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The EORTC Breast Cancer Group (BCG), created in 1962, is a multidisciplinary group involving surgeons, medical oncologists, radiation oncologists, pathologists, basic scientists, and clinical research fellows. Currently, more than 80 member's institutions across Europe are participating in the group studies. The main goal of the BCG is to conduct high-quality international clinical trials covering all areas of breast cancer care: from loco-regional to systemic disease control, and from in situ carcinoma to metastatic disease. Over 50 years, the BCG has performed dozens of clinical studies including several thousands of patients. Many practice-changing trials and major achievements were conducted optimizing local control, improving systemic therapy in early and metastatic breast cancer, pioneering work in clinical-translational trials and collaboration within intergroup trials. The strategic plan of the BCG for future research includes three distinct albeit overlapping areas: loco-regional therapy, (neo-)adjuvant systemic therapy, trials in the metastatic setting, and niche population studies. For each of these areas the group has considered the prevailing EORTC strategy of focusing on practice-changing studies and translational research, with an emphasis on niche trials. During five decades, the BCG has successfully performed a series of practice-changing trials enrolling several thousands of patients. These studies have contributed to the clinical knowledge on the treatment of breast cancer and have influenced clinical practice and breast cancer patients' outcome worldwide. [ABSTRACT FROM AUTHOR]

Gene expression data obtained in large studies hold great promises for discovering disease signatures or subtypes through data analysis. It is also prone to technical variation, whose removal is essential to avoid spurious discoveries. Because this variation is not always known and can be confounded with biological signals, its removal is a challenging task. Here we provide a step-wise procedure and comprehensive analysis of the MINDACT microarray dataset. The MINDACT trial enrolled 6693 breast cancer patients and prospectively validated the gene expression signature MammaPrint for outcome prediction. The study also yielded a full-transcriptome microarray for each tumor. We show for the first time in such a large dataset how technical variation can be removed while retaining expected biological signals. Because of its unprecedented size, we hope the resulting adjusted dataset will be an invaluable tool to discover or test gene expression signatures and to advance our understanding of breast cancer. Laurent Jacob et al. develop a workflow and analytical pipeline to remove technical variation from the MINDACT microarray dataset. Their method preserved biological signals and the normalized datasets can be repurposed for the discovery of other biomarkers and signatures for breast cancer. [ABSTRACT FROM AUTHOR]

Background: Pathological complete response has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival, event-free survival (EFS), and overall survival (OS). We had four key objectives: to establish the association between pathological complete response and EFS and OS, to establish the definition of pathological complete response that correlates best with long-term outcome, to identify the breast cancer subtypes in which pathological complete response is best correlated with long-term outcome, and to assess whether an increase in frequency of pathological complete response between treatment groups predicts improved EFS and OS. Methods: We searched PubMed, Embase, and Medline for clinical trials of neoadjuvant treatment of breast cancer. To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years. We compared the three most commonly used definitions of pathological complete response—ypT0 ypN0, ypT0/is ypN0, and ypT0/is—for their association with EFS and OS in a responder analysis. We assessed the association between pathological complete response and EFS and OS in various subgroups. Finally, we did a trial-level analysis to assess whether pathological complete response could be used as a surrogate endpoint for EFS or OS. Findings: We obtained data from 12 identified international trials and 11 955 patients were included in our responder analysis. Eradication of tumour from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was better associated with improved EFS (ypT0 ypN0: hazard ratio [HR] 0•44, 95% CI 0•39—0•51; ypT0/is ypN0: 0•48, 0•43—0•54) and OS (0•36, 0•30—0•44; 0•36, 0•31—0•42) than was tumour eradication from the breast alone (ypT0/is; EFS: HR 0•60, 95% CI 0•55—0•66; OS 0•51, 0•45—0•58). We used the ypT0/is ypN0 definition for all subsequent analyses. The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast cancer (EFS: HR 0•24, 95% CI 0•18—0•33; OS: 0•16, 0•11—0•25) and in those with HER2-positive, hormone-receptor-negative tumours who received trastuzumab (EFS: 0•15, 0•09—0•27; OS: 0•08, 0•03, 0•22). In the trial-level analysis, we recorded little association between increases in frequency of pathological complete response and EFS (R2=0•03, 95% CI 0•00—0•25) and OS (R2=0•24, 0•00—0•70). Interpretation: Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumour subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Progressive disease (PD) per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 is defined as growth of measurable target lesions, presence of new lesions or unequivocal progression of non-target disease. In this manuscript we explored whether a more refined categorisation of tumour response and/or these components of progression, varying over time, can improve prediction of overall survival (OS) in the RECIST database. Methods: Data were randomly selected from 13 randomised clinical trials (3758 patients with breast, lung or colorectal cancer). A maximum of five target lesions contributed to the sum of longest diameters. At each measurement time we determined: best target response as best % improvement from baseline; tumour growth of target lesions as worst % change and worst rate of increase (mm/week) from nadir; presence of new lesions and occurrence of non-target PD. OS was analysed by tumour type using Cox regression, adjusting for baseline sum and including these parameters as time-dependent covariates. Results: 36% of patients had new lesions, 28% non-target PD and 49% experienced target lesion growth (median strongest growth 1.5mm/week). Regardless of tumour type, presence of new lesions (hazard ratio (HR) ranging 1.5–2.3) and non-target PD (HR 1.5–2.0) were strongly associated with worse OS. The explanatory value of tumour growth for OS was low compared to the other components. Conclusion: Modelling target lesion tumour growth did not show a marked improvement in OS prediction over and above the other components. These analyses enable a better understanding of the role of each component in PD evaluation. Work is ongoing to incorporate this information into an updated version of RECIST with enhanced prediction of subsequent survival. [ABSTRACT FROM AUTHOR]

Purpose: There is no consensus on how to estimate kidney function for the assessment of eligibility in clinical cancer trials., Patients and Methods: We recalculated the creatinine clearance (CrCl)/glomerular filtration rate (GFR) at baseline in a total of 1768 patients enrolled in twelve clinical trials using the Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI 2021) and European Kidney Function Consortium (EKFC) formulas. Patients were classified as having renal impairment (RI; CrCl/GFR <60 mL/min) or no renal impairment (NRI; CrCl/GFR ≥60 mL/min) with each of the four formulas, respectively. Furthermore, we analyzed the number of adverse events (AE) per month under study treatment using measures of central tendency, variability and regression models., Results: Using CG, EKFC, MDRD and CKD-EPI 2021, 152 (8 %), 140 (8 %), 110 (6 %), and 61 (4 %) patients had RI respectively. Indeed, 47 (3 %) patients had RI using all 4 formulas, while 158 (9 %) had RI by at least one but not all four methods. CG showed the broadest variability and inconsistencies with other methods. All calculation methods performed similarly for excluding patients at risk of severe AE. EKFC demonstrated superior predictive ability for excluding patients at risk of renal and urinary tract AE., Conclusion: This post hoc analysis highlights the importance of choosing accurate and representative methods for kidney function estimation in clinical cancer trials. CG should be replaced by newer methods. While CKD-EPI 2021 may maximize trial accrual, EKFC should be considered for treatment affecting kidney function., Competing Interests: Declaration of Competing Interest HCP has received travel support from Eli Lilly, MSD, Novartis, Pfizer, Pierre Fabre and Roche and received lecture honoraria from Eli Lilly. MP has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen, Adastra, Gan & Lee Pharmaceuticals, Janssen, Servier, Miltenyi, Böhringer-Ingelheim, Telix, Medscape., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Radiomics, the science of extracting quantifiable data from routine medical images, is a powerful tool that has many potential applications in oncology. The Response Evaluation Criteria in Solid Tumors Working Group (RWG) held a workshop in May 2022, which brought together various stakeholders to discuss the potential role of radiomics in oncology drug development and clinical trials, particularly with respect to response assessment. This article summarizes the results of that workshop, reviewing radiomics for the practicing oncologist and highlighting the work that needs to be done to move forward the incorporation of radiomics into clinical trials.

Purpose: To describe the attitudes of healthcare professionals and drug regulators about progression-free survival (PFS) as efficacy endpoint in clinical trials with patients with advanced cancer and to explore to what extent these attitudes influence the willingness to trade between PFS and toxicity., Methods: Cross-sectional survey with regulators from the European Medicines Agency (EMA), and healthcare professionals (HCP) from the "Stichting Hemato-Oncologie voor Volwassenen Nederland" (HOVON) collaborative group and the European Organisation for Research and Treatment of Cancer (EORTC). Attitudes towards PFS were elicited using 5-point Likert items. The respondents' willingness to trade between PFS and grade 3 or 4 (G34) toxicity was assessed using the threshold technique and quantified in terms of their maximum acceptable risk (MAR)., Results: Responses were collected from 287 HCPs and 64 regulators with mainly clinical expertise. Attitudes towards PFS were often spread out in both groups and related to beliefs about PFS being a likely surrogate for clinical benefit, being an intrinsic benefit to be distinguished from OS, or on the importance given to OS. Being a regulator or holding stronger beliefs about PFS being a likely surrogate or an intrinsic benefit were associated with a higher MAR. Presence of a supportive trend in OS was stated as important but was not associated with MAR. There was agreement on the need to address bias in the adjudication of PFS and the need for improving communication to patients about meaning, strengths, and limitations of improvements in PFS., Conclusion: Attitudes towards PFS were spread out and were associated with individual differences in the willingness to trade between toxicity and PFS. There was agreement on the need to address bias in the adjudication of PFS and improving communication to patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Tailored recommendation for adjuvant chemotherapy in breast cancer patients is of great importance. This survey assessed agreement among oncologists on risk assessment and chemotherapy recommendation, the impact of adding the 70-gene signature to clinical-pathological characteristics, and changes over time., Methods: A survey consisting of 37 discordant patient cases from the MINDACT trial (T1-3N0-1M0) was sent to European breast cancer specialists for assessment of risk (high or low) and chemotherapy administration (yes or no). In 2015 the survey was sent twice (survey 1 and 2), several weeks apart, and in 2021 a third time (survey 3). Only the second and third surveys included the 70-gene signature result., Results: 41 breast cancer specialists participated in all three surveys. Overall agreement between respondents decreased slightly between survey 1 and 2, but increased again in survey 3. Over time there was an increase in agreement with the 70-gene signature result on risk assessment, 23% in survey 2 versus 1 and 11% in survey 3 versus 2. With information available indicating a low risk 70-gene signature (n = 25 cases), 20% of risk assessments changed from high to low and 19% of recommendations changed from yes to no chemotherapy in survey 2 versus 1, further increasing with 18% and 21%, respectively, in survey 3 versus 2., Conclusion: There is a variability in risk assessment of early breast cancer patients among breast cancer specialists. The 70-gene signature provided valuable information, resulting in fewer patients being assessed as high risk and fewer recommendations for chemotherapy, increasing over time., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Ivana Božović-Spasojević has received personal fees from Pfizer, Novartis, AstraZeneca, Gilead and Roche, outside the submitted work. Fatima Cardoso has received personal fees from Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Debiopharm, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Iqvia, Macrogenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seagen, Teva and Touchime outside the submitted work. Emiel Rutgers has received personal fees from Guerbet outside the submitted work. The other authors report no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The emergence of the precision medicine paradigm in oncology has led to increasing interest in the integration of real-world data (RWD) into cancer clinical research. As sources of real-world evidence (RWE), such data could potentially help address the uncertainties that surround the adoption of novel anticancer therapies into the clinic following their investigation in clinical trials. At present, RWE-generating studies which investigate antitumour interventions seem to primarily focus on collecting and analysing observational RWD, typically forgoing the use of randomisation despite its methodological benefits. This is appropriate in situations where randomised controlled trials (RCTs) are not feasible and non-randomised RWD analyses can offer valuable insights. Nevertheless, depending on how they are designed, RCTs have the potential to produce strong and actionable RWE themselves. The choice of which methodology to employ for RWD studies should be guided by the nature of the research question they are intended to answer. Here, we attempt to define some of the questions that do not necessarily require the conduct of RCTs. Moreover, we outline the strategy of the European Organisation for Research and Treatment of Cancer (EORTC) to contribute to the generation of robust and high-quality RWE by prioritising the execution of pragmatic trials and studies set up according to the trials-within-cohorts approach. If treatment allocation cannot be left up to random chance due to practical or ethical concerns, the EORTC will consider undertaking observational RWD research based on the target trial principle. New EORTC-sponsored RCTs may also feature concurrent prospective cohorts composed of off-trial patients., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R.S.: Nothing to declare. M.V.H.: Nothing to declare. J.B.: Nothing to declare. C.M.B.: Nothing to declare. J.J.C.: Nothing to declare. A.D.: I have received institutional research funding from Janssen and IQVIA, speaker honoraria from Janssen and Medtronic, and am founder, shareholder and employee of Medical Data Works B.V. E.A.E.: Nothing to declare. A.F.: Nothing to declare. A.G.: Nothing to declare. M.A.H.: My research is supported by funding from NIH, the US Veterans Administration, and PCORI. I am a consultant for Cytel, data science adviser for ProPublica, and member of the scientific advisory board of ADIA Lab. None of these interests or relationships have influenced my contribution to this paper. F.H.: I report that a party related to me is employed by Janssen-Cilag GmbH as principal data scientist. P.O.: I have performed consultancy work for AAA, Bayer, Curium, MSD, Janssen and have received research grants from Bayer. P.S.: I have had advisory relationships with Merck-Serono, Servier, and Merck Sharp & Dohme Corp in the last three years. H.M.V.: Nothing to declare. M.W.: I have received research grants from Quercis and Versameb, and honoraria for lectures or advisory board participation or consulting from Bayer, Curevac, Medac, Novartis, Novocure, Orbus, Philogen, Roche and Sandoz. R.W.: Nothing to declare. D.L.: I am member of the EMA Management Board, member of the EMA Health Care Professionals Working Party and of the EMA Healthcare Professionals Policy Officers’ Group, and co-chair of the EMA Cancer Medicines Forum. W.T.V.D.G.: I have performed advisory work for SpringWorks, PTC Therapeutics, Agenus and received research funding from Eli Lilly, all fees going to the institute., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Currently, guidelines for PET with 18F-fluorodeoxyglucose (FDG-PET) interpretation for assessment of therapy response in oncology primarily involve visual evaluation of FDG-PET/CT scans. However, quantitative measurements of the metabolic activity in tumors may be even more useful in evaluating response to treatment. Guidelines based on such measurements, including the European Organization for Research and Treatment of Cancer Criteria and PET Response Criteria in Solid Tumors, have been proposed. However, more rigorous analysis of response criteria based on FDG-PET measurements is needed to adopt regular use in practice., Experimental Design: Well-defined boundaries of repeatability and reproducibility of quantitative measurements to discriminate noise from true signal changes are a needed initial step. An extension of the meta-analysis from de Langen and colleagues (2012) of the test-retest repeatability of quantitative FDG-PET measurements, including mean, maximum, and peak standardized uptake values (SUVmax, SUVmean, and SUVpeak, respectively), was performed. Data from 11 studies in the literature were used to estimate the relationship between the variance in test-retest measurements with uptake level and various study-level, patient-level, and lesion-level characteristics., Results: Test-retest repeatability of percentage fluctuations for all three types of SUV measurement (max, mean, and peak) improved with higher FDG uptake levels. Repeatability in all three SUV measurements varied for different lesion locations. Worse repeatability in SUVmean was also associated with higher tumor volumes., Conclusions: On the basis of these results, recommendations regarding SUV measurements for assessing minimal detectable changes based on repeatability and reproducibility are proposed. These should be applied to differentiate between response categories for a future set of FDG-PET-based criteria that assess clinically significant changes in tumor response., (©2022 American Association for Cancer Research.)

Twenty years after its initial introduction, Response Evaluation Criteria in Solid Tumors (RECIST) remains today a unique standardized tool allowing uniform objective evaluation of response in solid tumors in clinical trials across different treatment indications. Several attempts have been made to update or replace RECIST, but none have realized the general traction or uptake seen with RECIST. This communication provides an overview of some challenges faced by RECIST in the rapidly changing oncology landscape, including the incorporation of PET with 18 F-fluorodeoxyglucose tracer as a tool for response assessment and the validation of criteria for use in trials involving immunotherapeutics. The latter has mainly been slow due to lack of data sharing. Work is ongoing to try to address this.We also aim to share our view as statistician representatives on the RECIST Working Group on what would be needed to validate new imaging endpoints for clinical trial use, with a specific focus on RECIST. Whether this could lead to an update of RECIST or replace RECIST altogether, depends on the changes being proposed. The ultimate goal remains to have a well defined, repeatable, confirmable and objective standard as provided by RECIST today., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The MINDACT trial showed excellent 5-year distant metastasis-free survival of 94·7% (95% CI 92·5-96·2) in patients with breast cancer of high clinical and low genomic risk who did not receive chemotherapy. We present long-term follow-up results together with an exploratory analysis by age., Methods: MINDACT was a multicentre, randomised, phase 3 trial done in 112 academic and community hospitals in nine European countries. Patients aged 18-70 years, with histologically confirmed primary invasive breast cancer (stage T1, T2, or operable T3) with up to three positive lymph nodes, no distant metastases, and a WHO performance status of 0-1 were enrolled and their genomic risk (using the MammaPrint 70-gene signature) and clinical risk (using a modified version of Adjuvant! Online) were determined. Patients with low clinical and low genomic risk results did not receive chemotherapy, and patients with high clinical and high genomic risk did receive chemotherapy (mostly anthracycline-based or taxane-based, or a combination thereof). Patients with discordant risk results (ie, patients with high clinical risk but low genomic risk, and those with low clinical risk but high genomic risk) were randomly assigned (1:1) to receive chemotherapy or not based on either the clinical risk or the genomic risk. Randomisation was done centrally and used a minimisation technique that was stratified by institution, risk group, and clinical-pathological characteristics. Treatment allocation was not masked. The primary endpoint was to test whether the distant metastasis-free survival rate at 5 years in patients with high clinical risk and low genomic risk not receiving chemotherapy had a lower boundary of the 95% CI above the predefined non-inferiority boundary of 92%. In the primary test population of patients with high clinical risk and low genomic risk who adhered to the treatment allocation of no chemotherapy and had no change in risk post-enrolment. Here, we present updated follow-up as well as an exploratory analysis of a potential age effect (≤50 years vs >50 years) and an analysis by nodal status for patients with hormone receptor-positive and HER2-negative disease. These analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00433589, and the European Clinical Trials database, EudraCT2005-002625-31. Recruitment is complete and further long-term follow-up is ongoing., Findings: Between Feb 8, 2007, and July 11, 2011, 6693 patients were enrolled. On Feb 26, 2020, median follow-up was 8·7 years (IQR 7·8-9·7). The updated 5-year distant metastasis-free survival rate for patients with high clinical risk and low genomic risk receiving no chemotherapy (primary test population, n=644) was 95·1% (95% CI 93·1-96·6), which is above the predefined non-inferiority boundary of 92%, supporting the previous analysis and proving MINDACT as a positive de-escalation trial. Patients with high clinical risk and low genomic risk were randomly assigned to receive chemotherapy (n=749) or not (n=748); this was the intention-to-treat population. The 8-year estimates for distant metastasis-free survival in the intention-to-treat population were 92·0% (95% CI 89·6-93·8) for chemotherapy versus 89·4% (86·8-91·5) for no chemotherapy (hazard ratio 0·66; 95% CI 0·48-0·92). An exploratory analysis confined to the subset of patients with hormone receptor-positive, HER2-negative disease (1358 [90.7%] of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) shows different effects of chemotherapy administration on 8-year distant metastasis-free survival according to age: 93·6% (95% CI 89·3-96·3) with chemotherapy versus 88·6% (83·5-92·3) without chemotherapy in 464 women aged 50 years or younger (absolute difference 5·0 percentage points [SE 2·8, 95% CI -0·5 to 10·4]) and 90·2% (86·8-92·7) versus 90·0% (86·6-92·6) in 894 women older than 50 years (absolute difference 0·2 percentage points [2·1, -4·0 to 4·4]). The 8-year distant metastasis-free survival in the exploratory analysis by nodal status in these patients was 91·7% (95% CI 88·1-94·3) with chemotherapy and 89·2% (85·2-92·2) without chemotherapy in 699 node-negative patients (absolute difference 2·5 percentage points [SE 2·3, 95% CI -2·1 to 7·2]) and 91·2% (87·2-94·0) versus 89·9% (85·8-92·8) for 658 patients with one to three positive nodes (absolute difference 1·3 percentage points [2·4, -3·5 to 6·1])., Interpretation: With a more mature follow-up approaching 9 years, the 70-gene signature shows an intact ability of identifying among women with high clinical risk, a subgroup, namely patients with a low genomic risk, with an excellent distant metastasis-free survival when treated with endocrine therapy alone. For these women the magnitude of the benefit from adding chemotherapy to endocrine therapy remains small (2·6 percentage points) and is not enhanced by nodal positivity. However, in an underpowered exploratory analysis this benefit appears to be age-dependent, as it is only seen in women younger than 50 years where it reaches a clinically relevant threshold of 5 percentage points. Although, possibly due to chemotherapy-induced ovarian function suppression, it should be part of informed, shared decision making. Further study is needed in younger women, who might need reinforced endocrine therapy to forego chemotherapy., Funding: European Commission Sixth Framework Programme., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: MINDACT demonstrated that 46% of patients with early breast cancer at high clinical but low genomic risk on the basis of MammaPrint may safely avoid adjuvant chemotherapy. A second random assignment (R-C) compared docetaxel-capecitabine with an anthracycline-based regimen., Patients and Methods: R-C randomly assigned patients 1:1 between standard anthracycline-based regimens, with or without taxanes (control) and experimental docetaxel 75 mg/m 2 intravenously plus oral capecitabine 825 mg/m 2 two times per day for 14 days (DC) every 3 weeks for 6 cycles. The primary end point was disease-free survival (DFS). Secondary end points included overall survival and safety., Results: Of 2,832 patients, 1,301 (45%) were randomly assigned, and 97% complied with R-C assignment. In the control arm, 29.6% only received taxanes (0.5% of N0 patients). DFS events (n = 148) were much less than required (n = 422) as a result of a lower-than-expected accrual and event rate. At 5 years of median follow-up, DFS was not different between DC (n = 652) and control (n = 649; 90.7% [95% CI, 88% to 92.8%] v 88.8% [95% CI, 85.9% to 91.1%]; hazard ratio [HR], 0.83 [95% CI, 0.60 to 1.15]; P = .26). Overall survival (HR, 0.91 [95% CI, 0.54 to 1.53]) and DFS in the clinical high and genomic high-risk subgroup (86.1% v 88.1%; HR, 0.83 [95% CI, 0.58 to 1.21]) were similar in both arms. DC led to more grade 1 neuropathy (27.1% v 11.2%) and more grade 2 hand/foot syndrome (28.5% v 3.3%) and diarrhea (13.7% v 5.8%). Serious cardiac events occurred in 9 patients (control, n = 4; DC, n = 5). Fifty-three patients developed second cancers (control, n = 32; DC, n = 21; leukemia: 2 v 1). Five treatment-related deaths occurred (control, 2 [0.3%]; DC, 3 [0.5%])., Conclusion: Although underpowered, this second randomization in MINDACT did not show any improvement in outcome or safety with the use of DC compared with anthracycline-based chemotherapy.

In Europe, most of the cancer clinical research dedicated to therapeutic innovations aims primarily at regulatory approval. Once an anticancer drug enters the common market, each member state determines its real-world use based on its own criteria: pricing, reimbursement and clinical indications. Such an innovation-centred clinical research landscape might neglect patient-relevant issues in real-world setting, such as comparative effectiveness of distinct treatment options or long-term safety monitoring. The European Organisation for Research and Treatment of Cancer (EORTC) advocates reforming the current 'innovation-centred' system to a truly 'patient-centred' paradigm with systematically coordinated applied clinical research in conjunction with drug development, featuring the following strategy., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The European Society for Medical Oncology (ESMO) has developed the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS), a tool to assess the magnitude of clinical benefit from new cancer therapies. Grading is guided by a dual rule comparing the relative benefit (RB) and the absolute benefit (AB) achieved by the therapy to prespecified threshold values. The ESMO-MCBS v1.0 dual rule evaluates the RB of an experimental treatment based on the lower limit of the 95%CI (LL95%CI) for the hazard ratio (HR) along with an AB threshold. This dual rule addresses two goals: inclusiveness: not unfairly penalising experimental treatments from trials designed with adequate power targeting clinically meaningful relative benefit; and discernment: penalising trials designed to detect a small inconsequential benefit., Methods: Based on 50 000 simulations of plausible trial scenarios, the sensitivity and specificity of the LL95%CI rule and the ESMO-MCBS dual rule, the robustness of their characteristics for reasonable power and range of targeted and true HRs, are examined. The per cent acceptance of maximal preliminary grade is compared with other dual rules based on point estimate (PE) thresholds for RB., Results: For particularly small or particularly large studies, the observed benefit needs to be relatively big for the ESMO-MCBS dual rule to be satisfied and the maximal grade awarded. Compared with approaches that evaluate RB using the PE thresholds, simulations demonstrate that the MCBS approach better exhibits the desired behaviour achieving the goals of both inclusiveness and discernment., Conclusions: RB assessment using the LL95%CI for HR rather than a PE threshold has two advantages: it diminishes the probability of excluding big benefit positive studies from achieving due credit and, when combined with the AB assessment, it increases the probability of downgrading a trial with a statistically significant but clinically insignificant observed benefit., Competing Interests: Competing interests: The authors have declared the following: JB: director of EORTC. EORTC conducts many studies sponsored by, or otherwise supported by, a large number of companies. EORTC is an independent research organisation. MJP: board member: Radius. Consultant (honoraria): AstraZeneca, Lilly, MSD, Novartis, Pfizer, Roche-Genentech, Crescendo Biologics, Periphagen, Huya, Debiopharm and PharmaMar. Research grants to institute: AstraZeneca, Lilly, MDS, Novartis, Pfizer, Roche-Genentech, Synthon, Radius and Servier. Speakers bureau/stock ownership: none. GP: consulting and advisory services, and research support: Amgen, Merck, AstraZeneca, Roche, BMS, MSD and Lilly. J-YD: compensated participation to advisory boards, lecture and symposia: Amgen, Merck Serono, Bayer, Roche/Genentech, Sanofi, AstraZeneca, Boehringer-Ingelheim and Sirtex until April 2016. No further compensated participation in industry events from May 2016 onwards. JT: advisory boards for Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Genentech, Lilly, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho and Takeda. CCZ: honoraria: AstraZeneca, Celgene, Roche, Novartis, Bristol Myers Squibb, MSD, Ariad and Newgen. EGEdV: currently conducting research sponsored by the following companies: Amgen, Roche/Genentech, Chugai Pharma, Synthon, AstraZeneca, Radius Health, CytomX Therapeutics and Nordic Nanovector (all payments to the institution). Consulting or advisory role for the following companies: Synthon, Medication and Merck (all payments to the institution). Not a member of any speakers' bureau.

Survival discrepancy between patients treated in a clinical trial and routine practice is well recognized. No study has assessed the health-related quality of life (HRQL) of long-term Hodgkin's lymphoma survivors (HLS) according to trial participation. We applied a population-based approach to examine the differences in HRQL, healthcare utilization, and satisfaction with healthcare among long-term HLS who had participated in a trial (tHLS) and those treated in routine care (rHLS). All HLS diagnosed during the period 1989-1998 and living in southern Netherlands were selected from the Netherlands Cancer Registry in 2004 to participate in the Patient Reported Outcomes Following Initial treatment and Long-term Evaluation of Survivorship registry study. Data linkage with the European Organisation for Research and Treatment of Cancer was performed in 2015 to identify trial participation. The 65 tHLS and 67 rHLS had comparable demographic and clinical characteristics. Unadjusted and adjusted models indicated no association between trial participation and HRQL. There was no evidence of differences in healthcare satisfaction. Trial participation was associated with 48% more visits to specialists in the past year (adjusted 95% confidence interval: 10-99). No association of trial participation with cancer-related contacts was observed. tHLS and rHLS had comparable long-term HRQL. Although trial participation was associated with more specialist visits, there was no evidence of an association with healthcare satisfaction and the number of cancer-related visits. Identification of trial participation in population-based cancer registry through data linkage with clinical trials enables a population-based approach to examine patient-reported outcomes differences between tHLS and rHLS.

Tumours respond differently to immunotherapies compared with chemotherapeutic drugs, raising questions about the assessment of changes in tumour burden-a mainstay of evaluation of cancer therapeutics that provides key information about objective response and disease progression. A consensus guideline-iRECIST-was developed by the RECIST working group for the use of modified Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) in cancer immunotherapy trials, to ensure consistent design and data collection, facilitate the ongoing collection of trial data, and ultimate validation of the guideline. This guideline describes a standard approach to solid tumour measurements and definitions for objective change in tumour size for use in trials in which an immunotherapy is used. Additionally, it defines the minimum datapoints required from future trials and those currently in development to facilitate the compilation of a data warehouse to use to later validate iRECIST. An unprecedented number of trials have been done, initiated, or are planned to test new immune modulators for cancer therapy using a variety of modified response criteria. This guideline will allow consistent conduct, interpretation, and analysis of trials of immunotherapies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) are publishing a new edition of the ESMO/ASCO Global Curriculum (GC) thanks to contribution of 64 ESMO-appointed and 32 ASCO-appointed authors. First published in 2004 and updated in 2010, the GC edition 2016 answers to the need for updated recommendations for the training of physicians in medical oncology by defining the standard to be fulfilled to qualify as medical oncologists. At times of internationalisation of healthcare and increased mobility of patients and physicians, the GC aims to provide state-of-the-art cancer care to all patients wherever they live. Recent progress in the field of cancer research has indeed resulted in diagnostic and therapeutic innovations such as targeted therapies as a standard therapeutic approach or personalised cancer medicine apart from the revival of immunotherapy, requiring specialised training for medical oncology trainees. Thus, several new chapters on technical contents such as molecular pathology, translational research or molecular imaging and on conceptual attitudes towards human principles like genetic counselling or survivorship have been integrated in the GC. The GC edition 2016 consists of 12 sections with 17 subsections, 44 chapters and 35 subchapters, respectively. Besides renewal in its contents, the GC underwent a principal formal change taking into consideration modern didactic principles. It is presented in a template-based format that subcategorises the detailed outcome requirements into learning objectives, awareness, knowledge and skills. Consecutive steps will be those of harmonising and implementing teaching and assessment strategies., Competing Interests: JBe received research support to Karolinska Institutet and University Hospital from Amgen, AstraZeneca, Bayer, Merck, Roche and Sanofi-Aventis. JBu received travel accommodations from Genentech/Roche. FC received a consultant honoraria in Astellas/Medivation, AstraZeneca, Celgene, Daiitchi-Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline (GSK), Merck-Scharp, Merus BV, Novartis, Pfizer, Pierre-Fabre, Roche, Sanofi, Teva. HC has worked in a consulting or advisory role in Amgen received speakers’ bureau in Baxalta, Celgene and received research funding from Celgene. PC received honoraria for consultancy/advisory role and/or for lectures from Bayer, Blueprint Medicines, Eisai, Eli Lilly, Glaxo SK, Merck SD, Merck Serono, Nektar Ther., Novartis, Pfizer, PharmaMar. AC received honoraria from MerckSerono, Roche, Amgen, Bayer, Lilly and speakers’ bureau from Roche and MerckSerono. RC received research funding from Genentech/Roche, Puma Biotechnology, Novartis and travel, accommodations, expenses from Novartis. LDP received fees as consultant or for lectures (no speakers’ bureau) from F. Hoffmann-La Roche, Pfizer, Bristol Meyer Squibb, AstraZeneca, Qiagen, Boehringer Ingelheim. All fees were paid to Institution. MDS received honoraria and consultation fees from Amgen, Astellas, Bayer, Celgene, Dendreon, Eisai Inc, ESSA, Ferring, GSK, Janssen Cilag, Merck, Novartis, Pfizer, Pierre Fabre Oncologie, Roche, Sanofi Aventis, Shionogi, Synthon, Takeda, Teva/OncoGenex; received research grant from Pierre Fabre Oncologie. EGEdV received research grants to the institute from Roche/Genentech, Amgen, Novartis, Pieris, Servier, is part of data monitoring committee in Biomarin and of advisory board in Synthon. CD received (un)restricted research grants donated to the research institute from Amgen, AstraZeneca, Bayer, Celgene, Eisai, Boehringer Ingelheim, Merck, MSD, Mundipharma, Novartis, Pfizer Corporation, PharmaMar, Pierre Fabre, Roche Austria, Sanofi-aventis, Takeda; received honoraria for consulting from AstraZeneca, Eli Lilly, Merck, Novartis Pharma, Roche Austria. DSD has worked in a consulting or advisory role for UpToDate and received research funding from Aeterna Zentaris (to Institution). LRD received research funding from GlaxoSmithKline (to Institution), Millennium (to Institution), Bristol-Myers Squibb (to Institution), Aeterna Zentaris (to Institution), Millenuim (to Institution) and has other relationship with Genentech. NES received honoraria from Roche, Novartis, MSD Oncology; received research funding from GlaxoSmithKline, Roche; received travel, accommodations, expenses from Novartis, Roche, Celgene. AE conduct research sponsored by Roche, GSK, Novartis, AstraZeneca, Celltrion, Apotex Inc. ME has stock and other ownership interests with Bristol-Myers Squibb, GE Healthcare, Nestle SA, Pfizer, CVS CAREMARK; has worked in a consulting or advisory role from Merck, Bristol-Myers Squibb, ALKERMES; received research funding from Altor BioScience, Bristol-Myers Squibb, Merck, Alkermes, Polynoma; received travel, accommodations, expenses from Myriad Genetics, Bristol-Myers Squibb, Merck. EF has worked as a consultant for Boehringer Ingelheim, Eli Lilly, Pfizer, Roche, BMS, MSD, Novartis; received speaker's bureau from Eli Lilly, BMS, Novartis. MFF has owned stock from Novartis. PKG research funding from Abbvie (to Institution) and Onyx (to Institution). AG has worked in a consulting or advisory role for Genentech/Roche (to Institution), Bayer (to Institution), Sanofi (to Institution), Bristol-Myers Squibb (to Institution), Lilly (to Institution), Boston Biomedical (to Institution), Amgen (to Institution); received research funding from Genentech/Roche (to Institution), Bayer (to Institution), Pfizer (to Institution), Eisai (to Institution), Sanofi (to Institution), Lilly (to Institution), Boston Biomedical (to Institution); received travel, accommodations, expenses from Genentech/Roche, Bayer, Bristol-Myers Squibb, Boston Biomedical, Amgen. SMH has stock and other ownership interests with Liquid Biotech, USA; has patents, royalties, other intellectual property with Liquid Biotech, USA. JH received advisory board and speaker fee from Tesaro and honorarium from SOBI. DVJ has worked in a consulting or advisory role for Bayer. UK received honoraria from Amgen, BMS, GSK, Glycotope, MerckSerono, Merck/MSD, Pfizer; received research support from Pfizer, MerckSerono, Innate, Sirtec. RK conduct research supported by Roche; a member of speaker's bureau of Roche, Meda, Novartis. SK received research funding from Novartis (to Institution), Merck (to Institution), Threshold Pharmaceuticals (to Institution), Gilead Sciences (to Institution), Bayer/Onyx (to Institution); received travel, accommodation, expenses from Novartis. C-HK received honoraria from Merck/Darmstadt, Amgen. MK is on speakers’ bureau for Astellas Pharma, Genentech/Roche, Sanofi, Lilly, Bayer; received research funding from Genentech/Roche (to Institution) and Merck Serono (to Institution). H-JL has received honoraria from Merck Serono, Roche, Celgene, Bayer, Boehringer Ingelheim; has served in a consulting or advisory role for Merck Serono, Roche, Bayer; received travel, accommodations, expenses from Merck Serono, Bayer, Roche. LL has served as a consultant/advisory for EISAI, BMS, MSD, Merck-Serono, Boehringer Ingelheim, DEBIOPHARM, SOBI, Novartis, AstraZeneca, Bayer and Roche; received research funds to institute for clinical studies from EISAI, MSD, Merck-Serono, Boehringer Ingelheim, Novartis, AstraZeneca and Roche; received travel coverage for medical meetings from Merck-Serono, DEBIOPHARM, SOBI, Bayer. PJL received research funding from Novartis (to Institution), Celgene (to Institution), ImClone Systems (to Institution), Taiho Pharmaceutical (to Institution); has patents, royalties, other intellectual property US PPA/61/499,988 Gene Expression Analysis of Thymic Neoplasms Inventors Sunil Badve, Yesim Gokmen-Polar, Patrick Loehrer (to Institution). RIL has served in consulting or advisory role for Roche, Novartis, Janssen; received speakers’ bureau from Roche, Novartis, Janssen. MJM received research funding from Astex Pharmaceuticals (to Institution). TN has ownership interest with Bioclassifier LLC; has role for invention of PAM50 breast cancer assay, which has been licensed to NanoString technologies and being marketed as Prosigna; has served as a consultant for NanoString. KÖ received speaker bureau from Novartis, Ipsen. PÖ received consulting fees, honoraria, travel grants or lecturing fees from Amgen, Bayer, Baxalta, Celgene, EliLilly, Merck, Nordic Drugs, Prime Oncology, Sanofi Oncology. AP received honoraria and consultancy fee from Amgen, Novartis, Bristol-Myers Squibb, Genmab A/S, Celgene, Janssen-Cilag, Millennium Pharmaceuticals, Onyx Pharmaceuticals, Sanofi Aventis. MR received honoraria from AstraZeneca; has served in a consulting or advisory role for Bayer, Pfizer, McKesson; received research funding from AstraZeneca (to Institution), AbbVie (to Institution), Myriad Genetics (to Institution), Biomarin (to Institution); received travel, accommodations, expenses from AstraZeneca, Biomarin. LS has served in a consulting or advisory role for bioTheranostics. MS conduct research sponsored by AstraZeneca, Bayer, Eisai, Exelixis, Genzyme. H-JS is an advisor for Roche, Bayer. LS has served in leadership for Eviti; has served in a consulting or advisory role for Merck; has patents, royalties, other intellectual property; as Co-Editor-in-Chief of UpToDate, Oncology. JS is an employee of Genentech; received honoraria, speakers’ bureau, travel, accommodations, expenses from Genentech. CNS received honoraria or research grant from Novartis, GSK, Pfizer, Merck, Lilly, BMS, Astellas, Bayer, Janssen, Sanofi. FS received unrestricted industry grants for clinical research from Celgene, Fresenius, Helsinn; FS participates in Novartis-lead clinical trials and received punctual advisorship (boards, expert meetings) from Acacia, ACRAF, Amgen, Baxter, Celgene, Danone, Fresenius, GlaxoSmithKline, Grünenthal, Helsinn, ISIS Global, Millennium/Takeda, Mundipharma, Novartis, Novelpharm, Nycomed, Obexia, Otsuka, Ono, Pharm-Olam, Pfizer, Psioxus, PrIME, Santhera, Sunstone, Teva, Vifor. RS received honoraria or consulting fee (paid to institution) from Roche, Merck KGaA/EMD-Serono, MSD/Merck & Co, Pfizer, Ipsen Pharma, Novartis. JT has worked in a consultant/advisory role for Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho and Takeda. EV has stock and other ownership interests with McKesson; has worked in a consulting or advisory role for Abbvie, AstraZeneca, Boehringer Ingelheim, Celgene, Clovis Oncology, GeneCentric, Genentech, Merck, Synta, VentiRx, Eisai, Lilly, Transgene; received speakers’ bureau for Amgen; received research funding from Abbvie (to Institution), Bristol-Myers Squibb (to Institution), Gen Vec Inc, (to Institution), Sanofi (to Institution), Monsanto (to Institution), Cyclacel (to Institution); received travel, accommodations, expenses from Amgen. JSW has stock and other ownership interests with Altor BioScience, Celldex, cCam Biotherapeutics; received honoraria from Bristol-Myers Squibb, Merck, Genentech, Abbvie, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Eisai, Altor BioScience, Lion Biotechnologies, Amgen, Roche, Ichor Medical Systems, Celldex, cCam Biotherapeutics, Pieris; has worked in a consulting or advisory role for Celldex, Ichor Medical Systems, cCam Biotherapeutics, Lion Biotechnologies, Pieris, Altor BioScience, Bristol-Myers Squibb, Merck, Genentech, Roche, Amgen, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo, Abbvie, Eisai; received research funding from Bristol-Myers Squibb (to Institution), Merck (to Institution), GlaxoSmithKline (to Institution), Genentech (to Institution), Astellas Pharma (to Institution), Incyte (to Institution), Roche (to Institution), Novartis (to Institution); received travel, accommodations, expenses from Bristol-Myers Squibb, GlaxoSmithKline, Daiichi Sankyo, Pieris, cCam Biotherapeutics, Lion Biotechnologies, Roche, Celldex, Amgen, Merck, AstraZeneca, Genentech.

Background: If treatment of the axilla is indicated in patients with breast cancer who have a positive sentinel node, axillary lymph node dissection is the present standard. Although axillary lymph node dissection provides excellent regional control, it is associated with harmful side-effects. We aimed to assess whether axillary radiotherapy provides comparable regional control with fewer side-effects., Methods: Patients with T1-2 primary breast cancer and no palpable lymphadenopathy were enrolled in the randomised, multicentre, open-label, phase 3 non-inferiority EORTC 10981-22023 AMAROS trial. Patients were randomly assigned (1:1) by a computer-generated allocation schedule to receive either axillary lymph node dissection or axillary radiotherapy in case of a positive sentinel node, stratified by institution. The primary endpoint was non-inferiority of 5-year axillary recurrence, considered to be not more than 4% for the axillary radiotherapy group compared with an expected 2% in the axillary lymph node dissection group. Analyses were by intention to treat and per protocol. The AMAROS trial is registered with ClinicalTrials.gov, number NCT00014612., Findings: Between Feb 19, 2001, and April 29, 2010, 4823 patients were enrolled at 34 centres from nine European countries, of whom 4806 were eligible for randomisation. 2402 patients were randomly assigned to receive axillary lymph node dissection and 2404 to receive axillary radiotherapy. Of the 1425 patients with a positive sentinel node, 744 had been randomly assigned to axillary lymph node dissection and 681 to axillary radiotherapy; these patients constituted the intention-to-treat population. Median follow-up was 6·1 years (IQR 4·1-8·0) for the patients with positive sentinel lymph nodes. In the axillary lymph node dissection group, 220 (33%) of 672 patients who underwent axillary lymph node dissection had additional positive nodes. Axillary recurrence occurred in four of 744 patients in the axillary lymph node dissection group and seven of 681 in the axillary radiotherapy group. 5-year axillary recurrence was 0·43% (95% CI 0·00-0·92) after axillary lymph node dissection versus 1·19% (0·31-2·08) after axillary radiotherapy. The planned non-inferiority test was underpowered because of the low number of events. The one-sided 95% CI for the underpowered non-inferiority test on the hazard ratio was 0·00-5·27, with a non-inferiority margin of 2. Lymphoedema in the ipsilateral arm was noted significantly more often after axillary lymph node dissection than after axillary radiotherapy at 1 year, 3 years, and 5 years., Interpretation: Axillary lymph node dissection and axillary radiotherapy after a positive sentinel node provide excellent and comparable axillary control for patients with T1-2 primary breast cancer and no palpable lymphadenopathy. Axillary radiotherapy results in significantly less morbidity., Funding: EORTC Charitable Trust., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: This phase I study assessed the pharmacokinetic (PK), tolerability, safety and preliminary clinical activity of tamoxifen (T) and lapatinib (L) in patients with metastatic breast cancer (MBC)., Methods: Patients (pts) with hormone receptor positive MBC, irrespective of HER-2 status, were randomly assigned to T → T + L group, tamoxifen in cycle 1 for 28 days then adding lapatinib on day 1 of cycle 2; or L → T + L group, lapatinib in cycle 1 for 14 days, then adding tamoxifen on day 1 of cycle 2 to evaluate the potential drug-drug PK interaction at steady-state. The dose of tamoxifen was 20 mg/day and lapatinib 1500 mg/day., Results: Twenty-five pts were enrolled of which 23 started treatment, five (22%) of them were HER-2 positive. Median age was 59 years and 96% had PS ≤1. Eleven (91.7%) pts in the T → T + L group and 10 (76.9%) in L → T + L group received at least 2 cycles of treatment. The most frequently reported drug-related adverse events (>25% of patients) were diarrhoea (62%), anaemia (56%), rash (52%), fatigue (52%), dermatology other (34%) and leukopenia (28%). Grade 3-4 drug-related toxicities were infrequent (<10%). No cardiotoxicity was observed. T plasma concentrations did not appeared to be affected by the presence of lapatinib. L steady-state plasma concentrations were 20% lower after 28 days of co-administration with T. Eight (36.4%) patients experienced stable disease and median progression free survival was 2.7 months., Conclusions: The combination of L and T was safe and clinically active. T affected L plasma concentrations, which remained within the therapeutic index., (Copyright © 2014 Elsevier Ltd. All rights reserved.)