By Kailin Yang, MD, PhD, and Jacob G. Scott, MD, DPhil, Cleveland Clinic
Aadel Chaudhuri, MD, PhD, along with Jeffrey Szymanski, MD, PhD; Paul Jones, BS; Peter Harris, PhD; and Angela Hirbe, MD, PhD, from Washington University in St. Louis (WashU) Siteman Cancer Center, and Taylor Sundby, MD; Alex Pan, MS; and Jack Shern, MD, from the National Cancer Institute (NCI) reported the results of a cohort study that evaluated cell-free DNA fragmentomics in the detection of malignant transformation in NF1 patients with plexiform neurofibromas. Malignant peripheral nerve sheath tumors (MPNSTs) exhibit intrinsic resistance to radiation therapy and chemotherapy, portending a poor prognosis and a low survival rate. Patients with neurofibromatosis type 1 (NF1) who also harbor plexiform neurofibromas (PN) are at increased risk to develop MPNST. Earlier detection of malignant transformation (MPNST), and pre-malignant transformation (atypical neurofibroma; AN) represents a novel strategy to guide personalized precision management for these patients, with the goal of significantly improving their survival.
In this study from WashU and the NCI, a total of 223 patients were enrolled, including 113 with PN, 39 with AN, and 71 with MPNST, in addition to 21 healthy controls. Low-pass whole genome sequencing was performed on the plasma cell-free DNA samples from these participants. Per-fragment cell-free DNA analysis was performed through tracking 4-nucleotide end motifs, which was augmented using a fragmentomic machine learning approach called DELFI that integrates the ratios of short (100-150 bps) vs. long (151-200 bps) cell-free DNA fragments in five megabase bins across the genome. End motifs were compared between healthy controls, PN and MPNST, and DELFI fragmentomic scores were used to more granularly distinguish between malignant and pre-malignant nerve sheath tumor disease states.
DELFI-based cell-free DNA fragmentomics across the genome, aided by ROC analysis, generated the following accuracies: MPNST vs. AN (acc 0.62), MPNST vs. PN (acc 0.83), MPNST vs. healthy (acc 0.86), AN vs. PN (acc 0.87), AN vs. healthy (acc 0.72) and PN vs. healthy (acc 0.88). The authors found that DELFI-based cell-free DNA fragmentomics was superior to their previously published ichorCNA-based cell-free DNA copy number alteration classifier (Szymanski, Sundby..., Shern, Hirbe, Chaudhuri, PLOS Medicine, 2021) for all group comparisons. Two AN cases with DELFI scores resembling MPNST were independently found by the clinical care teams to exhibit very high-risk features, including new onset of pain and rapid growth on imaging in a paraspinal AN patient, and increased FDG update of multiple AN lesions in a supraclavicular field treated years earlier with radiation. These findings highlight the power of cell-free DNA fragmentomics as predictive biomarkers that can distinguish between cancerous and pre-cancerous states, and potentially guide patient management.
Furthermore, measurement of cell-free DNA fragment end motifs among different patient groups showed that the CTCA end motif was more commonly present in cell-free DNA from MPNST and PN patients compared to healthy donors (p-value < 0.001 after Bonferroni correction). Indeed, cell-free DNA fragment end analysis could represent another novel way to subclassify peripheral nerve sheath tumor disease states and ascertain risk of pre-malignancy versus frank malignancy.
Overall, this study offers an exciting noninvasive liquid biopsy approach to precisely detect the risk of developing MPNST (and its pre-malignant precursor states) among NF1 patients, in order to improve patient outcomes through early cancer (and potentially pre-cancer) detection. Cell-free DNA fragmentomics outperformed prior methodologies and accurately predicted pre-malignant and malignant nerve sheath tumor disease states. Clinically, cell-free DNA fragmentomics could thus guide the risk stratification of neurofibroma patients to identify those at greatest risk for developing deadly malignant disease, thus empowering clinicians to act sooner in a data-driven way to facilitate better outcomes.
“Our study paves the way for earlier detection of both cancer and pre-cancer in hereditarily predisposed cancer types such as NF1,” said Dr. Chaudhuri who presented these results at ASTRO. “In the future, surveillance of these patients with a simple blood draw could allow clinicians to anticipate malignant transformation, thus facilitating earlier interception to avert deadly or morbid outcomes.”
Abstract 134 - Cell-Free DNA Fragmentomics for Early Detection of Malignant Transformation in NF1 Patients Harboring Plexiform Neurofibromas was presented on October 2, 2023, during the SS 07 - Bio 2: Genomics, Biomarkers, and Tumor Biology session at the 2023 ASTRO Annual Meeting. Dr. Chaudhuri received the ASTRO Basic/Translational Science Award (Clinical category) as a Senior Investigator.
