In a common genetic disorder, blood test reveals when benign tumors turn cancerous
Neurofibromatosis type 1, or NF1, is a genetic disorder that causes non-cancerous, or benign, tumors to grow along nerves. These tumors can occasionally evolve into aggressive malignancies, but there hasn't been a reliable technique to tell if this has happened.
Researchers from the National Cancer Institute's (NCI) Center for Cancer Research and Washington University School of Medicine in St. Louis have developed a blood test that they believe will one day give a highly sensitive and low-cost method of detecting cancer early in persons with NF1. Doctors may be able to use the blood test to track how well patients are responding to cancer treatment.
The most prevalent cancer predisposition syndrome, NF1, affects one out of every 3,000 persons worldwide. The disease is almost invariably identified in childhood and is caused by a mutation in the NF1 gene. Plexiform neurofibromas are large, benign tumors that occur on nerves in almost half of persons with NF1.
These benign tumors can evolve into an aggressive form of cancer known as malignant peripheral nerve sheath tumor, or MPNST, in up to 15% of patients with plexiform neurofibromas. MPNST patients have a bad prognosis since the malignancy can spread quickly and is generally resistant to chemotherapy and radiation. Eighty percent of persons diagnosed with MPNST die within five years.
“Imagine having a cancer predisposition condition like NF1 in your life. According to research co-author Jack F. Shern, M.D., a Lasker Clinical Research Scholar at the NCI's Pediatric Oncology Branch, "it's like a ticking bomb." “The doctors will be looking for carcinogenic tumors, and you will be looking for them as well, but you want to catch that transformation to cancer as soon as possible.”
To detect if plexiform neurofibromas have changed into MPNST, doctors presently use imaging tests (MRI or PET scan) or biopsies. However, because tumors develop along nerves, biopsy results aren't always correct, and the process can be exceedingly unpleasant for patients. Imaging tests, on the other hand, are both costly and inaccurate.
“What we don't have right now is a tool to assist us figure out if something nasty is cooking inside that enormous, bulky benign plexiform neurofibroma and it's evolving into an MPNST,” Dr. Shern said. “So we thought, ‘What if instead of a full-body MRI or a fancy PET scan, we just sample a tube of blood and say whether or not the patient has an MPNST somewhere?'”
Dr. Shern, study co-leaders Aadel A. Chaudhuri, M.D., Ph.D., and Angela C. Hirbe, M.D., Ph.D., of Washington University School of Medicine, and their collaborators collected blood samples from 23 people with plexiform neurofibromas, 14 patients with MPNST who had not yet been treated, and 16 healthy people without NF1 in order to achieve this goal. The majority of the participants in the study were adolescents and young adults, the age group in which MPNST is most common. The researchers extracted cell-free DNA from blood samples, which is DNA shed from cells into the blood, and used whole-genome sequencing technology to check for changes in the genetic material between the three groups.
The cell-free DNA from MPNST patients displayed many characteristics that set it apart from the DNA from the other two groups. Patients with MPNST, for example, have shorter fragments of cell-free DNA than those with plexiform neurofibromas or without NF1. Furthermore, the proportion of cell-free DNA from tumors in blood samples was substantially higher in patients with MPNST than in those with plexiform neurofibromas (dubbed the "plasma tumor fraction"). These characteristics together allowed the researchers to distinguish between patients with plexiform neurofibromas and those with MPNST with 86 percent accuracy.
The plasma tumor fraction was likewise related to how well MPNST patients reacted to treatment in the trial. To put it another way, if their plasma tumor fraction fell after therapy, their tumor size and number (as evaluated by imaging scans) decreased as well. Metastatic recurrence was linked to an increase in plasma tumor fraction.
“Imagine administering a chemotherapy program to a patient. Dr. Shern stated, "This blood test could readily and quickly allow us to identify whether the disease is going down or even going away totally." “And if you had surgery and removed an MPNST, and the blood test came back negative, you might utilize that to keep an eye on the patient in the future to see whether the tumor returns.”
Despite the fact that it included persons with NF1 from two prominent hospitals, Dr. Shern pointed out that one disadvantage of the current study is its modest size. A larger trial with additional patients is being planned by the researchers. The team's goal, according to Dr. Shern, is to improve the blood test's accuracy from 86 percent to closer to 100 percent. One strategy would be to focus the genetic investigation on genes that have been linked to MPNST.
Dr. Shern believes that a simple and inexpensive blood test to diagnose MPNST early in NF1 patients would be particularly valuable in developing countries and other resource-poor locations where access to imaging equipment and expertise is limited.
Patients with additional cancer-predisposing genetic abnormalities, such as multiple endocrine neoplasia, in which benign tumors can turn malignant, or Li-Fraumeni syndrome, which raises one's risk of acquiring numerous types of cancer, can benefit from blood testing of this type.
“This is the ideal time to utilize these technologies because we can screen an at-risk group with a simple blood test,” Dr. Shern added. “If the test results are abnormal, we know we need to act and look for a tumor.”