The Drug Rediscovery protocol facilitates the expanded use of existing anticancer drugs.

The large-scale genetic profiling of tumours can identify potentially actionable molecular variants for which approved anticancer drugs are available1-3. However, when patients with such variants are treated with drugs outside of their approved label, successes and failures of targeted therapy are not systematically collected or shared. We therefore initiated the Drug Rediscovery protocol, an adaptive, precision-oncology trial that aims to identify signals of activity in cohorts of patients, with defined tumour types and molecular variants, who are being treated with anticancer drugs outside of their approved label. To be eligible for the trial, patients have to have exhausted or declined standard therapies, and have malignancies with potentially actionable variants for which no approved anticancer drugs are available. Here we show an overall rate of clinical benefit-defined as complete or partial response, or as stable disease beyond 16 weeks-of 34% in 215 treated patients, comprising 136 patients who received targeted therapies and 79 patients who received immunotherapy. The overall median duration of clinical benefit was 9 months (95% confidence interval of 8-11 months), including 26 patients who were experiencing ongoing clinical benefit at data cut-off. The potential of the Drug Rediscovery protocol is illustrated by the identification of a successful cohort of patients with microsatellite instable tumours who received nivolumab (clinical benefit rate of 63%), and a cohort of patients with colorectal cancer with relatively low mutational load who experienced only limited clinical benefit from immunotherapy. The Drug Rediscovery protocol facilitates the defined use of approved drugs beyond their labels in rare subgroups of cancer, identifies early signals of activity in these subgroups, accelerates the clinical translation of new insights into the use of anticancer drugs outside of their approved label, and creates a publicly available repository of knowledge for future decision-making.

Antibody-drug conjugates in lung and breast cancer: current evidence and future directions-a position statement from the ETOP IBCSG Partners Foundation.

Following the approval of the first antibody-drug conjugates (ADCs) in the early 2000s, development has increased dramatically, with 14 ADCs now approved and >100 in clinical development. In lung cancer, trastuzumab deruxtecan (T-DXd) is approved in human epidermal growth factor receptor 2 (HER2)-mutated, unresectable or metastatic non-small-cell lung cancer, with ADCs targeting HER3 (patritumab deruxtecan), trophoblast cell-surface antigen 2 [datopotamab deruxtecan and sacituzumab govitecan (SG)] and mesenchymal-epithelial transition factor (telisotuzumab vedotin) in late-stage clinical development. In breast cancer, several agents are already approved and widely used, including trastuzumab emtansine, T-DXd and SG, and multiple late-stage trials are ongoing. Thus, in the coming years, we are likely to see significant changes to treatment algorithms. As the number of available ADCs increases, biomarkers (of response and resistance) to better select patients are urgently needed. Biopsy sample collection at the time of treatment selection and incorporation of translational research into clinical trial designs are therefore critical. Biopsy samples taken peri- and post-ADC treatment combined with functional genomics screens could provide insights into response/resistance mechanisms as well as the impact of ADCs on tumour biology and the tumour microenvironment, which could improve understanding of the mechanisms underlying these complex molecules. Many ADCs are undergoing evaluation as combination therapy, but a high bar should be set to progress clinical evaluation of any ADC-based combination, particularly considering the high cost and potential toxicity implications. Efforts to optimise ADC dosing/duration, sequencing and the potential for ADC rechallenge are also important, especially considering sustainability aspects. The ETOP IBCSG Partners Foundation are driving strong collaborations in this field and promoting the generation/sharing of databases, repositories and registries to enable greater access to data. This will allow the most important research questions to be identified and prioritised, which will ultimately accelerate progress and help to improve patient outcomes.

Translational insights and overall survival in the U31402-A-U102 study of patritumab deruxtecan (HER3-DXd) in EGFR-mutated NSCLC.

BACKGROUND: Human epidermal growth factor receptor 3 (HER3) is broadly expressed in non-small-cell lung cancer (NSCLC) and is the target of patritumab deruxtecan (HER3-DXd), an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. U31402-A-U102 is an ongoing phase I study of HER3-DXd in patients with advanced NSCLC. Patients with epidermal growth factor receptor (EGFR)-mutated NSCLC that progressed after EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy (PBC) who received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks had a confirmed objective response rate (cORR) of 39%. We present median overall survival (OS) with extended follow-up in a larger population of patients with EGFR-mutated NSCLC and an exploratory analysis in those with acquired genomic alterations potentially associated with resistance to HER3-DXd. PATIENTS AND METHODS: Safety was assessed in patients with EGFR-mutated NSCLC previously treated with EGFR TKI who received HER3-DXd 5.6 mg/kg; efficacy was assessed in those who also had prior PBC. RESULTS: In the safety population (N = 102), median treatment duration was 5.5 (range 0.7-27.5) months. Grade ≥3 adverse events occurred in 76.5% of patients; the overall safety profile was consistent with previous reports. In 78/102 patients who had prior third-generation EGFR TKI and PBC, cORR by blinded independent central review (as per RECIST v1.1) was 41.0% [95% confidence interval (CI) 30.0% to 52.7%], median progression-free survival was 6.4 (95% CI 4.4-10.8) months, and median OS was 16.2 (95% CI 11.2-21.9) months. Patients had diverse mechanisms of EGFR TKI resistance at baseline. At tumor progression, acquired mutations in ERBB3 and TOP1 that might confer resistance to HER3-DXd were identified. CONCLUSIONS: In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy.

Development of a Patient-Reported Outcomes Measurement Information System (PROMIS®) short form for measuring physical function in geriatric rehabilitation patients.

PURPOSE: To develop and test the validity of a Patient-Reported Outcomes Measurement Information System (PROMIS®) short form for measuring physical function of geriatric rehabilitation patients. METHODS: Experts selected items from the Dutch-Flemish PROMIS v1.2 Physical Function (PROMIS-PF) item bank and proposed new items to develop the PROMIS-PF short form for geriatric rehabilitation (PROMIS-PF-GR). Patients evaluated its content validity. Structural validity was assessed by evaluating unidimensionality (confirmatory, exploratory, and bi-factor analyses [criterion: Omega H > 0.80 and ECV > 0.60]), local independence (criterion: residual correlation < 0.20) ,and monotonicity (criterion: Hi-coefficient ≥ 0.30). Measurement invariance was assessed by evaluating Differential Item Functioning (DIF) between geriatric rehabilitation patients and people from the general population using ordinal logistic regression. Internal consistency was assessed by calculating Cronbach's alpha (criterion: alpha ≥ 0.70). RESULTS: Experts selected 24 items from the PROMIS-PF item bank and proposed one new item which was not included in the short form. Patients considered the 24 items relevant and containing essential information. The PROMIS-PF-GR's psychometric properties were evaluated in 207 patients (mean age ± SD, 80.0 ± 8.3 year; 58% female). The 24 items were found to be sufficiently unidimensional (Omega H = 0.82, ECV = 0.70), locally independent (98.7% item pairs), and monotone (all ≥ 0.32). Five items were flagged for DIF, but their impact on the total score was negligible. Cronbach's alpha was 0.94. CONCLUSION: The PROMIS-PF-GR was developed from the PROMIS-PF and has good content validity, structural validity, measurement invariance, and internal consistency in Dutch geriatric rehabilitation patients. We recommend to confirm the content validity of the PROMIS-PF-GR in other countries.

Valproic acid promotes mitochondrial dysfunction in primary human hepatocytes in vitro; impact of C/EBPα-controlled gene expression.

Valproic acid (VPA) is a frequently prescribed anti-epileptic drug which is known to cause liver toxicity and steatosis through mitochondrial dysfunction. Nevertheless the mechanisms underlying these adverse effects are incompletely understood. In this study, we determined the effect of relatively short (3 h) or prolonged (72 h) exposure to VPA on mitochondrial function in primary human hepatocytes (PHHs). While 3 h VPA exposure did not affect oxygen consumption rates (OCRs) in PHHs, prolonged exposure (24-72 h) significantly reduced basal and maximal OCRs. Given that in particular prolonged VPA exposure is required to cause mitochondrial dysfunction, we investigated gene expression data after VPA exposure for 24, 48, 72 h and 72 h VPA followed by a 72 h washout period. We were able to reduce the comprehensive gene expression changes into a more comprehensible set of 18 TFs that were predicted to be persistently activated after 72 h of VPA exposure. Lentiviral knock-down of one of the candidate TFs, C/EBPα, partly rescued VPA-induced mitochondrial dysfunction. Furthermore, RNA-Seq analysis of shC/EBPα and shGFP control PHHs identified 24 genuine C/EBPα target genes that are regulated in response to prolonged VPA exposure in PHHs. Altogether this provides new insights on the involvement of C/EBPα in driving VPA-induced mitochondrial dysfunction in human liver cells. This hub gene, with its downstream regulators involved in this deregulation, thus represent potential new biomarkers for VPA-induced mitochondrial dysfunction.

How to make the best use of immunotherapy as first-line treatment of advanced/metastatic non-small-cell lung cancer.

Antibodies that target programmed death 1 (PD-1) or its ligand [programmed death ligand 1 (PD-L1)] have become a mainstay of first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC) without targetable genetic alterations. In this review, we summarize results from recent clinical trials that have evaluated the anti-PD-1 antibodies pembrolizumab and nivolumab and the anti-PD-L1 antibodies atezolizumab and durvalumab as first-line treatment as monotherapy and in combination with chemotherapy, other immunotherapies, and antiangiogenesis agents. We discuss factors that may influence treatment selection, including patient baseline clinical and demographic characteristics, tumor histology, and biomarkers such as PD-L1 expression and tumor mutation burden. While immunotherapy has become a central component of first-line treatment of most patients with advanced NSCLC, important questions remain about how treatment should be managed for individual patients.

Predicting response to cancer immunotherapy using noninvasive radiomic biomarkers.

INTRODUCTION: Immunotherapy is regarded as one of the major breakthroughs in cancer treatment. Despite its success, only a subset of patients responds-urging the quest for predictive biomarkers. We hypothesize that artificial intelligence (AI) algorithms can automatically quantify radiographic characteristics that are related to and may therefore act as noninvasive radiomic biomarkers for immunotherapy response. PATIENTS AND METHODS: In this study, we analyzed 1055 primary and metastatic lesions from 203 patients with advanced melanoma and non-small-cell lung cancer (NSCLC) undergoing anti-PD1 therapy. We carried out an AI-based characterization of each lesion on the pretreatment contrast-enhanced CT imaging data to develop and validate a noninvasive machine learning biomarker capable of distinguishing between immunotherapy responding and nonresponding. To define the biological basis of the radiographic biomarker, we carried out gene set enrichment analysis in an independent dataset of 262 NSCLC patients. RESULTS: The biomarker reached significant performance on NSCLC lesions (up to 0.83 AUC, P < 0.001) and borderline significant for melanoma lymph nodes (0.64 AUC, P = 0.05). Combining these lesion-wide predictions on a patient level, immunotherapy response could be predicted with an AUC of up to 0.76 for both cancer types (P < 0.001), resulting in a 1-year survival difference of 24% (P = 0.02). We found highly significant associations with pathways involved in mitosis, indicating a relationship between increased proliferative potential and preferential response to immunotherapy. CONCLUSIONS: These results indicate that radiographic characteristics of lesions on standard-of-care imaging may function as noninvasive biomarkers for response to immunotherapy, and may show utility for improved patient stratification in both neoadjuvant and palliative settings.

Baseline bio-accumulation concentrations and resulting oxidative stress in Synodontis zambezensis after an acute laboratory exposure to 4,4'-DDT.

The use of 1,1'-(2,2,2-Trichloro-1,1-ethanediyl)bis(4-chlorobenzene) (DDT) as a pesticide for the control of insects vectors responsible for the spread of many life threatening diseases was officially banned in 1972 by the United States Environmental Protection Agency (USEPA). It was banned throughout the world, in most developed countries, because of the toxic effects it causes in wildlife, including birds and fish. However, DDT is still used in approximately 43 African countries, including South Africa, to control the spread of malaria. The lipophilic nature of DDT and therefore its persistence in the environment makes it extremely important for laboratory based studies to be conducted in an effort to evaluate the accumulation potential and possible physiological effects of DDT in aquatic organisms under controlled conditions. The aim of this study was to establish baseline bioaccumulation concentrations within Synodontis zambezensis following an acute exposure to 4,4'-DDT. The three metabolites analysed were 4,4'-DDE, 4,4'-DDD and 4,4'-DDT. None of the 2,4'-isomers were analysed in this study since the acute exposure used a solution of 98.7% pure 4,4'-DDT (Sigma-Aldrich PESTANAL®, Analytical Standard, CAS-No 50-29-3, Batch number SZBE057XV) and not a mixture of 4,4'-DDT and 2,4'-DDT as found in technical grade DDT. Soxhlet extraction of tissue samples and liquid/liquid extraction of water samples followed by analysis through Gas-chromatography mass-spectrophotometry was completed. Mean 4,4'-DDE, 4,4'-DDD and 4,4'-DDT concentrations ranged from 15.34 ng/g to 45.34 ng/g, 28.16 ng/g to 63.25 ng/g and 28.64 ng/g to 96.21 ng/g respectively. All of the accumulated concentrations fell within environmentally relevant concentrations with no input through the food web. The accumulated concentrations of 4,4'-DDT and its three metabolites resulted in oxidative stress responses within the gills and the liver tissue of S. zambezensis. Significant differences (p ≤ .05) were observed between malondialdehyde (MDA) and reduced glutathione (GSH) within the liver and in superoxide dismutase (SOD), catalase (CAT) and reduced glutathione (GSH) in the gills.

Outcomes and costs of single-step hepatitis C testing in primary care, Birmingham, United Kingdom.

OBJECTIVES: In UK laboratories, the diagnostic algorithm for chronic hepatitis C (HCV) infection commonly requires two serological assays to confirm anti-HCV-antibody positivity in a serum sample followed by HCV RNA detection in a second whole-blood sample (two-step testing algorithm). A single-step algorithm (both anti-HCV antibodies and RNA tested on an initial serum specimen) has been advocated to reduce attrition rates from the care pathway. STUDY DESIGN: To investigate the feasibility, clinical impact and relative costs of switching from a two-step to single-step testing algorithm in the laboratory, a pilot study on unselected primary care requests was undertaken. METHODS: All primary care patients tested for HCV infection from December 2013 to April 2016 were included. The single-step testing algorithm was introduced in March 2015. Before this, the two-step algorithm was used. Patients were followed up until August 2016. RESULTS: RNA quantitation in plasma was within one log of serum values for 21 paired samples. Although all patients in the single-step algorithm received an RNA test, only 70% completed the two-step testing algorithm; differences in referral rates to specialist care was due to 30% of HCV antibody-positive patients in the two-step algorithm not having follow-up whole-blood sampling for HCV RNA testing. Costs per new diagnosis and new diagnosis referred to specialist care were lower in single-step testing by £94.32 and £144.25, respectively. CONCLUSION: This study provides further evidence that a single-step testing algorithm, as recommended in the UK Standards for Microbiology Investigation, works in practice and should be the standard of care for screening for chronic HCV.

Predictive biomarkers for response to EGFR-directed monoclonal antibodies for advanced squamous cell lung cancer.

Background: Upregulated expression and aberrant activation of the epidermal growth-factor receptor (EGFR) are found in lung cancer, making EGFR a relevant target for non-small-cell lung cancer (NSCLC). Treatment with anti-EGFR monoclonal antibodies (mAbs) is associated with modest improvement in overall survival in patients with squamous cell lung cancer (SqCLC) who have a significant unmet need for effective treatment options. While there is evidence that using EGFR gene copy number, EGFR mutation, and EGFR protein expression as biomarkers can help select patients who respond to treatment, it is important to consider biomarkers for response in patients treated with combination therapies that include EGFR mAbs. Design: Randomized trials of EGFR-directed mAbs cetuximab and necitumumab in combination with chemotherapy, immunotherapy, or antiangiogenic therapy in patients with advanced NSCLC, including SqCLC, were searched in the literature. Results of associations of potential biomarkers and outcomes were summarized. Results: Data from phase III clinical trials indicate that patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein (H-score of ≥200) and/or gene copy numbers of EGFR (e.g. ≥40% cells with ≥4 EGFR copies as detected by fluorescence in situ hybridization; gene amplification in ≥10% of analyzed cells) derive greater therapeutic benefits from EGFR-directed mAbs. Biomarker data are limited for EGFR mAbs used in combination with immunotherapy and are absent when used in combination with antiangiogenic agents. Conclusions: Therapy with EGFR-directed mAbs in combination with chemotherapy is associated with greater clinical benefits in patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein and/or have increased EGFR gene copy number. These data support validating the role of these as biomarkers to identify those patients who derive the greatest clinical benefit from EGFR mAb therapy. However, data on biomarkers for EGFR-directed mAbs combined with immunotherapy or antiangiogenic agents remain limited.

Prevalence and clinical association of gene mutations through multiplex mutation testing in patients with NSCLC: results from the ETOP Lungscape Project.

Background: Reported prevalence of driver gene mutations in non-small-cell lung cancer (NSCLC) is highly variable and clinical correlations are emerging. Using NSCLC biomaterial and clinical data from the European Thoracic Oncology Platform Lungscape iBiobank, we explore the epidemiology of mutations and association to clinicopathologic features and patient outcome (relapse-free survival, time-to-relapse, overall survival). Methods: Clinically annotated, resected stage I-III NSCLC FFPE tissue was assessed for gene mutation using a microfluidics-based multiplex PCR platform. Mutant-allele detection sensitivity is >1% for most of the ∼150 (13 genes) mutations covered in the multiplex test. Results: Multiplex testing has been carried out in 2063 (76.2%) of the 2709 Lungscape cases (median follow-up 4.8 years). FFPE samples mostly date from 2005 to 2008, yet recently extracted DNA quality and quantity was generally good. Average DNA yield/case was 2.63 µg; 38 cases (1.4%) failed QC and were excluded from study; 95.1% of included cases allowed the complete panel of mutations to be tested. Most common were KRAS, MET, EGFR and PIK3CA mutations with overall prevalence of 23.0%, 6.8%, 5.4% and 4.9%, respectively. KRAS and EGFR mutations were significantly more frequent in adenocarcinomas: PIK3CA in squamous cell carcinomas. MET mutation prevalence did not differ between histology groups. EGFR mutations were found predominantly in never smokers; KRAS in current/former smokers. For all the above mutations, there was no difference in outcome between mutated and non-mutated cases. Conclusion: Archival FFPE NSCLC material is adequate for multiplex mutation analysis. In this large, predominantly European, clinically annotated stage I-III NSCLC cohort, none of the mutations characterized showed prognostic significance.

Under-vaccinated groups in Europe and their beliefs, attitudes and reasons for non-vaccination; two systematic reviews.

BACKGROUND: Despite effective national immunisation programmes in Europe, some groups remain incompletely or un-vaccinated ('under-vaccinated'), with underserved minorities and certain religious/ideological groups repeatedly being involved in outbreaks of vaccine preventable diseases (VPD). Gaining insight into factors regarding acceptance of vaccination of 'under-vaccinated groups' (UVGs) might give opportunities to communicate with them in a trusty and reliable manner that respects their belief system and that, maybe, increase vaccination uptake. We aimed to identify and describe UVGs in Europe and to describe beliefs, attitudes and reasons for non-vaccination in the identified UVGs. METHODS: We defined a UVG as a group of persons who share the same beliefs and/or live in socially close-knit communities in Europe and who have/had historically low vaccination coverage and/or experienced outbreaks of VPDs since 1950. We searched MEDLINE, EMBASE and PsycINFO databases using specific search term combinations. For the first systematic review, studies that described a group in Europe with an outbreak or low vaccination coverage for a VPD were selected and for the second systematic review, studies that described possible factors that are associated with non-vaccination in these groups were selected. RESULTS: We selected 48 articles out of 606 and 13 articles out of 406 from the first and second search, respectively. Five UVGs were identified in the literature: Orthodox Protestant communities, Anthroposophists, Roma, Irish Travellers, and Orthodox Jewish communities. The main reported factors regarding vaccination were perceived non-severity of traditional "childhood" diseases, fear of vaccine side-effects, and need for more information about for example risk of vaccination. CONCLUSIONS: Within each UVG identified, there are a variety of health beliefs and objections to vaccination. In addition, similar factors are shared by several of these groups. Communication strategies regarding these similar factors such as educating people about the risks associated with being vaccinated versus not being vaccinated, addressing their concerns, and countering vaccination myths present among members of a specific UVG through a trusted source, can establish a reliable relationship with these groups and increase their vaccination uptake. Furthermore, other interventions such as improving access to health care could certainly increase vaccination uptake in Roma and Irish travellers.

The role of the care sport connector in the Netherlands.

INTRODUCTION: To stimulate physical activity and guide primary care patients towards local sport facilities, Care Sport Connectors (CSC), to whom a broker role has been ascribed, were introduced in 2012 in the Netherlands. The aim of this study was to explore CSCs' role in connecting the primary care sector and the PA sector. METHOD: Fifteen CSCs were selected to participate in this study and were followed in their work of connecting both sectors. Over the course of one year, three rounds of interviews were held with these CSCs on the topics of their role and the connection between the primary care and the PA sector. Both top-down and bottom-up codes were used to analyse the interviews. RESULTS: CSCs fulfilled three roles: 1) broker, 2) referral, 3) organiser. The extent to which CSCs fulfilled these roles was influenced by the way municipalities implemented the CSC funding. CSCs set up two forms of collaboration structures: 1) project basis and 2) referral scheme. CSCs perceived the following barriers to connecting the primary care and the PA sector: lack of knowledge and time, primary care professionals' own interests, and lack of suitable sport activities for the target group. CONCLUSION: The CSC role seems to hold the promise of improving collaboration between the primary care and the PA sector, especially, because the roles that CSCs perceive themselves as having seem to be directed at eliminating barriers in this connection. Future research is needed to study whether CSCs are capable of establishing a connection over time.

The operational context of care sport connectors in the Netherlands.

To stimulate physical activity (PA) and guide primary care patients towards local sport facilities, Care Sport Connectors (CSCs), to whom a broker role has been ascribed, were introduced in 2012 in the Netherlands. The aim of this study is to describe CSCs' operational context. A theoretical framework was developed and used as the starting point for this study. Group interviews were held with policymakers in nine participating municipalities, and, when applicable, the CSC's manager was also present. Prior to the interviews, a first outline of the operational context was mapped, based on the analysis of policy documents and a questionnaire completed by the policymakers. A deductive content analysis, based on the theoretical framework, was used to analyse the interviews. Differences were found in CSCs' operational context in the different municipalities, especially the extent to which municipalities adopted an integral approach. An integral approach consists of an integral policy in combination with an imbedding of this policy in partnerships at management level. This integral approach is reflected in the activities of other municipal operations, for example the implementation of health and PA programs by different organisations. Given the CSC mandate, we think that this integral approach may be supportive of the CSCs' work, because it is reflected in other operations of the municipalities and thus creates conditions for the CSCs' work. Further study is required to ascertain whether this integral approach is actually supporting CSCs in their work to connect the primary care and the PA sector.

Molecular Tumor Boards: current practice and future needs.

BACKGROUND: Due to rapid technical advances, steeply declining sequencing costs, and the ever-increasing number of targeted therapies, it can be expected that extensive tumor sequencing such as whole-exome and whole-genome sequencing will soon be applied in standard care. Clinicians will thus be confronted with increasingly complex genetic information and multiple test-platforms to choose from. General medical training, meanwhile, can hardly keep up with the pace of innovation. Consequently, there is a rapidly growing gap between clinical knowledge and genetic potential in cancer care. Multidisciplinary Molecular Tumor Boards (MTBs) have been suggested as a means to address this disparity, but shared experiences are scarce in literature and no quality requirements or guidelines have been published to date. METHODS: Based on literature review, a survey among hospitals in The Netherlands, and our own experience with the establishment of a nationally operating MTB, this article evaluates current knowledge and unmet needs and lays out a strategy for successful MTB implementation. RESULTS: Having access to an MTB can improve and increase the application of genetics-guided cancer care. In our survey, however, <50% of hospitals and only 5% of nonacademic hospitals had access to an MTB. In addition, current MTBs vary widely in terms of composition, tasks, tools, and workflow. This may not only lead to variation in quality of care but also hinders data sharing and thus creation of an effective learning community. CONCLUSIONS: This article acknowledges a leading role for MTBs to govern (extensive) tumor sequencing into daily practice and proposes three basic necessities for successful MTB implementation: (i) global harmonization in cancer sequencing practices and procedures, (ii) minimal member and operational requirements, and (iii) an appropriate unsolicited findings policy. Meeting these prerequisites would not only optimize MTB functioning but also improve general interpretation and application of genomics-guided cancer care.

SELECT-2: a phase II, double-blind, randomized, placebo-controlled study to assess the efficacy of selumetinib plus docetaxel as a second-line treatment of patients with advanced or metastatic non-small-cell lung cancer.

BACKGROUND: Combination of selumetinib plus docetaxel provided clinical benefit in a previous phase II trial for patients with KRAS-mutant advanced non-small-cell lung cancer (NSCLC). The phase II SELECT-2 trial investigated safety and efficacy of selumetinib plus docetaxel for patients with advanced or metastatic NSCLC. PATIENTS AND METHODS: Patients who had disease progression after first-line anti-cancer therapy were randomized (2 : 2 : 1) to selumetinib 75 mg b.i.d. plus docetaxel 60 or 75 mg/m2 (SEL + DOC 60; SEL + DOC 75), or placebo plus docetaxel 75 mg/m2 (PBO + DOC 75). Patients were initially enrolled independently of KRAS mutation status, but the protocol was amended to include only patients with centrally confirmed KRAS wild-type NSCLC. Primary end point was progression-free survival (PFS; RECIST 1.1); statistical analyses compared each selumetinib group with PBO + DOC 75 for KRAS wild-type and overall (KRAS mutant or wild-type) populations. RESULTS: A total of 212 patients were randomized; 69% were KRAS wild-type. There were no statistically significant improvements in PFS or overall survival for overall or KRAS wild-type populations in either selumetinib group compared with PBO + DOC 75. Overall population median PFS for SEL + DOC 60, SEL + DOC 75 compared with PBO + DOC 75 was 3.0, 4.2, and 4.3 months, HRs: 1.12 (90% CI: 0.8, 1.61) and 0.92 (90% CI: 0.65, 1.31), respectively. In the overall population, a higher objective response rate (ORR; investigator assessed) was observed for SEL + DOC 75 (33%) compared with PBO + DOC 75 (14%); odds ratio: 3.26 (90% CI: 1.47, 7.95). Overall the tolerability profile of SEL + DOC was consistent with historical data, without new or unexpected safety concerns identified. CONCLUSION: The primary end point (PFS) was not met. The higher ORR with SEL + DOC 75 did not translate into prolonged PFS for the overall or KRAS wild-type patient populations. No clinical benefit was observed with SEL + DOC in KRAS wild-type patients compared with docetaxel alone. No unexpected safety concerns were reported. TRIAL IDENTIFIER: Clinicaltrials.gov NCT01750281.

Recent trends and patterns in HIV-1 transmitted drug resistance in the United Kingdom.

OBJECTIVES: Transmission of drug-resistant HIV-1 has decreased in the UK since the early 2000s. This analysis reports recent trends and characteristics of transmitted drug resistance (TDR) in the UK from 2010 to 2013. METHODS: Resistance tests conducted in antiretroviral treatment (ART)-naïve individuals between 2010 and 2013 were analysed for the presence of transmitted drug resistance mutations (TDRMs), defined as any mutations from a modified 2009 World Health Organization surveillance list, or a modified 2013 International Antiviral Society-USA list for integrase tests. Logistic regression was used to examine associations between demographics and the prevalence of TDRMs. RESULTS: TDRMs were observed in 1223 (7.5%) of 16 425 individuals; prevalence declined from 8.1% in 2010 to 6.6% in 2013 (P = 0.02). The prevalence of TDRMs was higher among men who have sex with men (MSM) compared with heterosexual men and women (8.7% versus 6.4%, respectively) with a trend for decreasing TDRMs among MSM (P = 0.008) driven by a reduction in nucleoside reverse transcriptase inhibitor (NRTI)-related mutations. The most frequently detected TDRMs were K103N (2.2%), T215 revertants (1.6%), M41L (0.9%) and L90M (0.7%). Predicted phenotypic resistance to first-line ART was highest to the nonnucleoside reverse transcriptase inhibitors (NNRTIs) rilpivirine and efavirenz (6.2% and 3.4%, respectively) but minimal to NRTIs, including tenofovir, and protease inhibitors (PIs). No major integrase TDRMs were detected among 101 individuals tested while ART-naïve. CONCLUSIONS: We observed a decrease in TDRMs in recent years. However, this was confined to the MSM population and rates remained stable in those with heterosexually acquired HIV infection. Resistance to currently recommended first-line ART, including integrase inhibitors, remained reassuringly low.

Virological and Social Outcomes of HIV-Infected Adolescents and Young Adults in The Netherlands Before and After Transition to Adult Care.

BACKGROUND: As a result of effective combination antiretroviral therapy (cART) and advanced supportive healthcare, a growing number of human immunodeficiency virus (HIV)-infected children survive into adulthood. The period of transition to adult care is often associated with impaired adherence to treatment and discontinuity of care. We aimed to evaluate virological and social outcomes of HIV-infected adolescents and young adults (AYAs) before and after transition, and explore which factors are associated with virological failure. METHODS: We included 59 HIV-infected AYAs from the Netherlands who had entered into pediatric care and transitioned from pediatric to adult healthcare. We used HIV RNA load and cART data from the Dutch Stichting HIV Monitoring database (1996-2014), and collected social and treatment data from patients' medical records from all Dutch pediatric HIV treatment centers and 14 Dutch adult treatment centers involved. We evaluated risk factors for virological failure (VF) in a logistic regression model adjusted for repeated measurements. RESULTS: HIV VF occurred frequently during the study period (14%-36%). During the transition period (from 18 to 19 years of age) there was a significant increase in VF compared with the reference group of children aged 12-13 years (odds ratio, 4.26 [95% confidence interval, 1.12-16.28]; P = .03). Characteristics significantly associated with VF were low educational attainment and lack of autonomy regarding medication adherence at transition. CONCLUSIONS: HIV-infected AYAs are vulnerable to VF, especially during the transition period. Identification of HIV-infected adolescents at high risk for VF might help to improve treatment success in this group.