Cancer screening with cell-free DNA in LI-fraumeni syndrome: feasibility study prior to national trial

The National Cancer Institute awarded The Children's Hospital of Philadelphia a $427,064 cooperative agreement on July 16, 2026, under the Cancer Detection and Diagnosis Research program (CFDA 93.394) to generate pilot and feasibility data for a planned randomized controlled trial evaluating circulating tumor DNA (ctDNA) screening in individuals with Li-Fraumeni syndrome.

The award funds development of pilot and feasibility protocols that will precede a larger national trial assessing the addition of ctDNA testing to standard-of-care cancer screening in Li-Fraumeni syndrome populations. The EDISYN Consortium, working in collaboration with the ECOG-ACRIN Cancer Research Group, the CHARM Consortium, and patient advocacy organizations, will pilot ctDNA cancer screening using a test developed and validated by the CHARM Consortium. The work addresses the high cancer risk in Li-Fraumeni syndrome individuals—who face an 80–90 percent lifelong chance of malignancy—and aims to improve upon existing imaging-based screening protocols, which carry high false positive rates and significant anxiety for patients and families. Early cancer detection through ctDNA holds potential to enable earlier intervention and improved survival while reducing treatment-related morbidity and secondary malignancy risk.

The Children's Hospital of Philadelphia Research Institute is the recipient. Performance occurs in Philadelphia, Pennsylvania. The award period runs through June 30, 2029.

Abstract

Individuals with LI-fraumeni syndrome (LFS) are at high risk of developing cancer, with 80-90% lifelong chance of malignancy. Screening protocols - leaning heavily on imaging surveillance - have been shown to improve survival through early cancer detection. However, these protocols are imperfect, with high false positive rates and the inability to detect all cancers prior to onset of symptoms. Additionally, screening is associated with significant anxiety and distress in people with LFS and their families. Improved methods of cancer screening are crucial for this at-risk population, as earlier cancer detection is tied to improved survival, improved treatment-related morbidity, and decreased secondary malignancy risk if radiation therapy can be avoided. Early cancer detection through testing of circulating tumor DNA (CTDNA) holds great promise for individuals with LFS. The edisyn (early detection in syndromic cancers) consortium is planning a randomized controlled trial (RCT) evaluating the efficacy of adding CTDNA screening to standard of care screening protocols in detecting cancer earlier in individuals with LFS. This trial is being planned in collaboration with the ecog-acrin cancer research group, the charm (cell-free DNA in hereditary and high-risk malignancies) consortium, and patient advocacy organizations. We plan to recruit over 1,000 pediatric and adult participants with LFS at many centers across the united states, and thus pilot and feasibility data are required prior to study initiation. In this U34 proposal, the edisyn consortium will generate pilot and feasibility data that will ensure success of the planned RCT assessing the addition of CTDNA testing to cancer screening in LFS. In aim 1, we will pilot CTDNA cancer screening using a test developed and validated by the charm consortium, with the hypothesis that we will provide clinically actionable results within 4 weeks to all participants, and that subjects with a positive result will then undergo follow up testing to evaluate for malignancy with limited cost and barriers to care. In aim 2, we will pilot a battery of patient-reported outcome measures (PROM) to obtain baseline data and assess acceptability of these measures for the future trial. Our hypothesis is that PROM will describe a range of logistical and psychological barriers that will be actionable in planning the future RCT. We expect that the completion of the above aims will inform the design of an impactful RCT hypothesizing that CTDNA screening will improve time to cancer detection in individuals with LFS. Furthermore, these pilot data are crucial to achieving the primary outcome of the planned RCT or - should pilot data reveal lack of feasibility of the planned RCT - modifying the primary outcome prior to trial initiation.