An Inside Look at Diagnostics
This case study illustrates the evolution of the diagnostic industry across different continents, diagnostic companies' evolving business models, stak...
There was considerable discussion around liquid biopsy at ASCO 2017 at a time when questions about its clinical utility are still to be addressed. Marianna Sciortino, Associate Director, Diaceutics, assesses the current landscape and looks at the European initiatives aiming to steer the technology clear of the classic adoption barriers.
During the American Society of Clinical Oncology (ASCO) annual meeting held in June 2017 in Chicago, there was considerable discussion around liquid biopsy, a largely non-invasive alternative to surgical biopsies. Several presentations and posters were dedicated to this topic as it is an area in which many questions around utility are being asked but have not yet been fully answered.
There has, however, been a major step forward in this field represented by the European Medicines Agency approval in January 2015 of the first liquid biopsy test, the Therascreen RGQ PCR Kit (Qiagen), and the FDA approval in June 2016 of the Cobas® EGFR Mutation Test v2 (Roche). In September 2016, the FDA approved this test as a companion diagnostic (CDx) to discriminate NSCLC patients with EGFR exon 19 deletions or L858R mutations eligible for Erlotinib (Tarceva, AstraZeneca) as first line treatment and NSCLC patients with T790M mutations eligible for Osimertinib (Tagrisso, AstraZeneca). This regulatory milestone led to the increase in Europe of CE-marked liquid biopsy kits so that the market now offers a choice of tests from 41 companies involved in liquid biopsy CDx development and commercialization. This is despite low adoption of the clinical practice by pathology laboratories to date.
Clinical utility and the current landscape
The key message coming from the ASCO/AACR (American Association for Cancer Research) joint session on liquid biopsy1 during ASCO 2017 is the importance of strong evidence concerning its clinical utility. The diagnostic algorithm recommended by the FDA is to perform tissue biopsy when a negative result arises from a liquid biopsy. Although tissue biopsy is still an irreplaceable source of clinical information the FDA recommendation underlines that liquid biopsy can be used as frontline testing, especially for those lung cancer patients who cannot be biopsied or who have difficult-to-reach metastatic lesions. Moreover, a consensus has been obtained in NSCLC about the role of liquid biopsy in monitoring therapy efficacy and resistance, as represented by the FDA approval extension, as it helps clinicians monitor the presence of resistance-associated molecular alterations at earlier stages and thereby consider other therapeutic possibilities should resistance occur2.
Beyond NSCLC, over 30 studies are currently trying to address the clinical validity and utility of liquid biopsy in tumors such as prostate, bladder, colorectal and breast cancer, aiming to get insights into the appropriate positioning of this technology: is it for early diagnosis, or therapy and resistance monitoring? Indeed, even though in metastatic breast cancer the count of circulating tumor cells (CTCs) has been well established for its prognostic value, this is still challenging in early cancer diagnosis. The ASCO/AACR session also opened up the discussion on Minimal Residual Disease (MRD) monitoring, showing that circulating tumor DNA (ctDNA) detection in plasma after surgery or other therapeutic treatment suggests an incomplete eradication of the disease. This has been demonstrated, however, with personalized assays that are not robust and applicable to most solid tumors, a fact that still stirs debate about the real clinical utility of liquid biopsy for MRD monitoring.
The laboratory perspective: what labs need
Diaceutics works to enable seamless integration of diagnostic and therapeutic pathways and recognizes the crucial role of laboratories, but we know certain barriers can negatively impact on liquid biopsy adoption, a subject also discussed in Chicago. These barriers include lack of harmonization for what concerns the pre-analytical step (reagents, platforms, quantity of cells, etc.), no clear indication of when liquid biopsy has to be used in a specific cancer type, the clinical utility of the test result and clear testing algorithms (tissue versus liquid biopsy).
Standardization of the pre-analytical phase:
Pre-analytical variability (for example, in the blood collection procedure, CTC/ctDNA purification and quantification) can significantly alter the testing result. This issue, in our experience, plagues a number of diagnostic testing approaches, but is of particular importance in liquid biopsy where insufficient or poor quality DNA for analysis can impact the results.
Which is the best assay to use? A PCR-based test or an NGS one? Ambiguity regarding the optimum methodology can be a barrier to laboratory adoption of a test. Pathology labs understand the importance of the testing results so harmonization studies and comparative studies are crucial to provide clear evidence of clinical utility and strong recommendations to the testing laboratories.
Clinical utility at diagnosis rather than for monitoring is still being investigated and results cannot easily be translated between multiple cancer types. The current clinical trials are also aiming to identify new biomarkers present in human fluids like blood, urine or saliva that can be associated with tumor progression and therapy response and resistance, including exosomes, miRNAs and the number of CTCs and amount of ctDNA itself.
No guidelines for liquid biopsy have been released yet, but the scientific community recognizes the need for precise indications to render the test reliable in every lab. As a result, ASCO/CAP is developing a formal position statement. Different initiatives are also underway in Europe to reach consensus on and harmonize liquid biopsy testing: the CANCER ID Project, a public-private partnership consortium with 36 partners from 13 countries, is dedicated to establishing standard protocols for the clinical validation of blood-based biomarkers. Another study presented at ASCO was the CTC-SCAN Project, which aims to find a validated protocol for CTC detection to better stratify prostate cancer patients for adjuvant therapies.
From a clinical perspective, Diaceutics’ research reveals Europe is diverse in its use and adoption of liquid biopsy. Switzerland, for example, is currently using liquid biopsy as routine clinical practice for NSCLC resistance monitoring. In Germany, the number of laboratories offering this technology in lung cancer will likely increase, thanks to financial support provided by the German Federal Ministry of Education and Research to genetic testing firm CeGaT for the development of liquid biopsy and analysis of ctDNA3. In Italy, there is an increasing tendency to adopt and validate liquid biopsy even though no national funding is available. Notably, the European Molecular Biology Laboratory offers practical training on liquid biopsy, covering the most common techniques to detect and analyse CTC and ctDNA, highlighting the obvious interest of the European scientific community4.
The pharma perspective: what pharma needs
With AstraZeneca entering the market with Tarceva (January 2015) and Tagrisso (September 2016), therapies associated with liquid biopsy CDx kits, we expect an increase in the CDx liquid biopsy testing performed. What will be important for a pharma company to know?
Diaceutics’ experience suggests that for the same test many diagnostic partnerships can be established, and it is crucial for pharma to understand which test will produce a clinically valid and meaningful result and to partner accordingly. Is it a qualitative test for early cancer diagnosis and therapy selection or a quantitative one for tumor monitoring?
Lack of, or inadequate reimbursement, especially in some European countries, can negatively impact on testing adoption. All the studies addressing the clinical utility of this technology, and the possibility of finding new biomarkers, will be crucial for liquid biopsy developers and the reimbursement issues they face. The possibility of earlier diagnosis enabling patients to access the right treatment at the right time and avoid drug resistance, could be a likely source of cost savings, thereby encouraging liquid biopsy adoption and appropriate reimbursement.
The patient perspective: liquid biopsy in the treatment pathway
There are aspects of the process of testing, diagnosis and treatment that strongly affect the patient’s quality of life. One of these is turnaround time (TAT), the time from the testing request to the result reporting. In some cases, patients have a long wait to obtain a result that is critical and fundamental to their treatment pathway. Liquid biopsy can overcome long waiting times with a quick and easy-to-perform test. Another aspect concerns monitoring, as physicians and patients need to understand how the treatment is progressing. If treatment is not progressing as planned, liquid biopsy can be used for therapy and resistance monitoring, opening up timely opportunities to change strategy.
Overcoming the barriers
The promising new opportunities that liquid biopsy can provide in the diagnostic field are the subject of active and exciting debate. We observe that even though liquid biopsy can overcome some of the issues with CDx, it is not without its own pitfalls when it comes to adoption.
Reimbursement, the reliability of the test results and questions around methodology choice remain barriers to widespread adoption of liquid biopsy in clinical practice. Potential for NGS use in liquid biopsy itself poses additional questions — Diaceutics’ June 2017 webinar investigating the reality of NGS today and in the future, revealed that many aspects, like tissue quantity, long TAT, cost-effectiveness, cost challenges and the management of huge amounts of data, can negatively influence NGS adoption. However, it is important to consider that there are potential barriers related to each methodology used for human fluids-associated testing.
Liquid biopsy testing is a promising field that is triggering many clinical trials and proof-of-concept studies around the world, with Europe particularly active in providing laboratories with standard protocols for clinical activity. The pharmaceutical industries are investing huge resources for the development of liquid biopsy testing that could support a rapid growth of test offerings in the landscape. The instruments to solve the problems arising with this testing method already exist but using them effectively requires a joint effort from the scientific community, pharma, diagnostic companies and national authorities. Laboratories and pharma companies need to work together to overcome the limitations of the present technology. When the barriers are finally overcome we will have a powerful tool for patient diagnosis and treatment that can contribute to major changes in the future of precision medicine healthcare.