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• This ESMO–EONS–EANO Clinical Practice Guideline provides key recommendations on the management of therapy-induced peripheral and central neurotoxicity. • Authorship includes a multidisciplinary group of experts from different institutions and countries in Europe. • Recommendations are based on available scientific data and the authors' collective expert opinion. • An algorithm on the practical approach to assessing chemotherapy-induced peripheral neurotoxicity is provided. [ABSTRACT FROM AUTHOR]

Biomarkers play an essential role in the management of patients with invasive breast cancer. For selecting patients likely to respond to endocrine therapy, both oestrogen receptors (ERs) and progesterone receptors (PRs) should be measured on all newly diagnosed invasive breast cancers. On the other hand, for selecting likely response to all forms of anti-HER2 therapy (trastuzumab, pertuzumab, lapatinib or ado-trastuzumab emtansine), determination of HER2 expression or gene copy number is mandatory. Where feasible, measurement of ER, PR and HER2 should be performed on recurrent lesions and the primary invasive tumour. Although methodological problems exist in the determination of Ki67, because of its clearly established clinical value, wide availability and low costs relative to the available multianalyte signatures, Ki67 may be used for determining prognosis, especially if values are low or high. In oestrogen receptor (ER)-positive, HER2-negative, lymph node–negative patients, multianalyte tests such as urokinase plasminogen activator (uPA)-PAI-1, Oncotype DX, MammaPrint, EndoPredict, Breast Cancer Index (BCI) and Prosigna (PAM50) may be used to predict outcome and aid adjunct therapy decision-making. Oncotype DX, MammaPrint, EndoPredict and Prosigna may be similarly used in patients with 1–3 metastatic lymph nodes. All laboratories measuring biomarkers for patient management should use analytically and clinically validated assays, participate in external quality assurance programs, have established assay acceptance and rejection criteria, perform regular audits and be accredited by an appropriate organisation. [ABSTRACT FROM AUTHOR]

The European Breast Cancer Council (EBCC) traditionally identifies controversies or major deficiencies in the management of patients with breast cancer and selects a multidisciplinary expert team to collaborate in setting crucial principles and recommendations to improve breast cancer care. The 2024 EBCC manifesto focuses on disparities in the care of patients with metastatic breast cancer. There are several reasons for existing disparities both between and within countries. Our recommendations aim to address the stigma of metastatic disease, which has led to significant disparities in access to innovative care regardless of the gross national income of a country. These recommendations are for different stakeholders to promote the care of patients with metastatic breast cancer across Europe and worldwide., Competing Interests: Declaration of Competing Interest MI reports speaker fees/honoraria from Novartis, Seattle Genetics, Daichi, Menarini/Stemline and Gilead, research grants (to institution) from Pfizer, Roche, Inivata Inc, Natera Inc and Gilead, and meeting/travel grants from Roche, AstraZeneca and Gilead (all outside the submitted work). TS reports personal fees for advisory board participation from MSD and Roche and for invited speaker engagements at regional conferences from Roche and Pfizer (outside the submitted work). EB reports honoraria from Pfizer, Lilly and Incyte, consulting/advisory roles for Pfizer, Sandoz-Novartis, Daiichi Sankyo/AstraZeneca and Menarini, and travel/accommodation/expenses from Pfizer and Novartis. DL reports payment (to institution) from the European Medicines Agency for board participation and payment (to institution) from the ESMO Sarcoma and Rare Cancers meeting for participation as a guest speaker. GSS reports institutional research support from Agendia, AstraZeneca, Merck, Novartis, Roche and Seagen. He is a board member of the Dutch Medicines Evaluation Board. AV-S reports speaker honoraria from Ibex Medical Analytics, Myriad, AstraZeneca, Roche and MSD, advisory board participation for Ibex Medical Analytics and Primaa, travel support from Ibex Medical Analytics and AstraZeneca, research grants from Ibex Medical Analytics, Owkin, Primaa, AstraZeneca and MSD Avenir, and stock options for Ibex Medical Analytics. IM declares small fees as honoraria for advisory boards supported by Eli Lilly, Novartis, Pfizer, SeaGen, Daiichi Sankyo, AstraZeneca, Gilead, and Menarini Stemline. PA reports honoraria from Synthon, Roche and Gilead, consulting or advisory roles for MacroGenics, Boehringer Ingelheim, Novartis, amcure, Roche, Novartis, Amgen, Servier, G1 Therapeutics, Radius Health, Deloitte, Menarini, Gilead Sciences, Incyte and Lilly, research funding from Roche (to institution) and travel/accommodation/expenses from Amgen, MSD Oncology, Roche Belgium, Pfizer, Daiichi Sankyo/AstraZeneca and Gilead Sciences. FC reports consultancy roles for Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, Gilead, GlaxoSmithKline, IQVIA, MacroGenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seagen, Teva and TouchIME. VPR reports no conflict of interest related to the current article and reports grants from Agendia BV more than 5 years ago. DC reports non-personal relationships (any fees go to employer) with AstraZeneca, Eisai, Seagen, Roche, Pfizer, Lilly, Novartis, Synthon, GSK, Gilead, Daichi and Menarini/Stemline; he is Chair of the Board of the non-profit “Make 2nds Count” charity and the Breast International Group. FP, FVD, OK-P and FL report no conflicts of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Cancer research is a crucial pillar for countries to deliver more affordable, higher quality, and more equitable cancer care. Patients treated in research-active hospitals have better outcomes than patients who are not treated in these settings. However, cancer in Europe is at a crossroads. Cancer was already a leading cause of premature death before the COVID-19 pandemic, and the disastrous effects of the pandemic on early diagnosis and treatment will probably set back cancer outcomes in Europe by almost a decade. Recognising the pivotal importance of research not just to mitigate the pandemic today, but to build better European cancer services and systems for patients tomorrow, the Lancet Oncology European Groundshot Commission on cancer research brings together a wide range of experts, together with detailed new data on cancer research activity across Europe during the past 12 years. We have deployed this knowledge to help inform Europe's Beating Cancer Plan and the EU Cancer Mission, and to set out an evidence-driven, patient-centred cancer research roadmap for Europe. The high-resolution cancer research data we have generated show current activities, captured through different metrics, including by region, disease burden, research domain, and effect on outcomes. We have also included granular data on research collaboration, gender of researchers, and research funding. The inclusion of granular data has facilitated the identification of areas that are perhaps overemphasised in current cancer research in Europe, while also highlighting domains that are underserved. Our detailed data emphasise the need for more information-driven and data-driven cancer research strategies and planning going forward. A particular focus must be on central and eastern Europe, because our findings emphasise the widening gap in cancer research activity, and capacity and outcomes, compared with the rest of Europe. Citizens and patients, no matter where they are, must benefit from advances in cancer research. This Commission also highlights that the narrow focus on discovery science and biopharmaceutical research in Europe needs to be widened to include such areas as prevention and early diagnosis; treatment modalities such as radiotherapy and surgery; and a larger concentration on developing a research and innovation strategy for the 20 million Europeans living beyond a cancer diagnosis. Our data highlight the important role of comprehensive cancer centres in driving the European cancer research agenda. Crucial to a functioning cancer research strategy and its translation into patient benefit is the need for a greater emphasis on health policy and systems research, including implementation science, so that the innovative technological outputs from cancer research have a clear pathway to delivery. This European cancer research Commission has identified 12 key recommendations within a call to action to reimagine cancer research and its implementation in Europe. We hope this call to action will help to achieve our ambitious 70:35 target: 70% average 10-year survival for all European cancer patients by 2035., Competing Interests: Declaration of interests ML declares honoraria from Bayer, Carnall Farrar, EMD Serono, Novartis, Pfizer, and Roche unrelated to this work and membership of the board of the European Cancer Organisation (ECO). AA declares Advanced NIH Fellowship unrelated to this work. AMB declares honorarium from Roche unrelated to this work and Presidency of Lung Cancer Europe. MC declares membership of the board of ECO and the European Society of Oncology Pharmacy. FC declares consultancy and advisory board membership of Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, Gilead, GlaxoSmithKline, Iqvia, Macrogenics, Medscape, Merck-Sharp, Merus, Mylan, Mundipharma, Novartis, Pfizer, PierreFabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seagen, Teva, and Touchime unrelated to this work. TC declares honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Roche, Merck Sharpe & Dohme, Pfizer, and Takeda unrelated to this work. LD declares consultancy from the International Cancer Research Partnership unrelated to this work. FDN declares grants from the AIRC Foundation for Cancer Research, Associazione Italiana per la Ricerca sul Cancro, and Fondazione Piemontese per la Ricerca sul Cancro-ONLUS, and consultancy from Pierre Fabre unrelated to this work. JJ declares consultancy from AstraZeneca, Exact Sciences, and Merck Sharpe & Dohme unrelated to this work. DK declares honoraria from Merck Sharpe & Dohme unrelated to this work. TKo declares grants from Ipsen, AAA Pharma, Novartis, Isotope Technologies Munich, Victory Net Foundation, and Camulus, and honoraria or support from Cor2Ed, Ipsen, ECO, International Cancer Genome Consortium unrelated to this work. CLV received support from AIRC Foundation. YL is chair of the HERO VBHC and member of the European Society for Radiotherapy and Oncology (ESTRO) Scientific Committee, the Belgian College of Oncology, and a personal investigator on the European Organization for Research and Treatment of Cancer/ESTRO E2-RADIATE project. PS declares support from ECO and the European School of Oncology. SO, KO, AS, CA, PN, KA, MA, AC, MPC, ACo, CLD, AE, SE, MG, BJo, OK, TKu, GL, FM, JP, TP, RP, BR, ITR, MJS, GSB, JVH, EV, WW, UW, and RS declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Breast cancer is the most commonly diagnosed cancer worldwide, and its burden has been rising over the past decades. In this article, we examine and describe the global burden of breast cancer in 2020 and predictions for the year 2040., Methods: Estimates of new female breast cancer cases and deaths in 2020 were abstracted from the GLOBOCAN database. Age-standardized incidence and mortality rates were calculated per 100,000 females by country, world region, and level of human development. Predicted cases and deaths were computed based on global demographic projections for the year 2040., Results: Over 2.3 million new cases and 685,000 deaths from breast cancer occurred in 2020. Large geographic variation across countries and world regions exists, with incidence rates ranging from <40 per 100,000 females in some Asian and African countries, to over 80 per 100,000 in Australia/New Zealand, Northern America, and parts of Europe. Smaller geographical variation was observed for mortality; however, transitioning countries continue to carry a disproportionate share of breast cancer deaths relative to transitioned countries. By 2040, the burden from breast cancer is predicted to increase to over 3 million new cases and 1 million deaths every year because of population growth and ageing alone., Conclusion: Breast cancer is the most common cancer worldwide and continues to have a large impact on the global number of cancer deaths. Global efforts are needed to counteract its growing burden, especially in transitioning countries where incidence is rising rapidly, and mortality rates remain high., (Copyright © 2022 World Health Organization. Published by Elsevier Ltd.. All rights reserved.)

Key stakeholders from the cancer research continuum met in May 2021 at the European Cancer Research Summit in Porto to discuss priorities and specific action points required for the successful implementation of the European Cancer Mission and Europe's Beating Cancer Plan (EBCP). Speakers presented a unified view about the need to establish high-quality, networked infrastructures to decrease cancer incidence, increase the cure rate, improve patient's survival and quality of life, and deal with research and care inequalities across the European Union (EU). These infrastructures, featuring Comprehensive Cancer Centres (CCCs) as key components, will integrate care, prevention and research across the entire cancer continuum to support the development of personalized/precision cancer medicine in Europe. The three pillars of the recommended European infrastructures - namely translational research, clinical/prevention trials and outcomes research - were pondered at length. Speakers addressing the future needs of translational research focused on the prospects of multiomics assisted preclinical research, progress in Molecular and Digital Pathology, immunotherapy, liquid biopsy and science data. The clinical/prevention trial session presented the requirements for next-generation, multicentric trials entailing unified strategies for patient stratification, imaging, and biospecimen acquisition and storage. The third session highlighted the need for establishing outcomes research infrastructures to cover primary prevention, early detection, clinical effectiveness of innovations, health-related quality-of-life assessment, survivorship research and health economics. An important outcome of the Summit was the presentation of the Porto Declaration, which called for a collective and committed action throughout Europe to develop the cancer research infrastructures indispensable for fostering innovation and decreasing inequalities within and between member states. Moreover, the Summit guidelines will assist decision making in the context of a unique EU-wide cancer initiative that, if expertly implemented, will decrease the cancer death toll and improve the quality of life of those confronted with cancer, and this is carried out at an affordable cost., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: Substance use in European adolescents remains a serious health concern. Assessing what affects adolescents' substance use is crucial for implementing effective prevention. This study aims to examine alcohol and cannabis use-related behavioral, social, and attitudinal variables that might directly be considered to guide prevention responses for adolescents., Methods: Cross-sectional data of 78,554 15-16-year-old school students from the 2011 European School Survey Project on Alcohol and Other Drugs (ESPAD) from 26 European countries were analyzed. Self-reported drunkenness in the last 30 days and cannabis use in the last 12 months served as dependent variables. To investigate which factors are associated with risky substance use, multivariable logistic regressions were used., Results: 17.7% of respondents reported drunkenness in the last 30 days, and 14.9% used cannabis in the last 12 months. The most important predictor for risky substance use was the perception that most/all of their friends engaged in substance use behavior, followed by lack of parental support, low personal adherence to rules, and low school performance., Conclusion: Interventions addressing the perceived descriptive norms either directly or by changing environmental cues, opportunities, and regulations, as well as effective parenting and academic support may prevent and reduce risky substance use behavior among adolescents.

In Europe, inappropriate reimbursement and funding rules and regulations act as disincentives to best breast cancer care or, at worst, hinder best care. This problem was the focus of the 12th European Breast Cancer Conference (EBCC) manifesto, discussed during the virtual conference. As patient involvement is indispensable in driving changes to clinical practice, Europa Donna the European patient advocacy group was closely involved in the 12th manifesto. Reimbursement policies have rarely evolved with advances in breast cancer care such as outpatient (ambulatory) care rather than inpatient admission, use of oral or subcutaneous anti-cancer drugs rather than day-hospital intravenous administration, oncoplastic surgery techniques to minimize mastectomy rates, breast reconstructive surgery, risk-reducing surgery for BRCA mutation carriers, or use of hypo-fractionated breast radiation therapy. Although each European country, region and centre will have to understand how their reimbursement policies may hinder best care and find their own solutions, the problems are similar throughout Europe and some solutions can be broadly applied. This manifesto is not calling for more funding or demanding changes that will result in more expensive care. Reimbursement, if better aligned with guidelines and optimal clinical practice, will deliver more cost-effective healthcare. This will release resources, support more equitable use of finite funding and resources, so allowing more European breast cancer patients to benefit from evidence-based treatment recommended by national and international guidelines., Competing Interests: Declaration of competing interests Elizabeth Bergsten Nordström, Alexandru Enui, and Fiona MacNeill report no conflicts of interest. Philip Poortmans is medical advisor of Sordina IORT Technologies spa since April 1, 2020. Francesco Sardanelli reports grants from Horizon 2020 project funding, grants and personal fees from General Electric Healthcare, grants and personal fees from Bracco Group, grants and personal fees from Bayer Healthcare, outside the submitted work. Fatima Cardoso reports consultancy roles for: Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, prIME Oncology, Roche, Samsung Bioepis, Sanofi, Seattle Genetics, and Teva. Frédérique Penault-Llorca reports consultancy roles and hospital grants for AstraZeneca, BMS, Daiichi-Sankyo, Eisai, Genomic Health, Lilly, Medscape, MSD, Myriad Genetics, Nanostring, Novartis, Pfizer, Pierre-Fabre, Roche, Sanofi., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This article is an update of the requirements of a specialist breast centre, produced by EUSOMA and endorsed by ECCO as part of Essential Requirements for Quality Cancer Care (ERQCC) programme, and ESMO. To meet aspirations for comprehensive cancer control, healthcare organisations must consider the requirements in this article, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis, to treatment, to survivorship., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The academia-industry interface is important, and, despite challenges that inevitably occur, bears the potential for positive synergies to emerge. Perceived barriers to wider collaboration in academia-industry oncology research in Europe need to be addressed, current academic cooperative group and industry models for collaboration need to be discussed, and a common terminology to facilitate understanding of both sectors' concerns needs to be established with an eye towards improving academia-industry partnerships on clinical trials for the benefit of patients with cancer., Methodology: CAREFOR (Clinical Academic Cancer Research Forum), a multi-stakeholder platform formed to improve the direction for academic clinical trials in the field of oncology in Europe, formed the CAREFOR-Industry Working Group comprised of experienced professionals from European academic cooperative groups joined by industry representatives selected based on their activities in the area of medical oncology. They jointly discussed academic cooperative groups, clinical trials conducted between academic cooperative groups and industry, examples of successful collaborative models, common legal negotiation points in clinical trial contracts, data access, and principles of interaction., Results: Four principles of interaction between the academia and industry are proposed: (1) clarify the roles and responsibilities of all partners involved in the study, (2) involve legal teams from an early stage; (3) acknowledge that data is an important output of the study, (4) agree on the intent of the trial prior to its start., Conclusions: The CAREFOR-Industry Working Group describes current models, challenges, and effective strategies for academia-industry research in Europe with an eye towards improving academia-industry partnerships on clinical trials for patients with cancer. Current perceived challenges are explained, and future opportunities/recommendations for improvement are described for the areas of most significant impact. Challenges are addressed from both the academic and industry perspectives, and principles of interaction for the optimal alignment between academia and industry in selected areas are proposed., Competing Interests: Competing interests: RAS reports: In the past two years, I have received honoraria as a consultant at advisory boards from Abbvie, Astra Zeneca, MSD, Pfizer, Regeneron, Roche and Takeda. In the past two years, I have received honoraria as a speaker from Astra Zeneca, Boehringer Ingelheim, Eli Lilly, MSD and Roche. DMC in the last two years: Genentech/Roche and Takeda Financial Support of ETOP trials (president and scientific chair): AstraZeneca, BMS, Boehringer Ingelheim, Genentech, MSD, Roche and Pfizer; FC reports personal fees from Amgen, personal fees from Astellas/Medivation, personal fees from AstraZeneca, personal fees from Celgene, personal fees from Daiichi-Sankyo, personal fees from Eisai, personal fees from GE Oncology, personal fees from Genentech, personal fees from GlaxoSmithKline, personal fees from Macrogenics, personal fees from Medscape, personal fees from Merck-Sharp, personal fees from Merus BV, personal fees from Mylan, personal fees from Mundipharma, personal fees from Novartis, personal fees from Pfizer, personal fees from Pierre-Fabre, personal fees from prIME Oncology, personal fees from Roche, personal fees from Sanofi, personal fees from Seattle Genetics, personal fees from Teva, outside the submitted work; PGC reports personal fees from Bayer, personal fees from Deciphera, personal fees from Eisai, personal fees from Eli Lilly, personal fees from Nektar Ther, personal fees from Pfizer, grants from Advenchen Lab, grants from Amgen Dompé, grants from AROG, grants from Bayer, grants from Bluerint, grants from Daiichi Sankyo, grants from Deciphera, grants from Eisai, grants from Eli Lilly, grants from Epizyme, grants from Glaxo, grants from Karyopharm, grants from Novartis, grants from Pfizer, grants from PharmaMar, outside the submitted work; RM reports personal fees from Pfizer, outside the submitted work; AH reports grants and non-financial support from Abbott Molecular Inc, grants from Amgen (Europe) GmbH, grants and non-financial support from Amgen Inc, grants and non-financial support from Amgen Ltd, grants and non-financial support from AstraZeneca AG Switzerland, grants and non-financial support from AstraZeneca UK Ltd, grants from AstraZeneca Wilmington, grants and non-financial support from Biodesix Inc, grants and non-financial support from Boehringer Ingelheim RCV GmbH & Co. KG, grants from Boehringer Ingelheim (Schweiz) GmbH, grants from Bristol-Myers Squibb Company, grants and non-financial support from Bristol-Myers Squibb International Corporation, grants and non-financial support from Eli Lilly Export SA, grants from Eli Lilly Regional Operations GmbH, grants and non-financial support from F. Hoffmann-La Roche Ltd, grants and non-financial support from Genentech Inc, grants from Merck KGaA, grants and non-financial support from MSD MERCK SHARP & DOHME AG, grants from Pfizer Inc, grants from Pfizer Pharma GmbH, grants from Takeda, outside the submitted work., (© 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.)

Many ABC/MBC (advanced or metastatic breast cancer) patients describe feelings of isolation and lack of support [1], often exacerbated by inadequate and insensitive communication. To examine these issues and the changing landscape of the wider breast cancer (BC) community, eight BC patients from across Europe took part in an advisory board. Each patient generously gave up their time to discuss how communication could be enhanced; driven by a desire to improve the experience and bolster support for future ABC/MBC patients. The most powerful and touching message emerged; maintaining the feeling of hope was vitally important as was the knowledge they were not alone in their diagnosis, with patient-to-patient communication representing an important 'lifeline'. It transpired that patients found certain language difficult, confusing and shocking to deal with, particularly as their disease journey was very much an emotional rather than clinical one. For those communicating with ABC/MBC patients, adopting an empathic, patient and personalized language and approach was considered invaluable. Here we examine further the key findings of the advisory board to help shape how, step-by-step, we can change the language we use in practice to effectively and sensitively communicate with ABC/MBC patients., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Despite the high incidence of metastatic breast cancer and its related mortality in the elderly population, our knowledge about optimal treatment for older patients with cancer is far from adequate. We aimed to evaluate the efficacy of dual anti-HER2 treatment with or without metronomic chemotherapy in older patients with HER2-positive metastatic breast cancer., Methods: We did a multicentre, open-label, randomised, phase 2 trial in 30 centres from eight countries in Europe, in patients with histologically proven, HER2-positive metastatic breast cancer, without previous chemotherapy for metastatic disease, who were 70 years or older, or 60 years or older with confirmed functional restrictions defined by protocol, and had a life expectancy of more than 12 weeks and a performance status according to WHO scale of 0-3. Eligible patients were randomly assigned (1:1) by an online randomisation system based on the minimisation method to receive metronomic oral cyclophosphamide 50 mg per day plus trastuzumab and pertuzumab, or trastuzumab and pertuzumab alone. Trastuzumab was given intravenously with a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. Pertuzumab was given intravenously with a loading dose of 840 mg, followed by 420 mg every 3 weeks. Patients were stratified by hormone receptor positivity, previous HER2 treatment, and baseline geriatric screening. The primary endpoint was investigator-assessed progression-free survival at 6 months as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A difference of 10% or greater between the two groups was sought. Efficacy analyses were by intention to treat; safety was assessed in all patients who received at least one dose of study treatment. In case of progression, all patients were offered trastuzumab emtansine. This trial is registered with ClinicalTrials.gov, number NCT01597414, and is completed., Findings: Between July 2, 2013, and May 10, 2016, 80 patients, of whom 56 (70%) had a potential frailty profile according to the geriatric screening G8 score (≤14), were randomly assigned to receive trastuzumab and pertuzumab (n=39) or trastuzumab and pertuzumab plus metronomic oral cyclophosphamide (n=41). Estimated progression-free survival at 6 months was 46·2% (95% CI 30·2-60·7) with trastuzumab and pertuzumab versus 73·4% (56·6-84·6) with trastuzumab and pertuzumab plus metronomic oral cyclophosphamide (hazard ratio [HR] 0·65 [95% CI 0·37-1·12], p=0·12). At a median follow-up of 20·7 months (IQR 12·5-30·4), the median progression-free survival was 5·6 months (95% CI 3·6-16·8) with trastuzumab and pertuzumab versus 12·7 months (6·7-24·8) with the addition of metronomic oral cyclophosphamide. The most frequent grade 3-4 adverse events were hypertension (in six [15%] of 39 patients in the trastuzumab and pertuzumab group vs five [12%] of 41 in the trastuzumab and pertuzumab plus metronomic oral cyclophosphamide group), diarrhoea (four [10%] vs five [12%]), dyspnoea (two [5%] vs four [10%]), fatigue (three [8%] vs two [5%]), pain (two [5%] vs two [5%]), and a thromboembolic event (0 [0%] vs four [10%]). Severe cardiac toxicities were occasionally observed in both groups. In the trastuzumab and pertuzumab group four patients died without progression, due to cardiac arrest during treatment (n=1), peritoneal infection (n=1), respiratory failure (n=1), and sudden death without a specified cause (n=1). In the trastuzumab and pertuzumab plus metronomic oral cyclophosphamide group, one patient died from heart failure., Interpretation: Addition of metronomic oral cyclophosphamide to trastuzumab plus pertuzumab in older and frail patients with HER2-positive metastatic breast cancer increased median progression-free survival by 7 months compared with dual HER2 blockade alone, with an acceptable safety profile. Trastuzumab and pertuzumab plus metronomic oral cyclophosphamide, followed by trastuzumab emtansine after disease progression, might delay or supersede the need for taxane chemotherapy in this population., Funding: F Hoffmann-La Roche., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A distinctive subset of metastatic breast cancer (MBC) is oligometastatic disease, which is characterized by single or few detectable metastatic lesions. The existing treatment guidelines for patients with localized MBC include surgery, radiotherapy, and regional chemotherapy. The European School of Oncology-Metastatic Breast Cancer Task Force addressed the management of these patients in its first consensus recommendations published in 2007. The Task Force endorsed the possibility of a more aggressive and multidisciplinary approach for patients with oligometastatic disease, stressing also the need for clinical trials in this patient population. At the sixth European Breast Cancer Conference, held in Berlin in March 2008, the second public session on MBC guidelines addressed the controversial issue of whether MBC can be cured. In this commentary, we summarize the discussion and related recommendations regarding the available therapeutic options that are possibly associated with cure in these patients. In particular, data on local (surgery and radiotherapy) and chemotherapy options are discussed. Large retrospective series show an association between surgical removal of the primary tumor or of lung metastases and improved long-term outcome in patients with oligometastatic disease. In the absence of data from prospective randomized studies, removal of the primary tumor or isolated metastatic lesions may be an attractive therapeutic strategy in this subset of patients, offering rapid disease control and potential for survival benefit. Some improvement in outcome may also be achieved with optimization of systemic therapies, possibly in combination with optimal local treatment.

Purpose: The 70-gene prognosis-signature is a prognostic tool for early breast cancer analysis. In addition to scientific evidence, implementation of the signature in clinical trials and daily practice requires logistical feasibility. The aim of our study was to test logistics for gene expression profiling on fresh frozen tumour tissue in the preparation for the prospective, multinational Microarray In Node-negative Disease may Avoid ChemoTherapy (MINDACT) trial., Methods: Sixty-four patients were included in six European hospitals. Fresh frozen tumour samples were shipped on dry ice to Agendia B.V., where RNA was isolated and subsequently hybridised on the 70-gene prognosis-signature (MammaPrint)., Results: Tumour samples were obtained in 60 of 64 patients. Among the 60 samples, 11 contained insufficient tumour cells (<50%) and three contained insufficient RNA quality. All 46 samples eligible for genomic profiling were successfully hybridised, and the results were reported on average within 4-5d., Conclusion: Gene expression profiling on fresh frozen tissue is feasible in daily clinical practice.

Background: A 70-gene signature was previously shown to have prognostic value in patients with node-negative breast cancer. Our goal was to validate the signature in an independent group of patients., Methods: Patients (n = 307, with 137 events after a median follow-up of 13.6 years) from five European centers were divided into high- and low-risk groups based on the gene signature classification and on clinical risk classifications. Patients were assigned to the gene signature low-risk group if their 5-year distant metastasis-free survival probability as estimated by the gene signature was greater than 90%. Patients were assigned to the clinicopathologic low-risk group if their 10-year survival probability, as estimated by Adjuvant! software, was greater than 88% (for estrogen receptor [ER]-positive patients) or 92% (for ER-negative patients). Hazard ratios (HRs) were estimated to compare time to distant metastases, disease-free survival, and overall survival in high- versus low-risk groups., Results: The 70-gene signature outperformed the clinicopathologic risk assessment in predicting all endpoints. For time to distant metastases, the gene signature yielded HR = 2.32 (95% confidence interval [CI] = 1.35 to 4.00) without adjustment for clinical risk and hazard ratios ranging from 2.13 to 2.15 after adjustment for various estimates of clinical risk; clinicopathologic risk using Adjuvant! software yielded an unadjusted HR = 1.68 (95% CI = 0.92 to 3.07). For overall survival, the gene signature yielded an unadjusted HR = 2.79 (95% CI = 1.60 to 4.87) and adjusted hazard ratios ranging from 2.63 to 2.89; clinicopathologic risk yielded an unadjusted HR = 1.67 (95% CI = 0.93 to 2.98). For patients in the gene signature high-risk group, 10-year overall survival was 0.69 for patients in both the low- and high-clinical risk groups; for patients in the gene signature low-risk group, the 10-year survival rates were 0.88 and 0.89, respectively., Conclusions: The 70-gene signature adds independent prognostic information to clinicopathologic risk assessment for patients with early breast cancer.