Blood-Based Biopsy for Cancer-Predisposed Patients

In patients with inherited conditions such as neurofibromatosis type 1 (NF1), tumors are a frequent occurrence. Although many of these tumors are benign, some can turn malignant – but there’s no easy way to tell which tumors do this and when. To address this gap, Aadel Chaudhuri and colleagues at the National Cancer Institute and Washington University School of Medicine have developed a new blood test that could free NF1 and other cancer-predisposed patients from painful biopsies and extensive imaging procedures (1).

How will the new test affect diagnostic professionals? “In the future, we see our research improving clinicians’ ability to detect and track cancer in high-risk patients predisposed to the disease, such as NF1 patients at risk for malignant peripheral nerve sheath tumors (MPNSTs). One could envision our test being run routinely in pathology labs to track high-risk individuals at each clinic visit, with pathology results integrated with the clinical picture and radiology results to inform decision-making and tumor board discussions.”

But the development process was not entirely smooth sailing; Chaudhuri and his colleagues encountered several challenges. When they first realized that a standard targeted hybrid-capture approach wouldn’t work well for NF1 MPNST due to the relatively low burden of single-nucleotide variant hotspots, they shifted to a low-pass whole genome sequencing approach to detect and track copy number aberrations such as aneuploidy – but even that approach was not sensitive enough.

“We then observed that MPNST patients have shorter cell-free DNA fragment sizes than their plexiform neurofibroma precursor counterparts,” Chaudhuri says. “Applying cell-free DNA selection for short fragment sizes and then performing genome-wide copy number analysis yielded the sensitive, specific approach we showcased in our paper for distinguishing MPNST patients from those harboring only the benign precursor lesion. We also showed that our test enables precise tracking of MPNST tumor burden, including the detection of minimal residual disease in plasma prior to radiographic recurrence.” Taken together, the results suggest that plasma cell-free DNA analysis in NF1 patients has the potential to facilitate early detection of MPNST, which would enable earlier intervention and improve patient survival.