Publications by authors named "Maureen Cronin"

45 Publications

A prospective, randomized, single-blinded, crossover trial to investigate the effect of a wearable device in addition to a daily symptom diary for the Remote Early Detection of SARS-CoV-2 infections (COVID-RED): a structured summary of a study protocol for a randomized controlled trial.

Trials 2021 Oct 11;22(1):694. Epub 2021 Oct 11.

Julius Clinical, Zeist, the Netherlands.

Objectives: It is currently thought that most-but not all-individuals infected with SARS-CoV-2 develop symptoms, but the infectious period starts on average 2 days before the first overt symptoms appear. It is estimated that pre- and asymptomatic individuals are responsible for more than half of all transmissions. By detecting infected individuals before they have overt symptoms, wearable devices could potentially and significantly reduce the proportion of transmissions by pre-symptomatic individuals. Using laboratory-confirmed SARS-CoV-2 infections (detected via serology tests [to determine if there are antibodies against the SARS-CoV-2 in the blood] or SARS-CoV-2 infection tests such as polymerase chain reaction [PCR] or antigen tests) as the gold standard, we will determine the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the following two algorithms to detect first time SARS-CoV-2 infection including early or asymptomatic infection: • The algorithm using Ava bracelet data when coupled with self-reported Daily Symptom Diary data (Wearable + Symptom Data Algo; experimental condition) • The algorithm using self-reported Daily Symptom Diary data alone (Symptom Only Algo; control condition) In addition, we will determine which of the two algorithms has superior performance characteristics for detecting SARS-CoV-2 infection including early or asymptomatic infection as confirmed by SARS-CoV-2 virus testing.

Trial Design: The trial is a randomized, single-blinded, two-period, two-sequence crossover trial. The study will start with an initial learning phase (maximum of 3 months), followed by period 1 (3 months) and period 2 (3 months). Subjects entering the study at the end of the recruitment period may directly start with period 1 and will not be part of the learning phase. Each subject will undergo the experimental condition (the Wearable + Symptom Data Algo) in either period 1 or period 2 and the control condition (Symptom Only Algo) in the other period. The order will be randomly assigned, resulting in subjects being allocated 1:1 to either sequence 1 (experimental condition first) or sequence 2 (control condition first). Based on demographics, medical history and/or profession, each subject will be stratified at baseline into a high-risk and normal-risk group within each sequence.

Participants: The trial will be conducted in the Netherlands. A target of 20,000 subjects will be enrolled. Based on demographics, medical history and/or profession, each subject will be stratified at baseline into a high-risk and normal-risk group within each sequence. This results in approximately 6500 normal-risk individuals and 3500 high-risk individuals per sequence. Subjects will be recruited from previously studied cohorts as well as via public campaigns and social media. All data for this study will be collected remotely through the Ava COVID-RED app, the Ava bracelet, surveys in the COVID-RED web portal and self-sampling serology and PCR kits. More information on the study can be found in www.covid-red.eu . During recruitment, subjects will be invited to visit the COVID-RED web portal. After successfully completing the enrolment questionnaire, meeting eligibility criteria and indicating interest in joining the study, subjects will receive the subject information sheet and informed consent form. Subjects can enrol in COVID-RED if they comply with the following inclusion and exclusion criteria: Inclusion criteria: • Resident of the Netherlands • At least 18 years old • Informed consent provided (electronic) • Willing to adhere to the study procedures described in the protocol • Must have a smartphone that runs at least Android 8.0 or iOS 13.0 operating systems and is active for the duration of the study (in the case of a change of mobile number, the study team should be notified) • Be able to read, understand and write Dutch Exclusion criteria: • Previous positive SARS-CoV-2 test result (confirmed either through PCR/antigen or antibody tests; self-reported) • Current suspected (e.g. waiting for test result) COVID-19 infection or symptoms of a COVID-19 infection (self-reported) • Participating in any other COVID-19 clinical drug, vaccine or medical device trial (self-reported) • Electronic implanted device (such as a pacemaker; self-reported) • Pregnant at the time of informed consent (self-reported) • Suffering from cholinergic urticaria (per the Ava bracelet's user manual; self-reported) • Staff involved in the management or conduct of this study INTERVENTION AND COMPARATOR: All subjects will be instructed to complete the Daily Symptom Diary in the Ava COVID-RED app daily, wear their Ava bracelet each night and synchronize it with the app each day for the entire period of study participation. Provided with wearable sensor and/or self-reported symptom data within the last 24 h, the Ava COVID-RED app's underlying algorithms will provide subjects with a real-time indicator of their overall health and well-being. Subjects will see one of three messages, notifying them that no seeming deviations in symptoms and/or physiological parameters have been detected; some changes in symptoms and/or physiological parameters have been detected and they should self-isolate; or alerting them that deviations in their symptoms and/or physiological parameters could be suggestive of a potential COVID-19 infection and to seek additional testing. We will assess the intraperson performance of the algorithms in the experimental condition (Wearable + Symptom Data Algo) and control conditions (Symptom Only Algo). Note that both algorithms will also instruct to seek testing when any SARS-CoV-2 symptoms are reported in line with those defined by the Dutch national institute for public health and the environment 'Rijksinstituut voor Volksgezondheid en Milieu' (RIVM) guidelines.

Main Outcomes: The trial will evaluate the use and performance of the Ava COVID-RED app and Ava bracelet, which uses sensors to measure breathing rate, pulse rate, skin temperature and heart rate variability for the purpose of early and asymptomatic detection and monitoring of SARS-CoV-2 in general and high-risk populations. Using laboratory-confirmed SARS-CoV-2 infections (detected via serology tests, PCR tests and/or antigen tests) as the gold standard, we will determine the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for each of the following two algorithms to detect first-time SARS-CoV-2 infection including early or asymptomatic infection: the algorithm using Ava bracelet data when coupled with the self-reported Daily Symptom Diary data and the algorithm using self-reported Daily Symptom Diary data alone. In addition, we will determine which of the two algorithms has superior performance characteristics for detecting SARS-CoV-2 infection including early or asymptomatic infection as confirmed by SARS-CoV-2 virus testing. The protocol contains an additional twenty secondary and exploratory objectives which address, among others, infection incidence rates, health resource utilization, symptoms reported by SARS-CoV-2-infected participants and the rate of breakthrough and asymptomatic SARS-CoV-2 infections among individuals vaccinated against COVID-19. PCR or antigen testing will occur when the subject receives a notification from the algorithm to seek additional testing. Subjects will be advised to get tested via the national testing programme and report the testing result in the Ava COVID-RED app and a survey. If they cannot obtain a test via the national testing programme, they will receive a nasal swab self-sampling kit at home, and the sample will be tested by PCR in a trial-affiliated laboratory. In addition, all subjects will be asked to take a capillary blood sample at home at baseline (between month 0 and 3.5 months after the start of subject recruitment), at the end of the learning phase (month 3; note that this sampling moment is skipped if a subject entered the study at the end of the recruitment period), period 1 (month 6) and period 2 (month 9). These samples will be used for SARS-CoV-2-specific antibody testing in a trial-affiliated laboratory, differentiating between antibodies resulting from a natural infection and antibodies resulting from COVID-19 vaccination (as vaccination will gradually be rolled out during the trial period). Baseline samples will only be analysed if the sample collected at the end of the learning phase is positive, or if the subject entered the study at the end of the recruitment period, and samples collected at the end of period 1 will only be analysed if the sample collected at the end of period 2 is positive. When subjects obtain a positive PCR/antigen or serology test result during the study, they will continue to be in the study but will be moved into a so-called COVID-positive mode in the Ava COVID-RED app. This means that they will no longer receive recommendations from the algorithms but can still contribute and track symptom and bracelet data. The primary analysis of the main objective will be executed using the data collected in period 2 (months 6 through 9). Within this period, serology tests (before and after period 2) and PCR/antigen tests (taken based on recommendations by the algorithms) will be used to determine if a subject was infected with SARS-CoV-2 or not. Within this same time period, it will be determined if the algorithms gave any recommendations for testing. The agreement between these quantities will be used to evaluate the performance of the algorithms and how these compare between the study conditions.

Randomization: All eligible subjects will be randomized using a stratified block randomization approach with an allocation ratio of 1:1 to one of two sequences (experimental condition followed by control condition or control condition followed by experimental condition). Based on demographics, medical history and/or profession, each subject will be stratified at baseline into a high-risk and normal-risk group within each sequence, resulting in approximately equal numbers of high-risk and normal-risk individuals between the sequences.

Blinding (masking): In this study, subjects will be blinded to the study condition and randomization sequence. Relevant study staff and the device manufacturer will be aware of the assigned sequence. The subject will wear the Ava bracelet and complete the Daily Symptom Diary in the Ava COVID-RED app for the full duration of the study, and they will not know if the feedback they receive about their potential infection status will only be based on the data they entered in the Daily Symptom Diary within the Ava COVID-RED app or based on both the data from the Daily Symptom Diary and the Ava bracelet.

Numbers To Be Randomized (sample Size): A total of 20,000 subjects will be recruited and randomized 1:1 to either sequence 1 (experimental condition followed by control condition) or sequence 2 (control condition followed by experimental condition), taking into account their risk level. This results in approximately 6500 normal-risk and 3500 high-risk individuals per sequence.

Trial Status: Protocol version: 3.0, dated May 3, 2021. Start of recruitment: February 19, 2021. End of recruitment: June 3, 2021. End of follow-up (estimated): November 2021 TRIAL REGISTRATION: The Netherlands Trial Register on the 18 of February, 2021 with number NL9320 ( https://www.trialregister.nl/trial/9320 ) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.
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http://dx.doi.org/10.1186/s13063-021-05643-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8503725PMC
October 2021

Generalisability of Randomised Controlled Trials in Heart Failure with Reduced Ejection Fraction.

Eur Heart J Qual Care Clin Outcomes 2021 Oct 1. Epub 2021 Oct 1.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

Background: Heart failure (HF) trials have stringent in- and ex- clusion criteria, but limited data exists regarding generalisability of trials. We compared patient characteristics and outcomes between patients with HF and reduced ejection fraction (HFrEF) in trials and observational registries.

Methods And Results: Individual patient data for 16922 patients from five randomised clinical trials and 46914 patients from two HF registries were included. The registry patients were categorised into trial-eligible and non-eligible groups using the most commonly used in- and ex-clusion criteria. A total of 26104 (56%) registry patients fulfilled the eligibility criteria. Unadjusted all-cause mortality rates at one year were lowest in the trial population (7%), followed by trial-eligible patients (12%) and trial-non-eligible registry patients (26%). After adjustment for age and sex, all-cause mortality rates were similar between trial participants and trial-eligible registry patients (standardised mortality ratio (SMR) 0.97; 95% confidence interval (CI) 0.92 -1.03) but cardiovascular mortality was higher in trial participants (SMR 1.19; 1.12 -1.27). After full case-mix adjustment, the SMR for cardiovascular mortality remained higher in the trials at 1.28 (1.20- 1.37) compared to RCT-eligible registry patients.

Conclusion: In contemporary HF registries, over half of HFrEF patients would have been eligible for trial enrolment. Crude clinical event rates were lower in the trials, but, after adjustment for case-mix, trial participants had similar rates of survival as registries. Despite this, they had about 30% higher cardiovascular mortality rates. Age and sex were the main drivers of differences in clinical outcomes between HF trials and observational HF registries.
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http://dx.doi.org/10.1093/ehjqcco/qcab070DOI Listing
October 2021

A prospective, randomized, single-blinded, crossover trial to investigate the effect of a wearable device in addition to a daily symptom diary for the remote early detection of SARS-CoV-2 infections (COVID-RED): a structured summary of a study protocol for a randomized controlled trial.

Trials 2021 Jun 22;22(1):412. Epub 2021 Jun 22.

Julius Clinical, Zeist, the Netherlands.

Objectives: It is currently thought that most-but not all-individuals infected with SARS-CoV-2 develop symptoms, but that the infectious period starts on average two days before the first overt symptoms appear. It is estimated that pre- and asymptomatic individuals are responsible for more than half of all transmissions. By detecting infected individuals before they have overt symptoms, wearable devices could potentially and significantly reduce the proportion of transmissions by pre-symptomatic individuals. Using laboratory-confirmed SARS-CoV-2 infections (detected via serology tests [to determine if there are antibodies against the SARS-CoV-2 in the blood] or SARS-CoV-2 infection tests such as polymerase chain reaction [PCR] or antigen tests) as the gold standard, we will determine the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the following two algorithms to detect first time SARS-CoV-2 infection including early or asymptomatic infection: the algorithm using Ava bracelet data when coupled with self-reported Daily Symptom Diary data (Wearable + Symptom Data Algo; experimental condition) the algorithm using self-reported Daily Symptom Diary data alone (Symptom Only Algo; control condition) In addition, we will determine which of the two algorithms has superior performance characteristics for detecting SARS-CoV-2 infection including early or asymptomatic infection as confirmed by SARS-CoV-2 virus testing.

Trial Design: The trial is a randomized, single-blinded, two-period, two-sequence crossover trial. All subjects will participate in an initial Learning Phase (varying from 2 weeks to 3 months depending on enrolment date), followed by two contiguous 3-month test phases, Period 1 and Period 2. Each subject will undergo the experimental condition (the Wearable + Symptom Data Algo) in one of these periods and the control condition (Symptom Only Algo) in the other period. The order will be randomly assigned, resulting in subjects being allocated 1:1 to either Sequence 1 (experimental condition first) or Sequence 2 (control condition first). Based on demographics, medical history and/or profession, each subject will be stratified at baseline into a high-risk and normal-risk group within each sequence.

Participants: The trial will be conducted in the Netherlands. A target of 20,000 subjects will be enrolled. Based on demographics, medical history and/or profession, each subject will be stratified at baseline into a high-risk and normal-risk group within each sequence. This results in approximately 6,500 normal-risk individuals and 3,500 high-risk individuals per sequence. Subjects will be recruited from previously studied cohorts as well as via public campaigns and social media. All data for this study will be collected remotely through the Ava COVID-RED app, the Ava bracelet, surveys in the COVID-RED web portal, and self-sampling serology and PCR kits. During recruitment, subjects will be invited to visit the COVID-RED web portal ( www.covid-red.eu ). After successfully completing the enrolment questionnaire, meeting eligibility criteria and indicating interest in joining the study, subjects will receive the subject information sheet and informed consent form. Subjects can enrol in COVID-RED if they comply with the following inclusion and exclusion criteria.

Inclusion Criteria: Resident of the Netherlands At least 18 years old Informed consent provided (electronic) Willing to adhere to the study procedures described in the protocol Must have a smartphone that runs at least Android 8.0 or iOS 13.0 operating systems and is active for the duration of the study (in the case of a change of mobile number, study team should be notified) Be able to read, understand and write Dutch Exclusion criteria: Previous positive SARS-CoV-2 test result (confirmed either through PCR/antigen or antibody tests; self-reported) Previously received a vaccine developed specifically for COVID-19 or in possession of an appointment for vaccination in the near future (self-reported) Current suspected (e.g., waiting for test result) COVID-19 infection or symptoms of a COVID-19 infection (self-reported) Participating in any other COVID-19 clinical drug, vaccine, or medical device trial (self-reported) Electronic implanted device (such as a pacemaker; self-reported) Pregnant at time of informed consent (self-reported) Suffering from cholinergic urticaria (per the Ava bracelet's User Manual; self-reported) Staff involved in the management or conduct of this study INTERVENTION AND COMPARATOR: All subjects will be instructed to complete the Daily Symptom Diary in the Ava COVID-RED app daily, wear their Ava bracelet each night and synchronise it with the app each day for the entire period of study participation. Provided with wearable sensor and/or self-reported symptom data within the last 24 hours, the Ava COVID-RED app's underlying algorithms will provide subjects with a real-time indicator of their overall health and well-being. Subjects will see one of three messages, notifying them that: no seeming deviations in symptoms and/or physiological parameters have been detected; some changes in symptoms and/or physiological parameters have been detected and they should self-isolate; or alerting them that deviations in their symptoms and/or physiological parameters could be suggestive of a potential COVID-19 infection and to seek additional testing. We will assess intraperson performance of the algorithms in the experimental condition (Wearable + Symptom Data Algo) and control conditions (Symptom Only Algo).

Main Outcomes: The trial will evaluate the use and performance of the Ava COVID-RED app and Ava bracelet, which uses sensors to measure breathing rate, pulse rate, skin temperature, and heart rate variability for the purpose of early and asymptomatic detection and monitoring of SARS-CoV-2 in general and high-risk populations. Using laboratory-confirmed SARS-CoV-2 infections (detected via serology tests, PCR tests and/or antigen tests) as the gold standard, we will determine the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for each of the following two algorithms to detect first-time SARS-CoV-2 infection including early or asymptomatic infection: the algorithm using Ava Bracelet data when coupled with the self-reported Daily Symptom Diary data, and the algorithm using self-reported Daily Symptom Diary data alone. In addition, we will determine which of the two algorithms has superior performance characteristics for detecting SARS-CoV-2 infection including early or asymptomatic infection as confirmed by SARS-CoV-2 virus testing. The protocol contains an additional seventeen secondary outcomes which address infection incidence rates, health resource utilization, symptoms reported by SARS-CoV-2 infected participants, and the rate of breakthrough and asymptomatic SARS-CoV-2 infections among individuals vaccinated against COVID-19. PCR or antigen testing will occur when the subject receives a notification from the algorithm to seek additional testing. Subjects will be advised to get tested via the national testing programme, and report the testing result in the Ava COVID-RED app and a survey. If they cannot obtain a test via the national testing programme, they will receive a nasal swab self-sampling kit at home, and the sample will be tested by PCR in a trial-affiliated laboratory. In addition, all subjects will be asked to take a capillary blood sample at home at baseline (Month 0), and at the end of the Learning Phase (Month 3), Period 1 (Month 6) and Period 2 (Month 9). These samples will be used for SARS-CoV-2-specific antibody testing in a trial-affiliated laboratory, differentiating between antibodies resulting from a natural infection and antibodies resulting from COVID-19 vaccination (as vaccination will gradually be rolled out during the trial period). Baseline samples will only be analysed if the sample collected at the end of the Learning Phase is positive, and samples collected at the end of Period 1 will only be analysed if the sample collected at the end of Period 2 is positive. When subjects obtain a positive PCR/antigen or serology test result during the study, they will continue to be in the study but will be moved into a so-called "COVID-positive" mode in the Ava COVID-RED app. This means that they will no longer receive recommendations from the algorithms but can still contribute and track symptom and bracelet data. The primary analysis of the main objective will be executed using data collected in Period 2 (Month 6 through 9). Within this period, serology tests (before and after Period 2) and PCR/antigen tests (taken based on recommendations by the algorithms) will be used to determine if a subject was infected with SARS-CoV-2 or not. Within this same time period, it will be determined if the algorithms gave any recommendations for testing. The agreement between these quantities will be used to evaluate the performance of the algorithms and how these compare between the study conditions.

Randomisation: All eligible subjects will be randomized using a stratified block randomization approach with an allocation ratio of 1:1 to one of two sequences (experimental condition followed by control condition or control condition followed by experimental condition). Based on demographics, medical history and/or profession, each subject will be stratified at baseline into a high-risk and normal-risk group within each sequence, resulting in equal numbers of high-risk and normal-risk individuals between the sequences.

Blinding (masking): In this study, subjects will be blinded as to study condition and randomization sequence. Relevant study staff and the device manufacturer will be aware of the assigned sequence. The subject will wear the Ava bracelet and complete the Daily Symptom Diary in the Ava COVID-RED app for the full duration of the study, and they will not know if the feedback they receive about their potential infection status will only be based on data they entered in the Daily Symptom Diary within the Ava COVID-RED app or based on both the data from the Daily Symptom Diary and the Ava bracelet.

Numbers To Be Randomised (sample Size): 20,000 subjects will be recruited and randomized 1:1 to either Sequence 1 (experimental condition followed by control condition) or Sequence 2 (control condition followed by experimental condition), taking into account their risk level. This results in approximately 6,500 normal-risk and 3,500 high-risk individuals per sequence.

Trial Status: Protocol version: 1.2, dated January 22, 2021 Start of recruitment: February 22, 2021 End of recruitment (estimated): April 2021 End of follow-up (estimated): December 2021 TRIAL REGISTRATION: The trial has been registered at the Netherlands Trial Register on the 18 of February, 2021 with number NL9320 ( https://www.trialregister.nl/trial/9320 ) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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http://dx.doi.org/10.1186/s13063-021-05241-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218271PMC
June 2021

Big data from electronic health records for early and late translational cardiovascular research: challenges and potential.

Eur Heart J 2018 04;39(16):1481-1495

Research Department of Clinical Epidemiology, The Farr Institute of Health Informatics Research, University College London, 222 Euston Road, London NW1 2DA, UK.

Aims: Cohorts of millions of people's health records, whole genome sequencing, imaging, sensor, societal and publicly available data present a rapidly expanding digital trace of health. We aimed to critically review, for the first time, the challenges and potential of big data across early and late stages of translational cardiovascular disease research.

Methods And Results: We sought exemplars based on literature reviews and expertise across the [email protected] Consortium. We identified formidable challenges including: data quality, knowing what data exist, the legal and ethical framework for their use, data sharing, building and maintaining public trust, developing standards for defining disease, developing tools for scalable, replicable science and equipping the clinical and scientific work force with new inter-disciplinary skills. Opportunities claimed for big health record data include: richer profiles of health and disease from birth to death and from the molecular to the societal scale; accelerated understanding of disease causation and progression, discovery of new mechanisms and treatment-relevant disease sub-phenotypes, understanding health and diseases in whole populations and whole health systems and returning actionable feedback loops to improve (and potentially disrupt) existing models of research and care, with greater efficiency. In early translational research we identified exemplars including: discovery of fundamental biological processes e.g. linking exome sequences to lifelong electronic health records (EHR) (e.g. human knockout experiments); drug development: genomic approaches to drug target validation; precision medicine: e.g. DNA integrated into hospital EHR for pre-emptive pharmacogenomics. In late translational research we identified exemplars including: learning health systems with outcome trials integrated into clinical care; citizen driven health with 24/7 multi-parameter patient monitoring to improve outcomes and population-based linkages of multiple EHR sources for higher resolution clinical epidemiology and public health.

Conclusion: High volumes of inherently diverse ('big') EHR data are beginning to disrupt the nature of cardiovascular research and care. Such big data have the potential to improve our understanding of disease causation and classification relevant for early translation and to contribute actionable analytics to improve health and healthcare.
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http://dx.doi.org/10.1093/eurheartj/ehx487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019015PMC
April 2018

New medicinal products for chronic heart failure: advances in clinical trial design and efficacy assessment.

Eur J Heart Fail 2017 06 27;19(6):718-727. Epub 2017 Mar 27.

Bristol-Myers Squibb, Paris, France.

Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health-related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure. The draft version of the Guideline was released for public consultation in January 2016. The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two-day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline: (i) assessment of efficacy (i.e. endpoint selection and statistical analysis); (ii) clinical trial design (i.e. issues pertaining to patient population, optimal medical therapy, run-in period); and (iii) research approaches for testing novel therapeutic principles (i.e. cell therapy). This paper summarizes the key outputs from the workshop, reviews areas of expert consensus, and identifies gaps that require further research or discussion. Collaboration between regulators, industry, clinical trialists, cardiologists, health technology assessment bodies, payers, and patient organizations is critical to address the ongoing challenge of heart failure and to ensure the development and market access of new therapeutics in a scientifically robust, practical and safe way.
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http://dx.doi.org/10.1002/ejhf.809DOI Listing
June 2017

Safety of intravenous ferric carboxymaltose versus oral iron in patients with nondialysis-dependent CKD: an analysis of the 1-year FIND-CKD trial.

Nephrol Dial Transplant 2017 Sep;32(9):1530-1539

Department of Renal Medicine, King's College Hospital, London, UK.

Background: The evidence base regarding the safety of intravenous (IV) iron therapy in patients with chronic kidney disease (CKD) is incomplete and largely based on small studies of relatively short duration.

Methods: FIND-CKD (ClinicalTrials.gov number NCT00994318) was a 1-year, open-label, multicenter, prospective study of patients with nondialysis-dependent CKD, anemia and iron deficiency randomized (1:1:2) to IV ferric carboxymaltose (FCM), targeting higher (400-600 µg/L) or lower (100-200 µg/L) ferritin, or oral iron. A post hoc analysis of adverse event rates per 100 patient-years was performed to assess the safety of FCM versus oral iron over an extended period.

Results: The safety population included 616 patients. The incidence of one or more adverse events was 91.0, 100.0 and 105.0 per 100 patient-years in the high ferritin FCM, low ferritin FCM and oral iron groups, respectively. The incidence of adverse events with a suspected relation to study drug was 15.9, 17.8 and 36.7 per 100 patient-years in the three groups; for serious adverse events, the incidence was 28.2, 27.9 and 24.3 per 100 patient-years. The incidence of cardiac disorders and infections was similar between groups. At least one ferritin level ≥800 µg/L occurred in 26.6% of high ferritin FCM patients, with no associated increase in adverse events. No patient with ferritin ≥800 µg/L discontinued the study drug due to adverse events. Estimated glomerular filtration rate remained the stable in all groups.

Conclusions: These results further support the conclusion that correction of iron deficiency anemia with IV FCM is safe in patients with nondialysis-dependent CKD.
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http://dx.doi.org/10.1093/ndt/gfw264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837517PMC
September 2017

Hepcidin Response to Iron Therapy in Patients with Non-Dialysis Dependent CKD: An Analysis of the FIND-CKD Trial.

PLoS One 2016 8;11(6):e0157063. Epub 2016 Jun 8.

Department of Renal Medicine, King's College Hospital, London, United Kingdom.

Hepcidin is the key regulator of iron homeostasis but data are limited regarding its temporal response to iron therapy, and response to intravenous versus oral iron. In the 56-week, open-label, multicenter, prospective, randomized FIND-CKD study, 626 anemic patients with non-dialysis dependent chronic kidney disease (ND-CKD) and iron deficiency not receiving an erythropoiesis stimulating agent were randomized (1:1:2) to intravenous ferric carboxymaltose (FCM), targeting higher (400-600μg/L) or lower (100-200μg/L) ferritin, or to oral iron. Serum hepcidin levels were measured centrally in a subset of 61 patients. Mean (SD) baseline hepcidin level was 4.0(3.5), 7.3(6.4) and 6.5(5.6) ng/mL in the high ferritin FCM (n = 17), low ferritin FCM (n = 16) and oral iron group (n = 28). The mean (SD) endpoint value (i.e. the last post-baseline value) was 26.0(9.1),15.7(7.7) and 16.3(11.0) ng/mL, respectively. The increase in hepcidin from baseline was significantly smaller with low ferritin FCM or oral iron vs high ferritin FCM at all time points up to week 52. Significant correlations were found between absolute hepcidin and ferritin values (r = 0.65, p<0.001) and between final post-baseline increases in both parameters (r = 0.70, p<0.001). The increase in hepcidin levels over the 12-month study generally mirrored the cumulative iron dose in each group. Hepcidin and transferrin saturation (TSAT) absolute values showed no correlation, although there was an association between final post-baseline increases (r = 0.42, p<0.001). Absolute values (r = 0.36, p = 0.004) and final post-baseline increases of hepcidin and hemoglobin (p = 0.30, p = 0.030) correlated weakly. Baseline hepcidin levels were not predictive of a hematopoietic response to iron therapy. In conclusion, hepcidin levels rose in response to either intravenous or oral iron therapy, but the speed and extent of the rise was greatest with intravenous iron targeting a higher ferritin level. However neither the baseline level nor the change in hepcidin was able to predict response to therapy in this cohort.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157063PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4898697PMC
July 2017

Accelerating the Development and Validation of New Value-Based Diagnostics by Leveraging Biobanks.

Public Health Genomics 2016;19(3):160-9. Epub 2016 Jun 1.

Genomic Health International SARL, Geneva, Switzerland.

The challenges faced in developing value-based diagnostics has resulted in few of these tests reaching the clinic, leaving many treatment modalities without matching diagnostics to select patients for particular therapies. Many patients receive therapies from which they are unlikely to benefit, resulting in worse outcomes and wasted health care resources. The paucity of value-based diagnostics is a result of the scientific challenges in developing predictive markers, specifically: (1) complex biology, (2) a limited research infrastructure supporting diagnostic development, and (3) the lack of incentives for diagnostic developers to invest the necessary resources. Better access to biospecimens can address some of these challenges. Methodologies developed to evaluate biomarkers from biospecimens archived from patients enrolled in randomized clinical trials offer the greatest opportunity to develop and validate high-value molecular diagnostics. An alternative opportunity is to access high-quality biospecimens collected from large public and private longitudinal observational cohorts such as the UK Biobank, the US Million Veteran Program, the UK 100,000 Genomes Project, or the French E3N cohort. Value-based diagnostics can be developed to work in a range of samples including blood, serum, plasma, urine, and tumour tissue, and better access to these high-quality biospecimens with clinical data can facilitate biomarker research.
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http://dx.doi.org/10.1159/000446534DOI Listing
February 2017

Next generation sequencing of exceptional responders with BRAF-mutant melanoma: implications for sensitivity and resistance.

BMC Cancer 2015 Feb 18;15:61. Epub 2015 Feb 18.

Center for Personalized Cancer Therapy, Moores Cancer Center, The University of California San Diego, 3855 Health Sciences Drive, La Jolla, CA, 92093, USA.

Background: Patients with BRAF mutation-positive advanced melanoma respond well to matched therapy with BRAF or MEK inhibitors, but often quickly develop resistance.

Methods: Tumor tissue from ten patients with advanced BRAF mutation-positive melanoma who achieved partial response (PR) or complete response (CR) on BRAF and/or MEK inhibitors was analyzed using next generation sequencing (NGS) assay. Genomic libraries were captured for 3230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to average median depth of 734X with 99% of bases covered >100X.

Results: Three of the ten patients (median number of prior therapies = 2) attained prolonged CR (duration = 23.6+ to 28.7+ months); seven patients achieved either a PR or a short-lived CR. One patient who achieved CR ongoing at 28.7+ months and had tissue available close to the time of initiating BRAF inhibitor therapy had only a BRAF mutation. Abnormalities in addition to BRAF mutation found in other patients included: mutations in NRAS, APC and NF1; amplifications in BRAF, aurora kinase A, MYC, MITF and MET; deletions in CDKN2A/B and PAX5; and, alterations in RB1 and ATM. Heterogeneity between patients and molecular evolution within patients was noted.

Conclusion: NGS identified potentially actionable DNA alterations that could account for resistance in patients with BRAF mutation-positive advanced melanoma who achieved a PR or CR but whose tumors later progressed. A subset of patients with advanced melanoma may harbor only a BRAF mutation and achieve a durable CR on BRAF pathway inhibitors.
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http://dx.doi.org/10.1186/s12885-015-1029-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340232PMC
February 2015

A targeted next-generation sequencing assay detects a high frequency of therapeutically targetable alterations in primary and metastatic breast cancers: implications for clinical practice.

Oncologist 2014 May 7;19(5):453-8. Epub 2014 Apr 7.

Yale University School of Medicine, New Haven, Connecticut, USA; Foundation Medicine, Cambridge, Massachusetts, USA; MD Anderson Cancer Center, Houston, Texas, USA.

The aim of this study was to assess the frequency of potentially actionable genomic alterations in breast cancer that could be targeted with approved agents or investigational drugs in clinical trials using a next-generation sequencing-based genomic profiling assay performed in a Clinical Laboratory Improvement Amendments-certified and College of American Pathologists-accredited commercial laboratory. Methods. Fifty-one breast cancers were analyzed, including primary tumor biopsies of 33 stage I-II and 18 stage IV cancers (13 soft tissue, 3 liver, and 2 bone metastases). We assessed 3,230 exons in 182 cancer-related genes and 37 introns in 14 genes often rearranged in cancer for base substitutions, indels, copy number alterations, and gene fusions. The average median sequencing depth was 1,154×. Results. We observed 158 genomic alterations in 55 genes in 48 of 51 (94%) tumors (mean 3.1, range 0-9). The average number of potentially therapeutically relevant alterations was similar in primary (1.6, range 0-4) and in heavily pretreated metastatic cancers (2.0, range 0-4) (p = .24). The most common actionable alterations were in PIK3CA (n = 9, phosphatidylinositol 3-kinase [PI3K]/mammalian target of rapamycin [mTOR] inhibitors), NF1 (n = 7, PI3K/mTOR/mitogen-activated protein kinase inhibitors), v-akt murine thymoma viral oncogene homolog 1-3 (n = 7, PI3K/mTOR/AKT inhibitors), BRCA1/2 (n = 6, poly[ADP-ribose] polymerase inhibitors), and CCND1,2 and CCNE (n = 8)/cycline dependent kinase (CDK)6 (n = 1) (CDK4/6 inhibitors), KIT (n = 1, imatinib/sunitinib), ALK (n = 1, crizotinib), FGFR1,2 (n = 5, fibroblast growth factor receptor inhibitors), and EGFR (n = 2, epidermal growth factor receptor inhibitors). Our sequencing assay also correctly identified all six cases with HER2 (ERBB2) amplification by fluorescence in situ hybridization when tumor content was adequate. In addition, two known activating HER2 mutations were identified, both in unamplified cases. Conclusion. Overall, 84% of cancers harbored at least one genomic alteration linked to potential treatment options. Systematic evaluation of the predictive value of these genomic alterations is critically important for further progress in this field.
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http://dx.doi.org/10.1634/theoncologist.2013-0377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012963PMC
May 2014

Concordance of genomic alterations between primary and recurrent breast cancer.

Mol Cancer Ther 2014 May 7;13(5):1382-9. Epub 2014 Mar 7.

Authors' Affiliations: Departments of Investigational Cancer Therapeutics, Surgical Oncology, Bioinformatics and Computational Biology, Pathology, Systems Biology, and Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Foundation Medicine, Cambridge, Massachusetts; Albany Medical College, Albany, New York; Fundacion para la Investigacion; Departments of Hematology-Oncology and Pathology, Hospital Clinico Universitario de Valencia; and INCLIVA Biomedical Research Institute, Valencia, Spain.

There is growing interest in delivering genomically informed cancer therapy. Our aim was to determine the concordance of genomic alterations between primary and recurrent breast cancer. Targeted next-generation sequencing was performed on formalin-fixed paraffin-embedded (FFPE) samples, profiling 3,320 exons of 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer. Point mutations, indels, copy-number alterations (CNA), and select rearrangements were assessed in 74 tumors from 43 patients (36 primary and 38 recurrence/metastases). Alterations potentially targetable with established or investigational therapeutics were considered "actionable." Alterations were detected in 55 genes (mean 3.95 alterations/sample, range 1-12), including mutations in PIK3CA, TP53, ARID1A, PTEN, AKT1, NF1, FBXW7, and FGFR3 and amplifications in MCL1, CCND1, FGFR1, MYC, IGF1R, MDM2, MDM4, AKT3, CDK4, and AKT2. In 33 matched primary and recurrent tumors, 97 of 112 (86.6%) somatic mutations were concordant. Of identified CNAs, 136 of 159 (85.5%) were concordant: 37 (23.3%) were concordant, but below the reporting threshold in one of the matched samples, and 23 (14.5%) discordant. There was an increased frequency of CDK4/MDM2 amplifications in recurrences, as well as gains and losses of other actionable alterations. Forty of 43 (93%) patients had actionable alterations that could inform targeted treatment options. In conclusion, deep genomic profiling of cancer-related genes reveals potentially actionable alterations in most patients with breast cancer. Overall there was high concordance between primary and recurrent tumors. Analysis of recurrent tumors before treatment may provide additional insights, as both gains and losses of targets are observed.
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http://dx.doi.org/10.1158/1535-7163.MCT-13-0482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348062PMC
May 2014

Kinase fusions are frequent in Spitz tumours and spitzoid melanomas.

Nat Commun 2014 ;5:3116

Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 415 E 68th Street, New York, New York 10065, USA.

Spitzoid neoplasms are a group of melanocytic tumours with distinctive histopathological features. They include benign tumours (Spitz naevi), malignant tumours (spitzoid melanomas) and tumours with borderline histopathological features and uncertain clinical outcome (atypical Spitz tumours). Their genetic underpinnings are poorly understood, and alterations in common melanoma-associated oncogenes are typically absent. Here we show that spitzoid neoplasms harbour kinase fusions of ROS1 (17%), NTRK1 (16%), ALK (10%), BRAF (5%) and RET (3%) in a mutually exclusive pattern. The chimeric proteins are constitutively active, stimulate oncogenic signalling pathways, are tumourigenic and are found in the entire biologic spectrum of spitzoid neoplasms, including 55% of Spitz naevi, 56% of atypical Spitz tumours and 39% of spitzoid melanomas. Kinase inhibitors suppress the oncogenic signalling of the fusion proteins in vitro. In summary, kinase fusions account for the majority of oncogenic aberrations in spitzoid neoplasms and may serve as therapeutic targets for metastatic spitzoid melanomas.
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http://dx.doi.org/10.1038/ncomms4116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4084638PMC
October 2015

Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer.

Clin Cancer Res 2014 Apr 7;20(7):1757-1767. Epub 2014 Jan 7.

Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, 450 Brookline Ave. Boston, MA 02215.

Purpose: We undertook this study to determine the prevalence of estrogen receptor (ER) α (ESR1) mutations throughout the natural history of hormone-dependent breast cancer and to delineate the functional roles of the most commonly detected alterations.

Experimental Design: We studied a total of 249 tumor specimens from 208 patients. The specimens include 134 ER-positive (ER(+)/HER2(-)) and, as controls, 115 ER-negative (ER(-)) tumors. The ER(+) samples consist of 58 primary breast cancers and 76 metastatic samples. All tumors were sequenced to high unique coverage using next-generation sequencing targeting the coding sequence of the estrogen receptor and an additional 182 cancer-related genes.

Results: Recurring somatic mutations in codons 537 and 538 within the ligand-binding domain of ER were detected in ER(+) metastatic disease. Overall, the frequency of these mutations was 12% [9/76; 95% confidence interval (CI), 6%-21%] in metastatic tumors and in a subgroup of patients who received an average of 7 lines of treatment the frequency was 20% (5/25; 95% CI, 7%-41%). These mutations were not detected in primary or treatment-naïve ER(+) cancer or in any stage of ER(-) disease. Functional studies in cell line models demonstrate that these mutations render estrogen receptor constitutive activity and confer partial resistance to currently available endocrine treatments.

Conclusions: In this study, we show evidence for the temporal selection of functional ESR1 mutations as potential drivers of endocrine resistance during the progression of ER(+) breast cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-2332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3998833PMC
April 2014

Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets.

Cancer Discov 2014 Feb 19;4(2):232-45. Epub 2013 Dec 19.

Departments of 1Medicine, 2Pathology, Microbiology & Immunology, 3Cancer Biology, and 4Biochemistry; 5Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee; Departments of 6Cell & Tissue Biology and 7Medicine, University of California, San Francisco, San Francisco, California; 8Foundation Medicine, Cambridge, Massachusetts; 9Oncosalud; and 10Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima, Perú

Unlabelled: Neoadjuvant chemotherapy (NAC) induces a pathologic complete response (pCR) in approximately 30% of patients with triple-negative breast cancers (TNBC). In patients lacking a pCR, NAC selects a subpopulation of chemotherapy-resistant tumor cells. To understand the molecular underpinnings driving treatment-resistant TNBCs, we performed comprehensive molecular analyses on the residual disease of 74 clinically defined TNBCs after NAC, including next-generation sequencing (NGS) on 20 matched pretreatment biopsies. Combined NGS and digital RNA expression analysis identified diverse molecular lesions and pathway activation in drug-resistant tumor cells. Ninety percent of the tumors contained a genetic alteration potentially treatable with a currently available targeted therapy. Thus, profiling residual TNBCs after NAC identifies targetable molecular lesions in the chemotherapy-resistant component of the tumor, which may mirror micrometastases destined to recur clinically. These data can guide biomarker-driven adjuvant studies targeting these micrometastases to improve the outcome of patients with TNBC who do not respond completely to NAC.

Significance: This study demonstrates the spectrum of genomic alterations present in residual TNBC after NAC. Because TNBCs that do not achieve a CR after NAC are likely to recur as metastatic disease at variable times after surgery, these alterations may guide the selection of targeted therapies immediately after mastectomy before these metastases become evident.
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http://dx.doi.org/10.1158/2159-8290.CD-13-0286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3946308PMC
February 2014

Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing.

Nat Biotechnol 2013 Nov 20;31(11):1023-31. Epub 2013 Oct 20.

1] Foundation Medicine, Cambridge, Massachusetts, USA. [2].

As more clinically relevant cancer genes are identified, comprehensive diagnostic approaches are needed to match patients to therapies, raising the challenge of optimization and analytical validation of assays that interrogate millions of bases of cancer genomes altered by multiple mechanisms. Here we describe a test based on massively parallel DNA sequencing to characterize base substitutions, short insertions and deletions (indels), copy number alterations and selected fusions across 287 cancer-related genes from routine formalin-fixed and paraffin-embedded (FFPE) clinical specimens. We implemented a practical validation strategy with reference samples of pooled cell lines that model key determinants of accuracy, including mutant allele frequency, indel length and amplitude of copy change. Test sensitivity achieved was 95-99% across alteration types, with high specificity (positive predictive value >99%). We confirmed accuracy using 249 FFPE cancer specimens characterized by established assays. Application of the test to 2,221 clinical cases revealed clinically actionable alterations in 76% of tumors, three times the number of actionable alterations detected by current diagnostic tests.
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http://dx.doi.org/10.1038/nbt.2696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710001PMC
November 2013

Targeted next-generation sequencing of head and neck squamous cell carcinoma identifies novel genetic alterations in HPV+ and HPV- tumors.

Genome Med 2013 29;5(5):49. Epub 2013 May 29.

UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK.

Background: Human papillomavirus positive (HPV+) head and neck squamous cell carcinoma (HNSCC) is an emerging disease, representing a distinct clinical and epidemiological entity. Understanding the genetic basis of this specific subtype of cancer could allow therapeutic targeting of affected pathways for a stratified medicine approach.

Methods: Twenty HPV+ and 20 HPV- laser-capture microdissected oropharyngeal carcinomas were used for paired-end sequencing of hybrid-captured DNA, targeting 3,230 exons in 182 genes often mutated in cancer. Copy number alteration (CNA) profiling, Sequenom MassArray sequencing and immunohistochemistry were used to further validate findings.

Results: HPV+ and HPV- oropharyngeal carcinomas cluster into two distinct subgroups. TP53 mutations are detected in 100% of HPV negative cases and abrogation of the G1/S checkpoint by CDKN2A/B deletion and/or CCND1 amplification occurs in the majority of HPV- tumors.

Conclusion: These findings strongly support a causal role for HPV, acting via p53 and RB pathway inhibition, in the pathogenesis of a subset of oropharyngeal cancers and suggest that studies of CDK inhibitors in HPV- disease may be warranted. Mutation and copy number alteration of PI3 kinase (PI3K) pathway components appears particularly prevalent in HPV+ tumors and assessment of these alterations may aid in the interpretation of current clinical trials of PI3K, AKT, and mTOR inhibitors in HNSCC.
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http://dx.doi.org/10.1186/gm453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4064312PMC
August 2014

Next-generation sequencing reveals high concordance of recurrent somatic alterations between primary tumor and metastases from patients with non-small-cell lung cancer.

J Clin Oncol 2013 Jun 29;31(17):2167-72. Epub 2013 Apr 29.

Institut National de la Santé et de la Recherche Médicale (INSERM) U981, Villejuif, France.

Purpose: Characterization of the genomic changes that drive an individual patient's disease is critical in management of many cancers. In patients with non-small-cell lung cancer (NSCLC), obtaining tumor samples of sufficient size for genomic profiling on recurrence is often challenging. We undertook this study to compare genomic alterations identified in archived primary tumors from patients with NSCLC with those identified in metachronous or synchronous metastases.

Patients And Methods: Primary and matched metastatic tumor pairs from 15 patients were analyzed by using a targeted next-generation sequencing assay in a Clinical Laboratory Improvement Amendments laboratory. Genomic libraries were captured for 3,230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to high coverage.

Results: Among 30 tumors, 311 genomic alterations were identified of which 63 were known recurrent (32 in primary tumor, 31 in metastasis) and 248 were nonrecurrent (likely passenger). TP53 mutations were the most frequently observed recurrent alterations (12 patients). Tumors harbored two or more (maximum four) recurrent alterations in 10 patients. Comparative analysis of recurrent alterations between primary tumor and matched metastasis revealed a concordance rate of 94% compared with 63% for likely passenger alterations.

Conclusion: This high concordance suggests that for the purposes of genomic profiling, use of archived primary tumor can identify the key recurrent somatic alterations present in matched NSCLC metastases and may provide much of the relevant genomic information required to guide treatment on recurrence.
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http://dx.doi.org/10.1200/JCO.2012.47.7737DOI Listing
June 2013

Targeted genomic sequencing of pediatric Burkitt lymphoma identifies recurrent alterations in antiapoptotic and chromatin-remodeling genes.

Blood 2012 Dec 22;120(26):5181-4. Epub 2012 Oct 22.

Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

To ascertain the genetic basis of pediatric Burkitt lymphoma (pBL), we performed clinical-grade next-generation sequencing of 182 cancer-related genes on 29 formalin-fixed, paraffin embedded primary pBL samples. Ninety percent of cases had at least one mutation or genetic alteration, most commonly involving MYC and TP53. EBV(-) cases were more likely than EBV(+) cases to have multiple mutations (P < .0001). Alterations in tumor-related genes not previously described in BL were identified. Truncating mutations in ARID1A, a member of the SWI/SNF nucleosome remodeling complex, were seen in 17% of cases. MCL1 pathway alterations were found in 22% of cases and confirmed in an expanded panel. Other clinically relevant genomic alterations were found in 20% of cases. Our data suggest the roles of MCL1 and ARID1A in BL pathogenesis and demonstrate that comprehensive genomic profiling may identify additional treatment options in refractory disease.
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http://dx.doi.org/10.1182/blood-2012-06-437624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537311PMC
December 2012

Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity.

Eur Urol 2013 May 5;63(5):920-6. Epub 2012 Sep 5.

Department of Medicine, Division of Hematology and Medical Oncology, Weill Medical College of Cornell University, New York, NY 10065, USA.

Background: Most personalized cancer care strategies involving DNA sequencing are highly reliant on acquiring sufficient fresh or frozen tissue. It has been challenging to comprehensively evaluate the genome of advanced prostate cancer (PCa) because of limited access to metastatic tissue.

Objective: To demonstrate the feasibility of a novel next-generation sequencing (NGS)-based platform that can be used with archival formalin-fixed paraffin-embedded (FFPE) biopsy tissue to evaluate the spectrum of DNA alterations seen in advanced PCa.

Design, Setting, And Participants: FFPE samples (including archival prostatectomies and prostate needle biopsies) were obtained from 45 patients representing the spectrum of disease: localized PCa, metastatic hormone-naive PCa, and metastatic castration-resistant PCa (CRPC). We also assessed paired primaries and metastases to understand disease heterogeneity and disease progression.

Intervention: At least 50 ng of tumor DNA was extracted from FFPE samples and used for hybridization capture and NGS using the Illumina HiSeq 2000 platform.

Outcome Measurements And Statistical Analysis: A total of 3320 exons of 182 cancer-associated genes and 37 introns of 14 commonly rearranged genes were evaluated for genomic alterations.

Results And Limitations: We obtained an average sequencing depth of >900X. Overall, 44% of CRPCs harbored genomic alterations involving the androgen receptor gene (AR), including AR copy number gain (24% of CRPCs) or AR point mutation (20% of CRPCs). Other recurrent mutations included transmembrane protease, serine 2 gene (TMPRSS2):v-ets erythroblastosis virus E26 oncogene homolog (avian) gene (ERG) fusion (44%); phosphatase and tensin homolog gene (PTEN) loss (44%); tumor protein p53 gene (TP53) mutation (40%); retinoblastoma gene (RB) loss (28%); v-myc myelocytomatosis viral oncogene homolog (avian) gene (MYC) gain (12%); and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α gene (PIK3CA) mutation (4%). There was a high incidence of genomic alterations involving key genes important for DNA repair, including breast cancer 2, early onset gene (BRCA2) loss (12%) and ataxia telangiectasia mutated gene (ATM) mutations (8%); these alterations are potentially targetable with poly(adenosine diphosphate-ribose)polymerase inhibitors. A novel and actionable rearrangement involving the v-raf murine sarcoma viral oncogene homolog B1 gene (BRAF) was also detected.

Conclusions: This first-in-principle study demonstrates the feasibility of performing in-depth DNA analyses using FFPE tissue and brings new insight toward understanding the genomic landscape within advanced PCa.
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http://dx.doi.org/10.1016/j.eururo.2012.08.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615043PMC
May 2013

Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies.

Nat Med 2012 Feb 12;18(3):382-4. Epub 2012 Feb 12.

Foundation Medicine, Cambridge, Massachusetts, USA.

Applying a next-generation sequencing assay targeting 145 cancer-relevant genes in 40 colorectal cancer and 24 non-small cell lung cancer formalin-fixed paraffin-embedded tissue specimens identified at least one clinically relevant genomic alteration in 59% of the samples and revealed two gene fusions, C2orf44-ALK in a colorectal cancer sample and KIF5B-RET in a lung adenocarcinoma. Further screening of 561 lung adenocarcinomas identified 11 additional tumors with KIF5B-RET gene fusions (2.0%; 95% CI 0.8-3.1%). Cells expressing oncogenic KIF5B-RET are sensitive to multi-kinase inhibitors that inhibit RET.
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http://dx.doi.org/10.1038/nm.2673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916180PMC
February 2012

Estrogen receptor (ESR1) mRNA expression and benefit from tamoxifen in the treatment and prevention of estrogen receptor-positive breast cancer.

J Clin Oncol 2011 Nov 26;29(31):4160-7. Epub 2011 Sep 26.

National Surgical Adjuvant Breast and Bowel Project, Division of Pathology, 1307 Federal St, Pittsburgh, PA 15212, USA.

Purpose: Several mechanisms have been proposed to explain tamoxifen resistance of estrogen receptor (ER) -positive tumors, but a clinically useful explanation for such resistance has not been described. Because the ER is the treatment target for tamoxifen, a linear association between ER expression levels and the degree of benefit from tamoxifen might be expected. However, such an association has never been demonstrated with conventional clinical ER assays, and the ER is currently used clinically as a dichotomous marker. We used gene expression profiling and ER protein assays to help elucidate molecular mechanism(s) responsible for tamoxifen resistance in breast tumors.

Patients And Methods: We performed gene expression profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1). This was a retrospective subset analysis based on available materials.

Results: In B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined, including PGR and ERBB2. On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than two-fold in ER-positive cancer events in the tamoxifen arm (P < .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression.

Conclusion: These data suggest that low-level expression of ESR1 is a determinant of tamoxifen resistance in ER-positive breast cancer. Strategies should be developed to identify, treat, and prevent such tumors.
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http://dx.doi.org/10.1200/JCO.2010.32.9615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3208536PMC
November 2011

Whole cancer genome sequencing by next-generation methods.

Am J Clin Pathol 2011 Oct;136(4):527-39

Department of Pathology, Albany Medical College, 47 New Scotland Ave., Albany, NY 12208, USA.

Traditional approaches to sequence analysis are widely used to guide therapy for patients with lung and colorectal cancer and for patients with melanoma, sarcomas (eg, gastrointestinal stromal tumor), and subtypes of leukemia and lymphoma. The next-generation sequencing (NGS) approach holds a number of potential advantages over traditional methods, including the ability to fully sequence large numbers of genes (hundreds to thousands) in a single test and simultaneously detect deletions, insertions, copy number alterations, translocations, and exome-wide base substitutions (including known "hot-spot mutations") in all known cancer-related genes. Adoption of clinical NGS testing will place significant demands on laboratory infrastructure and will require extensive computational expertise and a deep knowledge of cancer medicine and biology to generate truly useful "clinically actionable" reports. It is anticipated that continuing advances in NGS technology will lower the overall cost, speed the turnaround time, increase the breadth of genome sequencing, detect epigenetic markers and other important genomic parameters, and become applicable to smaller and smaller specimens, including circulating tumor cells and circulating free DNA in plasma.
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http://dx.doi.org/10.1309/AJCPR1SVT1VHUGXWDOI Listing
October 2011

Comprehensive next-generation cancer genome sequencing in the era of targeted therapy and personalized oncology.

Biomark Med 2011 Jun;5(3):293-305

Foundation Medicine, Cambridge, MA, USA.

DNA sequence analysis has become a significant laboratory test in oncology, permitting treatment to become increasingly personalized for both solid tumors and hematologic malignancies. Traditional approaches to sequence analysis, including Sanger sequencing, pyrosequencing and allele-specific PCR, are now widely used to guide therapy for patients diagnosed with lung and colorectal cancer as well as for melanoma, sarcomas (e.g., gastrointestinal stromal tumors) and subtypes of leukemia and lymphoma. Traditional sequence analysis has been limited in bandwidth and throughput and as a result, has been focused exclusively on testing the most common aberrations in key genes or fully sequencing single genes. The massively parallel or next-generation sequencing (NGS) approach to DNA analysis holds a number of potential advantages over the traditional methods, including the ability to fully sequence large numbers of genes (hundreds to thousands) in a single test. Furthermore, NGS can simultaneously detect deletions, insertions, copy number alterations, translocations and exome-wide base substitutions (including known hot-spot mutations) in all known cancer-related genes. However, significant challenges, particularly with respect to demands on expertise and infrastructure, will have to be overcome to translate NGS to the bedside of the cancer patient. Extensive computational expertise is required to bring NGS into clinical context, and a deep knowledge of cancer medicine and cancer biology will be required to generate truly useful, so-called 'clinically actionable' reports for clinicians. While NGS is on the cusp of being launched as a clinical test, it may be expected that the near future will continue to bring major advances in the technology that will lower the overall cost, speed up the turnaround time, increase the breadth of genome sequencing, and detect epigenetic markers and other important genomic parameters, while becoming applicable to smaller and smaller specimens, including circulating tumor cells and circulating free DNA in plasma.
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http://dx.doi.org/10.2217/bmm.11.37DOI Listing
June 2011

RT-PCR-based gene expression profiling for cancer biomarker discovery from fixed, paraffin-embedded tissues.

Methods Mol Biol 2011 ;724:239-57

Genomic Health, Inc., Redwood City, CA, USA.

A molecular test providing clear identification of individuals at highest risk for developing metastatic disease from among early stage breast cancer patients has proven to be of great benefit in breast cancer treatment planning and therapeutic management. Patients with high risk of disease recurrence can also get an estimate of the magnitude of benefit to be gained by adding chemotherapy to surgery and hormonal therapy. Developing this clinical test was made possible by the availability of technologies capable of identifying molecular biomarkers from the gene expression profiles of preserved surgical specimens. Molecular tests such as the Oncotype DX(®) breast cancer test are proving to be more effective tools for individualized patient stratification and treatment planning than traditional methods such as patient demographic variables and histopathology indicators.Molecular biomarkers must be clinically validated before they can be effectively applied toward patient management in clinical practice. The most effective and efficient means of clinical validation is to use archived surgical specimens annotated with well-characterized clinical outcomes. However, carrying out this type of clinical study requires optimization of traditional molecular expression profiling techniques to analyze RNA from fixed, paraffin-embedded (FPE) tissues. In order to develop our clinically validated breast cancer assay, we modified molecular methods for RNA extraction, RNA quantitation, reverse transcription, and quantitative PCR to work optimally in archived clinical samples. Here, we present an updated description of current best practices for isolating both mRNA and microRNA from FPE tissues for RT-PCR-based expression profiling.
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http://dx.doi.org/10.1007/978-1-61779-055-3_15DOI Listing
June 2011

Rt-PCR gene expression profiling of RNA from paraffin-embedded tissues prepared using a range of different fixatives and conditions.

Methods Mol Biol 2011 ;724:205-37

Genomic Health, Inc., Redwood City, CA, USA.

Although RNA is isolated from archival fixed tissues routinely for reverse transcription polymerase chain reaction (RT-PCR) and microarray analyses to identify biomarkers of cancer prognosis and therapeutic response prediction, the sensitivity of these molecular profiling methods to variability in pathology tissue processing has not been described in depth. As increasing numbers of expression analysis studies using fixed archival tumor specimens are reported, it is important to examine how dependent these results are on tissue-processing methods.We carried out a series of studies to systematically evaluate the effects of various tissue-fixation reagents and protocols on RNA quality and RT-PCR gene expression profiles. Human placenta was selected as a model specimen for these studies since it is relatively easily obtained and has proliferative and invasive qualities similar to solid tumors. In addition, each specimen is relatively homogeneous and large enough to provide sufficient tissue to systematically compare a range of fixation conditions and reagents, thereby avoiding the variability inherent in studying collections of tumor tissue specimens. Since anatomical pathology laboratories generally offer hundreds of different tissue-fixation protocols, we focused on fixation reagents and conditions used to process the most common solid tumors for primary cancer diagnosis. Fresh placentas donated under an IRB-approved protocol were collected at delivery and immediately submerged in cold saline for transport to a central pathology laboratory for processing. RNA was extracted from each specimen, quantified, and analyzed for size distribution and analytical performance using a panel of 24 RT-PCR gene expression assays. We found that different tissue-fixation reagents and tissue-processing conditions resulted in widely varying RNA extraction yields and extents of RNA fragmentation. However, the RNA extraction method and RT-PCR assays could be optimized to achieve successful gene expression analysis for nearly all fixation conditions represented in these studies.
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http://dx.doi.org/10.1007/978-1-61779-055-3_14DOI Listing
June 2011

Rate of pregnancy after using drospirenone and other progestin-containing oral contraceptives.

Obstet Gynecol 2009 Sep;114(3):616-622

From Bayer Schering Pharma AG, and ZEG-Center for Epidemiology and Health Research, Berlin, Germany.

Objectives: To determine whether prior oral-contraceptive use has a negative effect on the ability of women to conceive in both the short-term and long-term.

Methods: The European Active Surveillance Study on Oral Contraceptives (EURAS-OC) was a controlled, prospective, noninterventional cohort study of 59,510 users of oral contraceptives containing drospirenone or other progestins in clinical practice in seven European countries. In a planned secondary analysis, pregnancy outcomes were investigated in 2,064 participants in EURAS-OC who stopped oral-contraceptive use after study entry because of planned pregnancy. The influence of age, parity, progestin type, ethinylestradiol dose, duration of oral-contraceptive use, and smoking status on the rate of pregnancy was assessed.

Results: Overall, 21.1% (95% confidence interval [CI] 19.4-23.0%) of the past oral-contraceptive users were pregnant one cycle after oral-contraceptive cessation. This rate increased to 79.4% (95% CI 77.6-81.1%) at 1 year (13 cycles). Progestin type, ethinylestradiol dose, duration of oral-contraceptive use, and parity had no major influence on the rate of pregnancy after oral-contraceptive cessation. Up to age 35 years, age had only a minor influence on the rate of pregnancy. Rates of pregnancy were reduced in women older than 35 years and in current smokers.

Conclusion: Previous oral-contraceptive use does not negatively affect initial and 1-year rates of pregnancy after oral-contraceptive cessation. A comparison of these data with data external to this study indicates that the negative effect of aging on fecundity is not amplified by oral-contraceptive use.

Level Of Evidence: II.
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http://dx.doi.org/10.1097/AOG.0b013e3181b46f54DOI Listing
September 2009

Oral contraceptive effectiveness according to body mass index, weight, age, and other factors.

Am J Obstet Gynecol 2009 Sep 30;201(3):263.e1-9. Epub 2009 May 30.

ZEG-Center for Epidemiology and Health Research, Berlin, Germany.

Objective: The purpose of this study was to assess the use-effectiveness of oral contraceptives (OCs) in Europe according to body mass index (BMI), weight, age, and other factors.

Study Design: In a planned secondary analysis, we used data from the European Active Surveillance Study on Oral Contraceptives, which was a prospective active cohort surveillance study of 59,510 OC users, to assess the effectiveness of OCs overall and by BMI, weight, age, duration of use, ethinylestradiol dose, regimen type, starting/switching status, and parity. Self-reported unplanned pregnancies during OC use were confirmed by interview.

Results: An analysis of OC effectiveness (112,659 women-years of exposure and 545 unplanned pregnancies) found little variation in effectiveness by BMI/weight. Failure rates decreased after 30 years of age and with an increasing duration of use.

Conclusion: OC users in Europe reported high contraceptive effectiveness with "typical use." Failure rates decreased with age and duration of use. BMI and weight had little, if any, influence on effectiveness.
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http://dx.doi.org/10.1016/j.ajog.2009.03.017DOI Listing
September 2009

Tumor marker discovery by expression profiling RNA from formalin fixed paraffin embedded tissues.

Methods Mol Biol 2009 ;520:177-93

Research Department, Genomic Health, Inc., Redwood City, CA, USA.

Clear identification among early-stage cancer patients of those at highest risk of having metastatic disease would be of great benefit in treatment planning and management. Considerable additional benefit would accrue to high-risk patients if their responses to specific therapeutic alternatives could be predicted. Molecular biomarkers in the form of gene expression profiles are proving to be more effective tools for both prognostic and predictive patient stratification than more traditional methods such as patient demographics and histopathology indicators. Such biomarkers must be clinically validated before they can be effectively used to manage patients in clinical studies or clinical practice. This can be most efficiently accomplished by analyzing archived clinical samples with well-characterized clinical outcomes. Doing studies of this type requires reoptimization of traditional molecular expression profiling techniques to analyze RNA from fixed paraffin-embedded tissues. We have modified molecular methods for RNA extraction, RNA quantification, reverse transcription, and quantitative PCR to work optimally in archived clinical samples in order to develop a clinically validated assay for breast cancer prognosis and prediction of patient response to hormonal and chemotherapy.
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http://dx.doi.org/10.1007/978-1-60327-811-9_13DOI Listing
May 2009
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