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Introduction: Advancements in monoclonal antibodies, tyrosine kinase inhibitors, and antibody drug conjugates (ADCs) have notably enhanced outcomes for metastatic HER2-positive breast cancer patients. Despite the expanding treatment options and clinical complexities, determining the optimal sequence of HER2-targeted therapies remains partly uncertain, influenced by various factors., Methods: To refine HER2-positive metastatic breast cancer management, particularly regarding tucatinib's position, a Steering Committee of leading oncologists in breast cancer care devised a panel of statements via a Delphi approach, focusing on five key topics: general clinical management, therapeutic approaches for patients with HER2-positive breast cancer and brain metastases, treatment sequence, and tucatinib's safety and efficacy., Results: A total of 29 statements were deliberated, with strong consensus achieved for most. However, no consensus emerged regarding the management of brain progression alongside stable extracranial disease: 48 % advocated for switching to tucatinib, while 53 % favored a stereotactic brain radiotherapy (SBRT) approach if feasible., Conclusion: The unanimous consensus attained in this Delphi panel, particularly regarding tucatinib's efficacy and safety, underscores oncologists' recognition of its clinical significance based on existing trial data. These findings align closely with current literature, shedding light on areas necessitating further investigation, not thoroughly explored in prior studies. Moreover, the results underscore the scarcity of data on managing brain progression alongside stable extracranial disease, emphasizing the imperative for dedicated research to address these gaps and yield definitive insights., Competing Interests: Declaration of competing interest PC: Consulting or Advisory Role: Daiichi Sankyo/Lilly, Reveal Genomics, Gilead Sciences; Speakers' Bureau: Roche/Genentech, Novartis, AstraZeneca, Lilly, BMS; Research Funding: Merck KGaA (Inst); Patents, Royalties, Other Intellectual Property: HER2Dx patent; Expert Testimony: AstraZeneca. EC: reports consulting fees from Novartis, Lilly, Pfizer, Roche, AstraZeneca, and Daiichi Sankyo; speaker's bureau from Lilly, Pfizer, AstraZeneca, and Daiichi Sankyo; and travel and accommodations from Pfizer and Roche. GC: received honoraria for speaker's engagement: Roche, Seattle Genetics, Novartis, Lilly, Pfizer, Foundation Medicine, NanoString, Samsung, Celltrion, BMS, MSD; Honoraria for providing consultancy: Roche, Seattle Genetics, NanoString; Honoraria for participating in Advisory Board: Roche, Lilly, Pfizer, Foundation Medi-cine, Samsung, Celltrion, Mylan; Honoraria for writing engagement: Novartis, BMS; Honoraria for participation in Ellipsis Scientific Affairs Group; Institutional research funding for conducting phase I and II clinical trials: Pfizer, Roche, Novartis, Sanofi, Celgene, Servier, Orion, AstraZeneca, Seattle Genetics, AbbVie, Tesaro, BMS, Merck Serono, Merck Sharp Dome, Janssen-Cilag, Philogen, Bayer, Medivation, MedI- mmune MDL: advisory boards, activities as a speaker, travel grants, consultancy: Eli Lilly, Novartis, Seagen, Takeda, Roche, Daiichi Sankyo, Tomalab, Gilead, Genetic, Menarini, Sophos, AstraZeneca, Pfizer, Sanofi, Ipsen, Pierre Fabre, GSK. AG: research funding to the Institution: AstraZeneca, Pfizer, Janssen, Roche, MSD, Daichii-Sankyo, GSK/Tesaro, HiFiBio, Merck, Boehringer-Ingelheim, Exelixis, Bayer, Incyte, Bayer, Aileron; travel, accommodation, expenses: Gentili. LDM: advisory role for Agendia, Amgen, AstraZeneca, Collage SpA, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead, GSK, Havas Life, Pfizer, Pierre Fabre, Roche, Seagen Int, Stemline Menarini and Uvet; personal fees as an invited speaker for Accademia Nazionale Medicina, Andromeda E20, Aristea, Delphi international, Editree, Eli Lilly, Ipsen, Meeting SrL, MSD, Novartis, Over Srl, Prex Srl, Symposia and Vyvamed Srl; personal fees for writing engagements for Edizioni Minerva Medica, Pensiero Scientifico Editore and Roche; personal consultancy fees from Eli Lilly, Gilead, Kardo Srl and Sharing Progress in Cancer Care (SPCC)—Switzerland; personal fees for author slide kits from Forum service and Think2it; personal fees for interviews from Infomedica Srl and Think2it; institutional funding as a local PI from AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, Novartis, Novella Clinical, Roche and Seagen; institutional funding as a national coordinating PI from Roche; institutional research grant from Pfizer; and non-remunerated product samples from FoundationOne. AG: received advisory role from AstraZeneca, Daiichi, Eisai, Lilly, Novartis, Pfizer, Roche, Seagen, Gilead, Teva, and Gentili; lecture honoraria from Novartis, Pfizer, Gilead, Roche, Eisai, Seagen, Teva, and Gentili; and research support from Roche, Eisai, Gilead, and Pharmanutra AL: Research support: Roche, Agendia, Lilly, Pfizer, Novartis, Merck Sharp&Dhome, Gilead, Daiichi Sankyo; Consulting/advisor: Lilly, Roche, Pfizer, Novartis; Speaker's Bureaus: Lilly, Astrazeneca, Merck Sharp&Dhome, Pfizer, Novartis; Travel support: Roche, Pfizer, Astrazeneca, Merck Sharp&Dhome. MM: Honoraria: Roche/Genentech, Lilly, Pfizer, Novartis, Pierre Fabre, Seagen; Consulting or Advisory Role: Roche/Genentech, Novartis, Pfizer, Lilly, AstraZeneca, Daiichi-Sankyo; Speakers' Bureau: Lilly/ImClone, Lilly/ImClone, Roche/Genentech, Pierre Fabre; Research Funding: Novartis (Inst), Roche (Inst), Puma Biotechnology (Inst); Travel, Accommodations, Expenses: Daiichi-Sankyo; Other Relationship: Roche, Novartis. FPo: advisory board from AstraZeneca; speaking honoraria and travel grants from Eli Lilly, Novartis, Seagen, Daichii Sankyo, and Gilead. AP: reports grants and personal fees from NanoString Technologies, Veracyte, Novartis, AstraZeneca, DaiichiSankyo, and Roche; in addition, A. Prat has a patent for DNADX pending. FPu: reports honoraria for advisory boards, activities as a speaker, travel grants, research grants from Amgen - Astrazeneca - Daiichi Sankyo - Celgene - Eisai - Eli Lilly- Exact Sciences- Gilead - Ipsen – Menarini- MSD - Novartis - Pierre Fabre - Pfizer - Roche - Seagen - Takeda – Viatris; Research funding from Astrazeneca – Eisai – Roche. CS: consultancy or advisory role for AstraZeneca, Ax's Consulting, Byondis, Daiichi Sankyo, Eisai, Exact Sciences, Exeter, F. Hoffmann-La Roche Ltd., International Society for the Study and Exchange of evidence from Clinical research And Medical experience (ISSECAM), Medical Statistics Consulting, MediTech, Merck Sharp and Dohme Corp, Novartis, Pfizer, Philips, Pierre Fabre, PintPharma, Puma, Roche, Sanofi, Seagen, Zymeworks, and research funding from Aragon, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Byondis, CytomX, Daiichi Sankyo, F. Hoffmann-La Roche Ltd., Genentech, German Breast Group Forchungs, GlaxoSmithKline, Immunomedics, Innoup, International Breast Cancer Study Group (IBCSG), Lilly, Macrogenics, Medica Scientia Innovation Research, Menarini Ricerche, Merck Sharp and Dohme Corp, Merus, Millennium, Novartis, Pfizer, Piqur, Puma, Roche, Sanofi, Seagen, Synthon, and Zenith., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose of Review: Use of adjuvant chemotherapy significantly reduced the risk of recurrence and improved overall survival (OS) in patients with early-stage breast cancer. However few data are available on efficacy of different adjuvant chemotherapy regimens and schedules in patients with hormone receptor positive/HER2-negative (HR+/HER2-) breast cancer. We aim to summarize the available evidence on efficacy of adjuvant anthracycline-based chemotherapy and of the dose-dense schedule in this population. Moreover, current controversies in the management of patients with early-stage HR+/HER2- breast cancer are discussed., Recent Findings: Patient-level meta-analysis evaluating the role of the addition of anthracycline to taxane-based chemotherapy showed that recurrence rate was 14% lower [relative risk (RR) 0.86, P = 0.0004] among patients receiving anthracycline-based treatment.Patient-level meta-analysis evaluating the role of different schedules of chemotherapy administration showed that the use of adjuvant dose-dense chemotherapy is associated with significant reduction in breast cancer recurrences and breast cancer mortality. Less evidence is available in the neoadjuvant setting., Summary: For patients with high-risk HR+/HER2- breast cancer, (neo) adjuvant anthracycline and taxane-based chemotherapy, and a dose-dense regimen should still be considered the standard of care. However, in patients with intermediate-low risk breast cancer anthracycline-free regimens could be considered an option of treatment., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Locally advanced breast cancer (LABC) is a complex disease that requires a multidisciplinary approach. Neoadjuvant chemotherapy (NAC) is usually performed in order to achieve loco-regional radical resection; although its importance in the multidisciplinary approach to LABC is well recognized, a small number of patients show Progressive Disease (PD). No standard salvage treatment (ST) has been defined and different strategies can be adopted, such as second-line systemic therapies, radiation therapy, and surgery. Herein, a case of LABC in PD during NAC is reported with a literature review, with the aim of highlighting the importance of a tailored multidisciplinary treatment for each patient.

Purpose: We aimed to assess the impact of surgery of primary tumor in overall survival (OS) of women with de novo metastatic breast cancer., Methods: Nationwide, population-based retrospective cohort study of women diagnosed with de novo metastatic breast cancer in Belgium, between Jan/2010-Dec/2014. Data was obtained from the Belgian Cancer Registry and administrative databases. "Surgery" group was defined by surgery of primary tumor up to nine months after diagnosis. We excluded women who did not receive systemic treatment or did not complete nine months follow-up after diagnosis. All the subsequent analyses reporting on overall survival and the stratified outcome analyses were performed based on this nine-month landmark cohort. OS was estimated using Kaplan-Meier method and compared using adjusted Cox proportional hazards models controlling for confounders with 95% confidence intervals (CI). We performed a stratified analysis according to surgery timing and a propensity score matching analysis., Results: 1985 patients, 534 (26.9%) in the "Surgery" and 1451 (73.1%) in the "No Surgery" group. Patients undergoing surgery were younger (p < 0.001), had better performance status (PS) (p < 0.001), and higher proportion of HER2-positive and triple-negative breast cancer (p = 0.012). Median follow-up was 86.0 months (82.6-88.5). Median OS was 60.1 months (57.1-68.2) in the "Surgery" vs. 41.9 months (39.8-44.2) in the "No Surgery" group (adjusted HR 0.56; 0.49-0.64). OS was similar when surgery was performed upfront or after systemic treatment. Propensity score matching analysis confirmed the same findings., Conclusion: Among patients receiving systemic treatment for de novo metastatic breast cancer and surviving nine months or more, those who received surgery of the primary tumor within nine months of diagnosis have longer subsequent survival than those who did not., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: In estrogen receptor-positive (ER+) breast cancer, single-nucleotide polymorphisms (SNP) in the aromatase gene might affect aromatase inhibitors (AI) metabolism and efficacy. Here, we assessed the impact of SNP on prognosis and toxicity of patients receiving adjuvant letrozole., Experimental Design: We enrolled 886 postmenopausal patients in the study. They were treated with letrozole for 2 to 5 years after taking tamoxifen for 2 to 6 years, continuing until they completed 5 to 10 years of therapy. Germline DNA was genotyped for SNP rs4646, rs10046, rs749292, and rs727479. Log-rank test and Cox model were used for disease-free survival (DFS) and overall survival (OS). Cumulative incidence (CI) of breast cancer metastasis was assessed through competing risk analysis, with contralateral breast cancer, second malignancies and non-breast cancer death as competing events. CI of skeletal and cardiovascular events were assessed using DFS events as competing events. Subdistribution HR (sHR) with 95% confidence intervals were calculated through Fine-Gray method., Results: No SNP was associated with DFS. Variants rs10046 [sHR 2.03, (1.04-2.94)], rs749292 [sHR 2.11, (1.12-3.94)], and rs727479 [sHR 2.62, (1.17-5.83)] were associated with breast cancer metastasis. Three groups were identified on the basis of the number of these variants (0, 1, >1). Variant-based groups were associated with breast cancer metastasis (10-year CI 2.5%, 7.6%, 10.7%, P = 0.035) and OS (10-year estimates 96.5%, 93.0%, 89.6%, P = 0.030). Co-occurrence of rs10046 and rs749292 was negatively associated with 10-year CI of skeletal events (3.2% vs. 10%, P = 0.033). A similar association emerged between rs727479 and cardiovascular events (0.3% vs. 2.1%, P = 0.026)., Conclusions: SNP of aromatase gene predict risk of metastasis and AI-related toxicity in ER+ early breast cancer, opening an opportunity for better treatment individualization., (©2023 The Authors; Published by the American Association for Cancer Research.)

Understanding the brain functioning is essential for governing brain processes with the aim of managing pathological network dysfunctions. Due to the morphological and biochemical complexity of the central nervous system, the development of general models with predictive power must start from in vitro brain network engineering. In the present work, we realized a micro-electrode array (MEA)-based in vitro brain network and studied its emerging dynamical properties. We obtained four-neuron-clusters (4N) assemblies by plating rat embryo cortical neurons on 60-electrode MEA with cross-shaped polymeric masks and compared the emerging dynamics with those of sister single networks (1N). Both 1N and 4N assemblies exhibited spontaneous electrical activity characterized by spiking and bursting signals up to global activation by means of network bursts. Data revealed distinct patterns of network activity with differences between 1 and 4N. Rhythmic network bursts and dominant initiator clusters suggested pacemaker activities in both assembly types, but the propagation of activation sequences was statistically influenced by the assembly topology. We proved that this rhythmic activity was ivabradine sensitive, suggesting the involvement of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, and propagated across the real clusters of 4N, or corresponding virtual clusters of 1N, with dominant initiator clusters, and nonrandom cluster activation sequences. The occurrence of nonrandom series of identical activation sequences in 4N revealed processes possibly ascribable to neuroplasticity. Hence, our multi-network dissociated cortical assemblies suggest the relevance of pacemaker neurons as essential elements for generating brain network electrophysiological patterns; indeed, such evidence should be considered in the development of computational models for envisaging network behavior both in physiological and pathological conditions., (© 2023. Springer Nature Limited.)

Introduction: Breast cancer is the most commonly diagnosed malignancy during pregnancy. Breast cancer during pregnancy is a challenging clinical condition requiring proper and timely multidisciplinary management., Areas Covered: This review focuses on the management of breast cancer during pregnancy with a focus about the current state-of-the-art on the feasibility and safety of pharmacotherapy approaches in this setting., Expert Opinion: Multidisciplinary care is key for a proper diagnostic-therapeutic management of breast cancer during pregnancy. Engaging patients and their caregivers in the decision-making process is essential and psychological support should be provided. The treatment of patients with breast cancer during pregnancy should follow the same recommendations as those for breast cancer in young women outside pregnancy but taking into account the gestational age at the time of treatment.Anthracycline-, cyclophosphamide-, and taxane-based regimens can be safely administered during the second and third trimesters with standard protocols, preferring weekly regimens whenever possible. Endocrine therapy, immune checkpoint inhibitors, and targeted agents are contraindicated throughout pregnancy, also due to the very limited data available to guide their administration in this setting. During treatment, careful fetal growth monitoring is mandatory, and even after delivery proper health monitoring for the children exposed in utero to chemotherapy should be continued.

Goal of this work is to show how the developmental conditions of in vitro neuronal networks influence the effect of drug delivery. The proposed experimental neuronal model consists of dissociated cortical neurons plated to Micro-Electrode Arrays (MEAs) and grown according to different conditions (i.e., by varying both the adopted culture medium and the number of days needed to let the network grow before performing the chemical modulation). We delivered rising amount of bicuculline (BIC), a competitive antagonist of GABAA receptors, and we computed the firing rate dose-response curve for each culture. We found that networks matured in BrainPhys for 18 days in vitro exhibited a decreasing firing trend as a function of the BIC concentration, quantified by an average IC50 (i.e., half maximal inhibitory concentration) of 4.64 ± 4.02 µM. On the other hand, both cultures grown in the same medium for 11 days, and ones matured in Neurobasal for 18 days displayed an increasing firing rate when rising amounts of BIC were delivered, characterized by average EC50 values (i.e., half maximal excitatory concentration) of 0.24 ± 0.05 µM and 0.59 ± 0.46 µM, respectively.Clinical Relevance- This research proves the relevance of the experimental factors that can influence the network development as key variables when developing a neuronal model to conduct drug delivery in vitro, simulating the in vivo environment. Our findings suggest that not considering the consequences of the chosen growing conditions when performing in vitro pharmacological studies could lead to incomplete predictions of the chemically induced alterations.

Background: Prior exposure to adjuvant endocrine therapy (ET) and timing to recurrence are crucial factors for first-line treatment choices in patients with hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer (BC) and in clinical trial eligibility, classifying metastatic HR+/HER2- BC as endocrine sensitive (ES) or primary (1ER)/secondary (2ER) resistant. However, this classification is largely based on expert opinion and no proper evidence exists to date to support its possible prognostic and clinical impact., Methods: This analysis included individual patient-level data from 4 adjuvant phase III randomized trials by the Mammella InterGruppo (MIG) and Gruppo Italiano Mammella (GIM) study groups. The impact of endocrine resistance/sensitivity classification on overall survival (mOS, defined as time between date of distant relapse and death) was assessed in both univariate and multivariate Cox proportional hazards models., Findings: Between November 1992 and July 2012, 9058 patients were randomized in 4 trials, of whom 6612 had HR+/HER2- BC. Median follow-up was 9.1 years (interquartile range [IQR] 5.6-15.0). In the whole cohort, disease-free survival and OS were 90.4% and 96.6% at 5 years, and 79.1% and 89.4% at 10 years, respectively. The estimated hazard of recurrence raised constantly during the first 15 years from diagnosis, being more pronounced during the first 2 years and less pronounced after year 7. Among the 493 patients with a distant relapse as first disease-free survival event and available date on ET completion, 72 (14.6%), 207 (42.0%) and 214 (43.4%) were classified as having 1ER, 2ER and ES, respectively. Median follow-up from diagnosis of a distant relapse was 3.8 years (IQR 1.6-7.5). Patients with 1ER were significantly more likely to be younger, to have N2/N3 nodal status, grade 3 tumours and to develop visceral metastases. Site of first distant relapse was significantly different between the 3 groups (p = 0.005). In patients with 1ER, 2ER and ES breast cancer, median mOS was 27.2, 38.4 and 43.2 months, respectively (p = 0.03). As compared to patients with ES disease, a higher risk of death was observed in those with 1 ER (adjusted Hazard Ratio [aHR] 1.54; 95% CI 1.03-2.30) and 2ER (aHR 1.17; 95% CI 0.87-1.56) (p = 0.11)., Interpretation: This large analysis with long-term follow-up provides evidence on the prognostic and clinical impact of the currently adopted endocrine resistance/sensitivity classification in patients with HR+/HER2- advanced BC. This classification may be considered a valid tool to guide clinical decision-making and to design future ET trials in the metastatic setting., Funding: AIRC., Competing Interests: ML reports advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Gilead, MSD and Exact Sciences; speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, and Takeda; travel Grants from Gilead outside the submitted work. EB reports research grant (to the Institution) from Gilead Science. SDP reports honoraria from Roche, Novartis, Pfizer, Celgene, Eli Lilly, AstraZeneca, Clovis, Seagen, Daichii Sankyo, and MSD outside the submitted work. MDL reports personal fees from Pfizer, Novartis, Roche, AstraZeneca, Eli Lilly, MSD, Daiichi-Sankyo, GSK, Sanofi, Celtrion, Organon and Seagen, outside the submitted work. MM reports consulting fees/honoraria and participation on Advisory Board from Roche, Novartis, Lilly, Pfizer, MSD, Gilead, Seagen, Astra Zeneca, Gentili outside the submitted work. FM reports consultancy fees from Roche, Astra Zeneca, Daiichi Sankyo, SeaGen, MSD, Eli Lilly, Pierre Fabre, Novartis; travel Grants from Roche outside the submitted work. AFr reports advisory role for Roche, Astrazeneca, Lilly, Novartis, Seagen, Daiichi Sankyo, Gilead outside the submitted work. AT reports honoraria from Novartis, Pfizer, Lilly, Roche; travel/accommodation expenses from Roche, AstraZeneca, Gentili, Pfizer outside the submitted work. ST reports consultant fee for Incyte MSD, Roche, Merck, AStrazeneca outside the submitted work. RC reports consultant fees for Novartis, Lilly, Roche, MSD, Gilead, Daiichi Sankyo, AstraZeneca outside the submitted work. CDA reports consulting/advisory role for Roche, AstraZeneca, Lilly, GSK, Novartis, Pfizer, Seagen; speaker honoraria from Novartis, Pfizer, Lilly; research funding to the Institution: Novartis, Daiichi Sankyo; travel/accommodation expenses from Roche, AstraZeneca, Lilly, GSK, Novartis, Celgene, Pfizer outside the submitted work. EA reports consultancy fees/honoraria from Eli Lilly, Sandoz; travel grants from Novartis, Roche, Eli Lilly, Genetic, Istituto Gentili outside the submitted work. EdA reports honoraria and/or advisory board from Roche/GNE, Novartis, Seattle Genetics, Zodiac, Libbs and Pierre Fabre; Travel grants from Roche/GNE and GSK/Novartis; research grant to his institution from Roche/GNE, Astra-Zeneca, GSK/Novartis and Servier. FP reports participation on Advisory Board from AstraZeneca; consultancy fees/honoraria from Eli Lilly, and Novartis; travel grants from Daichii Sankyo, and Gilead outside the submitted work. LDM reports grants or contracts from Eli Lilly, Novartis, Roche, Daiichi Sankyo, and Seagan; fees/honoraria from Roche, Novartis, Pfizer, Eli Lilly, AstraZeneca, MSD, Seagen, Gilead, Pierre Fabre, Eisai, Exact Sciences, and Ipsen; support for attending meetings or travel from Roche, Pfizer, and Eisai; participation on a Data Safety Monitoring Board or Advisory Board from Novartis, Roche, Eli Lilly, Pfizer, Daiichi Sankyo, Exact Sciences, Gilead, Pierre Fabre, Eisai, and AstraZeneca outside the submitted work. All other authors declare no competing interests., (© 2023 The Author(s).)

Introduction: The goal of this work is to prove the relevance of the experimental model ( in vitro neuronal networks in this study) when drug-delivery testing is performed., Methods: We used dissociated cortical and hippocampal neurons coupled to Micro-Electrode Arrays (MEAs) arranged in different configurations characterized by modularity (i.e., the presence of interconnected sub-networks) and heterogeneity (i.e., the co-existence of neurons coming from brain districts). We delivered increasing concentrations of bicuculline (BIC), a neuromodulator acting on the GABAergic system, and we extracted the IC 50 values (i.e., the effective concentration yielding a reduction in the response by 50%) of the mean firing rate for each configuration., Results: We found significant lower values of the IC 50 computed for modular cortical-hippocampal ensembles than isolated cortical or hippocampal ones., Discussion: Although tested with a specific neuromodulator, this work aims at proving the relevance of ad hoc experimental models to perform neuropharmacological experiments to avoid errors of overestimation/underestimation leading to biased information in the characterization of the effects of a drug on neuronal networks., Competing Interests: MB was employed by ScreenNeuroPharm S.r.l. MT was employed by 3Brain GmbH. 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 © 2023 Brofiga, Poggio, Callegari, Tedesco and Massobrio.)

Objective: Neoadjuvant chemotherapy has become the preferred treatment in HER2-positive early breast cancer. Several trials investigated the neoadjuvant efficacy of dual HER2 blockade with anthracycline-free chemotherapy, whereas few data are available on single-agent trastuzumab and anthracycline-based regimens, which represent the standard of care in the adjuvant setting. This phase II, single-arm trial assessed anthracycline-based chemotherapy and trastuzumab as neoadjuvant treatment for high-risk HER2-positive breast cancer., Methods: Forty-three patients with stage II-III HER2-positive breast cancer were treated with 4 courses of neoadjuvant 5-fluorouracil 600 mg/m 2 , epirubicin 90 mg/m 2 , cyclophosphamide 600 mg/m 2 (FEC ×4) every 21 days, followed by 12 courses of weekly paclitaxel 80 mg/m 2 and trastuzumab 2 mg/Kg IV (loading dose 4 mg/kg)., Results: Pathologic complete response (pCR) was observed in 22 (51%) of 43 patients. After a median follow-up of 6 years, the 5-year disease-free survival and overall survival were 85.8% (95% confidence interval 75.9%-97%) and 89.6% (80.4%-99.8%), respectively. A temporary decrease in left ventricular ejection fraction was observed in two patients. No cardiac death or congestive heart failure occurred. One patient died due to febrile neutropenia., Conclusions: FEC ×4 followed by paclitaxel and trastuzumab was associated with high pCR rates and favorable long-term outcomes. However, this regimen was associated with relevant hematologic toxicity.

The creatine precursor Guanidinoacetic Acid (GAA) accumulates in the genetic deficiency of the GuanidinoAcetate Methyl Transferase (GAMT) enzyme and it is believed to cause the seizures that often occur in this condition. However, evidence that it is indeed epileptogenic is scarce and we previously found that it does not cause neuronal hyperexcitation in in vitro brain slices. Here, we used Micro-Electrode Arrays (MEAs) to further investigate the electrophysiological effects of its acute and chronic administration in the networks of cultured neurons, either neocortical or hippocampal. We found that: (1) GAA at the 1 µM concentration, comparable to its concentration in normal cerebrospinal fluid, does not modify any of the parameters we investigated in either neuronal type; (2) at the 10 µM concentration, very similar to that found in the GAMT deficiency, it did not affect any of the parameters we tested except the bursting rate of neocortical networks and the burst duration of hippocampal networks, both of which were decreased, a change pointing in a direction opposite to epileptogenesis; (3) at the very high and unphysiological 100 µM concentration, it caused a decrease in all parameters, a change that again goes in the direction opposite to epileptogenesis. Our results confirm that GAA is not epileptogenic.

Background: Previous analyses of the GIM (Gruppo Italiano Mammella) 2 study showed that addition of fluorouracil to epirubicin, cyclophosphamide, and paclitaxel in patients with node-positive early breast cancer does not improve outcome, whereas dose-dense chemotherapy induces a significant improvement in both disease-free survival and overall survival as compared with a standard schedule. Here, we present long-term results of the study., Methods: In this 2 × 2 factorial, open-label, randomised, phase 3 trial, we enrolled patients aged 18-70 years with operable, node-positive, breast cancer with Eastern Cooperative Oncology Group performance status of 0-1 from 81 hospitals in Italy. Eligible patients were randomly allocated (1:1:1:1) to one of the four following study groups: four cycles of standard-interval intravenous EC (epirubicin 90 mg/m 2 and cyclophosphamide 600 mg/m 2 ) on day 1 every 3 weeks, followed by four cycles of intravenous paclitaxel (175 mg/m 2 ) on day 1 every 3 weeks (q3EC-P group); four cycles of intravenous FEC (fluorouracil 600 mg/m 2 , epirubicin 90 mg/m 2 , and cyclophosphamide 600 mg/m 2 ) on day 1 every 3 weeks, followed by four cycles of intravenous paclitaxel (175 mg/m 2 ) on day 1 every 3 weeks (q3FEC-P group); dose-dense EC-P regimen, with the same doses and drugs as the q3EC-P group but administered every 2 weeks (q2EC-P group); and the dose-dense FEC-P regimen, with the same doses and drugs as the q3FEC-P group but given every 2 weeks (q2FEC-P). 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. The primary endpoint was disease-free survival in the intention-to-treat population, comparing different chemotherapy schedule (dose-dense vs standard-dose intervals) and regimen (FEC-P vs EC-P). Safety population included all patients that received at least one dose of any study drug according to the treatment received. This trial is registered with ClinicalTrials.gov, NCT00433420, and is now closed., Findings: Between April 24, 2003, and July 3, 2006, 2091 patients were randomly assigned to treatment: 545 to q3EC-P, 544 to q3FEC-P, 502 to q2EC-P, and 500 to q2FEC-P. 88 patients were enrolled in centres providing only standard interval schedule and were assigned only to q3FEC-P and q3EC-P; thus, 2091 patients were included in the intention-to-treat analysis for the comparison of EC-P (1047 patients) versus FEC-P (1044 patients) and 2003 patients were included in the intention-to-treat analysis for the comparison of dose-dense (1002 patients) versus standard interval analysis (1001 patients). After a median follow-up of 15·1 years (IQR 8·4-16·3), median disease-free survival was not significantly different between FEC-P and EC-P groups (17·09 years [95% CI 15·51-not reached] vs not reached [17·54-not reached]; unadjusted hazard ratio 1·12 [95% CI 0·98-1·29]; log-rank p=0·11). Median disease-free survival was significantly higher in the dose-dense interval group than the standard-interval group (not reached [95% CI 17·45-not reached] vs 16·52 [14·24-17·54]; 0·77 [95% CI 0·67-0·89]; p=0·0004). The most common grade 3-4 adverse events were neutropenia (200 [37%] of 536 patients in the q3EC-P group vs 257 [48%] of 533 in the q3FEC-P group vs 50 [10%] of 496 q2EC-P vs 97 [20%] of 492) and alopecia (238 [44%] vs 249 [47%] vs 228 [46%] vs 235 [48%]). During extended follow-up, no further grade 3-4 adverse events or deaths related to toxic-effects were reported. Treatment-related serious adverse events were reported in nine (2%) patients in the q3EC-P group, seven (1%) in the q3FEC-P group, nine (2%) in the q2EC-P group, and nine (2%) in the q2FEC-P group. No treatment-related deaths occurred., Interpretation: Updated results from the GIM2 study support that optimal adjuvant chemotherapy for patients with high-risk early breast cancer should not include fluorouracil and should use a dose-dense schedule., Funding: Bristol-Myers Squibb, Pharmacia, Dompè Biotec Italy, Italian Ministry of Health, Fondazione Italiana per la Ricerca sul Cancro, and Alliance Against Cancer., Competing Interests: Declaration of interests LDM reports grants or contracts from Eli Lilly, Novartis, Roche, Daiichi Sankyo, and Seagen; fees or honoraria from Roche, Novartis, Pfizer, Eli Lilly, AstraZeneca, MSD, Seagen, Gilead, Pierre Fabre, Eisai, Exact Sciences, and Ipsen; support for attending meetings or travel from Roche, Pfizer, and Eisai; and participation on a data safety monitoring board or advisory board from Novartis, Roche, Eli Lilly, Pfizer, Daiichi Sankyo, Exact Sciences, Gilead, Pierre Fabre, Eisai, and AstraZeneca outside the submitted work. FPo reports support for attending meeting from Daichii Sankyo and Gilead; participation on advisory board from AstraZeneca; and fees or honoraria from Eli Lilly and Novartis outside the submitted work. SDP reports honoraria from Roche, Novartis, Pfizer, Celgene, Eli Lilly, AstraZeneca, Clovis, Seagen, Daichii Sankyo, and MSD outside the submitted work. MG reports fees or honoraria from Lilly, Novartis, Pfizer, Roche, Seagen, AstraZeneca, Daichii Sankyo, MSD, and Genomic Health outside the submitted work. MDL reports personal fees from Pfizer, Novartis, Roche, Celgene, AstraZeneca, Eisai, Eli Lilly, Amgen, Pierre Fabre, MSD, Genomic Health, Daiichi-Sankyo, Gilead, and Seagen outside the submitted work. FC reports consulting fees or honoraria from GlaxoSmithKline, Roche, Astrazeneca, Eli Lilly, Pierre Fabre, Pfizer, Seagen, and Dompè outside the submitted work. AF reports consulting fees or honoraria and participation on an advisory board from Roche, Novartis, Lilly, Pfizer, MSD, Dompè, Pierre Fabre, Eisai, Sophos, Epionpharma, Gilead, Seagen, AstraZeneca, and Exact Science outside the submitted work. OG reports consulting fees or honoraria and participation on an advisory board from Daiichi Sanko, AstraZeneca, Seagen, Gilead, Eli-Lilly, and Novartis. MM reports consulting fees or honoraria and participation on an advisory board from Roche, Novartis, Lilly, Pfizer, MSD, Gilead, Seagen, AstraZeneca, and Gentili outside the submitted work. CB reports fees or honoraria from Novartis, Roche, and Eli Lilly outside the submitted work. FPu reports consulting fees or honoraria and participation on an advisory board from Amgen, Astrazeneca, Daichii Sankyo, Celgene, Eisai, Eli Lilly, Gilead, Ipsen, MSD–Novartis, Pierre Fabre, Pfizer, Roche, Seagen, Takeda, and Viatris outside the submitted work; and research grants and support from AstraZeneca, Eisai, and Roche outside the submitted work. FM reports fees or honoraria and participation on an advisory board from AstraZeneca, Eli Lilly, Roche, Novartis, Seagen, Pfizer, MSD, and Daiichi Sankyo outside the submitted work. ML reports consulting fees or honoraria from Roche, AstraZeneca, Novartis, Eli Lilly, Sandoz, and Takeda outside the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose of Review: Over the past 2 years, the COVID-19 pandemic has had short-term and long-term effects on the delivery of cancer care. Some European countries faced an unprecedented widespread crisis during the first year of the SARS-CoV-2 pandemic, only being able afterwards to gradually recover, thanks to the improvement in preventive measures, changes in public health and reactive processes in cancer care and a better understanding of the ongoing heath emergency., Recent Findings: The development of SARS-CoV-2 vaccines and COVID-19 specific treatments, the growing testing and tracking capability to limit virus diffusion, and research efforts to better define areas of action have all greatly limited the negative impact of the health emergency on routine cancer care.The need to protect those more vulnerable and to ensure continuity of care for oncology patients has been balanced across the pandemic, with the aim to guarantee an optimal standard of care., Summary: This article aims to provide an overview on the evolving scenario of cancer care throughout the COVID-19 pandemic in Europe, focusing on the particular features that characterized the pandemic course as well as the main differences that were observed across it., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Young age at breast cancer (BC) diagnosis has historically been a rationale for overtreatment. Limited data with short follow-up exist on the prognostic value of age at diagnosis in HER2-positive BC and the benefit of anti-HER2 therapy in young patients., Methods: APHINITY (NCT01358877) is an international, placebo-controlled, double-blind randomized phase III trial in HER2-positive early BC patients investigating the addition of pertuzumab to adjuvant chemotherapy plus trastuzumab. The prognostic and predictive value of age on invasive disease-free survival (IDFS) as continuous and dichotomous variable (aged 40 years or younger and older than 40 years) was assessed. A subpopulation treatment effect pattern plot analysis was conducted to illustrate possible treatment-effect heterogeneity based on age as a continuous factor., Results: Of 4804 included patients, 768 (16.0%) were aged 40 years or younger at enrollment. Median follow-up was 74 (interquartile range = 62-75) months. Young age was not prognostic either as dichotomous (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 0.84 to 1.33) or continuous (HR = 1.00, 95% CI = 1.00 to 1.01) variable. Lack of prognostic effect of age was observed irrespective of hormone receptor status and treatment arm. No statistically significant interaction was observed between age and pertuzumab effect (Pinteraction = 0.61). Adding pertuzumab improved IDFS for patients in the young (HR = 0.86, 95% CI = 0.56 to 1.32) and older (HR = 0.75, 95% CI = 0.62 to 0.92) cohorts. Similar results were observed irrespective of hormone receptor status. Subpopulation treatment effect pattern plot analysis confirmed the benefit of pertuzumab in 6-year IDFS across age subpopulations., Conclusions: In patients with HER2-positive early BC treated with modern anticancer therapies, young age did not demonstrate either prognostic or predictive value, irrespective of hormone receptor status., (© The Author(s) 2022. Published by Oxford University Press.)

The delivery of electrical stimuli is crucial to shape the electrophysiological activity of neuronal populations and to appreciate the response of the different brain circuits involved. In the present work, we used dissociated cortical and hippocampal networks coupled to Micro-Electrode Arrays (MEAs) to investigate the features of their evoked response when a low-frequency (0.2 Hz) electrical stimulation protocol is delivered. In particular, cortical and hippocampal neurons were topologically organized to recreate interconnected sub-populations with a polydimethylsiloxane (PDMS) mask, which guaranteed the segregation of the cell bodies and the connections among the sub-regions through microchannels. We found that cortical assemblies were more reactive than hippocampal ones. Despite both configurations exhibiting a fast (<35 ms) response, this did not uniformly distribute over the MEA in the hippocampal networks. Moreover, the propagation of the stimuli-evoked activity within the networks showed a late (35−500 ms) response only in the cortical assemblies. The achieved results suggest the importance of the neuronal target when electrical stimulation experiments are performed. Not all neuronal types display the same response, and in light of transferring stimulation protocols to in vivo applications, it becomes fundamental to design realistic in vitro brain-on-a-chip devices to investigate the dynamical properties of complex neuronal circuits.

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.)