The use of a routine blood test to assess and monitor patients with cancer, especially in a longitudinal manner, has long been the holy grail of cancer research. At the University of Arkansas for Medical Sciences (UAMS) Winthrop P. Rockefeller Cancer Institute, we have made big steps toward achieving that goal in the past 5 years.

With the analysis of a simple blood test, also known as a liquid biopsy, we can find circulating tumor DNA (ctDNA), which are nucleic acid biomolecules shed by a tumor into the blood and detected by next-generation sequencing (NGS). Some of these tests are commercially available and approved by the FDA for patients with advanced or metastatic disease. Investigators at UAMS are now working to translate foundational work into cutting-edge care for patients with cancer at all stages of disease and across tumor types and eventually for screening assays.

These investigative efforts have been made possible by recent advancements in molecular biology, scientific instrumentation including sequencing technology, computational science, and platforms that are able to manage massive amounts of data. The vision is to combine the power of these approaches with clinical knowledge to advance outcomes for patients with cancer and improve methods of drug development. 

UAMS is conducting a clinical trial (NCT02597738), which is funded by the FDA, to develop an advanced liquid biopsy method for diagnosing and monitoring lung cancer.

 In a related effort, we have been a key part of an FDA-funded international collaboration whose recently published findings reveal that 5 commercially available assays can reliably detect ctDNA of late-stage and metastatic cancers.

The study team who published the findings, in the April issue of Nature Biotechnology, includes investigators at the FDA’s National Center for Toxicological Research in Jefferson, Arkansas, and 12 laboratories in Europe, Australia, Asia, and the United States.

 Springer Nature’s Behind the Paper channel further explores aspects of how this research paper came to be and where subsequent research may lead.

Our team’s work at UAMS is part of the effort led by the FDA to develop standard protocols and quality control measures for NGS in precision medicine so that it can be brought into everyday practice for patients. The aim of the study is to lay the foundation for a transformation in oncology practice, clinical trials protocol, and drug development with the analytical validation of assays based on ctDNA. The ramifications of the liquid biopsy advances from this study were recently profiled in The Scientist.

The FDA has provided more than $3.5 million to liquid biopsy studies as part of the 21st Century Cures Act approved by Congress in 2016. 

This clinical trial for patients with lung cancer provides a glimpse into the near future of personalized cancer treatment (FIGURE

). Surgeons at UAMS provide our team with tumor samples and in the laboratory we perform NGS on the tumor and regrow the tumor using different methods. Then the team tests individual existing drugs and novel drug combinations to find the most effective treatment for that patient’s tumor.

FIGURE. Feasibility Study to Further the Development of Lung Cancer–Based Precision Medicine1 (NCT02597738)

The information can then be used to determine the best therapies should a patient’s cancer return. Additionally, information is compiled so investigators can identify patterns and trends regarding which treatments are most efficacious for different types of tumors. Patients in the clinical trial give blood samples at multiple stages (standard-of-care visits) of treatment. The investigative team will begin to measure whether the tests improve outcomes through earlier detection of cancer recurrence by the liquid biopsy longitudinal monitoring. 

The collaborative element is very important to this work. UAMS is working with prestigious National Cancer Institute comprehensive cancer centers, including Memorial Sloan Kettering Cancer Center in New York, New York, the University of Southern California in Los Angeles, and other Blood Profiling Atlas in Cancer (BloodPAC) members, to accelerate the development of liquid biopsies for cancer treatment guidance and less invasive clinical care.

The UAMS team has contributed to the following high-impact publications concerning liquid biopsies and NGS approaches for oncology:

: addresses how sample collection (blood draws) should be performed (ie, preanalytical variables) for liquid biopsies

: outlines a series of generic protocols addressing liquid biopsy

: reviews liquid biopsy approaches toward data harmonization

The analytical validity of liquid biopsy assays must be demonstrated before further steps, such as clinical validity and clinical utility, can be considered. Importantly, recently published findings in Nature Biotechnology establish the analytical validity for ctDNAbased NGS assays. Investigators of the multinational proficiency study used standardized reference materials, an associated analytical framework, and suggested best practices. Once the clinical validity and utility of liquid biopsies have been demonstrated by well-designed clinical trials, the ctDNA tests can be integrated into clinical practice via national guidelines, such as the National Comprehensive Cancer Network guidelines and FDA indications.

Liquid biopsies are the future of cancer medicine. Compared with traditional tissue biopsy approaches that may require a small operation or an interventional radiology approach, liquid biopsies are safer, faster and less expensive. They also provide a more effective approach toward longitudinal analysis, assessment of minimal residual disease, and decision-making for adjuvant therapy based on a patient’s quantitative data assessing burden of disease from their liquid biopsy assay. In summary, the liquid biopsy provides for more effective molecular diagnostics and improved drug development, and we are on the cusp of making it a more routine reality for our patients. 

A feasibility study to further the development of lung cancer-based precision medicine. ClinicalTrials.gov. Updated December 2, 2020. Accessed October 5, 2021. https://clinicaltrials.gov/ct2/show/NCT02597738

Deveson IW, Gong B, Lai K, et al; SEQC2 Oncopanel Sequencing Working Group. Evaluating the analytical validity of circulating tumor DNA sequencing assays for precision oncology. Nat Biotechnol. 2021;39(9):1115-1128. doi:10.1038/s41587-021-00857-z

Johann DJ, Deveson I, Mercer T, Xu J. Improving cancer outcomes—it’s written in blood. Nature Portfolio Bioengineering Community. April 12, 2021. Accessed October 7, 2021. go.nature.com/2YrnVR1

Banks MA. FDA-led consortium details improvements needed in liquid biopsies. The Scientist. Updated May 20, 2021. Accessed October 7, 2021. bit.ly/3v4e1RD 

Febbo PG, Martin AM, Scher HI, et al. Minimum technical data elements for liquid biopsy data submitted to public databases. Clin Pharmacol Ther. 2020;107(4):730-734. doi:10.1002/cpt.1747 

Godsey JH, Silvestro A, Barrett JC, et al. Generic protocols for the analytical validation of next-generation sequencing-based ctDNA assays: a joint consensus recommendation of the BloodPAC’s Analytical Variables Working Group. Clin Chem. 2020;66(9):1156-1166. doi:10.1093/clinchem/hvaa164 

Grossman RL, Dry JR, Hanlon SE, et al. BloodPac data commons for liquid biopsy data. JCO Clin Cancer Inform. 2021;5:479-486. doi:10.1200/CCI.20.00179

Articles

The use of a routine blood test to assess and monitor patients with cancer, especially in a longitudinal manner, has long been the holy grail of cancer research. 

DONALD J. JOHANN JR, MD, MSC

Articles

UAMS Winthrop P. Rockefeller Cancer Institute Pushes Liquid Biopsy Research Forward