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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.

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.

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.

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., SCOPUS: ar.j, info:eu-repo/semantics/published

BACKGROUND: The European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a validated, widely used tool developed to score the clinical benefit from cancer medicines reported in clinical trials. ESMO-MCBS scores assume valid research methodologies and quality trial implementation. Studies incorporating flawed design, implementation, or data analysis may generate outcomes that exaggerate true benefit and are not generalisable. Failure to either indicate or penalise studies with bias undermines the intention and diminishes the integrity of ESMO-MCBS scores. This review aimed to evaluate the adequacy of the ESMO-MCBS to address bias generated by flawed design, implementation, or data analysis and identify shortcomings in need of amendment. METHODS: As part of a refinement of the ESMO-MCBS, we reviewed trial design, implementation, and data analysis issues that could bias the results. For each issue of concern, we reviewed the ESMO-MCBS v1.1 approach against standards derived from Helsinki guidelines for ethical human research and guidelines from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, the Food and Drugs Administration, the European Medicines Agency, and European Network for Health Technology Assessment. RESULTS: Six design, two implementation, and two data analysis and interpretation issues were evaluated and in three, the ESMO-MCBS provided adequate protections. Seven shortcomings in the ability of the ESMO-MCBS to identify and address bias were identified. These related to (i) evaluation of the control arm, (ii) crossover issues, (iii) criteria for non-inferiority, (iv) substandard post-progression treatment, (v) post hoc subgroup findings based on biomarkers, (vi) informative censoring, and (vii) publication bias against quality-of-life data. CONCLUSION: Interpretation of the ESMO-MCBS scores requires critical appraisal of trials to understand caveats in trial design, imp, SCOPUS: re.j, info:eu-repo/semantics/published

Bringing therapeutic innovation and the latest science to routine patient care, while safeguarding principles of affordability and equality, is a challenging mission in the current complex multi-stakeholder environment. Precision oncology and new approaches to clinical trials (methods and clinical setting) have dramatically changed clinical research and the clinical development of new treatments. Improved understanding of molecular biology and immunology paves the way for innovative pharmacological approaches. However, we argue that the evidence generated during the clinical development of these new products for the purpose of obtaining marketing authorisations often does not address fundamental questions concerning the impact of these new interventions on the most relevant clinical outcomes: namely, quality of life and patient survival. Similarly, patient populations (for example defined by biomarkers), treatment duration, and sequence and combination of treatments within current treatment pathways are often poorly defined by clinical developments for regulatory purposes. Finally, the lack of integrated translational research within the pathway of development is a major limiting factor to delivering cost-effective and affordable, evidence-based care to clinical practice. This leaves many gaps in the knowledge on the efficacy and therapeutic use of medicines, which can impose a significant financial burden on healthcare systems, possibly to the detriment of more cost-effective interventions. We argue that policy changes are required to integrate clinical research and healthcare to inform clinical practice. New routes toward optimising the integration of drug development and care are being proposed to achieve this ultimate goal.

Academic, industry, regulatory leaders and patient advocates in cancer clinical research met in November 2018 at the Innovation and Biomarkers in Cancer Drug Development meeting in Brussels to address the existing dichotomy between increasing calls for personalised oncology approaches based on individual molecular profiles and the need to make resource and regulatory decisions at the societal level in differing health-care delivery systems around the globe. Novel clinical trial designs, the utility and limitations of real-world evidence (RWE) and emerging technologies for profiling patient tumours and tumour-derived DNA in plasma were discussed. While randomised clinical trials remain the gold standard approach to defining clinical utility of local and systemic therapeutic interventions, the broader adoption of comprehensive tumour profiling and novel trial designs coupled with RWE may allow patient and physician autonomy to be appropriately balanced with broader assessments of safety and overall societal benefit. (C) 2019 Published by Elsevier Ltd.

PURPOSE To better understand the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1) and the ASCO Value Framework Net Health Benefit score version 2 (ASCO-NHB v2), ESMO and ASCO collaborated to evaluate the concordance between the frameworks when used to assess clinical benefit attributable to new therapies. METHODS The 102 randomized controlled trials in the noncurative setting already evaluated in the field testing of ESMO-MCBS v1.1 were scored using ASCO-NHB v2 by its developers. Measures of agreement between the frameworks were calculated and receiver operating characteristic curves used to define thresholds for the ASCO-NHB v2 corresponding to ESMO-MCBS v1.1 categories. Studies with discordant scoring were identified and evaluated to understand the reasons for discordance. RESULTS The correlation of the 102 pairs of scores for studies in the noncurative setting is estimated to be 0.68 (Spearman’s rank correlation coefficient; overall survival, 0.71; progression-free survival, 0.67). Receiver operating characteristic curves identified thresholds for ASCO-NHB v2 for facilitating comparisons with ESMO-MCBS v1.1 categories. After applying pragmatic threshold scores of 40 or less (ASCO-NHB v2) and 2 or less (ESMO-MCBS v1.1) for low benefit and 45 or greater (ASCO-NHB v2) and 4 to 5 (ESMO-MCBS v1.1) for substantial benefit, 37 discordant studies were identified. Major factors that contributed to discordance were different approaches to evaluation of relative and absolute gain for overall survival and progression-free survival, crediting tail of the curve gains, and assessing toxicity. CONCLUSION The agreement between the frameworks was higher than observed in other studies that sought to compare them. The factors that contributed to discordant scores suggest potential approaches to improve convergence between the scales., SCOPUS: ar.j, DecretOANoAutActif, info:eu-repo/semantics/published

The molecular landscape of squamous cell carcinoma of the head and the neck (SCCHN) has been characterized and actionable or targetable genomic alterations have been identified. However, targeted therapies have very limited activity in unselected SCCHN, and the current treatment strategy is still based on tumor location and disease stage and not on tumor biology. Trying to select upfront the patients who will benefit from a specific treatment might be a way to improve patients' outcome. With the objective of optimizing the activity of targeted therapies and immunotherapy, we have designed an umbrella biomarker-driven study dedicated to recurrent and/or metastatic SCCHN patients (EORTC-1559-HNCG, NCT03088059). In this article, we review not only the different trial designs for biomarker-driven studies with their respective advantages and opportunities but also the potential pitfalls that led to the design of the EORTC-1559-HNCG protocol. We also discuss the scientific and logistic challenges of biomarker-driven trials.

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Purpose: This study compares immunohistochemical (IHC) versus molecular subtyping (BluePrint and MammaPrint) in the population of patients enrolled in MINDACT and outcome based on molecular subtyping (MS) versus surrogate pathological subtyping (PS) as defined by the 2013 St. Gallen guidelines. Methods: MS classified patients in the following subtypes: Luminal A, Luminal B, HER-2-, and Basal-type. IHC/FISH for pathological subtyping (ER, PgR, HER-2, and Ki67) was centrally assessed in the European Institute of Oncology (n = 5806). Hazard ratios for distant-metastasis-free survival (DMFS) by subtype were adjusted for chemotherapy and endocrine therapy administration and thus independent of adjuvant treatment allocation. Results: PS Luminal cancers classified as HER-2+ or Basal-type by MS did not have a significantly lower DMFS than the Luminal-type cancers by MS (95.9%): HR = 1.40, 95% CI 0.75–2.60 (p = 0.294). More patients were identified with Luminal A disease by MS (63%) as compared with PS (47%) with comparable 5-year DMFS (≥96.0%). Among the 500 patients with PS TN cancers, MS identified 24 (5%) patients as Luminal-type with 5-year DMFS estimated at 100% versus 71.4% for MS HER-2+ or 90.1% for MS Basal-type. Conclusions: MS was able to re-stratify 54% of patients with a Luminal-B PS subtype to a low-risk Luminal A-type group with comparable outcome. Among TN EBC, 5% were classified as Luminal by MS with Luminal-like outcome. Molecular classification can help to identify a larger group of patients with low risk of recurrence compared with the more contemporarily used classification methodology including high-quality assessed Ki67., SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: le.j, info:eu-repo/semantics/published

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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

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., SCOPUS: ar.j, info:eu-repo/semantics/published

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Background: The ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) version 1.0 (v1.0) was published in May 2015 and was the first version of a validated and reproducible tool to assess the magnitude of clinical benefit from new cancer therapies. The ESMO-MCBS was designed to be a dynamic tool with planned revisions and updates based upon recognition of expanding needs and shortcomings identified since the last review. Methods: The revision process for the ESMO-MCBS incorporates a nine-step process: Careful review of critiques and suggestions, and identification of problems in the application of v1.0; Identification of shortcomings for revision in the upcoming version; Proposal and evaluation of solutions to address identified shortcomings; Field testing of solutions; Preparation of a near-final revised version for peer review for reasonableness by members of the ESMO Faculty and Guidelines Committee; Amendments based on peer review for reasonableness; Near-final review by members of the ESMO-MCBS Working Group and the ESMO Executive Board; Final amendments; Final review and approval by members of the ESMO-MCBS Working Group and the ESMO Executive Board. Results: Twelve issues for revision or amendment were proposed for consideration; proposed amendments were formulated for eight identified shortcomings. The proposed amendments are classified as either structural, technical, immunotherapy triggered or nuanced. All amendments were field tested in a wide range of studies comparing scores generated with ESMO-MCBS v1.0 and version 1.1 (v1.1). Conclusions: ESMO-MCBS v1.1 incorporates 10 revisions and will allow for scoring of single-arm studies., SCOPUS: ar.j, info:eu-repo/semantics/published

BACKGROUND: The 70-gene signature test (MammaPrint) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer. We sought to provide prospective evidence of the clinical utility of the addition of the 70-gene signature to standard clinical-pathological criteria in selecting patients for adjuvant chemotherapy. METHODS: In this randomized, phase 3 study, we enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online). Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. The primary goal was to assess whether, among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval for the rate of 5-year survival without distant metastasis would be 92% (i.e., the noninferiority boundary) or higher. RESULTS: A total of 1550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor-positive, human epidermal growth factor receptor 2-negative, and either node-negative or node-positive disease. CONCLUSIONS: Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the r

The ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a standardised, generic, validated tool to stratify the magnitude of clinical benefit that can be anticipated from anticancer therapies. The ESMO-MCBS is intended to both assist oncologists in explaining the likely benefits of a particular treatment to their patients as well as to aid public health decision makers' prioritise therapies for reimbursement. From its inception the ESMO-MCBS Working Group has invited questions and critiques to promote understanding and to address misunderstandings regarding the nuanced use of the scale, and to identify shortcomings in the scale to be addressed in future planned revisions and updates. The ESMO-MCBS V.1.0 has attracted many questions regarding its development, structure and potential applications. These questions, together with responses from the ESMO-MCBS Working Group, have been edited and collated, and are herein presented as a supplementary resource., SCOPUS: re.j, info:eu-repo/semantics/published

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Les pathologies infectieuses, maladies causées par certains micro-organismes pathogènes parmi les bactéries, les virus, les champignons et les protozoaires, sont à l’origine des taux de mortalité et de morbidité élevés enregistrés surtout dans les pays en voie de développement où la majorité de la population n’a pas les moyens d'accéder aux soins de santé. Les résistances des micro-organismes aux antimicrobiens, observées actuellement dans la pratique médicale moderne, constituent un autre grand problème lié au traitement de ces maladies. Elles constituent l’une des menaces de santé les plus sérieuses et peuvent frapper n’importe qui dans le monde. Face à ces fléaux, il est urgent de découvrir de nouveaux agents antimicrobiens qui pourraient, éventuellement, présenter de nouveaux mécanismes d'action. Une bonne part des plantes utilisées en médecines traditionnelles contiennent des composants antimicrobiens utiles contre les infections et qui peuvent aider dans la lutte contre les maladies infectieuses liées à l’antibiorésistance. C’est dans cette optique que nous avons mené une enquête ethnobotanique sur les plantes médicinales utilisées contre les infections microbiennes en médecine traditionnelle Burundaise. Nous en avons inventorié 155 et sélectionné 5 d'entre elles (Justicia subsessilis Oliv. (Acanthaceae); Platostoma rotundifolium (Briq.) A. J. Paton (Lamiaceae), Virectaria major (Schum.) Verdc. (Rubiaceae), Pavetta ternifolia (Oliv.) Hiern (Rubiaceae), et Stomatanthes africanus (Oliv. & Hiern) R. M. King & H. Rob. (Asteraceae)) pour en étudier la composition phytochimique et les propriétés biologiques. Les extraits de ces plantes ont été évalués notamment pour leurs effets antibactériens direct (bactéricide ou bactériostatique) et indirect (modulation des mécanismes de résistance qui augmente ou restaure l’activité des antibiotiques sur des souches résistantes). Les cinq plantes retenues ont montré une activité antibactérienne, justifiant ainsi leur usage cont, Infectious pathologies are diseases caused by the transmission of some pathogenic microorganisms among bacteria, viruses, fungi and protozoa. They drive the high mortality and morbidity rates recorded especially in developing countries, where the majority of the population cannot afford to access health care. The antimicrobial resistances currently observed in modern medical practice represent another major problem in the treatment of these diseases. These resistances are one of the most serious population health threats and can strike anyone in the world. It has thus become urgent to discover new antimicrobial agents that could possibly have novel mechanisms of action.Many plants used in traditional medicines against infections harbor useful antimicrobial components that can help in the fight against infectious diseases and antibiotic resistances. In this context, we conducted an ethnobotanical survey of medicinal plants used in Burundian traditional medicine to treat microbial infections. We inventoried 155 herbs from which 5 (Justicia subsessilis Oliv. (Acanthaceae); Platostoma rotundifolium (Briq.) A. J. Paton (Lamiaceae), Virectaria major (Schum.) Verdc. (Rubiaceae), Pavetta ternifolia (Oliv.) Hiern (Rubiaceae), and Stomatanthes africanus (Oliv. & Hiern) R. M. King & H. Rob. (Asteraceae) were selected for phytochemical screening and biological assays. The extracts of these plants were evaluated for their antibacterial effects, direct (bacteriostatic or bactericidal) and indirect (inhibition of resistance mechanisms by increasing or restoring the activity of antibiotics against resistant strains). All the selected plants species have shown antibacterial activity, justifying their use against microbial infections in Burundian traditional medicine, and more particularly Platostoma rotundifolium, whose extracts showed direct and indirect antibacterial effects on susceptible and resistant (MRSA) strains. The extracts from Platostoma rotundifolium also presented inhi, Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie), info:eu-repo/semantics/nonPublished

BACKGROUND: The 70-gene signature test (MammaPrint) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer. We sought to provide prospective evidence of the clinical utility of the addition of the 70-gene signature to standard clinical-pathological criteria in selecting patients for adjuvant chemotherapy. METHODS: In this randomized, phase 3 study, we enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online). Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. The primary goal was to assess whether, among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval for the rate of 5-year survival without distant metastasis would be 92% (i.e. the noninferiority boundary) or higher. RESULTS: A total of 1550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemother apy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor-positive, human epidermal growth factor receptor 2-negative, and either node-negative or node-positive disease. CONCLUSIONS: Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the r, SCOPUS: ar.j, info:eu-repo/semantics/published

Accurate identification of breast cancer patients most likely to benefit from adjuvant systemic therapies is crucial. Better understanding of differences between methods can lead to an improved ER, PgR, and HER-2 assessment. The purpose of this preplanned translational research is to investigate the correlation of central IHC/FISH assessments with microarray mRNA readouts of ER, PgR, and HER-2 status in the MINDACT trial and to determine if any discordance could be attributed to intratumoral heterogeneity or the DCIS and normal tissue components in the specimens. MINDACT is an international, prospective, randomized, phase III trial investigating the clinical utility of MammaPrint in selecting patients with early breast cancer for adjuvant chemotherapy (n = 6694 patients). Gene-expression data were obtained by TargetPrint; IHC and/or FISH were assessed centrally (n = 5788; 86 %). Macroscopic and microscopic evaluation of centrally submitted FFPE blocks identified 1427 cases for which the very same sample was submitted for gene-expression analysis. TargetPrint ER had a positive agreement of 98 %, and a negative agreement of 95 % with central pathology. Corresponding figures for PgR were 85 and 94 % and for HER-2 72 and 99 %. Agreement of mRNA versus central protein was not different when the same or a different portion of the tumor tissue was analyzed or when DCIS and/or normal tissue was included in the sample subjected to mRNA assays. This is the first large analysis to assess the discordance rate between protein and mRNA analysis of breast cancer markers, and to look into intratumoral heterogeneity, DCIS, or normal tissue components as a potential cause of discordance. The observed difference between mRNA and protein assessment for PgR and HER-2 needs further research; the present analysis does not support intratumoral heterogeneity or the DCIS and normal tissue components being likely causes of the discordance., SCOPUS: ar.j, info:eu-repo/semantics/published

Background Preclinical data suggest that epidermal growth factor receptor (EGFR) inhibitors (e.g. gefitinib) can delay endocrine resistance in breast cancer. A double-blind, placebo-controlled, phase II trial investigated whether adding gefitinib (G) to anastrozole (A) would improve outcome in advanced breast cancer (ABC). Methods Postmenopausal pre-treated hormone receptor-positive ABC patients (locally recurrent or metastatic) were 1:1 randomized to A (1 mg/d) plus G 250 mg/d or plus placebo (P). Patients who had prior treatment with an aromatase inhibitor in metastatic setting or with trastuzumab, anti-EGFR or anti-VEGF agents were excluded. Treatment was given until disease progression, unacceptable toxicity or patient withdrawal. Progression-free survival (PFS) rate at 1 year was assessed according to Response Evaluation Criteria in Solid Tumours, version 1.0. Results Of 108 planned patients, 71 were recruited (36 in A/G and 35 in A/P). The trial closed prematurely due to slow recruitment; 31 patients had prior chemotherapy and 53 prior endocrine therapy (all except one received tamoxifen); 60% in adjuvant and 16% in metastatic setting received tamoxifen; 59 patients had visceral disease. Median follow-up was 18 months. PFS rate at 1 year was 35% for A/G and 32% for A/P arm. Objective responses were six (22%) in the A/G and nine (28%) in the A/P arm. Median duration of response was 13.8 and 18.6 months in the A/G and A/P arms, respectively. Fatigue (35%), diarrhoea (31%), rash (32%), dry skin (27%), and arthralgia/myalgia (27%) were the commonest adverse events in the A/G arm. Conclusions This phase II study, although prematurely closed, did not show a signal that adding G to A improves PFS at 1 year and its use is not supported. Gastrointestinal and skin toxicities were more pronounced with G resulting in premature therapy interruption in almost 1 in 3 patients (ClinicalTrials.gov number, NCT00066378)., SCOPUS: ar.j, info:eu-repo/semantics/published