Clinical characteristics and outcomes of germline and sporadic NF1-associated gastrointestinal stromal tumors: Insights from a real-world patient registry.

Abstract

11538 Background: Neurofibromatosis type 1 (NF1)-associated gastrointestinal stromal tumor (GIST) is a rare, distinct molecular subtype, typically lacking KIT or PDGFRA mutations. Standard KIT-targeted therapies show limited efficacy, highlighting the need for alternative systemic approaches. Real-world data on the clinical features, treatment patterns, and outcomes of NF1-associated GIST are limited. Methods: The Life Raft Group (est. 2000) Registry is an international, observational registry. Patients with GIST and documented NF1 mutations without another primary oncogenic alteration were included. Demographic, tumor, and treatment characteristics were summarized; group differences were assessed using Fisher’s exact test, and disease-free survival (DFS) and overall survival (OS) were estimated by Kaplan–Meier methods. Results: A total of 38 patients were identified (1.3% of the total registry, n = 2990) and stratified as germline NF1 (n = 18) and sporadic NF1 (n = 20). Median age at diagnosis was 57 years; 53% (n = 20) of patients were female, with a higher proportion of germline NF1 than sporadic NF1 (60%, n = 12 vs 40%, n = 8). Conversely, among males, sporadic NF1 was more common than germline NF1 (67%, n = 12 vs 33%, n = 6). Tumors predominantly arose in the small bowel (79%). Germline NF1 patients exhibited significantly higher rates of multifocal disease compared with sporadic NF1 patients (85% vs 15%, p = 0.0006). Most patients presented with localized disease (84%, n = 32), with similar proportions between germline and sporadic NF1 (78%, n = 14 vs 90%, n = 18). All localized patients underwent surgical resection, achieving R0 margins in 72% of cases. Among patients who developed advanced disease (de novo metastatic or recurrent disease; n = 18), 67% received systemic therapy including MEK inhibitors in 22% (n = 4). One patient achieved durable disease control on selumetinib for nearly six years and remains on treatment. Median follow-up was 37.6 months (2.5–185). In localized patients, 5-year DFS was 65% (95% CI: 39–100) for germline and 46% (95% CI: 25–84) for sporadic NF1; median DFS was 55.4 months in sporadic NF1 and not reached in germline NF1. 10-year OS was 78% (95% CI: 62–98) overall, 88% (95% CI: 67–100) for germline, and 83% (95% CI: 64–100) for sporadic localized patients. Survival estimates in metastatic patients were highly variable due to small numbers. Conclusions: In this real-world registry analysis, NF1-associated GIST shows small bowel predominance and frequent multifocality, particularly in germline NF1. Most patients achieve disease control with surgery. MEK inhibitors may demonstrate potential activity in advanced NF1 GIST. These findings highlight phenotypic differences between germline and sporadic NF1-associated GIST and support further evaluation of MEK-targeted therapy in patients with metastatic disease.