is unknown. In this exploratory analysis of the Gruppo Italiano Mammella 2 (GIM2) trial, we investigated DD efficacy according to luminal-like subtypes., Methods: Patients with node-positive early breast cancer were randomised to receive either DD or standard-interval (SI) anthracycline-based chemotherapy followed by paclitaxel. In our analysis, luminal A-like cohort was identified as having a Ki67 < 20% and a progesterone receptor (PgR) ≥ 20%; luminal B-like cohort as having a Ki67 ≥ 20% and/or a PgR < 20%., Results: Out of 2003 patients enrolled in the GIM2 trial, 412 had luminal A-like and 638 luminal B-like breast cancer. After a median follow-up of 7.9 years, disease-free survival (DFS) was 80.8% (95% confidence interval [CI] 76.4-84.5) and 70.5% (66.5-74.2) in luminal A-like and luminal B-like cohorts; overall survival (OS) was 91.6% (88.2-94.1) and 85.1% (81.7-87.9), respectively. We found no significant interaction between treatment and luminal subtype (interaction p = 0.603 and 0.535 for DFS and OS, respectively). When DD efficacy was investigated separately in each cohort, luminal-B like cohort appeared to benefit more from the DD schedule both in terms of DFS (unadjusted hazard ratio [HR] 0.72 [95% CI 0.54-0.96]) and OS (unadjusted HR 0.61 [95% CI 0.40-0.94]), compared with the luminal A-like cohort (unadjusted HR for DFS 0.89 [95% CI 0.59-1.33]; unadjusted HR for OS 0.83 [95% CI 0.45-1.54])., Conclusions: No significant interaction between luminal-like subtype and treatment was observed. Patients in the luminal B-like cohort seemed to benefit more from DD schedule., Competing Interests: Conflict of interest statement L.D.M. declares honoraria from Roche, Pfizer, Ipsen, Eli Lilly, Eisai, Novartis, Takeda and MSD and Seattle Genetics; a consulting and advisory role for Roche and Eli Lilly and fees for travel, accommodation and expenses from Roche, Pfizer and Celgene outside the submitted work. M.L. served as a consultant for Teva and received speaker honoraria from Theramex outside the submitted work. O.G. received personal fees from Celgene, Eisai, Pfizer, Amgen, Eli Lilly and Novartis; travel and accommodation expenses from Celgene, Roche and Pfizer and research funding from Eisai outside the submitted work. F.P. received honoraria for advisory boards, activities as a speaker, travel grants, research grants from Agmen, Celgene, Eli Lilly, Ipsen, MSD, Novartis, Pierre-Fabre, Pfizer and Takeda and received research funding from Astrazeneca, Eisai and Roche outside the submitted work. M.D.L. declares consulting fees from Pfizer, Novartis, Eli Lilly, Roche, Eisai and Celgene outside the submitted work., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: In the prepertuzumab era, we evaluated the clinical outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who underwent first-line trastuzumab-based or lapatinib-based therapy according to prior exposure to (neo)adjuvant trastuzumab., Materials and Methods: In this multicentre retrospective cohort study conducted in 14 Italian centres of the Gruppo Italiano Mammella, consecutive patients undergoing first-line trastuzumab or lapatinib-based therapy were included. Analyses were performed according to the type of first-line therapy for metastatic disease (trastuzumab or lapatinib). Dichotomous clinical outcomes were analysed using logistic regression and time-to-event outcomes using Cox proportional hazard models controlling for relevant demographic, clinicopathological and therapy characteristics., Results: Out of 450 patients included in the study, 416 (92%) received trastuzumab and 34 (7.5%) lapatinib. As compared with the trastuzumab cohort, more patients in the lapatinib cohort had a trastuzumab-free interval <1 month (37% vs 13.9%; p=0.017) and brain metastasis as first site of relapse (38.2% vs 9.4%; p<0.001). Among the 128 patients who relapsed after prior (neo)adjuvant trastuzumab, 101 (78.9%) received first-line trastuzumab and 27 (21.1%) first-line lapatinib. The following outcomes were observed with first-line lapatinib or trastuzumab, respectively: overall response rate 45.5% vs 61.3% (p=0.184), clinical benefit rate 68.2% vs 72.5% (p=0.691), median progression-free survival (PFS) 11.4 vs 12.0 months (p=0.814) and median overall survival (OS) 34.7 vs 48.2 months (p=0.722). In patients with brain metastasis as first site of relapse, median PFS was 12.2 vs 9.9 months (p=0.093) and median OS 33.7 vs 28.5 months (p=0.280), respectively., Conclusions: In patients with HER2-positive breast cancer relapsing after prior (neo)adjuvant trastuzumab, first-line treatment with trastuzumab or lapatinib was not associated with a significant difference in the clinical outcomes. A non-significant trend favouring the use of lapatinib was observed in patients with brain metastasis as the first site of relapse., Competing Interests: Competing interests: ARF received travel grant directed to his institution to participate in scientific meeting from Roche and Novartis outside of the submitted work. FP served as a consultant and received honoraria, outside the submitted work, from Amgen, Eli Lilly, MSD, Novartis, Pierre-Fabre, Pfizer, Roche; received research funding from Astrazeneca, Eisai, Roche outside the submitted work and received travel grants from Celgene, Roche, Servier outside the submitted work. FM served as a consultant and/or received speaker’s honoraria from Novartis, Pfizer, Eli Lilly, Pierre Fabre, Roche and Daiichi Sankyo. ML served as a consultant for Teva and received honoraria from Theramex and Takeda outside the submitted work. LDM served as a consultant and received honoraria, outside the submitted work, from Roche, Novartis, Astrazeneca, Eisai, Eli lilly, MSD, Genomic health, Takeda, Ipsen, Pfeizer, Seattle Genetics., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Dose-dense adjuvant chemotherapy is standard of care in high-risk early breast cancer patients. However, its role in HER2-positive patients is still uncertain. In this exploratory analysis of the GIM2 trial, we investigated the efficacy of dose-dense chemotherapy in HER2-positive breast cancer patients with or without exposure to trastuzumab. In the GIM2 trial, node-positive early breast cancer patients were randomized to receive four cycles of (fluorouracil)epirubicin/cyclophosphamide followed by four cycles of paclitaxel administered every 2 (dose-dense) or 3 (standard-interval) weeks. After approval of adjuvant trastuzumab, protocol was amended in April 2006 to allow use of trastuzumab for 1 year after chemotherapy completion in HER2-positive patients. The efficacy of dose-dense chemotherapy in terms of disease-free survival (DFS) and overall survival (OS) was assessed according to HER2 status and trastuzumab use. Out of 2,003 breast cancer patients, HER2 status was negative/unknown in 1,551 patients; among the 452 patients with HER2-positive breast cancer, chemotherapy alone or followed by trastuzumab was given to 320 and 132 patients, respectively. Median follow-up was 8.1 years. No significant interaction between HER2 status, trastuzumab use and chemotherapy treatment was observed for both DFS (p = 0.698) and OS (p = 0.708). Nevertheless, there was no apparent benefit in the HER2-positive group treated with trastuzumab (DFS: HR, 0.99; 95% CI 0.52-1.89; OS: HR, 0.95; 95% CI 0.37-2.41). Although dose-dense chemotherapy was associated with a significant survival improvement in high-risk breast cancer patients, its benefit appeared to be smaller (if any) in patients with HER2-positive disease who received adjuvant trastuzumab., (© 2019 UICC.)

Breast cancer is the most frequent malignancy diagnosed in premenopausal women. In this age group, breast tumors tend to be diagnosed at more advanced stages and to harbor more aggressive biological features. In addition, specific age-related issues including genetic counseling, fertility preservation, impact on social and couple relationships, working life, and management of long-term side effects should be considered highly relevant when managing early breast cancer in premenopausal women. Therefore, the care of these patients is particularly complex and a multidisciplinary approach is mandatory. The present review summarizes the current state of art in the adjuvant systemic treatment of premenopausal women with early breast cancer focusing on the optimal chemotherapy, endocrine therapy, and targeted therapy approaches in this specific patient population., Competing Interests: Declaration of conflicting interests:M.T. received travel grants from Roche, Bristol-Myers Squibb, AstraZeneca, Takeda, and Honoraria as medical writer from Novartis outside the submitted work. M.L. served as consultant for Roche and Novartis, and received speaker honoraria from Roche, Takeda, Lilly, Novartis and Theramex outside the submitted work. The other authors declare no conflicts of interests., (© The Author(s) 2020.)

Background: Adjuvant chemotherapy is the standard of care in high-risk early breast cancer patients. Dose-dense should be the preferred schedule of administration. However, its long-term benefit is unknown., Methods: In the Italian multicentre Phase 3 randomised MIG-1 trial, node-positive and high-risk node- negative breast cancer patients were randomised to receive six cycles of adjuvant fluorouracil, epirubicin and cyclophosphamide regimen administered every 3 (FEC21) or 2 (FEC14) weeks. The primary endpoint was overall survival (OS), and the secondary endpoint was event-free survival (EFS)., Results: From 1992 to 1997, 1214 patients were included. Median follow-up was 15.8 years. In all, 15-year OS was 71% and 68% in the FEC14 and FEC21 groups, respectively (HR = 0.89; p = 0.25). In all, 15-year EFS was 47% and 43% in the FEC14 and FEC21 groups, respectively (HR = 0.87; p = 0.18). In a pre-planned subgroup analysis, among patients with hormone receptor-negative tumours, 15-year OS was 70% and 65% in the FEC14 and FEC21 groups, respectively (HR = 0.73; 95% CI: 0.51-1.06); 15-year EFS was 58% and 43% in the FEC14 and FEC21 groups, respectively (HR = 0.70; 95% CI: 0.51-0.96)., Conclusions: Updated results from the MIG-1 study are numerically in favour of dose-dense chemotherapy, and suggest a long-term benefit of this approach in high-risk early breast cancer patients.

Background: T-DM1 improves progression-free survival (PFS) and overall survival (OS) in patients with metastatic human epidermal growth factor receptor 2-positive (HER2 + ) breast cancer progressing on prior trastuzumab plus a taxane. A paucity of data is available on T-DM1 efficacy after dual anti-HER2 blockade with pertuzumab and trastuzumab plus a taxane, which represents the current first-line standard of care. The present study is a retrospective/prospective evaluation of the efficacy and activity of second-line T-DM1 after front-line pertuzumab-based therapy., Patients and Methods: Eligible patients were identified within the Gruppo Italiano Mammella (GIM) 14/BIOMETA study, a retrospective/prospective multicenter study on treatment patterns and outcomes of patients with metastatic breast cancer (ClinicalTrials.gov Identifier: NCT02284581). We searched for patients who received second-line T-DM1 after taxane plus trastuzumab and pertuzumab between November 15, 2013 and May 31, 2018. We calculated median PFS, median time to treatment failure (TTF), prolonged duration of therapy (PDT), objective response rate (ORR), and 1-year OS., Results: Of 445 patients with HER2 + metastatic breast cancer, 77 were eligible for the analysis. At a median follow-up of 7 months, median PFS was 6.3 months (95% confidence intervals [CI], 4.8-7.7 months), and median TTF was 6.2 months (95% CI, 4-8.6 months). More than one-third of patients (37.6%; n = 29) experienced PDT with an ORR of 27.1%. At data cutoff, the median OS was not reached, and the 1-year OS was 82%., Conclusions: Our results show meaningful activity of T-DM1 after front-line pertuzumab plus trastuzumab and a taxane, with about 27% of patients having an objective response and 40% of patients achieving durable disease control., (Copyright © 2019. Published by Elsevier Inc.)

Purpose of Review: Adjuvant chemotherapy for breast cancer significantly reduces the risk of recurrence and improves overall survival (OS). The purpose of the current article is to review available evidence on dose-dense chemotherapy, also focusing on special population, including premenopausal women and those with HER2-positive disease., Recent Findings: A recent patient-level meta-analysis showed that the use of dose-dense chemotherapy is associated with significant reduction in disease recurrence, breast cancer mortality and improvement in OS. The benefit of dose-dense chemotherapy is irrespective from HER2 status, although women with HER2-positive disease enrolled in trials included in the meta-analysis did not receive the current standard of treatment with anti-HER2 agents. Among premenopausal women, dose-dense chemotherapy improved OS, and thus should be considered standard of care for them., Summary: In conclusion, high-risk early stage breast cancer patients should be treated with (neo)adjuvant dose-dense anthracycline-based chemotherapy followed by paclitaxel. In the era of trastuzumab, the benefit of dose-dense chemotherapy is still unclear for patients with HER2-positive breast cancer.

The use of chemotherapy in premenopausal cancer patients may lead to chemotherapy-induced premature ovarian failure. Pharmacological temporary ovarian suppression obtained with the gonadotropin-releasing hormone agonist (GnRHa) administered concomitantly with chemotherapy has been investigated as a technique capable to reduce the gonadotoxicity, reducing the risk of developing premature menopause. In recent years, important evidence has become available on the efficacy and safety of this strategy that should now be considered a standard option for ovarian function preservation in premenopausal breast cancer patients. However, in women interested in fertility preservation, this is not an alternative to cryopreservation strategies, which remains the first option to be proposed. The purpose of this review is to summarize the mechanisms of GnRHa in the preservation of fertility in premenopausal cancer patient candidates to receive chemotherapy, highlighting the areas of doubt that require further investigation., Competing Interests: Declaration of Conflicting Interests:The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Lucia Del Mastro received honoraria from Takeda and personal fees from Ipsen and Takeda outside the submitted work. Matteo Lambertini served as a consultant for Teva and received honoraria from Theramex outside the submitted work. All other authors declare no conflicts of interest.

Research Question: This study explored the knowledge, attitudes and practice of physicians towards fertility and pregnancy-related issues in young BRCA-mutated breast cancer patients., Design: Physicians attending two international breast cancer conferences completed a 26-item questionnaire exploring fertility preservation, pregnancy during (BCP) or after breast cancer. A statistical comparison was carried out of the responses exploring the same issues in young breast cancer patients overall or specifically in those with BRCA mutations., Results: The survey was completed by 273 physicians. Ovarian tissue cryopreservation (33% versus 40%; P = 0.009) and gonadotrophin-releasing hormone analogues during chemotherapy (74% versus 81%; P = 0.001) were less commonly suggested in BRCA-mutated patients than in the overall breast cancer population. 42% of respondents agreed or were neutral on the statement that ovarian stimulation should not be considered safe in BRCA-mutated breast cancer patients. 45% and 30% agreed or were neutral on the statement that pregnancy in breast cancer survivors may increase the risk of recurrence in BRCA-mutated patients or in the overall breast cancer population, respectively (P < 0.001). 15% and 3% disagreed that transplanting the cryopreserved ovarian tissue can be considered safe in BRCA-mutated patients or in the overall breast cancer population, respectively (P < 0.001). 33.3% were against the addition of platinum agents as neoadjuvant chemotherapy in BRCA-mutated patients with BCP., Conclusions: Several misconceptions on fertility preservation and pregnancy-related issues in breast cancer patients persist even among physicians directly involved in breast cancer care. Focused research efforts to address these issues in BRCA-mutated breast cancer patients and education to improve physicians' knowledge and adherence to available guidelines are urgently needed., (Copyright © 2019 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Purpose: Standard adjuvant chemotherapy for HER2-negative breast cancer consists generally in an anthracycline and taxane-based regimen (A+T). The TC (docetaxel and cyclophosphamide) regimen arises as a potential alternative, although individual randomized controlled trials (RCTs) could not demonstrate the non-inferiority of TC over A+T. This is a systematic review and meta-analysis of RCTs comparing 6 cycles of TC versus sequential A+T in the adjuvant treatment of HER2-negative breast cancer., Methods: A systematic literature search was performed to identify RCTs comparing TC versus A+T. Disease-free survival (DFS) and overall survival (OS) were assessed. Subgroup analyses of DFS according to hormone receptor status, lymph node involvement, and menopausal status were performed. Hazard ratios (HRs) and 95% confidence intervals (CI) for DFS and OS were extracted from each trial, and a pooled analysis was conducted using the random-effect model. The Higgins' I-Squared Test was used to quantify heterogeneity., Results: Seven RCTs were included (12,741 patients). Overall, no difference was observed between TC and A+T in DFS (HR 1.08, 95% CI 0.96-1.20) and OS (HR 1.05; 95% CI 0.90-1.22). A trend favoring A+T was observed in hormone receptor-negative (HR 1.12, 95% CI 0.93-1.34) and N2 patients (HR 1.25; 95% CI 0.82-1.90). Emesis/vomiting, mucositis, thrombocytopenia and sensory neuropathy were significantly more frequent with A+T., Conclusion: As adjuvant treatment of HER2-negative breast cancer, sequential A+T regimen was associated with increased risk of toxicities and no clear survival benefit as compared to 6 cycles of TC. Higher-risk patients may benefit the most from A+T, whilst TC may be an efficacious and less toxic alternative for lower-risk patients.

Background: Fertility and pregnancy-related issues are major concerns for young breast cancer patients. Limited data are available on physicians' knowledge, attitudes and practice in these fields., Methods: A 26-item questionnaire exploring 3 different topics (fertility preservation, pregnancy after breast cancer and breast cancer during pregnancy) was sent by email to physicians attending the 2016 3rd European School of Oncology (ESO) - European Society for Medical Oncology (ESMO) Breast Cancer in Young Women Conference (BCY3) and the 15th St. Gallen International Breast Cancer Conference 2017 (BCC 2017). Given the selected sample, survey respondents were expected to have a higher than average interest in the management of breast cancer patients. Descriptive analyses were performed., Results: A total of 273 physicians (105 at BCY3 and 168 at BCC 2017) completed the survey; 37.0%, 46.9% and 34.8% reported never having consulted the available international guidelines on fertility preservation, pregnancy after breast cancer and management of breast cancer during pregnancy, respectively. Up to 18.3% of respondents did not know if the different fertility preservation options were available in their country; 22.3% suggested that controlled ovarian stimulation should not be considered safe in patients with hormone receptor-positive disease. A total of 30.4% of respondents agreed or were neutral on the statement that pregnancy in breast cancer survivors may increase the risk of recurrence. Regarding breast cancer during pregnancy, 23.8% and 38.1% disagreed or were neutral on the statements that endocrine therapy and anti-HER2 agents should be avoided during pregnancy, respectively., Conclusions: Further educational initiatives are needed to improve physicians' knowledge and adherence to available guidelines when addressing fertility and pregnancy-related issues in young breast cancer patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Breast cancer is still the most frequent cancer diagnosed in women aged ≤40 years and the primary cause of death in this age group. The management of these patients needs a dedicated approach involving a multidisciplinary team that takes into account their treatment and survivorship issues. The present review aims to provide a perspective on the many challenges associated with treatment of young women with early breast cancer. We will focus on the standard (neo)adjuvant treatment, highlighting the paucity of age-specific results about the available genomic signatures, the groundbreaking landscape of adjuvant endocrine therapy and the relevant issue of the fertility preservation., Competing Interests: Competing interests: LDM received honoraria from Takeda and personal fees from Ipsen and Takeda outside the submitted work. ML served as a consultant for Teva and received honoraria from Theramex outside the submitted work.

Background: Despite the availability of different strategies for ovarian function and/or fertility preservation in young breast cancer patients candidates for chemotherapy, limited data are available on patients' actual need of these options., Patients and Methods: The PREFER study is a prospective cohort study including premenopausal women with newly diagnosed early stage breast cancer between the age of 18 and 45 years and candidates for chemotherapy. The study aimed to investigate patients' preferences and their choices of the different available strategies for ovarian function and/or fertility preservation (i.e. acceptance rate) and reasons for refusal., Results: A total of 131 consecutive patients referred from a single breast unit were included. Median age was 38.9 years with 92 patients (70.3%) diagnosed at ≤ 40 years. The majority of patients (122, 93.1%) were concerned about the risk of treatment-induced premature ovarian insufficiency (POI) and/or infertility. A total of 120 (91.6%) patients underwent temporary ovarian suppression with gonadotropin-releasing hormone agonists during chemotherapy for ovarian function preservation. Among patients with ≤40 years, only 11 (12.0%) decided to access cryopreservation strategies for fertility preservation. The main reason for not accessing the fertility unit was completion of family planning before breast cancer diagnosis; for patients who accessed the fertility unit, fear of the procedure was the main reason to refuse the proposed cryopreservation strategies., Conclusion: Despite the majority of young breast cancer patients are concerned about the risk of treatment-induced POI and/or infertility, only a limited number of them required to access the fertility unit to undergo cryopreservation strategies., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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.

Introduction: HER2-positive disease is an aggressive subtype of breast cancer that has been revolutionized by anti-HER2 directed therapies. Multiple drugs have been developed and are currently in clinical use, including trastuzumab, lapatinib, pertuzumab, T-DM1, and neratinib, alone or combined in 'dual HER2-blockade' regimens. Areas covered: A comprehensive literature review was performed regarding the current state and the future of combination regimens containing anti-HER2 agents, focusing on their efficacy, toxicity, and cost-effectiveness. Expert commentary: The combination of trastuzumab/pertuzumab is approved in all disease settings, while trastuzumab/neratinib is approved in the adjuvant setting and trastuzumab/lapatinib in metastatic disease. Meanwhile, as breast cancer biology and resistance mechanisms become clearer, combinations with drugs like PI3K/Akt/mTOR inhibitors, CDK4/6 inhibitors, anti-PD(L)1 antibodies, endocrine therapy, and new anti-HER2 agents (panHER and HER2 tyrosine kinase inhibitors, bispecific antibodies, anti-HER3 antibodies, and antibody-drug conjugates) are being extensively tested in clinical trials. More specific strategies for the 'triple-positive' (estrogen receptor-positive/HER2-positive) disease are also being explored. However, there is an urgent need for the development of predictive biomarkers for a better tailoring of anti-HER2 directed therapy. This is the only way to further improve clinical outcomes and quality of life and to decrease costs and toxicities of unnecessary treatments.

Single-agent poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have been approved as the first targeted therapy available for patients with BRCA -mutated HER2-negative metastatic breast cancer. This meta-analysis aimed to better evaluate activity, efficacy and safety of single-agent PARPi in this population. A systematic search of Medline, Embase and conference proceedings up to 31 January 2018 was conducted to identify randomised controlled trials (RCTs) investigating single-agent PARPi versus monochemotherapy in patients with BRCA -mutated HER2-negative metastatic breast cancer. Using the random-effect model, we calculated summary risk estimates (pooled HR and OR with 95% CI) for progression-free survival (PFS), overall survival (OS), objective response rate (ORR), any grade and grade 3-4 adverse events (AEs), treatment discontinuation rate and time to deterioration in quality of life (QoL). Two RCTs (n=733) were included. As compared with monochemotherapy, single-agent PARPi significantly improved PFS (HR 0.56(95% CI 0.45 to 0.70)) and ORR (OR 4.15 (95% CI 2.82 to 6.10)), with no difference in OS (HR 0.82 (95% CI 0.64 to 1.05)). Single-agent PARPi significantly increased risk of anaemia and any grade headache, but reduced risk of neutropenia and any grade palmar-plantar erythrodysesthesia syndrome as compared with monochemotherapy. No significant differences in other AEs and treatment discontinuation rate were observed. Patients treated with PARPi experienced a significant delayed time to QoL deterioration (HR 0.40 (95% CI 0.29 to 0.54)). Single-agent PARPi showed to be an effective, well tolerated and useful treatment in maintaining QoL of patients with BRCA -mutated HER2-negative metastatic breast cancer., Competing Interests: Competing interests: LDM received personal fees from Novartis Pharma AG, Roche-Genentech, Ipsen, Astrazeneca, Takeda, Eli Lilly outside the submitted work. EdA received honoraria from Roche-Genentech, research grant from Roche-Genentech (to the institution) and travel grants from Roche-Genentech and GlaxoSmithKline outside the submitted work. ML served as a consultant for Teva outside the submitted work.

Background: The aim of the study was to compare the patterns of care and clinical outcomes of HER2-positive metastatic breast cancer (MBC) patients with de novo or recurrent disease who underwent first-line trastuzumab-based therapy., Patients and Methods: This was a multicenter retrospective cohort study including consecutive patients with HER2-positive MBC who received first-line trastuzumab-based therapy. Analyses on treatment response and effectiveness were conducted according to type of metastatic presentation (ie, de novo vs. recurrent disease). Exploratory analyses were used to evaluate whether the use of surgery of the primary tumor in the de novo cohort influenced patients' survival., Results: From January 2000 to December 2013, 416 patients were included in the study, 113 (27.2%) presented with de novo MBC and 303 (72.8%) with recurrent disease. Compared with patients in the recurrence cohort, those in the de novo cohort had worse baseline characteristics, received more aggressive first-line treatments, and showed better survival, with an adjusted hazard ratio (HR) for progression-free survival (PFS) of 0.65 (95% confidence interval [CI], 0.43-0.97; P = .035) and for overall survival (OS) of 0.53 (95% CI, 0.30-0.95; P = .034). In the de novo cohort, the 54 patients (47.8%) who underwent surgery of the primary tumor had significantly better PFS (adjusted HR, 0.44; 95% CI, 0.26-0.72; P = .001) and OS (adjusted HR, 0.49; 95% CI, 0.26-0.93; P = .029) than those who did not undergo surgery., Conclusion: Patients with de novo HER2-positive MBC showed significantly better survival outcomes than those with recurrent disease. In this population, surgery of the primary breast tumor was associated with better outcomes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: The role of ovarian function suppression (OFS) through luteinizing hormone-releasing hormone agonists (LHRHa) in addition to tamoxifen has been questioned until recently. In 2015, two large clinical trials led to a paradigm shift in the adjuvant endocrine treatment of premenopausal women, introducing the use of LHRHa plus tamoxifen (or aromatase inhibitor, AI) into current clinical practice. Areas covered: The present review aims to provide an in-depth overview of the role of LHRHa+tamoxifen for the adjuvant treatment of premenopausal women with hormone receptor positive breast cancer (HR+BC). Expert opinion: The addition of LHRHa to endocrine treatment (either tamoxifen or AI) is effective in premenopausal women who are at high risk of relapse. To date, no clear recommendations are available for the choice between LHRHa+tamoxifen and LHRH+AI. Although recent data showed better DFS with LHRHa+AI, other issues should be considered: 1) approximately 20 out of 100 women do not reach complete OFS with LHRHa+AI; 2) there is no extended endocrine therapy option that can be applied to women who received 5 years of LHRHa+AI and remained premenopausal at the end of the fifth year. Long-term results of the SOFT-TEXT study are needed to establish if LHRHa+AI is superior to LHRHa+tamoxifen.

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.

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).

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., Competing Interests: HAA reports employment at Innate Pharma at the end of this study; this employment is not related in any sort to the subject of the current study. All the remaining authors declare no conflict of interest.

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.

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.

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.

Purpose: To evaluate the safest timing of pegfilgrastim administration in dose-dense anthracycline- and taxane-based chemotherapy, three different cohorts of patients enrolled in the Gruppo Italiano Mammella (GIM) 2 study and treated at the coordinating center received pegfilgrastim 24 h (cohort A) or 72 h (cohort B) or 96 h (cohort C) after chemotherapy., Methods: A total of 41 patients were included. The safety of pegfilgrastim administration in terms of occurrence of early and late leukocytosis and the behavior of white blood cells (WBC) counts in the three cohorts across all chemotherapy cycles were evaluated. Anthracycline and taxane cycles were analyzed separately., Results: The occurrence of early leukocytosis was a more common event in patients in cohort A in both anthracycline and taxane cycles (75 and 66.7%) as compared to cohort B (50 and 60%) and cohort C (66.7 and 33.3%). More patients in cohort C developed late leukocytosis in both anthracycline and taxane cycles (50 and 100%) as compared to cohort A (0 and 66.7%) and cohort B (35.7 and 86.7%). Patients in cohort A experienced the highest median value of WBC count 24 h after pegfilgrastim administration in both anthracycline and taxane cycles (61.2 × 10(3)/μl and 67.8 × 10(3)/μl). Patients in cohort C experienced the highest median value of WBC count at day 13 in both anthracycline and taxane cycles (19.4 × 10(3)/μl and 24.2 × 10(3)/μl)., Conclusions: For the prevention of leukocytosis, the safest timing of pegfilgrastim administration based on WBC count in dose-dense anthracycline- and taxane-based regimens seems to be 72 h after chemotherapy., Trial Registration: This study is registered with https://clinicaltrials.gov/ct2/show/NCT00433420.

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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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.

Background: Trastuzumab is a humanized monoclonal antibody (mAb) currently used for the treatment of breast cancer (BC) patients with HER-2 overexpressing tumor subtype. Previous data reported the involvement of FcγRIIIA/IIA gene polymorphisms and/or antibody-dependent cellular cytotoxicity (ADCC) in the therapeutic efficacy of trastuzumab, although results on these issues are still controversial. This study was aimed to evaluate in vitro the functional relationships among FcγRIIIA/IIA polymorphisms, ADCC intensity and HER-2 expression on tumor target cells and to correlate them with response to trastuzumab., Patients and Methods: Twenty-five patients with HER-2 overexpressing BC, receiving trastuzumab in a neoadjuvant (NEO) or metastatic (MTS) setting, were genotyped for the FcγRIIIA 158V>F and FcγRIIA 131H>R polymorphisms by a newly developed pyrosequencing assay and by multiplex Tetra-primer-ARMS PCR, respectively. Trastuzumab-mediated ADCC of patients' peripheral blood mononuclear cells (PBMCs) was evaluated prior to therapy and measured by (51)Chromium release using as targets three human BC cell lines showing different levels of reactivity with trastuzumab., Results: We found that the FcγRIIIA 158F and/or the FcγRIIA 131R variants, commonly reported as unfavorable in BC, may actually behave as ADCC favorable genotypes, in both the NEO (P ranging from 0.009 to 0.039 and from 0.007 to 0.047, respectively) and MTS (P ranging from 0.009 to 0.032 and P = 0.034, respectively) patients. The ADCC intensity was affected by different levels of trastuzumab reactivity with BC target cells. In this context, the MCF-7 cell line, showing the lowest reactivity with trastuzumab, resulted the most suitable cell line for evaluating ADCC and response to trastuzumab. Indeed, we found a statistically significant correlation between an increased frequency of patients showing ADCC of MCF-7 and complete response to trastuzumab in the NEO setting (P = 0.006)., Conclusions: Although this study was performed in a limited number of patients, it would indicate a correlation of FcγR gene polymorphisms to the ADCC extent in combination with the HER-2 expression levels on tumor target cells in BC patients. However, to confirm our findings further experimental evidences obtained from a larger cohort of BC patients are mandatory.

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., (©AlphaMed Press.)

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., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

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.