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ZusammenfassungKiesinseln können als naturbasierte Lösungen die ökologische Funktion von Gewässern verbessern und nachhaltig Habitate für aquatische und terrestrische Lebewesen schaffen. Ihre Anwendung als hydraulische Maßnahmen mit Auswirkungen auf die Hydrodynamik und Morphologie des Hauptstroms muss jedoch weiter untersucht werden. Ziel der vorliegenden Studie ist es, die Eignung von Kiesinseln zur Niederwasserregulierung im Rahmen der Schifffahrt zu bewerten. Zu diesem Zweck wurden verschiedene geometrische Variationen von Kiesstrukturen unter verschiedenen hydrologischen Bedingungen in der österreichischen Donau mit dem hydrodynamischen Modell RSim-3D und dem Sedimenttransportmodell iSed analysiert. Geschüttete Kiesinseln zeigen ähnliche Wirkungen in Bezug auf die Hydro- und Morphodynamik des Gewässer-Hauptstroms wie Buhnen. Die Implementierung der Insel verursacht eine lokale Abnahme des Wasserspiegels und eine lokale Erhöhung der Sohlschubspannung entlang der Struktur. Parallel zur Kiesstruktur treten relative Erosionstendenzen auf, die flussabwärts zu relativen Sedimentationstendenzen führen. Darüber hinaus treten in den untersuchten Gebieten keine Beeinträchtigungen der Schifffahrt und des Hochwasserschutzes auf. Neben ihrer flussbaulichen Funktion dienen künstliche Kiesstrukturen auch als Geschiebedepots und -quelle und bieten durch die fortschreitende Morphodynamik ökologisch wertvolle Lebensräume. Die gewonnenen Erkenntnisse verdeutlichen, dass Kiesinseln als effektive Alternative zu Buhnen für die Niederwasserregulierung eingesetzt werden können. Daher können die Ergebnisse dieser Studie in die zukünftige Forschung und Planung ökologischer Flussbaumaßnahmen einfließen.

Purpose BluePrint (BP) is an 80-gene molecular subtyping test that classifies early-stage breast cancer (EBC) into Basal, Luminal, and HER2 subtypes. In most cases, breast tumors have one dominant subtype, representative of a single activated pathway. However, some tumors show a statistically equal representation of more than one subtype, referred to as dual subtype. This study aims to identify and examine dual subtype tumors by BP to understand their biology and possible implications for treatment guidance. Methods The BP scores of over 15,000 tumor samples from EBC patients were analyzed, and the differences between the highest and the lowest scoring subtypes were calculated. Based upon the distribution of the differences between BP scores, a threshold was determined for each subtype to identify dual versus single subtypes. Results Approximately 97% of samples had one single activated BluePrint molecular subtype, whereas ~ 3% of samples were classified as BP dual subtype. The most frequently occurring dual subtypes were the Luminal-Basal-type and Luminal-HER2-type. Luminal-Basal-type displays a distinct biology from the Luminal single type and Basal single type. Burstein’s classification of the single and dual Basal samples showed that the Luminal-Basal-type is mostly classified as ‘luminal androgen receptor’ and ‘mesenchymal’ subtypes, supporting molecular evidence of AR activation in the Luminal-Basal-type tumors. Tumors classified as Luminal-HER2-type resemble features of both Luminal-single-type and HER2-single-type. However, patients with dual Luminal-HER2-type have a lower pathological complete response after receiving HER2-targeted therapies in addition to chemotherapy in comparison with patients with a HER2-single-type. Conclusion This study demonstrates that BP identifies tumors with two active functional pathways (dual subtype) with specific transcriptional characteristics and highlights the added value of distinguishing BP dual from single subtypes as evidenced by distinct treatment response rates.

Purpose: Most node-negative breast cancer patients are older and postmenopausal and are increasingly being offered adjuvant chemotherapy despite their low overall risk of distant relapse. A molecular diagnostic test with high negative predictive value (NPV) for distant metastasis in this subgroup would spare many older breast cancer patients adjuvant treatment.Experimental Design: We determined the NPV and positive predictive value of the MammaPrint assay in breast cancer patients who were consecutively diagnosed and treated at the Massachusetts General Hospital between 1985 and 1997. Primary tumors from 100 patients with node-negative, invasive breast cancer (median age, 62.5 years; median follow-up, 11.3 years) were subjected to MammaPrint analysis and classified as being at either low or high risk for distant metastasis.Results: The MammaPrint 70-gene signature displayed excellent NPV as in previous studies, correctly identifying 100% of women at low risk for distant metastases at 5 years. However, this assay had a lower positive predictive value (12% at 5 years) than previously observed.Conclusions: The MammaPrint assay was originally designed to identify younger breast cancer patients at low risk for distant metastasis, who might consequently be spared systemic treatment. We show here that the same signature has a very high NPV for distant recurrence after adjuvant treatment in older breast cancer patients.

Supplementary Table S1 from Analysis of the MammaPrint Breast Cancer Assay in a Predominantly Postmenopausal Cohort

Supplementary Table S1 from Mechanisms and Effects of Loss of Human Leukocyte Antigen Class II Expression in Immune-Privileged Site-Associated B-Cell Lymphoma

Purpose and Experimental Design: Loss of human leukocyte antigen (HLA) expression on tumor cells is frequent in diffuse large B-cell lymphoma (DLBCL) arising in immune-privileged sites, such as the testis and central nervous system, and is associated with small homozygous deletions of HLA-DQ/HLA-DR and larger hemizygous deletions of the MHC region. To better understand the significance of down-regulation of HLA class II expression in relation to the homozygous and hemizygous deletions, we analyzed global gene expression patterns in a series of 26 testicular DLBCL after characterization of these deletions.Results: Low levels of HLA-DR mRNA in whole testicular DLBCL samples were associated with a strong down-regulation of numerous immune-related genes specific for T cells, macrophages, antigen presentation and processing, lymphocyte activation, chemokines and chemokine receptors, and the complement system. The number of CD3+ tumor-infiltrating T cells was also significantly lower in low expressors of HLA-DR mRNA. Interestingly, hemizygous and homozygous deletions in the MHC region did not have any additional effect on global gene expression.Conclusion: In conclusion, we found that loss of HLA class II mRNA expression in testicular DLBCL is associated with a significant change in global gene expression patterns. This effect is independent of the mechanism causing the down-regulation of HLA class II genes in the lymphoma cells.

Purpose In the randomized phase III trial CeTeG/NOA-09, temozolomide (TMZ)/lomustine (CCNU) combination therapy was superior to TMZ in newly diagnosed MGMT methylated glioblastoma, albeit reporting more frequent hematotoxicity. Here, we analyze high grade hematotoxicity and its prognostic relevance in the trial population. Methods Descriptive and comparative analysis of hematotoxicity adverse events ≥ grade 3 (HAE) according to the Common Terminology of Clinical Adverse Events, version 4.0 was performed. The association of HAE with survival was assessed in a landmark analysis. Logistic regression analysis was performed to predict HAE during the concomitant phase of chemotherapy. Results HAE occurred in 36.4% and 28.6% of patients under CCNU/TMZ and TMZ treatment, respectively. The median onset of the first HAE was during concomitant chemotherapy (i.e. first CCNU/TMZ course or daily TMZ therapy), and 42.9% of patients with HAE receiving further courses experienced repeat HAE. Median HAE duration was similar between treatment arms (CCNU/TMZ 11.5; TMZ 13 days). Chemotherapy was more often discontinued due to HAE in CCNU/TMZ than in TMZ (19.7 vs. 6.3%, p = 0.036). The occurrence of HAE was not associated with survival differences (p = 0.76). Regression analysis confirmed older age (OR 1.08) and female sex (OR 2.47), but not treatment arm, as predictors of HAE. Conclusion Older age and female sex are associated with higher incidence of HAE. Although occurrence of HAE was not associated with shorter survival, reliable prediction of patients at risk might be beneficial to allow optimal management of therapy and allocation of supportive measures. Trial registration NCT01149109.

Background The CeTeG/NOA-09 trial assessed in a randomized phase 3 setting, whether combined treatment of lomustine together with temozolomide was superior to temozolomide treatment alone in newly diagnosed MGMT (O(6)-methylguanine-DNA-methyltransferase) promoter methylated glioblastoma patients. Survival was significantly improved from 31.4 months with temozolomide alone to 48.1 months with the combination of lomustine plus temozolomide. In view of this encouraging data - suggesting this combination could have a significant impact on the survival of newly diagnosed glioblastoma patients - we were curious to assess safety and efficacy of this regimen under real-life conditions. Material and Methods We collected clinical and radiographic data from adult newly diagnosed MGMT promoter methylated IDH (isocitrate dehydrogenase) wildtype glioblastoma patients treated at five neuro-oncology centers in Germany. As a requirement for inclusion, first-line treatment with lomustine plus temozolomide had to be performed for at least six weeks (one course). The available radiographic data was independently reviewed by an experienced board-certified neuro-radiologist. Results In total, 70 patients were included. Median progression-free survival of the full cohort was 14.4 months and median overall survival was 36.0 months. Patients who received TTFields (Tumor Treating Fields) treatment for eight weeks or longer together with the combination of lomustine plus temozolomide (n=22, 31%) had a prolonged progression-free survival compared to those patients who received TTFields treatment less than eight weeks or did not receive treatment with TTFields (n=48, 69%) (21.5 months versus 11.2 months; HR: 2.118, 95% CI: 1.245-3.605; p=0.0105). In a multivariable Cox regression analysis the use of TTFields for eight weeks or longer together with the combination of lomustine plus temozolomide as well as the application of at least five courses of CeTeG therapy emerged as independent prognostic factors for progression-free survival and overall survival. Pseudoprogression occurred in n=16 (33%) of the patients. We observed no treatment related deaths and high-grade hematotoxicity in n=31 (44%) of the patients. Conclusion The results from this multicentric trial that investigated newly diagnosed MGMT promoter methylated IDH wildtype glioblastoma under real-life conditions indicate toxicity and survival estimates comparable to the CeTeG/NOA-09 trial. The use of TTFields for at least eight weeks in combination with this regimen was independently associated with extended progression-free and overall survival.

Data on the long-term persistence of HCV resistance-associated substitutions (RASs) after treatment with direct-acting antivirals (DAAs) are limited. This study evaluated the persistence of NS3, NS5A, and NS5B RASs for up to 5 years after the end of treatment (EOT).We included samples from 678 individuals with an HCV genotype (GT) 1 or 3 infection and virologic DAA treatment failure collected in the European Resistance Database. NS3, NS5A, and NS5B were sequenced, and clinical parameters were evaluated.A total of 242 individuals with HCV GT1a (36%), 237 with GT1b (35%), and 199 (29%) with GT3 and a DAA failure were included. After protease inhibitor failure, the frequencies of NS3 RASs were 40-90% after the EOT. NS3 RASs disappeared rapidly in GT1b and GT3 after follow-up month 3 but were stable (≥60%) in GT1a owing to Q80K. The SOF-resistant NS5B RAS S282T was only found in individuals with GT3a. Non-nucleoside NS5B RASs were frequent in GT1 (56-80%) and decreased to 30% in GT1a but persisted in GT1b. NS5A RASs were very common in all GTs after NS5A inhibitor failure (88-95%), and even after follow-up month 24, their frequency was 65% and higher. However, RASs in GT1b had a stable course, whereas RASs in GT1a and GT3 declined slightly after follow-up month 24 (GT1a, 68%; GT1b, 95%; and GT3, 65%), mainly because of the slow decline of high-level resistant Y93H.We found that low-to medium-level RASs persisted, whereas high-level resistant RASs disappeared over time. Different patterns of RAS persistence according to HCV subtype could have implications for retreatment with first-generation DAAs and for global HCV elimination goals.There are little data on the long-term persistence of HCV resistance-associated substitutions (RASs) after DAA treatment failure, and RASs could have an impact on the efficacy of a rescue treatment. Especially in countries with limited availability of VOX/VEL/SOF or G/P/SOF, different patterns of RAS persistence could have implications for retreatment with first-generation DAAs and for global HCV elimination goals. The different patterns of RAS persistence identified in this study can be used to derive general rules regarding the persistence of RASs after DAA failure that could be applied by physicians in less developed countries to plan individualized HCV retreatment.

PURPOSE Patients with 70-gene signature ultralow-risk breast cancers have shown excellent survival in historic cohorts, including randomized trials. The ultralow-risk subgroup was characterized to help avoid overtreatment. We evaluated outcomes of ultralow-risk patients in the largest cohort to date. METHODS Of the 6,693 patients enrolled in the EORTC-10041/BIG-3-04 randomized phase III MINDACT trial, profiling revealed an ultralow-risk 70-gene signature in 1,000 patients (15%). Distant metastasis-free interval (DMFI) and breast cancer–specific survival (BCSS) were assessed in patients stratified by 70-gene signature result (high, low, and ultralow) by Kaplan-Meier analysis and hazard ratios with 95% CI from Cox regression. RESULTS Median follow-up was 8.7 years. Of the ultralow-risk patients (n = 1,000), 67% were > 50 years, 81% had tumors ≤ 2 cm, 80% were lymph node–negative, 96% had grade 1 or 2 tumors, and 99% were estrogen receptor (ER)-positive. Systemic therapy was received by 84% of patients (69% endocrine therapy, 14% endocrine therapy plus chemotherapy, 1% other) and 16% received no adjuvant systemic treatment. The 8-year DMFI for ultralow-risk patients was 97.0% (95% CI, 95.8 to 98.1), which was 2.5% higher than for patients with low-risk tumors (n = 3,295, 94.5% [95% CI, 93.6 to 95.3]). The hazard ratio for DMFI was 0.65 (95% CI, 0.45 to 0.94) for ultralow versus low risk, after adjusting for clinical-pathologic and treatment characteristics. The 8-year BCSS for ultralow-risk patients was 99.6% (95% CI, 99.1 to 100). CONCLUSION Patients with an ultralow-risk 70-gene signature have the best prognosis, distinctive from low risk, with 8-year BCSS above 99%, and very few patients developed distant metastases with an 8-year DMFI rate of 97%. These patients could be candidates for further de-escalation of treatment, to avoid overtreatment and the risk of side effects.

With increased neoadjuvant therapy recommendations for early-stage breast cancer patients due to the COVID-19 pandemic, it is imperative that molecular diagnostic assays provide reliable results from preoperative core needle biopsies (CNB). The study objective was to determine the concordance of MammaPrint and BluePrint results between matched CNB and surgical resection (SR) specimens.Matched tumor specimens (n = 121) were prospectively collected from women enrolled in the FLEX trial (NCT03053193). Concordance is reported using overall percentage agreement and Cohen's kappa coefficient. Correlation is reported using Pearson correlation coefficient.We found good concordance for MammaPrint results between matched tumor samples (90.9%, κ = 0.817), and a very strong correlation of MammaPrint indices (r = 0.94). The concordance of BluePrint subtyping in matched samples was also excellent (98.3%).CNB samples demonstrated high concordance with paired SR samples for MammaPrint risk classification and BluePrint molecular subtyping, suggesting that physicians are provided with accurate prognostic information that can be used to guide therapy decisions.

Background: The use of CDK4/6 inhibitors (CDK4/6i) is a promising therapeutic strategy for recurrent ER+, HER2- breast cancers that have escaped previous treatment targeting the endocrine pathway. A number of adjuvant and neoadjuvant trials with CDK4/6i in early breast cancer are also underway. However, no clear predictive biomarkers for resistance are available other than loss of the RB1 tumor suppressor gene. Cyclin E genes (CCNE1, CCNE2) play a critical role in cell cycle control with approximately 25% of breast cancer overexpressing CCNE2, and there is a significant correlation between CCNE2 and CCNE1 expression1,2,3. Furthermore, a positive correlation between expression of CCNE1 and resistance to CDK4/6i (i.e. palbociclib)4,5,6 has been reported in vitro and in a gene expression analysis from the PALOMA-3 trial. The 70-gene MammaPrint® (MP) signature is a prognostic assay that stratifies early-stage breast cancer (ESBC) patients into Low and High-risk of distant relapse. One of the 70 genes is CCNE2, shown to be associated with resistance to both endocrine therapy and CDK4 inhibition7. Considering the potential role of the Cyclin E genes as biomarker of resistance for CDK4/6i, we assessed the expression of CCNE2 in a large series of ESBCs with respect to their MP risk profile. Methods: The mRNA expression of CCNE2 (and CCNE1) was measured in a series of 5022 breast cancer samples for which FFPE microarray full-transcriptome data were available for testing. Intensities were Lowess normalized and log2 transformed. The 80-gene BluePrint (BP) profile8 was used in combination with MP to stratify patient samples based on their molecular subtype: Luminal A- (MP Low Risk, BP Luminal), Luminal B- (MP High Risk, BP Luminal), HER2- and Basal-type. Wilcoxon rank sum test was used to examine expression differences. Results: CCNE2 is significantly higher expressed in MP High risk compared to MP Low risk tumors when all samples are included (p Conclusions: Our preliminary results show that MP could help in stratifying BP Luminal-type B tumors in subgroups with differential CCNE2 expression. Since increased CCNE1 expression is correlated with CDK4/6i resistance, and CCNE2 is a functionally-related gene whose expression correlates to some extent with CCNE1, it is reasonable to speculate that high CCNE2 expression and MP High Risk Luminal B may also correlate with CDK4/6i resistance, a testable hypothesis. This warrants additional analyses that integrate treatment response data to support and further investigate these observations. Our exploratory analysis also highlights the added value of a multi-gene signature profile versus single-gene testing as tool for patient stratification and treatment recommendation. Refernces: 1. Asghar U et al Nat Rev Drug Discov. 2015 2. Caldon C et al Cell Div. 2010 3. Payton M et al Oncogene. 2002 4. Turner N et al. J Clin Oncol. 2019 5. Chandarlapaty S et al J Clin Oncol. 2019 6. Guarducci C et al NPJ Br Cancer. 2018 7. Caldon CE et al Mol Cancer Ther. 2012 8. Krijgsman O et al BRCT 2012 Citation Format: Lorenza Mittempergher, Joe McKelley, Rajith Bhaskaran, Sahra Uygun, René Bernards, Laura J van 't Veer, Annuska M Glas, William Audeh. Cyclin E overexpression is associated with high risk 70 gene signature, and may indicate intrinsic resistance to CDK4/6 inhibitors [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-24.

A previously developed and centrally validated MammaPrint® (MP) and BluePrint® (BP) targeted RNA next-generation sequencing (NGS) kit was implemented and validated in two large academic European hospitals. Additionally, breast cancer molecular subtypes by MP and BP RNA sequencing were compared with immunohistochemistry (IHC). Patients with early breast cancer diagnosed at University Hospitals Leuven and Curie Institute Paris were prospectively included between September 2017 and January 2018. Formalin-fixed paraffin-embedded tissue sections were analyzed with MP and BP NGS technology at the beta sites and with both NGS and microarray technology at Agendia. Raw NGS data generated on Illumina MiSeq instruments at the beta sites were interpreted and compared with NGS and microarray data at Agendia. MP and BP NGS molecular subtypes were compared to surrogate IHC breast cancer subtypes. Equivalence of MP and BP indices was determined by Pearson's correlation coefficient. Acceptable limits were defined a priori, based on microarray data generated at Agendia between 2012 and 2016. The concordance, the Negative Percent Agreement and the Positive Percent Agreement were calculated based on the contingency tables and had to be equal to or higher than 90%. Out of 124 included samples, 48% were MP Low and 52% High Risk with microarray. Molecular subtypes were BP luminal, HER2 or basal in 82%, 8% and 10% respectively. Concordance between MP microarray at Agendia and MP NGS at the beta sites was 91.1%. Concordance of MP High and Low Risk classification between NGS at the beta sites and NGS at Agendia was 93.9%. Concordance of MP and BP molecular subtyping using NGS at the beta sites and microarray at Agendia was 89.5%. Concordance between MP and BP NGS subtyping, and IHC was 71.8% and 76.6%, for two IHC surrogate models. The MP/BP NGS kit was successfully validated in a decentralized setting. ispartof: Translational Oncology vol:12 issue:12 pages:1557-1565 ispartof: location:United States status: Published online

Background Tumour Treating Fields therapy (TTFields; 200 kHz) is a noninvasive, loco-regional, antimitotic treatment approved for newly diagnosed glioblastoma (ndGBM) and mesothelioma. In the phase 3 EF-14 trial, TTFields/temozolomide (TMZ) significantly increased overall survival (OS) and progression-free survival (PFS) vs TMZ alone in patients with ndGBM. TTFields-related adverse events (AEs) were mainly dermatological with no increases in systemic toxicity. In preclinical models, the addition of TTFields to radiotherapy (RT) increased the therapeutic effect. In 2 clinical pilot phase 2 studies, TTFields added to RT/TMZ was reported as feasible and well-tolerated. Material and Methods TRIDENT (EF-32; NCT04471844) is an international, phase 3 randomised trial comparing TTFields (200 KHz, ≥ 18 h/day)/RT/TMZ vs RT/TMZ alone. Eligibility criteria include histologically confirmed ndGBM, ≥ 18 years of age (≥ 22 years of age; US), Karnofsky Performance Status ≥ 70, life expectancy ≥ 3 months, adequate organ function and eligible for RT/TMZ - participants will be stratified by extent-of-resection and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. During the initial 6-week investigational period, patients in the experimental arm will receive continuous TTFields and concomitant RT/TMZ whilst patients in the control arm will receive only RT/TMZ. Subsequently, all patients will receive TTFields and 6 cycles of maintenance TTFields/TMZ. TTFields will continue for 24 months or until second disease progression per Response Assessment in Neuro-Oncology (RANO), whichever occurs first. The primary endpoint is median OS. Secondary endpoints include median PFS (RANO), 1- and 2-year survival rates, overall radiological response (RANO), PFS6, PFS12, severity and frequency of AEs (Common Terminology Criteria for Adverse Events v5.0), post-treatment pathological changes in resected GBM tumours, quality-of-life per EORTC QLQ-C30, OS correlation to TTFields duration-of-usage, and neurological assessment per NANO (Neurological Assessment in Neuro-Oncology) and RANO criteria. Survival will be measured from time-of-randomisation. Sample size (N = 950; randomised 1:1) was powered for a hazard ratio < 0.8 with a 5% type I error. The hypothesis, that first-line TTFields/RT/TMZ can significantly improve OS vs RT/TMZ, will be tested using a stratified log-rank test. The study is currently open to enrollment in locations in Austria, Belgium, Czech Republic, France, Germany, Israel, Switzerland, and across the US.

Background Disease relapse almost inevitably occurs in patients with adult-type diffuse glioma. Standard of care treatment options at tumor relapse are still not well defined. Frequently used drugs for adult-type diffuse glioma recurrence include lomustine (CCNU) and bevacizumab. Few studies indicate that the combination of trofosfamide/etoposide, given their high lipid solubility with good blood-brain barrier penetrance, may be feasible in pediatric glioblastoma patients. In this retrospective analysis, we determined tolerability and feasibility of combined trofosfamide/etoposide treatment at disease recurrence of patients with adult-type diffuse glioma. Material and Methods We collected clinicopathological data from adult patients with adult-type diffuse glioma treated with the combination of trofosfamide/etoposide at the Division of Clinical Neurooncology at the University Hospital Essen. Only those patients were considered eligible who received trofosfamide/etoposide treatment for more than four weeks (one course). Trofosfamide (100mg/m2/day) and Etoposide (25mg/m2/day) was administered orally in a “one week on, one week off” scheme. A cohort of patients receiving empiric treatment at the investigators’ discretion balanced for tumor entity and canonical prognostic factors (number of previous treatments, MGMT promoter methylation, IDH mutation status, KPS, age, extent of resection) served as control. We collected toxicity data as it pertained to CTCAE (Common Terminology Criteria for Adverse Events, version 5.0) and survival data to explore putative efficacy. Results A total of 33 patients were eligible for this analysis. In the IDH wild-type glioblastoma (n=18) subgroup, median progression-free survival (3.8 months versus 2.9 months, HR: 2.09, 95% CI: 1.010-4.312, p=0.0227; PFS-6: 39% versus 6%) and median overall survival (10.4 months versus 5.7 months, HR: 3.05, 95% CI: 1.393-6.655, p=0.0008) were significantly prolonged as compared to the control cohort. In a multivariable Cox regression analysis, treatment with trofosfamide/etoposide emerged as statistically significant prognostic marker regarding progression-free survival and overall survival. We observed high-grade adverse events (CTCAE grade≥III ) in 21 (64%) of all recurrent glioma patients with hematotoxicity comprising most adverse events (n=18, 86%). Lymphopenia was by far the most observed hematotoxic adverse event (n=13, 62%). Among non-hematologic high-grade adverse events was transaminase elevation (n=3, 14%). Conclusion This study provides first indication that the combination of trofosfamide/etoposide is safe in patients with adult-type diffuse gliomas and may be associated with prolonged survival in adult patients with recurrent IDH wildtype glioblastoma. Our data provide a reasonable rationale for follow-up of a larger cohort in a prospective controlled trial.

Background Although Medulloblastoma (MB) is the most common primary malignant intracranial tumor in childhood, in adults it is extremely rare. Therefore, available data is scarce and experience with radiation and proton beam therapy (PBT) is very limited. The treatment typically includes tumour resection, irradiation of the craniospinal axis (CSI) followed by a boost, +/- concomitant chemotherapy, and maintenance therapy. Herein, we present our preliminary analysis of outcome and toxicity after PBT. Material and Methods Patients ≥ 18 years with primary MB treated with PBT between January 2017 and March 2020 enrolled in the prospective registry study (DRKS00004384) were evaluated in this analysis. Within the registry, adverse events were documented according to CTCAE v4.0 before, during, and after PT. The overall survival (OS), local control (LC) and higher-grade toxicity (≥ grade 3) were analyzed. Results A total of 19 patients (13 males, 6 females) with a median age of 23 years (range, 18.5- 39 years) were included in this study. Histopathology type were classic, desmoplastic /extensive nodularity or anaplastic MB in 52.6%, 26.3% and 21.1 % of patients, respectively. Complete tumor resection was performed in 57.8 % of patients. 68.4 % of patients had local disease without any metastases. Median total CSI dose was 35.2 Gy(RBE) (range, 23.4-40 Gy) with a median single dose of 1.6 Gy(RBE) (range, 1-1.8 Gy). All patients received either boost to the posterior fossa (57.9%) or to the tumor bed only (42.1%). The median total tumor dose was 18.8 Gy(RBE) (range, 54-68 Gy). Concomitant chemotherapy was given to 63.1% of patients. The median follow-up time after first diagnosis was 28.2 months (range, 8-56 months). No higher-grade acute or late adverse event was documented so far. One patient developed local disease progression. Another patient deceased due to an acute pulmonary embolism during maintenance chemotherapy without evidence of disease. The 3-year LC and OS rate were 89 % and 94 %, respectively. Conclusion Early results display good feasibility and high tumor control of PT in adult patient with MB. Results will need to be confirmed in larger cohort with longer follow-up time.

IntroductionWith an increase in neoadjuvant therapy recommendations for most early-stage breast cancer patients due to the COVID-19 pandemic, it has become increasingly imperative to ensure that molecular diagnostic assays provide reliable results from preoperative core needle biopsies. Therefore, the objective of this study was to determine the concordance of MammaPrint results (70-gene signature) and BluePrint results (80-gene signature) between core needle biopsies (CNB) and surgical resection (SR) specimens using prospectively collected matched tissues from patients enrolled in the FLEX trial (NCT03053193).MethodsWe analyzed 113 matched CNB and SR tumor specimens from women with early-stage breast cancer enrolled in the FLEX trial. Each patient enrolled in the trial receives a MammaPrint recurrence risk classification test with or without BluePrint molecular subtyping. Concordance of MammaPrint is reported using overall percentage agreement, positive predictive value (PPV, High Risk), negative predictive value (NPV, Low Risk), and Cohen’s kappa coefficient. Additionally, correlations between sample types are reported using Pearson correlation coefficient.ResultsWe found good concordance for MammaPrint results between CNB and SR tumor samples (90.3%, κ = 0.803), with a 95.1% NPV and 84.6% PPV. There was also a strong correlation of MammaPrint indices between CNB and SR specimens (r = 0.94). In addition to our primary objective, we determined the concordance of BluePrint subtyping in the matched tumor samples, and found excellent concordance (98.2%) and strong correlation of BluePrint scores within each subtype.ConclusionCNB samples demonstrated overall high concordance with paired SR samples for MammaPrint risk classification, ensuring that physicians are provided with accurate prognostic information for therapy decisions based on testing of core biopsy tissue. Further, BluePrint molecular subtyping also had good concordance between the sample types, outperforming concordance rates based on traditional IHC based classification. Overall, with an increase in neoadjuvant therapy, physicans and patients can be assured that MammaPrint and BluePrint provide reliable results that guide timely and appropriate therapies using preoperative CNB specimens.

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., info:eu-repo/semantics/published

In recent decades, major advances in the treatment of malignant diseases have significantly improved long-term survival. However, this has increased the spectrum of side effects of these treatment methods, particularly for the cardiovascular system. Cardiotoxicity can be acute and chronic, including hypertension, heart failure, arrhythmias, acute myocardial infarction, venous thromboembolism, stroke, and valvular heart disease. While the occurrence of cardiotoxicity is known for many older cancer therapies, it needs to be largely evaluated for newer forms of therapy. Diagnosing possible cardiotoxic side effects is essential for optimal treatment, but remains a challenge. Troponin and the natriuretic peptides play an essential role as cardiac biomarkers in the diagnosis of conventional heart diseases. However, they also appear to play an important role in the detection of cardiotoxicity, as well as in the treatment of cardio-oncology patients. Elevated troponin or B-type natriuretic peptide (BNP)/N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels are associated with increased overall mortality and were associated with the development of heart failure in selected cohorts. Troponin can also be used to identify myocarditis associated with immune checkpoint inhibitor therapy. This overview summarizes the current knowledge about biomarkers for the detection of cardiotoxicity due to tumor therapy. Possible clinical recommendations for the detection of cardiotoxic effects using biomarkers are also outlined.In den letzten Jahrzehnten konnten wesentliche Fortschritte in der Therapie maligner Erkrankungen das langfristige Überleben deutlich verbessern. Hierdurch wird allerdings das Nebenwirkungsspektrum der therapeutischen Verfahren insbesondere für das Herz-Kreislauf-System relevant. Kardiotoxizität kann sich akut und chronisch u. a. durch Bluthochdruck, Herzinsuffizienz, Arrhythmien, Herzinfarkte, venöse Thrombembolien, Schlaganfälle und Herzklappenerkrankungen bemerkbar machen. Während das Auftreten von Kardiotoxizität für viele ältere Tumortherapeutika bekannt ist, muss dies für neuere Therapieformen noch weitgehend evaluiert werden. Die Diagnose möglicher kardiotoxischer Nebenwirkungen ist für eine optimale Behandlung unerlässlich, bleibt jedoch eine Herausforderung. Troponin und natriuretische Peptide als kardiale Biomarker spielen eine wichtige Rolle in der Diagnostik primärer Herzerkrankungen. Sie scheinen aber auch bei der Erkennung von Kardiotoxizität und im Rahmen der Therapie onkokardiologischer Patienten einen wesentlichen Stellenwert zu besitzen. Erhöhte Spiegel von Troponin oder natriuretischem Peptid vom B‑Typ (BNP) bzw. N‑terminalem pro-natriuretischem Peptid vom B‑Typ (NT-proBNP) sind hierbei mit einer erhöhten Gesamtmortalität verbunden und waren in ausgewählten Kollektiven mit der Entwicklung einer Herzinsuffizienz assoziiert. Darüber hinaus kann Troponin zur Identifizierung einer Myokarditis im Rahmen einer Immuncheckpointinhibitortherapie verwendet werden. Diese Übersichtsarbeit soll das aktuelle Wissen über Biomarker bei tumortherapiebedingter Kardiotoxizität zusammenfassen. Wir beschreiben hierbei auch mögliche klinische Empfehlungen für den Nachweis und die Behandlung kardiotoxischer Wirkungen unter Verwendung von Biomarkern.

Background Many countries restrict patient material exchange to central diagnostic laboratories abroad, limiting access to assays like MammaPrint® (MP) and BluePrint® (BP). Both assays are microarray-based, with MP being prognostic for distant recurrence and BP for molecular subtyping of breast cancer (Luminal-, HER2-, and Basal-type). To increase accessibility, decentralization is required with Next Generation Sequencing (NGS) being the preferred testing platform given that most diagnostic laboratories have the technology in place. The aim of this beta testing study is to validate a previously developed and centrally validated MP and BP NGS kit for RNA samples in two large tertiary academic hospitals in Europe. Patients and Methods Patients with early breast cancer diagnosed at the Multidisciplinary Breast Center at University Hospitals Leuven and Curie Institute Paris were prospectively included between September 2017 and January 2018. Patients with bilateral breast cancer or presenting with more than 3 positive lymph nodes were excluded. Only patients with invasive ductal and invasive lobular carcinoma were included. Twenty tissue sections were cut from formalin-fixed, paraffin-embedded (FFPE) blocks; 10 tissue sections were analyzed at the local site using the MP and BP NGS kit, and 10 tissue sections were analyzed at Agendia using the same kit and procedure, as well as with the golden standard method (gene expression microarrays). Targeted RNA sequencing of the 70 MP and 80 BP signature genes was performed on Illumina MiSeq instruments. The raw NGS data generated at the local test sites was sent through a secure file transfer protocol server to Agendia for interpretation and comparison with microarray and NGS performed in the Agendia laboratories. We aimed for a minimum concordance rate between MP and BP outcome of 90% between each local site and Agendia's centralized site. Results In this study, 116 early breast cancer patients were included (73 from University Hospitals Leuven and 43 from Curie Institute). Out of these patients, 52% were MP Low Risk and 48% MP High Risk according to microarray. The patients had a BP luminal, HER2 or basal subtype in respectively 83%, 9% and 8%. Concordance between MP microarray obtained from Agendia and MP NGS obtained from the local sites was 91.4%. Concordance between MP High and Low Risk classification between NGS Leuven versus NGS Agendia was 92.1% and between NGS Curie versus NGS Agendia 95.3%. For BP subtype outcomes, the results from microarray versus NGS for all patients combined from both local sites gave a 98.3% concordance and NGS Agendia versus NGS from each local site gave a 100% concordance. Conclusion The MP and BP NGS kit was successfully validated in a decentralized setting, showing high concordance between results obtained at three different sites. There was a clear benefit of having well-trained NGS experienced diagnostic technical teams. The MP and BP NGS kit the first FFPE targeted RNA sequencing based multigene signature for breast cancer care, will provide a high and equal standard of MP and BP gene expression testing for breast cancer in a decentralized setting. Citation Format: Slembrouck L, Laurent C, Delahaye LJ, Mittempergher L, Vanden Bempt I, Vander Borght S, Darrigues L, Vliegen L, Sintubin P, Raynal V, Bohec M, Reyes C, Rapinat A, Helsmoortel C, Jongen L, Hoste G, Neven P, Wildiers H, Smeets A, Nevelsteen I, Punie K, Van Nieuwenhuysen E, Han S, Salomon AV, Faron EL, Cynober T, Witteveen AT, Neijenhuis S, Glas AM, Reyal F, Floris G. Decentralized beta testing of MammaPrint and BluePrint NGS kit at University Hospitals Leuven and Curie Institute Paris [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-25.

BACKGROUND TTFields therapy is applied at 200 kHz by arrays that are placed at the patients’ scalp. In the phase 3 EF-14 trial, survival rates were significantly improved when adding tumor-treating fields (TTFields) to adjuvant temozolomide-based chemotherapy in patients with newly diagnosed glioblastoma (nGBM). In preclinical studies, the combination of TTFields and radiotherapy synergistically impaired proliferation and growth of glioblastoma cells. Here, we present the PriCoTTF trial, which is enrolling nGBM patients and will assess the safety and efficacy of TTFields initiated prior and concomitant to radiochemotherapy. MATERIAL AND METHODS Following surgery and complete wound-healing, TTFields therapy is initiated in adult nGBM patients. TTFields therapy continues throughout radiochemotherapy and adjuvant chemotherapy for a total of approximately 9 months. During radiotherapy, the arrays - through which TTFields is delivered - remain on the patients’ scalp. Totally, thirty-three patients are planned to be enrolled in two treatment arms. In arm A, 20 patients receive normo-fractionated radiotherapy, whereas in the elderly arm, arm B, 13 patients receive hypo-fractionated radiotherapy. Concomitant and adjuvant chemotherapy follow institutional standards and interdisciplinary tumor conference recommendations. RESULTS The primary endpoint of this trial is safety and tolerance that will be gauged by a set of pre-specified treatment-limiting toxicities. Secondary endpoints include the frequency of adverse events, progression-free survival (PFS), and overall survival (OS). The trial is currently enrolling patients at four sites in Germany. At the time of abstract submission, 9 patients enrolled in Arm B. Patient recruitment for arm A has been completed with 20 patients enrolled. We will present initial practical experiences as well as preliminary safety and tolerance data. CONCLUSION There is a biological rationale for combining TTFields and radiotherapy to further improve survival of GBM patients. In the presented phase I/II trial, the safety and efficacy of TTFields initiated prior and concomitant to RT in nGBM will be assessed. In addition, initial efficacy data (phase II) may serve as a rationale for a putative randomized phase III trial.

Do popular films activate authoritarianism? We theorize that, because of the willing suspension of disbelief, films encourage social learning, which primes viewers to respond to messages activating latent personality traits such as authoritarianism. This activation then affects citizens’ political attitudes. To test our theory, we use a 1 × 3 posttest experimental design where treatment groups watch feature-length films. As treatments, subjects watch 300 and V for Vendetta, and the control film is 21 Jump Street. Consistent with our hypotheses, we find that 300 activates authoritarianism while V for Vendetta activates antiauthoritarianism. As expected, 21 Jump Street has no effect. In addition, we show that the activation of authoritarianism produces significant differences in attitudes on U.S. primacy, rights of protestors, immigration, and military service. This research demonstrates how the causal mechanism between entertainment media and latent personality activation affects political attitudes, which advances both the American political behavior and media politics literature.

Background: The MINDACT trial showed excellent 5-year distant metastasis-free survival (DMFS) of 94·7% (95%CI 92·5-96·2) in clinical high (C-High)/genomic low (G-Low) risk patients who did not receive chemotherapy. Long-term follow-up is presented. Methods: 6693 patients were enrolled 2007 to 2011. We reassessed DMFS rate at 5 years in C-High/G-Low patients not receiving chemotherapy (n=644) (primary analysis), updated DMFS and overall survival in C-High/G-Low patients receiving chemotherapy or not (n=749 and 748, respectively) (secondary analysis), and examined a potential age effect ( 50y) for women with HR+/HER2- disease. Findings: At a median follow-up of 8·7 years, the updated 5-year DMFS rate for C-High/G-Low patients receiving no chemotherapy is 95·1% (95%CI 93·1-96·6), above the predefined non-inferiority boundary of 92%, proving MINDACT as a positive de-escalation trial.The 5-year and 8-year outcome of C-High/G-Low patients show a respective 0·9% (SE ±1·1) 2·6% (SE ±1·6) difference in DMFS for chemotherapy versus no chemotherapy (HR 0·66; 95%CI 0·48-0·92), without differences in overall survival (95·7% vs 94·3%).The same comparisons confined to HR+/HER2- disease (91% of patients) generate different gain estimates from chemotherapy administration for DMFS according to age: 5% (SE ±2·8%) in women ≤50 years versus 0·2% (SE ±2·3%) in women > 50 years. Interpretation: The clinical utility of a low risk 70-gene signature for foregoing adjuvant chemotherapy in the presence of a high clinical risk (and up to 3 positive nodes) remains proven. In C-high/G-low patients > 50 years chemotherapy did not improve outcome across the whole follow-up trajectory. At longer follow-up in younger women, while underpowered, a clinically relevant benefit of about 5% was observed, possibly due to chemotherapy-induced ovarian function suppression, and should be part of informed, shared decision-making. Trial Registration: ClinicalTrials.gov number, NTC00433589; EudraCT number, 2005-002625-31. Funding Statement: Funded by the European Commission Sixth Framework Programme and other grants. Declaration of Interests: None to declare. Ethics Approval Statement: All patients gave written informed consent. The ethics committees of all participating sites approved the study, which involved collaboration of seven member groups under the Breast International Group umbrella.

In den letzten Jahrzehnten konnten wesentliche Fortschritte in der Therapie maligner Erkrankungen das langfristige Uberleben deutlich verbessern. Hierdurch wird allerdings das Nebenwirkungsspektrum der therapeutischen Verfahren insbesondere fur das Herz-Kreislauf-System relevant. Kardiotoxizitat kann sich akut und chronisch u. a. durch Bluthochdruck, Herzinsuffizienz, Arrhythmien, Herzinfarkte, venose Thrombembolien, Schlaganfalle und Herzklappenerkrankungen bemerkbar machen. Wahrend das Auftreten von Kardiotoxizitat fur viele altere Tumortherapeutika bekannt ist, muss dies fur neuere Therapieformen noch weitgehend evaluiert werden. Die Diagnose moglicher kardiotoxischer Nebenwirkungen ist fur eine optimale Behandlung unerlasslich, bleibt jedoch eine Herausforderung. Troponin und natriuretische Peptide als kardiale Biomarker spielen eine wichtige Rolle in der Diagnostik primarer Herzerkrankungen. Sie scheinen aber auch bei der Erkennung von Kardiotoxizitat und im Rahmen der Therapie onkokardiologischer Patienten einen wesentlichen Stellenwert zu besitzen. Erhohte Spiegel von Troponin oder natriuretischem Peptid vom B‑Typ (BNP) bzw. N‑terminalem pro-natriuretischem Peptid vom B‑Typ (NT-proBNP) sind hierbei mit einer erhohten Gesamtmortalitat verbunden und waren in ausgewahlten Kollektiven mit der Entwicklung einer Herzinsuffizienz assoziiert. Daruber hinaus kann Troponin zur Identifizierung einer Myokarditis im Rahmen einer Immuncheckpointinhibitortherapie verwendet werden. Diese Ubersichtsarbeit soll das aktuelle Wissen uber Biomarker bei tumortherapiebedingter Kardiotoxizitat zusammenfassen. Wir beschreiben hierbei auch mogliche klinische Empfehlungen fur den Nachweis und die Behandlung kardiotoxischer Wirkungen unter Verwendung von Biomarkern.

500 Background: Gene signatures have proven successful in identifying patients with a low risk of distant recurrence who could forego chemotherapy (CT) and are currently included in international treatment guidelines for breast cancer. For the 70-gene signature (MammaPrint) an additional threshold was established within the low risk category to identify patients with an ultralow risk of distant recurrence. In independent cohorts, these patients had excellent breast cancer specific survival at 15 years, suggesting that ultralow risk cancers represent indolent disease (Esserman, JAMA Oncol 2017, Delahaye, BC Res Treat 2017). Here we evaluate survival of patients with an ultralow risk 70-gene signature who participated in the randomized phase 3 MINDACT trial (Piccart, Lancet Oncol 2021). Methods: Of the 6,693 patients enrolled in the MINDACT trial (EORTC 10041/BIG 3-04) between 2007-2011, profiling revealed an ultralow risk 70-gene signature in 1,000 patients (15%). We assessed 5- and 8-year distant metastasis free interval (DMFI) and breast cancer specific survival (BCSS) in patients stratified by 70-gene signature result (high, low, ultralow), and within the ultralow risk group stratified by clinical risk. For these exploratory analyses, we used Kaplan-Meier estimates for time to event endpoints and Cox-regression models to calculate hazard ratio’s (HR). Results: Median follow-up was 8.7 years. Among the ultralow risk patients (n = 1,000), 67% were ≥50 years, 81% had tumors < 2cm, 80% were lymph node negative, 96% had grade 1 or 2 tumors and 99% were ER-positive. Systemic therapy was received by 83% of patients (69% endocrine therapy (ET), 14% ET + CT) and 16% received no adjuvant systemic treatment (AST). Survival estimates for all endpoints are shown in the table; 8-year DMFI was 97.0% (95% CI 95.8-98.1) for ultralow risk. The 8-year DMFI in ultralow risk patients who received no AST or ET only was 97.8% (95% CI 95.3-100) and 97.4% (95% CI 96.1-98.7), respectively. The HR for DMFI was 0.66 (95% CI 0.46-0.95) for ultralow vs low risk, after adjusting for tumor and treatment characteristics (preliminary results). Conclusions: In this prospective study, patients with an ultralow risk 70-gene signature have an excellent prognosis with 8-year BCSS above 99% regardless of clinical risk status, and with an 8-year DMFI of 95-98%.[Table: see text]

Background: The PARP inhibitor veliparib in combination with carboplatin (VC) was one of the experimental regimens evaluated in the phase 2 neoadjuvant I-SPY 2 standing trial for high risk breast cancer patients. VC graduated in the triple negative (TN) signature. However, not all TN patients achieved pathologic complete response (pCR) and some HR+HER2- patients responded. The I-SPY 2 biomarker component provides a platform for rigorous evaluation of mechanism-of-action-based markers in the context of established biomarkers (HR, HER2, MammaPrint) within the trial. Here, we report results from 5 investigator-submitted biomarker proposals and the MammaPrint High1/High 2 (MP1/2) classification as specific predictors of VC response. Methods: Data from 116 HER2- patients (VC: 72 and concurrent controls: 44) were available. BRCA1/2 germline mutation was assessed by Myriad Genetics. 3 expression signatures relating to DNA damage repair deficiency (PARPi-7, BRCAness and CIN70) and MP1/2 classification were evaluated on Agilent 44K arrays. PARP1 levels were measured using reverse phase protein arrays. We used logistic modeling to assess biomarker performance. A biomarker is considered a specific predictor of VC response if it associates with response in the V/C arm but not the control arm, and if the biomarker x treatment interaction is significant (likelihood ratio test, p Results: BRCA1/2 germline mutation status associates with VC response, but its low prevalence in the control arm precludes further evaluation. Of the biomarkers evaluated, three (PARPi-7, BRCAness, and MP1/2) associate with response in the VC arm but not the control arm, and have biomarker x treatment interactions with p < 0.05 that retains significance upon adjusting for HR status. These signatures are only moderately correlated. When we combined the PARPi-7 and MP1/2 classifications using a simple voting scheme, the 40% of TN patients who are PARPi7-high and MP2 have an estimated pCR rate of 79% in the VC arm. In contrast, TN patients negative for at least one of these signatures (PARPi7-low and/or MP1) only have an estimated pCR rate of 35%. Only 9% of HR+/HER2- patients are PARPi7-high and MP2; but these patients also appear more responsive to VC with estimated pCR rates of 49%, compared to 13% in 'biomarker-negative' HR+HER2- patients. Conclusion: If verified in a larger trial, PARPi7, BRCAness and MP1/2 signatures may help refine predictions of VC response, thereby improving patient care. Evaluation of the combined signature for patients treated with platinum-based chemotherapy is ongoing. Citation Format: Wolf DM, Yau C, Sanil A, Glas A, Petricoin C, Wulfkuhle J, Brown-Swigart L, Hirst G, I-SPY 2 TRIAL Investigators, Buxton M, DeMichele A, Hylton N, Symmans F, Yee D, Paoloni M, Esserman L, Berry D, Rugo H, Olapade O, van 't Veer L. DNA repair deficiency biomarkers and MammaPrint high1/(ultra)high2 risk as predictors of veliparib/carboplatin response: Results from the neoadjuvant I-SPY 2 trial for high risk breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S2-06.

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 receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy. Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy. (Funded by the European Commission Sixth Framework Program and others; ClinicalTrials.gov number, NCT00433589; EudraCT number, 2005-002625-31.).

MammaPrint is an FDA-cleared microarray-based test that uses expression levels of the 70 MammaPrint genes to assess distant recurrence risk in early-stage breast cancer. The prospective RASTER study proved that MammaPrint Low Risk patients can safely forgo chemotherapy, which is further subject of the prospective randomized MINDACT trial. While MammaPrint diagnostic results are obtained from mini-arrays, clinical trials may be performed on whole-genome arrays. Here we demonstrate the equivalence and reproducibility of the MammaPrint test. MammaPrint indices were collected for breast cancer samples: (i) on both customized certified array types (n = 1,897 sample pairs), (ii) with matched fresh and FFPE tissues (n = 552 sample pairs), iii) for control samples replicated over a period of 10 years (n = 11,333), and iv) repeated measurements (n = 280). The array type indicated a near perfect Pearson correlation of 0.99 (95 % CI: 0.989–0.991). Paired fresh and FFPE samples showed an excellent Pearson correlation of 0.93 (95 % CI 0.92–0.94), in spite of the variability introduced by intratumoral tissue heterogeneity. Control samples showed high consistency over 10 year's time (overall reproducibility of 97.4 %). Precision and repeatability are overall 98.2 and 98.3 %, respectively. Results confirm that the combination of the near perfect correlation between array types, excellent equivalence between tissue types, and a very high stability, precision, and repeatability demonstrate that results from clinical trials (such as MINDACT and I-SPY 2) are equivalent to current MammaPrint FFPE and fresh diagnostics, and can be used interchangeably. Electronic supplementary material The online version of this article (doi:10.1007/s10549-016-3764-5) contains supplementary material, which is available to authorized users.

Background: The rise of whole slide imaging systems has enabled pathologists to remotely view cases in high resolution to diagnose cancer, and efficiently archive images . The advent of machine learning techniques and their application in digital pathology have facilitated the identification of histological patterns for effective diagnosis of disease. Deep learning-based solutions have been developed to detect and recognize cancer types, and automatically grade and stage tumors through evaluation of pathological features and patterns. However, no image-based solutions have been able to replicate a multivariate test, such as a risk -of recurrence assay for early stage breast cancer. Traditionally, subtle differences in gene expression have been measured by microarray or NGS, however these changes may also be recognized phenotypically from hematoxylin and eosin stained (H&E) slides by digital biomarkers developed using novel machine learning techniques. The large repository of images with MammaPrint and BluePrint results may enable us to develop digital MammaPrint and digital BluePrint biomarkers that predict the risk of distant recurrences and the molecular subtypes of a tumor sample using only H&E stained digitized tumor slides. Methods: Using over70,000 H&E images of early stage breast cancer patients in combination with machine learning techniques, digital versions of MammaPrint and BluePrint were developed. In total 20,000 images were used for feasibility and algorithm optimization, another 50,000 images were used for further finetuning. MammaPrint indices and BluePrint scores and categorical results were used to train the system. After the algorithms were optimized, they were locked and validated in an independent set of 5000 H&E stained images. The MammaPrint and BluePrint predictions were compared to the original MammaPrint and BluePrint results obtained from the microarray assay. The finalized and locked algorithms were further validated for precision and reproducibility in a large data set of xx Images and processed multiple times. Multicenter clinical validation was performed in H&E stained images of multiple series with long term follow up (tbd), totaling ##k images. In this ##K cohort of patients, #% were HR+/HER2-, #% were clinically HER2+ and x% were triple negative. Results: Using an independent dataset of 5000 samples, we compared the MammaPrint and BluePrint predictions obtained from the H&E slides to the traditional versions of MammaPrint and BluePrint based on a microarray. The binary performance of the digital MammaPrint had a concordance of xx% (with an AUC of xx%),%NPA and %PPA when compared to the traditional MammaPrint high-low classification. For digital BluePrint, the system had a concordance of xx% and a classification accuracy of xx%. The analytical performance showed a precision and reproducibility of xx% In a multicenter clinical validation the DRFI was xx% in dMP low risk and yy% in dMP high risk groups. The xxx dataset the performance was similar to the microarray and better than compared to clinical parameters. Analyses will be available by the Placeholder Abstract deadline. Conclusions: The combination of machine learning and digital pathology has enabled development of rapid and highly accurate in silico versions of MammaPrint and BluePrint. Implementation of digital H&E based risk of recurrence and molecular subtyping could enable preservation of valuable diagnostic tissue, faster turnaround time for test results, and a more cost effective approach to treatment planning tools, especially in countries that do not allow send out of human tissue and this adoption of risk scoring is low. Final conclusions tbd Citation Format: Annuska M Glas, Jorge S Reis-Filho, Diederik Wehkamp, Belma Dodgas, Leonie Delahaye, Ran Godrich, Jeroen Mollink, Adam Casson, Anke Witteveen, Julian Viret, Donghun Lee, Matthew Lee, Hugo Horlings, Leo Grady, Thomas Fuchs, William Audeh, Christopher Kanan, Laura J van't Veer. Digital MammaPrint and BluePrint using machine learning and whole slide imaging [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD6-02.

Hepatitis C virus infection is causing chronic liver disease, cirrhosis, and hepatocellular carcinoma. By combining direct-acting antivirals (DAAs), high sustained virologic response rates (SVRs) can be achieved. Resistance-associated substitutions (RASs) are commonly observed after DAA failure, and especially nonstructural protein 5A (NS5A) RASs may impact retreatment options.1-3 Data on retreatment of DAA failure patients using first-generation DAAs are limited.4-7 Recently, a second-generation protease- and NS5A-inhibitor plus sofosbuvir (voxilaprevir/velpatasvir/sofosbuvir [VOX/VEL/SOF]) was approved for retreatment after DAA failure.8 However, this and other second-generation regimens are not available in many resource-limited countries or are not reimbursed by regular insurance, and recommendations regarding the selection of retreatment regimens using first-generation DAAs are very important. This study aimed to analyze patients who were re-treated with first-generation DAAs after failure of a DAA combination therapy.

To better understand the expression pattern of programmed death-ligand 1 (PD-L1) expression in different breast cancer types, we characterized PD-L1 expression in tumor and tumor-infiltrating immune cells, in relation to mutation rate, BRCA1-like status and survival. We analyzed 410 primary treatment-naive breast tumors comprising 162 estrogen receptor-positive (ER+) and HER2−, 101 HER2+ and 147 triple-negative (TN) cancers. Pathologists quantified tumor-infiltrating lymphocytes (TILs) and PD-L1 expression in tumor cells and TILs using whole slides and tissue microarray. Mutation rate was assessed by DNA sequencing, BRCA1-like status using multiplex ligation-dependent probe amplification, and immune landscape by multiplex image analyses of CD4, CD68, CD8, FOXP3, cytokeratin, and PD-L1. Half of PD-L1 scores evaluated by tissue microarray were false negatives compared to whole slide evaluations. We observed at least 1% of PD-L1-positive (PD-L1+) cells in 53.1% of ER+HER2−, 73.3% of HER2+, and 84.4% of TN tumors. PD-L1 expression was higher in ductal compared to lobular carcinomas, also within ER+HER2− tumors (p = 0.04). High PD-L1+ TILs score (> 50%) was independently associated with better outcome in TN tumors (HR = 0.27; 95%CI = 0.10–0.69). Within TN tumors, PD-L1 and TIL scores showed a modest but significant positive association with the number of silent mutations, but no association with BRCA1-like status. Multiplex image analyses indicated that PD-L1 is expressed on multiple immune cells (CD68+ macrophages, CD4+, FOXP3+, and CD8+ T cells) in the breast tumor microenvironment, independent of the PD-L1 status of the tumor cells. We found no evidence that levels of PD-L1+ TILs in TN breast cancer are driven by high mutation rate or BRCA1-like status.

BACKGROUND: Tumor Treating Fields (TTFields) is approved for the treatment of newly diagnosed and recurrent glioblastoma. The efficacy and safety of TTFields in newly diagnosed GBM was previously demonstrated in the EF-14 phase 3 trial (n=695). Optune + temozolomide significantly improved survival outcomes compared to temozolomide alone (median OS: 20.9 vs 16.0 months, p

OBJECTIVE: Tumor Treating Fields (TTFields) in combination with adjuvant temozolomide (TMZ) as therapy for newly diagnosed glioblastoma (GBM) patients showed significantly increased progression-free survival (PFS), overall survival (OS) and long-term survival rates in the EF-14 phase III trial. In the trial, patients were randomized after completion of radiochemotherapy, and TTFields therapy was initiated in combination with adjuvant chemotherapy. In preclinical settings, TTFields synergistically enhanced efficacy of radiotherapy in GBM, hypothetically by inhibiting DNA damage repair in irradiated cells. The presented phase I/II trial will evaluate safety and feasibilty of TTFields initiated prior and concomitant to combined radiochemotherapy in newly diagnosed GBM. METHODS: In arm A of this prospective multi-center trial, seven eligible patients with newly diagnosed GBM will be enrolled initially. Provided that treatment is tolerated well, enrollment will continue for up to 20 patients. Patients will be subjected to TTFields after complete wound-healing following surgery. TTFields treatment will be continued throughout radiochemotherapy and adjuvant chemotherapy for six cycles. In total, patients will receive TTFields therapy for approximately nine months. In arm B, elderly patients with a reduced KPS (50 or 60) will be treated with postsurgical TTFields therapy followed by TTFields therapy concomitant to hypofractionated radiotherapy with 40 Gy for three weeks. In line with arm A, TTFields therapy will continue beyond radiotherapy throughout adjuvant chemotherapy for a total of nine months. In the first stage, six patients will be accrued. Under the provision of an acceptable safety profile, seven additional patients will be accrued for a total of thirteen patients. RESULTS: The primary endpoint of the trial is safety and tolerance based on the frequency of a set of predefined treatment-limiting toxicities (TLTs). Secondary endpoints consist in particular of PFS, OS, radiologic response and frequency of adverse events. First experiences will be presented. CONCLUSION: The objective of this trial is to demonstrate that the administration of TTFields therapy prior and concomitant to radiotherapy and adjuvant chemotherapy is feasible and safe. Moreover, first data obtained on efficacy may serve as a basis for a potential randomized phase III trial.

The analytical performance of multigene signatures depends on many parameters, including precision, repeatability, reproducibility and intratumor heterogeneity. Indicators such as sensitivity, specificity, positive predictive value and negative predictive value are typically used to define the clinical performance of a diagnostic test.Here we study these performance characteristics of the MammaPrintThe clinical and analytical performance characteristics show that MammaPrint is a robust, reproducible, precise test, with a maximum variation of 5% in multiple samplings of the same tissue.MammaPrint is a reliable indicator of distant metastasis in early-stage breast cancer patients of all ages and is well suited for personalized medical care.

Are poor whites less likely to vote correctly when they vote for Republican presidential candidates? The rationality of poor white voters is perennially debated in American politics. To date, scholars and journalists have weighed in on this debate without using any objective measure of voter preferences, nor has anyone tested the extent to which those preferences match voters’ behavior in the ballot booth. To adjudicate this debate, we use Lau and Redlawsk's voting correctly data from 1972 to 2008 to test the popular hypothesis that poor white voters, specifically, vote against their interests by voting for Republican presidential candidates. A series of probit estimations demonstrate that, while poor whites are less likely to vote correctly than those who are not poor whites, there is no relationship between poor whites and voting correctly for Republican or Democratic candidates independently. This suggests that the longstanding debate about poor white voting for Republican candidates is much ado about little and obscures the larger debate about all voters being able to vote in line with their preferences more generally.

The Sentencing Reform Act of 1984 created the United States Sentencing Commission, which had the responsibility to promulgate sentencing guidelines. These guidelines created a range of determinate sentences for all categories of federal offenses and were binding on all federal judges. In a curious aftermath of legislation designed to toughen the response of courts to crime, scholars have noticed that federal judges’ conviction rates have fallen since the 1980s (Leipold 2004). This unexpected trend raises the possibility that the outcome of the Sentencing Act is opposite of what Congress intended. When faced with mandatory sentencing guidelines, judges sometimes try cases in which they believe the defendant to be guilty, but the legally mandated sentence is too harsh given the circumstances. In these cases, judges may choose to acquit. Since these defendants would have been convicted in the absence of guidelines, aggregate conviction rates should be lower when guidelines are in effect than otherwise. We te...

Background: Patients with BRCA1-like tumors correlate with improved response to DNA double-strand break-inducing therapy. A gene expression-based classifier was developed to distinguish between BRCA1-like and non-BRCA1-like tumors. We hypothesized that these tumors may also be more sensitive to PARP inhibitors than standard treatments.Methods: A diagnostic gene expression signature (BRCA1ness) was developed using a centroid model with 128 triple-negative breast cancer samples from the EU FP7 RATHER project. This BRCA1ness signature was then tested in HER2-negative patients (n = 116) from the I-SPY 2 TRIAL who received an oral PARP inhibitor veliparib in combination with carboplatin (V-C), or standard chemotherapy alone. We assessed the association between BRCA1ness and pathologic complete response in the V-C and control arms alone using Fisher's exact test, and the relative performance between arms (biomarker × treatment interaction, likelihood ratio p Results: We developed a gene expression signature to identify BRCA1-like status. In the I-SPY 2 neoadjuvant setting the BRCA1ness signature associated significantly with response to V-C (p = 0.03), but not in the control arm (p = 0.45). We identified a significant interaction between BRCA1ness and V-C (p = 0.023) after correcting for HR.Conclusions: A genomic-based BRCA1-like signature was successfully translated to an expression-based signature (BRC1Aness). In the I-SPY 2 neoadjuvant setting, we determined that the BRCA1ness signature is capable of predicting benefit of V-C added to standard chemotherapy compared to standard chemotherapy alone.Trial registration: I-SPY 2 TRIAL beginning December 31, 2009: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer (I-SPY 2), NCT01042379.

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. 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. 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. 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.