ACPMP Executive Director, Deborah Shelton, has over 20 years of experience providing legal counsel to clients navigating the complex regulations governing the testing and commercialization of FDA-regulated products, with a particular focus on pharmaceuticals and medical devices. Periodically provides insight on research topics of interest to our patient community.
The Unfolding Promise Of cTDNA
There are many promising scientific developments in the oncology space, one of which is the ongoing study and increased role of liquid biopsy assays that analyze circulating tumor DNA (ctDNA) in the blood. Currently, ctDNA is primarily being used in the advanced cancer context to conduct molecular profiling, select targeted therapies, monitor treatment response, and for long-term post-treatment surveillance.
There have been two recent public discussions about the rapidly evolving role of ctDNA. One was a webinar hosted by Genome Web and the other was a White Paper issued at the Friends of Cancer Research Annual Meeting, each of these is discussed in more detail below.
Webinar Hosted by Genome Web
A highly informative hour webinar focused on the current state of ctDNA was recently hosted by GenomeWeb. The webinar was titled “Evolving Role of ctDNA Analysis” and there were three expert panelists participating: Aparna Parikh, MD, Assistant Professor of Medicine, Harvard Medical School and the Director of the Massachusetts General Hospital Cancer Center’s Global Cancer Care Program; Victor Velculescu, M.D., Ph.D., Johns Hopkins University School of Medicine; and Dennis Lo, M.D., Ph.D., The Chinese University of Hong Kong. Each of the three expert panelists had interesting observations about the current strengths and challenges of ctDNA analysis. The good news is that there was unanimous consent about the current utility and future promise of this technology.
One of the key points made by a panelist about the current use of ctNDA is its value in genomic sequencing as an adjunct to tissue biopsy, particularly in cases where there may be a limited supply of tissue sample. Notably, however, one of the panelists posited that universal patient access to ctDNA testing is a significant challenge.
Interestingly, another panelist commented on a recent finding that different types of tumors may shed DNA differently at different stages of disease. Moreover, research suggests, that patients can have the same size and type of tumor but yet have different ctDNA results. The specific basis for this remains under investigation, as well as the potential effect of this finding on its utility. One supposition is that these differences could be attributed to different biologies between patients. Fortunately, however, the panelists generally concurred that ctDNA has benefit in the post-treatment monitoring setting across many solid tumors.
The panelists were also careful to note that the use of ctDNA for purposes of early diagnosis remains a work in progress. For example, the absence of a finding of ctDNA in investigating pancreatic cancer is not necessarily conclusive due to frequent low cellularity of that type of tumor. Although appendiceal tumors were not discussed, it seems that perhaps a similar challenge may exist at present.
Finally, in terms of next steps for the study of ctDNA as an early cancer detection screening tool, the panelists discussed numerous questions to be considered, including appropriate patient populations, generation of statistical evidence of efficacy, and types of tumors for which early intervention may matter most. The panel discussion concluded with a brief but lively discussion about the importance of having institutional capabilities in place to handle the potential in flux of positive results from ctDNA testing once it becomes more widely available.
White Paper Issued by Friends of Cancer Research
The Friends of Cancer Research (Friends), a non-profit cancer research think-tank and advocacy organization, recently issued a White Paper titled, “Assessing the Use of ctDNA as an Early Endpoint in Early-Stage Disease.” The White Paper can be found here: https://friendsofcancerresearch.org/sites/default/files/2021-11/Assessing_Use_of_ctDNA_Early_Endpoint_Early-Stage_Disease.pdf
This paper is the product of Friends convening a multi-stakeholder group of experts in ctDNA and early-stage disease. The working group included members of the FDA, drug sponsors, developers of ctDNA assays, and academic clinicians. The paper provides a clear and insightful summary of both the current and prospective uses of ctDNA. The authors point the numerous opportunities to utilize ctDNA in early-stage diseases that rely on the potential to detect disease burden earlier and in a less invasive manner than the current standard of care imaging and tissue biopsy.
As discussed in the paper, a significant category of use cases of ctDNA in early-stage disease pertains to informing and assessing the efficacy of a therapy. A brief summary of these uses cases is provided below, and are discussed in greater detail in the paper:
- ctDNA for Risk Stratification and Treatment Selection. The authors note that emerging study data highlights the potential of ctDNA to detect post-surgery measurable residual disease (MRD). Such detection can, in turn guide decisions on adjuvant therapy.
- ctDNA for Patient Selection. MRD-selected adjuvant trials utilizing ctDNA findings can help define a more homogenous patient population with higher relapse-event rates. This is an important development because it can increase efficiency in clinical trials and reduce the prospect of exposure of certain patients to treatments that they may not necessarily need. In other words, the use of ctDNA for patient selection may lead to smaller, higher-risk patient populations and reduced time to reach study endpoints.
- ctNDA to Monitor and Predict Treatment Response to the Neoadjuvant and Adjuvant Settings. The thinking here is that measuring ctDNA prior to and throughout treatment may be useful to monitor neoadjuvant treatment response as an early endpoint to potentially predict long-term outcomes. In addition, ctNDA can potentially be used to monitor and predict treatment response as an early endpoint in the adjuvant setting. The authors conclude that evidence from early phase studies suggests there is an opportunity in the both the neoadjuvant and adjuvant settings to further generate robust evidence.
The paper then provides a robust discussion of key technical and clinical questions for the use of ctNDA in early disease, and the need for alignment on a core set of data elements to assess the use of ctDNA in early-stage disease.
The authors conclude, in part, that the focus on establishing ctDNA as an early endpoint has the potential to expedite and improve confidence in the efficacy of novel therapies, bringing beneficial treatments to patients sooner. There are, however, numerous clinical and technical questions to be addressed, and alignment on key data elements in clinical studies will help to accelerate answers. Onward!