Early Detection Research Network Research Articles

Abstract 2525: Low frequency TP53 mutations in airway epithelial cells serve as lung cancer risk biomarker

Abstract Background: Lung cancer is the leading cause of cancer-related death in men and women in the United States. Based on evidence from controlled trials in the United States and Europe that low dose CT (LDCT) screening significantly reduces lung cancer mortality, the United States Preventative Services Tasks Force (USPSTF) recommends LDCT screening for individuals with high demographic risk based on age and smoking history. However, a large fraction of lung cancers occur in individuals who do not meet LDCT screening threshold criteria. Thus, there is a need for biomarkers that supplement demographic factors to more accurately detect those at highest lung cancer risk and include additional individuals who will benefit from LDCT screening. An initial study from this lab demonstrated that TP53 mutations with 0.05-1.0% variant allele fraction (VAF) were significantly more prevalent (p<0.005) in grossly normal airway epithelial cell (AEC) specimens from lung cancer cases compared to non-cancer controls matched for smoking and age. Here, we present an expanded follow-up study aimed at testing this biomarker according to PRospective-specimen-collection, retrospective-Blinded-Evaluation (PRoBE) design. Methods: AEC specimens were prospectively collected through the National Cancer Institute Early Detection Research Network (EDRN) program from 60 subjects at high demographic risk for lung cancer by bronchoscopic brush biopsy at Vanderbilt University Medical Center. Genomic (g)DNA was extracted from each AEC specimen and stored at -80 degrees Celsius. Subjects matched for age and smoking history who subsequently did or did not develop lung cancer were identified and gDNA specimens, blinded with respect to cancer status, were shipped to the University of Toledo. gDNA specimens were quantified and 50,000 gDNA copies were included in each NGS library preparation. Synthetic DNA internal standards (IS) were prepared for multiple lung cancer driver mutations within the TP53 gene and mixed with each AEC gDNA specimen prior to competitive multiplex PCR NGS library preparation. By controlling for technical error, this approach enables reliable detection of mutations with VAF as low as 5 x 10-4 (0.05%) (Craig et al, BMC Cancer, 2019). Results: Following library preparation and sequencing on Illumina Novaseq, there was sufficient library complexity to detect TP53 VAF <0.05% in >90% of AEC specimens. The data are currently in pipeline analysis. After analysis is complete, VCF files will be sent to Vanderbilt for unblinding and validation of the biomarker. Conclusions: Based on preliminary data, we expect that sufficient AEC gDNA is available from most subjects enrolled in the EDRN program for TP53 low VAF biomarker analysis, and the previously reported method (Craig et al, BMC Cancer, 2019) is reliable and feasible. The current study should provide additional information regarding validity of the biomarker. Citation Format: Daniel J. Craig, Erin L. Crawford, Pierre P. Massion, Thomas Morrison, James C. Willey. Low frequency TP53 mutations in airway epithelial cells serve as lung cancer risk biomarker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2525.

Abstract 252: Navigating networks of oncology biomarkers mined from the scientific literature: A new open research tool

Abstract Introduction: Oncology biomarkers have a pivotal role in diagnosis, prognosis, assessment of disease progression and the prediction of treatment efficacy. There are > 5000 known biomarkers; some are well characterised, while others are emerging as biomarkers of potential interest. Biomarker panels, incorporating combinations of biomarkers, are increasingly used to enhance the power and precision of testing. Objective: We sought to identify key emerging biomarkers and biomarker relationships by applying analytical techniques to the corpus of recent scientific publications using an artificial intelligence (AI)-driven platform. Methods: Biomarker targets were obtained from the Early Detection Research Network. Recent (<5 years old) publications mentioning biomarkers in six cancer types (bladder, breast, colorectal, lung, prostate and renal) were identified using Dimensions (a linked research knowledge system); emerging biomarkers were identified by number and growth in publications. For selected biomarkers, full text proximity searching was used to identify biomarker co-occurrence, which was visualized and characterized using network analysis and co-occurrence heatmaps per cancer type. Relationships between biomarkers were also assessed in an indication-agnostic dataset. Key biomarkers were identified by a measure of their network importance. Results: A total of 720 biomarkers were analyzed, and 41 clusters identified across the cancer types. Data visualizations are available at https://reports.dimensions.ai/mined-oncology-biomarkers/ Conclusion: Using large-scale analytics of published literature, biomarkers across six cancer types were successfully characterized in terms of their emergence in the published literature and the context in which they are described. This novel AI-driven approach could help identify biomarkers and biomarker panels for exploration in a clinical setting. Example clusters - growth rate is compound annual growth rate (CAGR)Cancer typeBiomarkers (n)Publications (n)Cluster key biomarkersCluster publication growth rate (%)Bladder49168CAV1/CXCL8/THBS153.1Breast2651593AREG/CXCL10/CXCL832.6Colorectal193921CAV1/CDCP1/MTHFR31.6Lung2231061SFTPC/C9/GPI41.4Prostate166717FABP5/FLNA/CAV131.6Renal44185CXCL10/CXCL8/CSNK2A149.5 Citation Format: Kim Wager, Dheepa Chari, Steffan Ho, Tomas J. Rees, Robert J. Schijvenaars. Navigating networks of oncology biomarkers mined from the scientific literature: A new open research tool [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 252.

The NCI Cancer Tissue Engineering Collaborative Research Program is a highly interdisciplinary and focused community

The NCI Cancer Tissue Engineering Collaborative Research Program is a highly interdisciplinary and focused community

International Liver Cancer Association (ILCA) White Paper on Biomarker Development for Hepatocellular Carcinoma

International Liver Cancer Association (ILCA) White Paper on Biomarker Development for Hepatocellular Carcinoma

Hybrid design evaluating new biomarkers when there is an existing screening test.

Development of cancer screening biomarkers usually follows the Early Detection Research Network 5-Phase guideline in Pepe et al. A key feature of this guide is that the phased development follows a sequential order, moving to the next phase only when the current phase study is complete and has met its target performance. Motivated by a newly funded Newly onset Diabetes cohort study, we propose a design evaluating new biomarkers to discriminate between cases and controls in the presence of an existing screening test. The proposed design achieves two goals: (1) avoiding bias in estimating sensitivity or specificity in predicting cancer at a given time period prior to clinical diagnosis, using data from both screening detected cancers in Phase IV study and clinically diagnosed cancers in Phase III study; and (2) building a panel with biomarkers for Phase III and IV studies based on all data. A simulation study shows that the proposed design outperforms both a conventional method using data in Phase III arm only and a naive method using data in Phase III and IV arms ignoring the difference between the time of screening the detected cancer and the time of clinical diagnosis. The proposed design yields a smaller standard error of the estimation and increases the statistical power to confirm biomarker performance. This proposed method has the potential to shorten the cancer screening biomarker development process, use resources more effectively, and bring benefits to patients quickly.

The Early Detection Research Network: A National Infrastructure to Support the Discovery, Development, and Validation of Cancer Biomarkers.

In 2000, the NCI (Rockville, MD) established the Early Detection Research Network (EDRN) to identify, develop, and validate biomarkers to improve the detection of early-stage cancers and risk assessment. This consortium of more than 300 investigators at academic institutions and in the private sector is working collaboratively to bring biomarkers and imaging methods to clinical fruition. Although significant roadblocks have hindered the field of biomarker discovery and validation, the EDRN has helped overcome many of them by setting well-defined strategies and milestones focused on solving defined unmet clinical needs. The EDRN has implemented measures to improve biomarker discovery and validation, such as data sharing, use of common data elements, generating multidisciplinary and multi-institutional collaborations within a cohesive and productive team environment, and putting emphasis on quality control and data replication for all candidate biomarkers for reaching a "go" or "no go" decision. A measure of the success of the EDRN is the number of biomarkers tests or devices approved by the FDA to which EDRN investigators have made significant contributions and the number of biomarkers tests developed by EDRN investigators that are available in Clinical Laboratory Improvement Amendments laboratories.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."

Adding Rigor to Biomarker Evaluations-EDRN Experience.

The cancer early-detection biomarker field was, compared with the therapeutic arena, in its infancy when the Early Detection Research Network (EDRN) was initiated in 2000. The EDRN has played a crucial role in changing the culture and the ways people conduct biomarker studies. The EDRN proposed biomarker developmental guidelines and biomarker pivotal trial study design standards, created biomarker reference sets and functioned as an unbiased broker for the field, implemented the most rigorous blinding policy in the biomarker field, developed an array of statistical and computational tools for early-detection biomarker evaluations, and developed a multidisciplinary team-science approach. We reviewed these contributions made by the EDRN and their impacts on maturing the field. Future challenges and opportunities in cancer early-detection biomarker translational research are discussed, particularly in strengthening biomarker discovery pipeline and conducting more efficient biomarker validation studies.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."

Biomarkers for Early Detection of Colorectal Cancer: The Early Detection Research Network, a Framework for Clinical Translation

Early detection by screening significantly reduces mortality from colorectal cancer, but 40% of guideline-eligible patients are not screened as recommended in the United States. Novel strategies to improve screening uptake overall and efforts to deploy best practices to underserved populations are a high priority for health care. This review focuses on existing biomarkers in practice and those in development with clinical relevance to early detection of colorectal neoplasia, with an emphasis on those developed by investigators of the NCI's Early Detection Research Network. Aberrantly methylated DNA markers (blood and stool), stool-based markers (including fecal immunochemical test-DNA), and a variety of blood-based marker assays in development (protein markers, glycoproteins including mucins, and cell-free DNA tests) are reviewed. Individual markers and biomarker panels, sample resources, and barriers to translating biomarkers to clinical practice are discussed.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."

Prostate Cancer Biomarker Development: National Cancer Institute's Early Detection Research Network Prostate Cancer Collaborative Group Review.

Prostate cancer remains the most common non-skin cancer and second leading cause of death among men in the United States. Although progress has been made in diagnosis and risk assessment, many clinical questions remain regarding early identification of prostate cancer and management. The early detection of aggressive disease continues to provide high curative rates if diagnosed in a localized state. Unfortunately, prostate cancer displays significant heterogeneity within the prostate organ and between individual patients making detection and treatment strategies complex. Although prostate cancer is common among men, the majority will not die from prostate cancer, introducing the issue of overtreatment as a major concern in clinical management of the disease. The focus of the future is to identify those at highest risk for aggressive prostate cancer and to develop prevention and screening strategies, as well as discerning the difference in malignant potential of diagnosed tumors. The Prostate Cancer Research Group of the National Cancer Institute's Early Detection Research Network has contributed to the progress in addressing these concerns. This summary is an overview of the activities of the group.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."

Biomarkers and Strategy to Detect Preinvasive and Early Pancreatic Cancer: State of the Field and the Impact of the EDRN.

Patients afflicted with pancreatic ductal adenocarcinoma (PDAC) face a dismal prognosis, but headway could be made if physicians could identify the disease earlier. A compelling strategy to broaden the use of surveillance for PDAC is to incorporate molecular biomarkers in combination with clinical analysis and imaging tools. This article summarizes the components involved in accomplishing biomarker validation and an analysis of the requirements of molecular biomarkers for disease surveillance. We highlight the significance of consortia for this research and highlight resources and infrastructure of the Early Detection Research Network (EDRN). The EDRN brings together the multifaceted expertise and resources needed for biomarker validation, such as study design, clinical care, biospecimen collection and handling, molecular technologies, and biostatistical analysis, and studies coming out of the EDRN have yielded biomarkers that are moving forward in validation. We close the article with an overview of the current investigational biomarkers, an analysis of their performance relative to the established benchmarks, and an outlook on the current needs in the field. The outlook for improving the early detection of PDAC looks promising, and the pace of further research should be quickened through the resources and expertise of the EDRN and other consortia.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."

The National Cancer Institute Early Detection Research Network: Two Decades of Progress.

Over the last two decades, substantial progress has been made in the development of cancer biomarkers and their application to unmet needs across the spectrum of cancer care. NCI's Early Detection Research Network (EDRN) has had an important role in facilitating this progress ([1][1]). Having been

Barrett's Esophagus and Esophageal Adenocarcinoma Biomarkers.

Esophageal adenocarcinoma is a major cause of cancer-related morbidity and mortality in Western countries. The incidences of esophageal adenocarcinoma and its precursor Barrett's esophagus have increased substantially in the last four decades. Current care guidelines recommend that endoscopy be used for the early detection and monitoring of patients with Barrett's esophagus; however, the efficacy of this approach is unclear. To prevent the increasing morbidity and mortality from esophageal adenocarcinoma, there is a tremendous need for early detection and surveillance biomarker assays that are accurate, low-cost, and clinically feasible to implement. The last decade has seen remarkable advances in the development of minimally invasive molecular biomarkers, an effort led in large part by the Early Detection Research Network (EDRN). Advances in multi-omics analysis, the development of swallowable cytology collection devices, and emerging technology have led to promising assays that are likely to be implemented into clinical care in the next decade. In this review, an updated overview of the molecular pathology of Barrett's esophagus and esophageal adenocarcinoma and emerging molecular biomarker assays, as well as the role of EDRN in biomarker discovery and validation, will be discussed.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."

Mesothelioma Biomarkers: A Review Highlighting Contributions from the Early Detection Research Network.

Malignant pleural mesothelioma (MPM) is an asbestos-related neoplasm, which can be treated successfully only if correctly diagnosed and treated in early stages. The asbestos-exposed population serves as a high-risk group that could benefit from sensitive and specific blood- or tissue-based biomarkers. This review details the recent work with biomarker development in MPM and the contributions of the NCI Early Detection Research Network Biomarker Developmental Laboratory of NYU Langone Medical Center. The literature of the last 20 years was reviewed to comment on the most promising of the blood- and tissue-based biomarkers. Proteomic, genomic, and epigenomic platforms as well as novel studies such as "breath testing" are covered. Soluble mesothelin-related proteins (SMRP) have been characterized extensively and constitute an FDA-approved biomarker in plasma with diagnostic, monitoring, and prognostic value in MPM. Osteopontin is found to be a valuable prognostic biomarker for MPM, while its utility in diagnosis is slightly lower. Other biomarkers, such as calretinin, fibulin 3, and High-Mobility Group Box 1 (HMGB1), remain under study and need international validation trials with large cohorts of cases and controls to demonstrate any utility. The EDRN has played a key role in the development and testing of MPM biomarkers by enlisting collaborations all over the world. A comprehensive understanding of previously investigated biomarkers and their utility in screening and early diagnosis of MPM will provide guidance for further future research.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."

Lung Cancer and Immunity Markers.

An in-depth understanding of lung cancer biology and mechanisms of tumor progression has facilitated significant advances in the treatment of lung cancer. There remains a pressing need for the development of innovative approaches to detect and intercept lung cancer at its earliest stage of development. Recent advances in genomics, computational biology, and innovative technologies offer unique opportunities to identify the immune landscape in the tumor microenvironment associated with early-stage lung carcinogenesis, and provide further insight in the mechanism of lung cancer evolution. This review will highlight the concept of immunoediting and focus on recent studies assessing immune changes and biomarkers in pulmonary premalignancy and early-stage non-small cell lung cancer. A protumor immune response hallmarked by an increase in checkpoint inhibition and inhibitory immune cells and a simultaneous reduction in antitumor immune response have been correlated with tumor progression. The potential systemic biomarkers associated with early lung cancer will be highlighted along with current clinical efforts for lung cancer interception. Research focusing on the development of novel strategies for cancer interception prior to the progression to advanced stages will potentially lead to a paradigm shift in the treatment of lung cancer and have a major impact on clinical outcomes.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."

Biomarkers and Strategies for Early Detection of Ovarian Cancer.

Early detection of ovarian cancer remains an important unmet medical need. Effective screening could reduce mortality by 10%-30%. Used individually, neither serum CA125 nor transvaginal sonography (TVS) is sufficiently sensitive or specific. Two-stage strategies have proven more effective, where a significant rise above a woman's baseline CA125 prompts TVS and an abnormal sonogram prompts surgery. Two major screening trials have documented that this strategy has adequate specificity, but sensitivity for early-stage (I-II) disease must improve to have a greater impact on mortality. To improve the first stage, different panels of protein biomarkers have detected cases missed by CA125. Autoantibodies against TP53 have detected 20% of early-stage ovarian cancers 8 months before elevation of CA125 and 22 months before clinical diagnosis. Panels of autoantibodies and antigen-autoantibody complexes are being evaluated with the goal of detecting >90% of early-stage ovarian cancers, alone or in combination with CA125, while maintaining 98% specificity in control subjects. Other biomarkers, including micro-RNAs, ctDNA, methylated DNA, and combinations of ctDNA alterations, are being tested to provide an optimal first-stage test. New technologies are also being developed with greater sensitivity than TVS to image small volumes of tumor.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."

The Potential of Circular RNAs as Cancer Biomarkers.

Circular RNA (circRNA) is a covalently closed RNA structure that has several proposed functions related to cancer development. Recently, cancer-specific and tissue-specific circRNAs have been identified by high-throughput sequencing and are curated in publicly available databases. CircRNAs have features that are ideal properties of biomarkers, including conservation, abundance, and stability in plasma, saliva, and urine. Many circRNAs with predictive and prognostic significance in cancer have been described, and functional mechanisms for some circRNAs have been suggested. CircRNA also has great potential as a noninvasive biomarker for early cancer detection, although further investigation is necessary before clinical application is feasible.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."

Noninvasive Diagnostics for Early Detection of Lung Cancer: Challenges and Potential with a Focus on Changes in DNA Methylation.

Lung cancer remains the leading cause of cancer deaths in the United States and the world. Early detection of this disease can reduce mortality, as demonstrated for low-dose computed tomography (LDCT) screening. However, there remains a need for improvements in lung cancer detection to complement LDCT screening and to increase adoption of screening. Molecular changes in the tumor, and the patient's response to the presence of the tumor, have been examined as potential biomarkers for diagnosing lung cancer. There are significant challenges to developing an effective biomarker with sufficient sensitivity and specificity for the early detection of lung cancer, particularly the detection of circulating tumor DNA, which is present in very small quantities. We will review approaches to develop biomarkers for the early detection of lung cancer, with special consideration to detection of rare tumor events, focus on the use of DNA methylation-based detection in plasma and sputum, and discuss the promise and challenges of lung cancer early detection. Plasma-based detection of lung cancer DNA methylation may provide a simple cost-effective method for the early detection of lung cancer.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."

Tumor DNA as a Cancer Biomarker through the Lens of Colorectal Neoplasia.

Biomarkers have a wide range of applications in the clinical management of cancer, including screening and therapeutic management. Tumor DNA released from neoplastic cells has become a particularly active area of cancer biomarker development due to the critical role somatic alterations play in the pathophysiology of cancer and the ability to assess released tumor DNA in accessible clinical samples, in particular blood (i.e., liquid biopsy). Many of the early applications of tumor DNA as a biomarker were pioneered in colorectal cancer due to its well-defined genetics and common occurrence, the effectiveness of early detection, and the availability of effective therapeutic options. Herein, in the context of colorectal cancer, we describe how the intended clinical application dictates desired biomarker test performance, how features of tumor DNA provide unique challenges and opportunities for biomarker development, and conclude with specific examples of clinical application of tumor DNA as a biomarker with particular emphasis on early detection.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."

Autoantibodies in Early Detection of Breast Cancer.

In spite of the progress made in treatment and early diagnosis, breast cancer remains a major public health issue worldwide. Although modern image-based screening modalities have significantly improved early diagnosis, around 15% to 20% of breast cancers still go undetected. In underdeveloped countries, lack of resources and cost concerns prevent implementing mammography for routine screening. Noninvasive, low-cost, blood-based markers for early breast cancer diagnosis would be an invaluable alternative that would complement mammography screening. Tumor-specific autoantibodies are excellent biosensors that could be exploited to monitor disease-specific changes years before disease onset. Although clinically informative autoantibody markers for early breast cancer screening have yet to emerge, progress has been made in the development of tools to discover and validate promising autoantibody signatures. This review focuses on the current progress toward the development of autoantibody-based early screening markers for breast cancer.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."

The Evolution of Our Understanding of the Biology of Cancer Is the Key to Avoiding Overdiagnosis and Overtreatment.

There has been a tremendous evolution in our thinking about cancer since the 1880s. Breast cancer is a particularly good example to evaluate the progress that has been made and the new challenges that have arisen due to screening that inadvertently identifies indolent lesions. The degree to which overdiagnosis is a problem depends on the reservoir of indolent disease, the disease heterogeneity, and the fraction of the tumors that have aggressive biology. Cancers span the spectrum of biological behavior, and population-wide screening increases the detection of tumors that may not cause harm within the patient's lifetime or may never metastasize or result in death. Our approach to early detection will be vastly improved if we understand, address, and adjust to tumor heterogeneity. In this article, we use breast cancer as a case study to demonstrate how the approach to biological characterization, diagnostics, and therapeutics can inform our approach to screening, early detection, and prevention. Overdiagnosis can be mitigated by developing diagnostics to identify indolent disease, incorporating biology and risk assessment in screening strategies, changing the pathology rules for tumor classification, and refining the way we classify precancerous lesions. The more the patterns of cancers can be seen across other cancers, the more it is clear that our approach should transcend organ of origin. This will be particularly helpful in advancing the field by changing both our terminology for what is cancer and also by helping us to learn how best to mitigate the risk of the most aggressive cancers.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."