Tumor fat composition predicts response to everolimus and supports low-dose therapy in TSC-associated renal angiomyolipomas: a multicenter prospective study.

BACKGROUND AND OBJECTIVE: Renal angiomyolipomas associated with tuberous sclerosis complex (TSC-RAML) may lead to progressive renal damage and hemorrhage. Everolimus is recommended as first-line therapy, but predictors of treatment response and optimal dosing strategies remain unclear. We aimed to evaluate the efficacy of everolimus and to determine whether tumor fat composition predicts treatment response, as well as whether a reduced-dose regimen provides comparable outcomes. METHODS: In this multicenter prospective cohort study conducted across multiple centers in China, 183 consecutive patients with TSC-RAML were enrolled. Three prespecified, outcome-specific analytical subsets were generated from the overall cohort according to the data required for each analysis: (1) standard-dose everolimus efficacy analysis, (2) CT-based tumor fat-composition analysis, and (3) exploratory dose-comparison analysis. Radiographic evaluations were performed at baseline, 3 months, and 6 months. The primary outcome was the RAML response rate, defined as ≥50% reduction in target tumor volume. KEY FINDINGS AND LIMITATIONS: A ≥50% reduction in tumor volume occurred in 44% (34/78) of patients at 3 months and 83% (60/72) at 6 months. Tumor reduction was significantly greater in fat-poor than in fat-rich lesions. No significant difference in response was observed between the standard- and low-dose groups. Oral mucositis was the most common adverse event but occurred less frequently in the low-dose group (P = .002). Tumor regrowth was observed after treatment discontinuation. Limitations include the nonrandomized design, in which dose selection was based on clinical criteria from previously published protocols, unequal group sizes in the dose-comparison analysis, and the open-label nature of treatment administration, which may introduce selection and ascertainment bias. CONCLUSIONS AND CLINICAL IMPLICATIONS: In this large Chinese cohort of patients with TSC-RAML, everolimus effectively reduces tumor volume, particularly in fat-poor lesions. CT-derived tumor fat composition may help predict treatment response. In this exploratory cohort, low-dose everolimus showed promising short-term activity with potentially improved tolerability, but randomized studies are needed to confirm comparative efficacy.