Genotype and subependymal lesion burden influence volumetric response to everolimus in tuberous sclerosis complex-associated subependymal giant cell astrocytoma: A 10-year real-world study

Everolimus, a mechanistic target of rapamycin (mTOR) inhibitor, effectively reduces subependymal giant cell astrocytoma (SEGA) volume in patients with tuberous sclerosis complex (TSC); however, biological determinants of therapeutic sensitivity remain poorly defined. In this 10-year real-world cohort, we retrospectively evaluated 43 patients (median age 12 years; 46.5% female) with TSC-associated SEGA treated with everolimus between 2013 and 2024. Over a median treatment duration of 79 months, SEGA volume significantly decreased and remained stable, with median reductions ranging from -21.6% to -26.6% from year one onward. Overall, 37.2% of patients achieved a ≥30% volume reduction, whereas 11.6% experienced SEGA progression; notably, none developed hydrocephalus or required surgical intervention during follow-up. Clinical and genetic analyses demonstrated that treatment responders, compared with non-responders, more frequently harbored TSC1 disease-causing variants (28.6% vs. 4.0%; p = 0.047) and were characterized by a significantly lower burden of baseline potential SEGAs-defined as non-growing subependymal lesions of 0.5-1 cm (12.5% vs. 55.6%; p = 0.018). These findings suggest genotype-dependent susceptibility to mTOR inhibition and highlight baseline imaging burden as key determinants of therapeutic response. Together, our results provide clinically relevant insights into treatment stratification and individualized response expectations for everolimus therapy in TSC-associated SEGA.