Risk of developing malignant peripheral nerve sheath tumors in patients with neurofibromatosis 1 receiving MEK inhibitor treatment for plexiform neurofibromas.

BACKGROUND: Mitogen activating protein kinase kinase inhibitors (MEKi) provide clinical benefit to patients with symptomatic, inoperable plexiform neurofibromas (PNs) in Neurofibromatosis type 1 (NF1). Several cases of MPNST developing in patients while receiving MEKi for PN have been reported, raising the question whether MEKi therapy might increase this risk. We report the incidence of MPNST in those who have received MEKi, non-MEKi (eg, mTOR inhibitors), and no PN-directed medical therapies and assess the risk of MPNST in patients who received MEKi. METHODS: Patients evaluated at the National Cancer Institute (NCI) with a clinical or genetic diagnosis of NF1 from 1/1/1998 to 12/31/2019 were included in this analysis (n = 296). Patients were categorized as MEKi (n = 29), non-MEKi (n = 91), both (n = 45), or no medical treatment (n = 131); only patients who received PN-directed medical treatment were included in the analysis of MPNST risk. Univariate evaluations of risk factors associated with MPNST were included in a multivariate model with treatment group as a time-dependent covariate. RESULTS: No difference in MPNST risk (HR: 1.09, 95% CI: 0.30-4.01) between MEKi as compared to non-MEKi treatment was observed after adjusting for radiation exposure. Radiation exposure was associated with a higher risk of MPNST (HR: 5.15, 95% CI: 1.15-23.04). Other patient characteristics, including NF1 inheritance pattern, were not associated with the risk of MPNST development in this cohort. CONCLUSION: Our data do not demonstrate a significant difference in the risk of MPNST development between patients with NF1-PN who received MEKi and non-MEKi treatments. Radiation exposure was significantly associated with a higher risk of MPNST development.