Affirming the Feasibility of cfDNA Sequencing Use in Li-Fraumeni Syndrome

Trevor Pugh, PhD, FACMG, spoke with CancerNetwork^® at the 7th International Li-Fraumeni Syndrome (LFS) Association Symposium about the methodology and ongoing efforts associated with a prospective, controlled, randomized trial intended to assess the ability of cell-free DNA (cfDNA) sequencing to detect cancers in patients with LFS and similar cancer predisposition syndromes.¹ In a presentation at the symposium, Pugh highlighted this trial as an initiative related to the cfDNA in Hereditary and High-Risk Malignancies (CHARM) Consortium.²

Pugh, an associate professor in the University of Toronto Department of Medical Biophysics, senior scientist at the Princess Margaret Cancer Centre, and director of Genomics and senior investigator at the Ontario Institute for Cancer Research, described how initial cfDNA testing among the first 200 patients enrolled on the trial yielded negative results since the trial opened in April 2023. However, he stated that these outcomes were expected, noting that a real signal may emerge when subsequent testing is performed for each patient.

Investigators of the ongoing prospective trial plan to enroll approximately 1000 individuals with a hereditary cancer syndrome such as LFS. In the experimental arm, patients will have blood samples collected every 4 months, which are then assessed via cfDNA sequencing; if a positive result occurs, a physician will arrange a follow-up MRI or colonoscopy to confirm the possibility of cancer. In the comparator arm, patients will have blood samples collected up to 3 times a year, which are then donated to the CHARM Consortium biobank for use in future research.

Transcript:

All our work so far had been done on bank samples, where we knew the patient outcomes. We knew whether they had cancer or not, and we learned a lot about how important it is to do a broad test. Rather than [testing] just 1 position in the genome, [we] instead test the entire genome.

We took what we learned from that retrospective study, and we set that up in our clinically accredited labs. We could start issuing clinical reports prospectively and return them to the managing physicians. In this study, the blood is collected every 4 months, and what’s different is [when] we now collect the blood, we sequence it as quickly as we can. Our current turnaround time is a month and a half. Then, we return these results to the genetics clinics, who will act upon them if the result is positive.

[The study is] still early. Our retrospective study showed the technical feasibility of doing this and being able to find signals in the cell-free DNA. The trial just opened in April [2023]. We’ve enrolled the first 200 patients with hereditary cancer syndromes. Every single test we’ve done so far is negative. That’s not an unexpected result, given the size of the cohort and the genetic carrier status of those patients. The real signal is going to come when we start to do the second test and the third test. By the time we’re done, we’ll have 20 tests for every patient. So far, patients have all [tested] negative, which is more or less what we would have expected at this stage.

References

1. Pugh T. The CHARM of it all: Putting cell-free DNA into practice in a prospective trial. Presented at the 7th International Li-Fraumeni Syndrome (LFS) Association Symposium; October 19-22, 2024; Philadelphia, PA.
2. About. CHARM Consortium. Accessed October 25, 2024. https://shorturl.at/qDN0f