National clinical study

Validation of ctDNA elimination during chemoradiotherapy for anal cancer

For the DCCC ctDNA Research Center it is very important to disseminate knowledge about ctDNA guided cancer treatment to the public and patients. Therefore, this knowledge is disseminated through popular science magazines and news media (radio and television), where the scientific insights are explained for non-specialist.

Abstract

Background: Squamous cell carcinoma of the anus (SCCA) is rare disease. Therefore, we do not have data to support individualized treatment, and patients are treated with standard dose chemoradiation therapy (CRT). SCCA is highly associated with human papilloma virus infection (HPV), and small fragments measured in the blood as circulating tumor DNA (plasma HPV) has shown potential as a biomarker to predict treatment response in patients with HPV positive tumors. Our fi rst dataset showed that slow elimination during treatment is associated with a high risk of treatment failure and these patients might benefi t from escalated treatment. How-ever, before clinical prospective testing, the elimination patterns need further validation to-gether with development of methods to evaluate ctDNA in patients with HPV negative tumors. We have now developed an organ specifi c ctDNA methylation assay for SCCA patients a prom-ising new method to detect ctDNA in both HPV positive and negative anal cancer, which needs further validation.

Aim: We aim to identify patients with a high risk of treatment failure in both HPV positive and HPV negative cases, based on their ctDNA elimination pattern during CRT and to validate the optimal strategi for ctDNA analysis.

Methods: The ctDNA elimination pattern during CRT will be validated in material from two na-tional prospective trials DACG-II (n=100) and the NOAC-9 (n=50, currently including n=300). Blood samples were drawn at baseline (n=150), mid-treatment (131) and by end-of-treatment (n=131). Three methods for ctDNA analysis will be formed on all material; Plasma-HPV analy-sis with a multiplex digital droplet PCR (ddPCR) method measuring HPV subtypes 16, 18, 31, 33, 51 and 58. cfDNA analysis on serum samples with direct fl uorescent assay (DFA) and a newly developed multiplex ddPCR assay targeting 5 CpG biomarker (Data to be presented at ESMO2024) hypermethylated in SCCA. A comparison of the three methods will be performed.

Feasibility: Blood samples from 150 patients collected during chemoradiotherapy from the DACG-II and the NOAC-9 studies are available and ready for analysis. The methods are estab-lished, and all analysis are planned to be performed before the end of 2024, with results avail-able in the fi rst quarter of 2025.

Perspectives: The results will be the foundation for fi nal design of a prospective clinical inter-vention trial, where high risk patients identifi ed by a slow ctDNA elimination pattern, will be randomized to either standard of care or a radiotherapy boost at end of treatment to potentially improve outcomes.

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