James V. Tricoli

MicroRNA: Potential for Cancer Detection, Diagnosis, and Prognosis.

The Cancer Diagnosis Program of the National Cancer Institute sponsored a workshop entitled “MicroRNA: Potential for Cancer Detection, Diagnosis, and Prognosis” in Rockville, Maryland on November 28 and 29, 2006. The purpose of this workshop was to bring together leaders in the microRNA (miRNA)

Detection of Prostate Cancer and Predicting Progression Current and Future Diagnostic Markers

Carcinoma of the prostate is the second leading cause of male cancer-related death in the United States. Better indicators of prostate cancer presence and progression are needed to avoid unnecessary treatment, predict disease course, and develop more effective therapy. Numerous molecular markers have been described in human serum, urine, seminal fluid, and histological specimens that exhibit varying capacities to detect prostate cancer and predict disease course. However, to date, few of these markers have been adequately validated for clinical use. The purpose of this review is to examine the current status of these markers in prostate cancer and to assess the diagnostic potential for future markers from identified genes and molecules that display loss, mutation, or alteration in expression between tumor and normal prostate tissues. In this review we cite 91 molecular markers that display some level of correlation with prostate cancer presence, disease progression, cancer recurrence, prediction of response to therapy, and/or disease-free survival. We suggest criteria to consider when selecting a marker for further development as a clinical tool and discuss five examples of markers (chromogranin A, glutathione S-transferase π 1, prostate stem cell antigen, prostate-specific membrane antigen, and telomerase reverse transcriptase) that fulfill some of these criteria. Finally, we discuss how to conduct evaluations of candidate prostate cancer markers and some of the issues involved in the validation process.

Criteria for the use of omics-based predictors in clinical trials

The US National Cancer Institute (NCI), in collaboration with scientists representing multiple areas of expertise relevant to ‘omics’-based test development, has developed a checklist of criteria that can be used to determine the readiness of omics-based tests for guiding patient care in clinical trials. The checklist criteria cover issues relating to specimens, assays, mathematical modelling, clinical trial design, and ethical, legal and regulatory aspects. Funding bodies and journals are encouraged to consider the checklist, which they may find useful for assessing study quality and evidence strength. The checklist will be used to evaluate proposals for NCI-sponsored clinical trials in which omics tests will be used to guide therapy.

Criteria for the use of omics-based predictors in clinical trials: explanation and elaboration

High-throughput ‘omics’ technologies that generate molecular profiles for biospecimens have been extensively used in preclinical studies to reveal molecular subtypes and elucidate the biological mechanisms of disease, and in retrospective studies on clinical specimens to develop mathematical models to predict clinical endpoints. Nevertheless, the translation of these technologies into clinical tests that are useful for guiding management decisions for patients has been relatively slow. It can be difficult to determine when the body of evidence for an omics-based test is sufficiently comprehensive and reliable to support claims that it is ready for clinical use, or even that it is ready for definitive evaluation in a clinical trial in which it may be used to direct patient therapy. Reasons for this difficulty include the exploratory and retrospective nature of many of these studies, the complexity of these assays and their application to clinical specimens, and the many potential pitfalls inherent in the development of mathematical predictor models from the very high-dimensional data generated by these omics technologies. Here we present a checklist of criteria to consider when evaluating the body of evidence supporting the clinical use of a predictor to guide patient therapy. Included are issues pertaining to specimen and assay requirements, the soundness of the process for developing predictor models, expectations regarding clinical study design and conduct, and attention to regulatory, ethical, and legal issues. The proposed checklist should serve as a useful guide to investigators preparing proposals for studies involving the use of omics-based tests. The US National Cancer Institute plans to refer to these guidelines for review of proposals for studies involving omics tests, and it is hoped that other sponsors will adopt the checklist as well.

Next steps for adolescent and young adult oncology workshop: An update on progress and recommendations for the future

Each year, 70,000 adolescents and young adults (AYAs) between ages 15 and 39 years in the United States are diagnosed with cancer. In 2006, a National Cancer Institute (NCI) Progress Review Group (PRG) examined the state of science associated with cancer among AYAs. To assess the impact of the PRG and examine the current state of AYA oncology research, the NCI, with support from the LIVESTRONG Foundation, sponsored a workshop entitled “Next Steps in Adolescent and Young Adult Oncology” on September 16 and 17, 2013, in Bethesda, Maryland. This report summarizes the findings from the workshop, opportunities to leverage existing data, and suggestions for future research priorities. Multidisciplinary teams that include basic scientists, epidemiologists, trialists, biostatisticians, clinicians, behavioral scientists, and health services researchers will be essential for future advances for AYAs with cancer. Cancer 2016;122:988–999.

Biologic and clinical characteristics of adolescent and young adult cancers: Acute lymphoblastic leukemia, colorectal cancer, breast cancer, melanoma, and sarcoma

Adolescent and young adult (AYA) patients with cancer have not attained the same improvements in overall survival as either younger children or older adults. One possible reason for this disparity may be that the AYA cancers exhibit unique biologic characteristics, resulting in differences in clinical and treatment resistance behaviors. This report from the biologic component of the jointly sponsored National Cancer Institute and LiveStrong Foundation workshop entitled “Next Steps in Adolescent and Young Adult Oncology” summarizes the current status of biologic and translational research progress for 5 AYA cancers; colorectal cancer breast cancer, acute lymphoblastic leukemia, melanoma, and sarcoma. Conclusions from this meeting included the need for basic biologic, genomic, and model development for AYA cancers as well as translational research studies to elucidate any fundamental differences between pediatric, AYA, and adult cancers. The biologic questions for future research are whether there are mutational or signaling pathway differences (for example, between adult and AYA colorectal cancer) that can be clinically exploited to develop novel therapies for treating AYA cancers and to develop companion diagnostics. Cancer 2016;122:1017–1028.

The Human Glucagon Gene Is Located on Chromosome 2

DNA samples prepared from a panel of human-mouse cell hybrids with different numbers and combinations of human chromosomes were examined for the presence of the human preproglucagon gene by hybridization with a cloned segment of the human gene. The segregation of the human glucagon gene specific DNA fragment and human chromosome 2 in these cell hybrids indicated that the preproglucagon gene (designated GCG) is on chromosome 2 in humans.

A mutational comparison of adult and adolescent and young adult (AYA) colon cancer: Comparison of Adult & AYA Colon Cancer

It is possible that the relative lack of progress in treatment outcomes among adolescent and young adult (AYA) patients with cancer is caused by a difference in disease biology compared with the corresponding diseases in younger and older individuals. There is evidence that colon cancer is more aggressive and has a poorer prognosis in AYA patients than in older adult patients.

Pediatric oncology enters an era of precision medicine

With the use of high-throughput molecular profiling technologies, precision medicine trials are ongoing for adults with cancer. Similarly, there is an interest in how these techniques can be applied to tumors in children and adolescents to expand our understanding of the biology of pediatric cancers and evaluate the clinical implications of genomic testing for these patients. This article reviews the early studies in pediatric oncology showing the feasibility of this approach, describe the future plans to evaluate the clinical implications in a multicenter clinical trial and identify the challenges of applying genomics in this patient population.

Criteria for use of omics-based predictors in NCI-sponsored clinical trials.

58 Background: High-throughput omics technologies (e.g., genomics, epigenomics, proteomics, metabolomics) offer exciting opportunities for new biological insights into cancer. The IOM report on translational omics defined omics as the study of related sets of biological molecules in a comprehensive fashion. (IOM (Institute of Medicine) 2012. Evolution of Translational Omics: Lessons Learned and the Path Forward. Washington, DC: The National Academic Press.) The promise of omics technologies has proven problematic to translate into clinically useful tests. Difficulty obtaining biospecimens, unrecognized preanalytical influences, and suboptimal assay analytical performance can lead to unreliable results and conflicting reports. Poor reporting of study details and limited access to data and computer code can thwart efforts to replicate published results or to detect flaws in study design and analysis methods. METHODS NCI held an interactive workshop for a wide variety of stakeholders to explore better approaches to omics-based test development and validation. This workshop heavily informed the ideas presented here. Recommendations are stated concisely, then explained. RESULTS A checklist of items to consider when evaluating the evidence for clinical use of an omics-based predictor, including in a trial where it will guide therapy, is presented. It covers specimen and assay requirements, the predictor model development process, clinical study design and conduct, and regulatory, ethical, and legal issues. The list applies to any trial involving investigational use of an omics test that will alter the clinical management of patients. The criteria also largely apply to situations in which the test will be evaluated retrospectively on specimens collected from patients who were prospectively enrolled on clinical studies. CONCLUSIONS The proposed checklist should serve as a useful guide to investigators planning to submit proposals for NCI-funded studies involving use of an omics-based test. Ideally, this checklist will be consulted in the assay planning and development phases so that the necessary evidence will have been collected in a well-documented fashion by the time definitive evaluation of the test is desired.