Exploring the Potential of Circulating Tumor DNA for Tailored Treatment Decisions in Oncology
Authors:   , Kramer Astrid 
Published: December 2024

In this thesis, we used different methods from the field of early health technology assessment (HTA) to study the potential value of circulating tumor DNA (ctDNA) as a biomarker for tailored treatment decisions in oncology. This evidence is crucial to facilitate the potential implementation process in the Netherlands.
To gain more insight into potential implementation pathways for four ctDNA-testing applications in colorectal cancer and non-small cell lung cancer, a scenario-drafting study was conducted in Chapter 2. A questionnaire with twelve scenarios and sixteen additional questions on the implementation of ctDNA testing in the Netherlands was elicited among ctDNA-experts. We found that demonstrating clinical utility was the main facilitator for ctDNA implementation in Dutch clinical practice, but there was no consensus amongst the experts regarding the evidence requirements to demonstrate this. We also found that barriers to the implementation process differed amongst clinical applications and tumor types. Thus, to facilitate the implementation, it is important to define the required evidence for demonstrating clinical utility of ctDNA, and to have knowledge on the specific barriers and facilitators of the implementation process associated with the specific clinical application and tumor type.
It is also important to get more insight into to the costs of ctDNA testing for both decision-making, and HTA research. Therefore, in Chapter 3, we developed a micro-costing framework for consistent cost calculation of ctDNA-testing, and it was used to calculate the costs for 6 case studies from three Dutch hospitals, using different ctDNA testing platforms. The micro-costing framework describes the diagnostic workflow from blood sample collection to diagnostic test result and included costs for personnel, materials, equipment, overhead, housing, and failures, considering the testing volume. The case studies showed a wide range of costs, sensitive to the platform, setting, and testing volume. The developed micro-costing framework can provide more insight into the costs associated with ctDNA testing for different workflows, which can be relevant for investment decisions and future cost-effectiveness analyses.
As ctDNA status is strongly prognostic after surgery, we explored the cost-effectiveness of ctDNA-guided adjuvant chemotherapy (ACT) decisions in stage II and stage III colon cancer in Chapter 4 and 5, respectively. In stage II colon cancer (Chapter 4), it is recommended to treat only high-risk patients based on clinicopathological factors. Our analyses showed that a strategy based solely on ctDNA was less effective than the current guideline, but a strategy that combines current guideline with ctDNA was more effective. However, these combination strategies were not yet cost-effective. In case of cost reduction, test improvement, or if patients with detectable ctDNA have a high ACT response, ctDNA-guided strategies have the potential to become cost-effective in stage II colon cancer. In stage III colon cancer (Chapter 5), all patients are currently offered ACT but ~55% are overtreated as they are already cured by the surgery only. Therefore, we investigated the cost-effectiveness of ctDNA-guided strategies for omitting ACT. Our results showed that these strategies are less effective than administrating ACT to everyone, but that are scenarios in which ACT could potentially safely withheld. However, substantial reduction in ctDNA costs are required to become cost-effective.
Finally, in Chapter 6, we reviewed published cost-effectiveness studies for three different biomarker applications. We examined how these studies dealt with limited evidence availability, the assumptions made, and how these choices affected the outcomes. Additionally, we looked at which outcomes were reported to express the impact of biomarkers. Based on these findings, 8 recommendations were proposed for future cost-effectiveness analyses of biomarkers, such as ctDNA. These recommendations can help researchers and policymakers conduct better cost-effectiveness studies and improve understanding of the (broader) impact of biomarker testing.