Collaborative Translational Research Research Articles

American College of Rheumatology White Paper: The Effects of Climate Change on Rheumatic Conditions-An Evolving Landscape and a Path Forward.

Increases in global temperatures and extreme weather events associated with climate change have complex yet poorly understood detrimental impacts on human health. We reviewed the current published literature on climate change-related effects and rheumatic conditions. To summarize our current understanding of the likely effects of climate change, including increased air pollution, on rheumatic disease, we searched the published, peer-reviewed English-language literature from January 2000 to December 2022. Articles were reviewed by a team of rheumatologists and clinical and translational science researchers. Systematic review articles were not included but informed additional literature searches. After extensive examination and adjudication, 88 articles met inclusion criteria and were selected for review. Much of the epidemiologic investigations assessed associations between air pollution and increased risk of development of rheumatoid arthritis, anti-citrullinated protein antibodies, flares of gout, and hospitalizations for systemic lupus erythematosus. Increased heat vulnerability was associated with higher odds of recurrent hospitalizations across rheumatic conditions. Mechanisms for observed associations are poorly understood but could include the effects of epigenetic changes, oxidative stress, and inflammatory cytokines. Studies had limitations, including restricted geography and populations studied without focus on historically marginalized communities at highest risk for adverse effects from pollution and climate change, the relative lack of mechanistic evaluations, and most with only indirect links to climate change. To date, the published literature lacks studies that directly examine effects of climate change on rheumatic diseases. Collaborative translational and epidemiologic research is needed to enhance our understanding and awareness in this area.

491 Outcomes of an Integrated Research Ethics Consultation Service

OBJECTIVES/GOALS: The need for mechanisms of ethical discourse and guidance has increased as translational research collaborations become more complex. The goal of this project is to analyze the stakeholder engagement and ethical issues our research ethics consultation service (RECS) conducted over a two year period. METHODS/STUDY POPULATION: We conducted a retrospective review of our RECS database from 2020 to 2022. We examined the nature of the research and ethical issues of concern from consult requestors, including whether or not consults were preventative. In addition, we assessed the educational outreach conducted during that timeframe as a measure of service awareness. RESULTS/ANTICIPATED RESULTS: There was a total of 42 consults conducted over the previous year. There were a wide variety of issues related to informed IRB-related processes (31%), consent (24%), QA/QI determination (12%), authorship (10%), confidentiality (7%), diversity/inclusion (7%), grant preparation (7%). Many of the consults (n=28, 67%) included secondary issues. A few consults (n=4, 10%) were preventative, meaning that the consult was requested in anticipation or consideration of a potential ethical issue. Outreach efforts extended to a diverse array of institutional stakeholders and trainees. DISCUSSION/SIGNIFICANCE: The RECS serves numerous constituencies throughout our institution on ethical issues spanning nearly all aspects of research design, conduct, and analysis. These data highlight initiatives to increase study efficiency (in collaboration with institutional research oversight) and helps to direct educational efforts and outreach.

Framework to assess Conference Outcome Assessment Tool (COAT) in educational institutions

The Science, Technology & Innovation (STI) Policy of India focuses to accelerate collaborative and interconnection translational research between the different stakeholders which enables addressing complex topics. To reach that level, conferences play an important role in the debate and exposure of these complex issues. HEIs spend lots of funds on organizing these conferences. However, the desired outcome assessment for sustainable impact is always lacking. The conference reports or proceedings ignore significant attributes of the stakeholders/ participants such as behavioural skills and motivational aspects such as attitude and ambition behind their participation in the conference. The objective of this paper is to identify parameters for conference outcome mapping and assessment which is useful to ascertain the translation of the discussions and presentations during conference in the prospects – career, research, outreach, etc., not only for participants but also for the organizing institutions. The Authors have developed the Conference Outcome Assessment Tool – COAT© to bring out the culture of Outcome and Quality enhancement in all aspects of research activities in HEIs with qualitative and quantitative assessments of their performance. To develop the Tool, the authors have identified various factors having a direct/indirect impact on all stakeholders throughout the conference. The Implementation of COAT© in HEIs will contribute to maintaining the overall research quality and provide the expected outcomes to researchers/scholars/scientists/industry. This will also boost the collaborations between academia and industry.

Trecode: A FAIR Eco-System for the Analysis and Archiving of Omics Data in a Combined Diagnostic and Research Setting

The increase in speed, reliability, and cost-effectiveness of high-throughput sequencing has led to the widespread clinical application of genome (WGS), exome (WXS), and transcriptome analysis. WXS and RNA sequencing is now being implemented as the standard of care for patients and for patients included in clinical studies. To keep track of sample relationships and analyses, a platform is needed that can unify metadata for diverse sequencing strategies with sample metadata whilst supporting automated and reproducible analyses, in essence ensuring that analyses are conducted consistently and data are Findable, Accessible, Interoperable, and Reusable (FAIR).We present “Trecode”, a framework that records both clinical and research sample (meta) data and manages computational genome analysis workflows executed for both settings, thereby achieving tight integration between analysis results and sample metadata. With complete, consistent, and FAIR (meta) data management in a single platform, stacked bioinformatic analyses are performed automatically and tracked by the database, ensuring data provenance, reproducibility, and reusability, which is key in worldwide collaborative translational research. The Trecode data model, codebooks, NGS workflows, and client programs are publicly available. In addition, the complete software stack is coded in an Ansible playbook to facilitate automated deployment and adoption of Trecode by other users.

SPINE20 recommendations 2022: spine care-working together to recover stronger.

Globally, spine disorders are the leading cause of disability, affecting more than half a billion individuals. However, less than 50% of G20 countries specifically identify spine health within their public policy priorities. Therefore, it is crucial to raise awareness among policy makers of the disabling effect of spine disorders and their impact on the economic welfare of G20 nations. In 2019, SPINE20 was established as the leading advocacy group to bring global attention to spine disorders. Recommendations were developed through two Delphi methods with international and multi-professional panels. In 2022, seven recommendations were delivered to the leaders of G20 countries, urging them to: Develop action plans to provide universal access to evidence-based spine care that incorporates the needs of minorities and vulnerable populations. Invest in the development of sustainable human resource capacity, through multisectoral and inter-professional competency-based education and training to promote evidence-based approaches to spine care, and to build an appropriate healthcare working environment that optimizes the delivery of safe health services. Develop policies using the best available evidence to properly manage spine disorders and to prolong functional healthy life expectancy in the era of an aging population. Create a competent workforce and improve the healthcare infrastructure/facilities including equipment to provide evidence-based inter-professional rehabilitation services to patients with spinal cord injury throughout their continuum of care. Build collaborative and innovative translational research capacity within national, regional, and global healthcare systems for state-of-the-art and cost-effective spine care across the healthcare continuum ensuring equality, diversity, and inclusion of all stakeholders. Develop international consensus statements on patient outcomes and how they can be used to define and develop pathways for value-based care. Recognize that intervening on determinants of health including physical activity, nutrition, physical and psychosocial workplace environment, and smoking-free lifestyle can reduce the burden of spine disabilities and improve the health status and wellness of the population. At the third SPINE20 summit 2022 which took place in Bali, Indonesia, in August 2022, 17 associations endorsed its recommendations. SPINE20 advocacy efforts focus on developing public policy recommendations to improve the health, welfare, and wellness of all who suffer from spinal pain and disability. We propose that focusing on facilitating access to systems that prioritize value-based care delivered by a competent healthcare workforce will reduce disability and improve the productivity of the G20 nations.

A Comparative Assessment of the Diagnosis of Swallowing Impairment and Gastroesophageal Reflux in Canines and Humans.

Swallowing impairment is a highly prevalent and clinically significant problem affecting people and dogs. There are myriad causes of swallowing impairment of which gastroesophageal reflux is the most common in both species. Similarities in anatomy and physiology between humans and canines results in analogous swallowing disorders including cricopharyngeus muscle achalasia, esophageal achalasia, hiatal herniation, and gastroesophageal reflux with secondary esophagitis and esophageal dysmotility. Accordingly, the diagnostic approach to human and canine patients with swallowing impairment is similar. Diagnostic procedures such as swallowing fluoroscopy, high-resolution manometry, pH/impedance monitoring, and endolumenal functional luminal imaging probe can be performed in both species; however, nasofacial conformation, increased esophageal length, and the difficulty of completing several of these procedures in awake dogs are inherent challenges that need to be considered. Human patients can convey their symptoms and respond to verbal cues, whereas veterinarians must rely on clinical histories narrated by pet owners followed by comprehensive physical examination and observation of the animal eating different food consistencies and drinking water. Dogs may also be unwilling to drink or eat in the hospital setting and may be resistant to physical restraint during diagnostic procedures. Despite the species differences and diagnostic challenges, dogs are a natural animal model for many oropharyngeal and esophageal disorders affecting people, which presents a tremendous opportunity for shared learnings. This manuscript reviews the comparative aspects of esophageal anatomy and physiology between humans and canines, summarizes the diagnostic assessment of swallowing impairment in both species, and discusses future considerations for collaborative medicine and translational research.

Large scale clinical trials: lessons from the COVID-19 pandemic

BackgroundThe COVID-19 pandemic has presented substantial new challenges to clinical and research teams. Our objective was to analyse the experience of investigators and research delivery staff regarding the research response...

Trends in big data analyses by multicenter collaborative translational research in psychiatry.

The underlying pathologies of psychiatric disorders, which cause substantial personal and social losses, remain unknown, and their elucidation is an urgent issue. To clarify the core pathological mechanisms underlying psychiatric disorders, in addition to laboratory‐based research that incorporates the latest findings, it is necessary to conduct large‐sample‐size research and verify reproducibility. For this purpose, it is critical to conduct multicenter collaborative research across various fields, such as psychiatry, neuroscience, molecular biology, genomics, neuroimaging, cognitive science, neurophysiology, psychology, and pharmacology. Moreover, collaborative research plays an important role in the development of young researchers. In this respect, the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) consortium and Cognitive Genetics Collaborative Research Organization (COCORO) have played important roles. In this review, we first overview the importance of multicenter collaborative research and our target psychiatric disorders. Then, we introduce research findings on the pathophysiology of psychiatric disorders from neurocognitive, neurophysiological, neuroimaging, genetic, and basic neuroscience perspectives, focusing mainly on the findings obtained by COCORO. It is our hope that multicenter collaborative research will contribute to the elucidation of the pathological basis of psychiatric disorders.

Identifying Community-Engaged Translational Research Collaboration Experience and Health Interests of Community-Based Organizations Outside of Metropolitan Atlanta

Identifying Community-Engaged Translational Research Collaboration Experience and Health Interests of Community-Based Organizations Outside of Metropolitan Atlanta

A large National Institute for Health\xa0Research (NIHR) Biomedical Research Centre facilitates impactful cross-disciplinary and collaborative translational research publications and research collaboration\xa0networks: a bibliometric evaluation study

BackgroundThe evaluation of translational health research is important for various reasons such as the research impact assessment, research funding allocation, accountability, and strategic research policy formulation. The purpose of this study was to evaluate the research productivity, strength and diversity of research collaboration networks and impact of research supported by a large biomedical research centre in the United Kingdom (UK).MethodsBibliometric analysis of research publications by translational researchers affiliated with the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) from April 2012 to March 2017.ResultsAnalysis included 2377 translational research publications that were published during the second 5-year funding period of the NIHR Oxford BRC. Author details were available for 99.75% of the publications with DOIs (2359 of 2365 with DOIs), and the number of authors per publication was median 9 (mean = 18.03, SD = 3.63, maximum = 2467 authors). Author lists also contained many consortia, groups, committees, and teams (n = 165 in total), with 1238 additional contributors, where membership was reported. The BRC co-authorship i.e., research collaboration network for these publications involved 20,229 nodes (authors, of which 1606 nodes had Oxford affiliations), and approximately 4.3 million edges (authorship linkages). Articles with a valid DOIs (2365 of 2377, 99.5%) were collectively cited more than 155,000 times and the average Field Citation Ratio was median 6.75 (geometric mean = 7.12) while the average Relative Citation Ratio was median 1.50 (geometric mean = 1.83) for the analysed publications.ConclusionsThe NIHR Oxford BRC generated substantial translational research publications and facilitated a huge collaborative network of translational researchers working in complex structures and consortia, which shows success across the whole of this BRC funding period. Further research involving continued uptake of unique persistent identifiers and the tracking of other research outputs such as clinical innovations and patents would allow a more detailed understanding of large research enterprises such as NIHR BRCs in the UK.

A diagnostic miRNA signature for pulmonary arterial hypertension using a consensus machine learning approach.

BackgroundPulmonary arterial hypertension (PAH) is a rare but life shortening disease, the diagnosis of which is often delayed, and requires an invasive right heart catheterisation. Identifying diagnostic biomarkers may improve screening to identify patients at risk of PAH earlier and provide new insights into disease pathogenesis. MicroRNAs are small, non-coding molecules of RNA, previously shown to be dysregulated in PAH, and contribute to the disease process in animal models.MethodsPlasma from 64 treatment naïve patients with PAH and 43 disease and healthy controls were profiled for microRNA expression by Agilent Microarray. Following quality control and normalisation, the cohort was split into training and validation sets. Four separate machine learning feature selection methods were applied to the training set, along with a univariate analysis.Findings20 microRNAs were identified as putative biomarkers by consensus feature selection from all four methods. Two microRNAs (miR-636 and miR-187-5p) were selected by all methods and used to predict PAH diagnosis with high accuracy. Integrating microRNA expression profiles with their associated target mRNA revealed 61 differentially expressed genes verified in two independent, publicly available PAH lung tissue data sets. Two of seven potentially novel gene targets were validated as differentially expressed in vitro in human pulmonary artery smooth muscle cells.InterpretationThis consensus of multiple machine learning approaches identified two miRNAs that were able to distinguish PAH from both disease and healthy controls. These circulating miRNA, and their target genes may provide insight into PAH pathogenesis and reveal novel regulators of disease and putative drug targets.

DNA-based screening and population health: a points to consider statement for programs and sponsoring organizations from the American College of Medical Genetics and Genomics (ACMG)

DNA-based screening and population health: a points to consider statement for programs and sponsoring organizations from the American College of Medical Genetics and Genomics (ACMG)

The Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat): Driving Multicentric Research and Implementation Science.

Dementia is becoming increasingly prevalent in Latin America, contrasting with stable or declining rates in North America and Europe. This scenario places unprecedented clinical, social, and economic burden upon patients, families, and health systems. The challenges prove particularly pressing for conditions with highly specific diagnostic and management demands, such as frontotemporal dementia. Here we introduce a research and networking initiative designed to tackle these ensuing hurdles, the Multi-partner consortium to expand dementia research in Latin America (ReDLat). First, we present ReDLat's regional research framework, aimed at identifying the unique genetic, social, and economic factors driving the presentation of frontotemporal dementia and Alzheimer's disease in Latin America relative to the US. We describe ongoing ReDLat studies in various fields and ongoing research extensions. Then, we introduce actions coordinated by ReDLat and the Latin America and Caribbean Consortium on Dementia (LAC-CD) to develop culturally appropriate diagnostic tools, regional visibility and capacity building, diplomatic coordination in local priority areas, and a knowledge-to-action framework toward a regional action plan. Together, these research and networking initiatives will help to establish strong cross-national bonds, support the implementation of regional dementia plans, enhance health systems' infrastructure, and increase translational research collaborations across the continent.

Treatment of low-risk gestational trophoblastic neoplasia.

Low-risk gestational trophoblastic neoplasia (GTN), defined as FIGO/WHO score 0-6, is highly curable with an overall survival rate, which is approximately 100%. For most low-risk GTN patients, first-line single-agent chemotherapy with either methotrexate or actinomycin-D is recommended with overall complete human chorionic gonadotrophin (hCG) response rates of 60%-90% in mostly retrospective, non-randomised studies. The few randomised trials that exist are not appropriately powered or designed to define the optimal first-line treatment. Approximately 25%-30% of low-risk patients will develop resistance to initial single-agent chemotherapy with an increase in the FIGO score, a diagnosis of choriocarcinoma, higher pre-treatment hCG and the presence of metastatic disease being associated with an increase in the risk of resistance. The optimal treatment of patients scoring WHO 5 and 6 remains poorly defined given that approximately 70%-80% of these patients develop resistance to first-line single-agent chemotherapy, and there is an urgent need to refine the FIGO/WHO scoring system so that these patients can be identified for more intensive therapy from the outset. Despite this, almost all low-risk patients who experience treatment failure with first-line monotherapy will be cured with either sequential single-agent chemotherapy or multiagent chemotherapy with or without surgery. Given the associated increased short and longer-term toxicities associated with multi-agent chemotherapy, promising strategies to reduce the exposure of women to combination chemotherapy in low-risk disease have been investigated, including the use of carboplatin and immune check-point inhibitors. Further evaluation is required to define optimal patient selection, particularly with the use of immunotherapeutic agents given their significant increased costs and lack of longer-term safety data. Although there is a clear need to revise the FIGO/WHO (2000) scoring system, consistent international use of this is recommended to facilitate the comparison of data along with future focus in the development of international collaborative translational and clinical research, including randomised controlled trials.

Infrastructuring an organizational node for a federated research and data network: A case study from a sociotechnical perspective.

Local nodes on federated research and data networks (FR&DNs) provide enabling infrastructure for collaborative clinical and translational research. Studies in other fields note that infrastructuring, that is, work to identify and negotiate relationships among people, technologies, and organizations, is invisible, unplanned, and undervalued. This may explain the limited literature on nodes in FR&DNs in health care. A retrospective case study of one PCORnet® node explored 3 questions: (1) how were components of infrastructure assembled; (2) what specific work was required; and (3) what theoretically grounded, pragmatic questions should be considered when infrastructuring a node for sustainability. Artifacts, work efforts, and interviews generated during node development and implementation were reviewed. A sociotechnical lens was applied to the analysis. Validity was established with internal and external partners. Resources, services, and expertise needed to establish the node existed within the organization, but were scattered across work units. Aligning, mediating, and institutionalizing for sustainability among network and organizational teams, governance, and priorities consumed more work efforts than deploying technical aspects of the node. A theoretically based set of questions relevant to infrastructuring a node was developed and organized within a framework of infrastructuring emphasizing enacting technology, organizing work, and institutionalizing; validity was established with internal and external partners. FR&DNs are expanding; we provide a sociotechnical perspective on infrastructuring a node. Future research should evaluate the applicability of the framework and questions to other node and network configurations, and more broadly the infrastructuring required to enable and support federated clinical and translational science.

Enhancing translational team effectiveness: The Wisconsin Interventions in Team Science framework for translating empirically informed strategies into evidence-based interventions.

Achieving the clinical, public health, economic, and policy benefits of translational science requires the integration and application of findings across biomedical, clinical, and behavioral science and health policy, and thus, collaboration across experts in these areas. To do so, translational teams need the skills, knowledge, and attitudes to mitigate challenges and build on strengths of cross-disciplinary collaboration. Though these competencies are not innate to teams, they can be built through the implementation of effective strategies and interventions. The Science of Team Science (SciTS) has contributed robust theories and evidence of empirically-informed strategies and best practices to enhance collaboration. Yet the field lacks methodological approaches to rigorously translate those strategies into evidence-based interventions to improve collaborative translational research. Here, we apply lessons from Implementation Science and Human-Centered Design & Engineering to describe the Wisconsin Interventions in Team Science (WITS) framework, a process for translating established team science strategies into evidence-based interventions to bolster translational team effectiveness. To illustrate our use of WITS, we describe how University of Wisconsin's Institute for Clinical and Translational Research translated the existing Collaboration Planning framework into a robust, scalable, replicable intervention. We conclude with recommendations for future SciTS research to refine and test the framework.

A distributed geospatial approach to describe community characteristics for multisite studies.

Understanding place-based contributors to health requires geographically and culturally diverse study populations, but sharing location data is a significant challenge to multisite studies. Here, we describe a standardized and reproducible method to perform geospatial analyses for multisite studies. Using census tract-level information, we created software for geocoding and geospatial data linkage that was distributed to a consortium of birth cohorts located throughout the USA. Individual sites performed geospatial linkages and returned tract-level information for 8810 children to a central site for analyses. Our generalizable approach demonstrates the feasibility of geospatial analyses across study sites to promote collaborative translational research.

Positive psychology in health care: defining key stakeholders and their roles.

Lifestyle-related diseases have common risk factors: physical inactivity, poor diet, inadequate sleep, high stress, substance use, and social isolation. Evidence is mounting for the benefits of incorporating effective methods that promote healthy lifestyle habits into routine health care treatments. Research has established that healthy habits foster psychological and physiological health and that emotional well-being is central to achieving total well-being. The Happiness Science and Positive Health Committee of the American College of Lifestyle Medicine aims to raise awareness about strategies for prioritizing emotional well-being. The Committee advocates for collaborative translational research to adapt the positive psychology and behavioral medicine evidence base into methodologies that address emotional well-being in nonmental health care settings. Another aim is to promote health system changes that integrate evidence-based positive-psychology interventions into health maintenance and treatment plans. Also, the Committee seeks to ameliorate health provider burnout through the application of positive psychology methods for providers' personal health. The American College of Lifestyle Medicine and Dell Medical School held an inaugural Summit on Happiness Science in Health Care in May 2018. The Summit participants recommended research, policy, and practice innovations to promote total well-being via lifestyle changes that bolster emotional well-being. These recommendations urge stakeholder collaboration to facilitate translational research for health care settings and to standardize terms, measures, and clinical approaches for implementing positive psychology interventions. Sample aims of joint collaboration include developing evidence-based, practical, low-cost behavioral and emotional assessment and monitoring tools; grants to encourage dissemination of pilot initiatives; medical record dashboards with emotional well-being and related aspects of mental health as vital signs; clinical best practices for health care teams; and automated behavioral programs to extend clinician time. However, a few simple steps for prioritizing emotional well-being can be implemented by stakeholders in the near-term.

Gαs (GNAS) suppression of the p53 genomic‐stability checkpoint unleashes RAS‐driven oncogenesis

As one of the most frequently mutated oncogenes, mutant RAS has been well established to drive proliferative cell programs that are exploited by cancer. Interestingly, RAS, like many oncogenes, has been found in benign tumors that never progress to cancer. Although seemingly counterintuitive, RAS mutant tumors require an additional mutational insult to progress to malignancy. Using an unbiased, pan‐cancer analysis from patient sequencing data, we discovered that RAS mutations significantly co‐occur with mutations in GNAS, the gene encoding the Gαs subunit of G protein couple receptors (GPCRs). Given the established tractability of GPCRs as drug targets, we aimed to explore GNAS as a potential co‐driver in RAS mutant cancers. To first validate the ability of mutations in RAS and GNAS to cooperate to induce malignancy, we expressed the constitutive active mutations, KRASG12D and GNASR201C in the skin of adult mice. These double mutant mice rapidly developed skin papillomas, while mice with either mutation alone had no phenotype. Furthermore, when GNASR201C mice were treated with the chemical carcinogen DMBA, known to induce Hras mutations, mice rapidly developed squamous cell carcinoma in only 3 weeks. Analysis of the lesions revealed a surprising lack of mutations in the Trp53 tumor suppressor gene, which controls genomic stability. In vitro experiments revealed that activation of signaling through Gαs, or its downstream kinase PKA, was sufficient to block DNA damage‐induced p53 protein accumulation. Analysis of the underlying mechanisms demonstrated that MDM2, the cognate p53 E3 ubiquitin ligase, is a direct substrate of PKA, which phosphorylates MDM2 on S166 resulting in enhanced ligase activity. In vitro ubiquitination assays revealed that activation of Gαs or PKA increased MDM2‐mediated p53 ubiquitination and degradation. In patients, appendix cancer is the best example of the GNAS‐KRAS co‐driver state, with 70% of patients harboring this co‐mutation. Ongoing experiments are aimed at validating the mechanism of Gαs‐PKA regulation of MDM2‐p53 growth checkpoints in relevant murine and human intestinal organoid models. In summary, we have uncovered a significant co‐occurrence of RAS and GNAS mutations in cancer and demonstrated that these mutations cooperate to initiate carcinogenesis in vivo. Mechanistically, the cooperation of RAS and GNAS can be explained by the ability of Gαs to functionally repress p53, through PKA mediated phosphorylation of MDM2, releasing the normal brakes that check aberrant RAS‐driven growth.Support or Funding InformationDana Steffen was supported by the National Science Foundation Graduate Research Fellowship Program (NSF GRFP) and the UCSD Graduate Training Program in Cellular and Molecular Pharmacology through an institutional training grant from the National Institute of General Medical Sciences (T32 GM007752). This study is supported in part by the San Diego NCI Cancer Centers Council (C3) Collaborative Translational Cancer Research Pilot Grant.

Abstract OT3-18-01: Detect III/IV study trial - The multicenter study program in patients with HER2-negative MBC and circulating tumor cells

Abstract Background: The collaborative DETECT study program represents a large program on metastatic breast cancer (MBC) worldwide. The main objective of the DETECT trial is to evaluate the efficacy of individualized breast cancer treatment based on the presence and phenotype setting of circulating tumor cells (CTCs). Thus, the DETECT study program is one of the first clinical trials translating the role of CTC enumeration/phenotyping directly into treatment intervention within different breast cancer subtypes. Trial design: The DETECT-III trial is a multicenter, randomized, phase III study comparing standard therapy alone versus standard therapy plus lapatinib in patients with initially HER2-negative MBC and HER2-positive CTCs. Patients with HER2-negative MBC and only HER2-negative CTCs can be included within the DETECT-IV trial, a prospective, multicenter, open-label, phase II study including patients with HER2-negative MBC. Within the DETECT-IV study setting postmenopausal patients with hormone-receptor positive MBC are treated with the CDK 4/6 inhibitor ribociclib and endocrine therapy, while women with triple negative MBC or a hormone-receptor positive tumor and indication for chemotherapy will receive eribulin. Specific aims: The DETECT study program offers various up-to-date treatment options, generating a wealth of clinical data including long-term follow-up data, evaluated in the controlled setting of a single large clinical trial program. The primary endpoint of the DETECT III trial is the comparison of efficacy as assessed using CTC clearance rate between patients receiving standard anticancer therapy with lapatinib and patients receiving standard anticancer therapy alone. The secondary objective of this trial is to assess the level of compliance to study procedures comparing the efficacy of lapatinib between given treatment groups. The primary objectives of the DETECT- IV trial are to evaluate CTC clearance rate for the ribociclib cohort and progression-free survival (defined as time interval from date of recruitment until progressive disease) for the eribulin cohort. The main focal point of the extensive collaborative translational oncology research projects is to apply innovative biomarkers and assays focusing on molecular characteristics of CTCs. This “biological status” of CTCs may provide new information about their potential function in terms of a repeatedly performed liquid biopsy to assess the patients’ response to therapy. Citation Format: Sabrina Krause, Thomas WP Friedl, Peter A Fasching, Andreas Schneeweiss, Volkmar Müller, Sabine Riethdorf, Klaus Pantel, Florin-Andrei Taran, Arkadius Polasik, Marie Tzschaschel, Amelie de Gregorio, Franziska Meier-Stiegen, Jens Huober, Wolfgang Janni, Tanja Fehm. Detect III/IV study trial - The multicenter study program in patients with HER2-negative MBC and circulating tumor cells [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-18-01.