When liquid biopsy first entered clinical cancer management (FDA approved the first liquid biopsy test in 2013 - CellSearch® CTC enumeration platform), lab scientists celebrated this promising non-invasive method for cancer detection being used beyond the bench. At the same time, some oncologists remained skeptical about its clinical application, while some pathologists believed it might replace traditional biopsies. Over the past decade we’ve learned that liquid biopsy won’t replace traditional biopsies (at least for tumor classification/staging), however, it has proved a valuable method in determining patient eligibility for a precision medicine where tumor tissue availability is a limitation.
Clinical utility increasingly recognized across tumor indications
Liquid biopsy's clinical utility has expanded beyond NSCLC (non-small cell lung cancer), where it was initially used for the monitoring of EGFR mutation following a TKI (Tyrosine kinase inhibitor) treatment, to various tumor indications due to improved sensitivity and tissue scarcity. The latest NCCN guidelines recommend liquid biopsy testing for at least 6 solid tumor indications, while ESMO issued recommendations on the use of ctDNA (circulating tumor DNA) test for solid tumor patients (Table 1). With numerous FDA-approved assays and over 40 European companies offering CE-IVD marked assays, liquid biopsy is now becoming an integral part of managing the most common tumor types.
Outlook in clinical utilization in early detection/stage
The future outlook for liquid biopsy shows promise in early detection and staging. In May 2022, the FDA issued guidance to help drug and IVD (in vitro diagnostic) manufacturers use ctDNA as a biomarker in early-stage solid tumor clinical trials and in seeking market approval for IVD assays, respectively.
ASCO 2023 featured over 124 abstracts and posters on liquid biopsy, highlighting its application in surveillance, MCED (multi-cancer early detection) assays for cancer screening, and MRD (minimal residual disease) tests for treatment response and disease relapse detection in solid tumors. Experts have recognized the role of liquid biopsy tests in early cancer management in the patient journey, reinforcing that liquid biopsies are here to stay.
Critical barriers to be addressed to ensure wide patient access
Despite these advancements, several barriers remain for wide patient access. Pre-analytical steps, method sensitivity, and reimbursement have been critical barriers for wide liquid biopsy adoption by labs and routine use by requesting physicians. While NGS (next-generation sequencing) and PCR (i.e., digital PCR) assays have had a huge spread from the more commonly used RUO kits (research use only) and LDT’s (laboratory developed test) with increased sensitivity to detect low MAF (minor allele frequency) of ctDNA, there are still no standardized guidelines for blood collection, extraction methods, and ctDNA/circulating tumor cell positivity assay cutoffs. For example, specific blood-collection tubes to stabilize cell-free DNA longer term exist in the market today, but they have not been widely adopted by labs mainly due to high costs (in general, they are 10 times more expensive than one EDTA tube).
Reimbursement by payers is also a critical issue, impacting patient costs and access. For patients, a liquid biopsy test increases costs, particularly when a negative result requires a reflex to tissue tests (which is often necessary when liquid biopsy results are negative). If the test is not fully covered, the patient will need to pay out-of-pocket. Although coverage of ctDNA panel testing increased from 2015 to 2019, in 2019 only 38% of private payers in the US covered some type of ctDNA-based NGS panel testing for patients with advanced disease for certain tumor types. Although Medicare does not have a national coverage determination (NCD) of ctDNA testing, it has a specific NCD for advanced cancer NGS tests with a caveat: the panel should be FDA approved, not favoring wide patient access to non-FDA approved assays. However, there is flexibility in the local coverage determinations (LCD) covering liquid biopsy which can facilitate a pan-cancer use of testing. The growth and adoption of liquid biopsy testing is expected to increase in the next few years, and we expect more LDTs coming to the US market (see our opinion article about FDA’s Minimum Characteristics Pilot Program), which should shift payers decisions on liquid biopsy tests coverage. In Europe, liquid biopsy test reimbursement is variable across countries. In Germany, for example, only EGFR testing in NSCLC patients is covered. In addition to that, for certain liquid biopsy tests to be reimbursed, the sensitivity should be down to 0.1% VAF (variant allele frequency), which is a technical challenge for most assays.
- Although guidelines are supportive of liquid biopsy usage only in advanced/metastatic disease, today more solid tumor patients in this setting are managed with precision therapies through liquid biopsy tests, compared to 10 years ago.
- Liquid biopsy is moving from a method used only in advanced/metastatic disease setting towards a screening/early disease management tool.
- There are still barriers to overcome the lack of wide utilization of liquid biopsy, for example test quality and reimbursement. External Quality Assessment (EQA) programs can support the improvement of clinical care through evaluation of analytical performance, test interpretation and test reporting. In addition, there is an increasing need for the industry to provide scientific and economic evidence that supports liquid biopsy clinical utility, which will likely result in positive coverage from regulatory bodies.
- In conclusion, liquid biopsy has come a long way, with increasing clinical utility and potential for early cancer management. However, challenges such as test quality and reimbursement need to be addressed. EQA programs and collaboration among industry stakeholders can play a crucial role in driving adoption and standardization.
Diaceutics has been actively involved in producing valuable content on liquid biopsy over the past few years. We released a report during ASCO 2017, which compiled essential information on liquid biopsy. Our discussions during the event revolved around the clinical utility of liquid biopsies in tumor indications beyond NSCLC. We addressed important considerations, such as whether to prioritize liquid biopsies as frontline testing or focus on tissue testing. Additionally, we explored its role as a resistance monitoring method and its potential for early cancer diagnosis.
In another published opinion article, we provided an overview of liquid biopsy, the methods used for ctDNA detection, its clinical applications in NSCLC, and insights into new patent requests from pharmaceutical and companion diagnostic companies.
In early 2022, the Diaceutics team co-authored an article highlighting the importance of industry engagement to accelerate the discovery, application, and adoption of MCED testing from the laboratory to the clinic. We emphasized the need for collaboration between academia, industry, regulatory bodies, guidelines, and reimbursement organizations to overcome technical challenges in MCED assay development and successfully position it in the market.
Recently, we have published the report “Current and anticipated future use of MRD in hematological and solid tumors”. This comprehensive study combines primary and secondary market research with proprietary Diaceutics data to provide valuable insights into the current and future applications of MRD in both hematological and solid tumor indications. The report also explores key factors influencing MRD strategies in drug development and commercialization.
With our continued efforts in research and collaboration, Diaceutics aims to contribute significantly to the advancement and implementation of innovative diagnostic technologies in the field of oncology.
Contact our expert team to understand more about the liquid biopsy testing landscape, EQA programs, and ring studies to advance precision medicine development and commercialization.
Table 1. Latest NCCN and ESMO guidelines recommendations for liquid biopsy testing
PIK3CA mutation testing can performed on tumor tissue or ctDNA in peripheral blood (liquid biopsy). If liquid biopsy is negative, tumor tissue testing is recommended; Somatic ESR1 mutation detection through NGS or PCR in blood (Version: 4.2023)
NGS comprehensive test using either a tissue or blood-based (e.g., liquid) biopsy (Version: 2.2023/Version: 3.2023, respectively)
Patients who have metastatic or advanced gastric cancer who may be unable to undergo a traditional biopsy, or for disease progression monitoring, testing using a validated NGS-based comprehensive genomic profiling assay performed in a CLIA-approved laboratory may be considered. A negative [liquid biopsy] result should be interpreted with caution, as this does not exclude the presence of tumor mutations or amplifications (Version: 1.2023)
Plasma ctDNA testing can be used in specific circumstances if 1) the patient is not medically fit for invasive tissue sampling; or 2) there is insufficient tissue for molecular analysis and follow-up tissue-based analysis will be done if an oncogenic driver is not identified; plasma genotyping (also known as plasma ctDNA testing or liquid biopsy) may be considered at progression instead of tissue biopsy to detect whether patients have T790M, however, if plasma ctDNA testing is negative, then tissue biopsy is recommended (Version: 3.2023)
Molecular analyses may be performed on
circulating tumor DNA (ctDNA or liquid biopsy) when tissue-based analysis is not clinically feasible (Version: 2.2023)
Metastatic biopsy for histologic and molecular evaluation. When unsafe or unfeasible, plasma circulating tumor (ctDNA) assay is an option, preferably collected during biochemical (PSA) and/or radiographic progression in order to maximize diagnostic yield (Version: 2.2023)
Validated and sensitive ctDNA assays can be used to genotype advanced cancers and select patients for targeted therapies; initial genotyping with ctDNA assays should be considered when rapid results are needed, and tissue is unavailable; Initial genotyping with ctDNA assays should be considered when rapid results are needed, and tissue is unavailable; use of ctDNA to detect molecular residual disease is not recommended, due to lack of evidence of its clinical utility
Author: Priscila Cirillo, Director, Research Analyst, Scientific & Advisory Services