Impact of mTOR pathway mutations on response to mTOR inhibition in neuroendocrine neoplasms (NENs).

Abstract

e16328 Background: NENs are a rare and diverse group of tumors with no consensus on the ideal sequencing of therapies in advanced and metastatic disease. Everolimus (eve), an mTOR inhibitor, is an established targeted therapy for NENs. Although mutations in mTOR pathway-related genes are frequently observed in NENs, it remains unclear whether these mutations predict response to mTOR inhibition. Using a large real-world dataset, we sought to address this question while characterizing the genomic landscape of mTOR mutant NENs. Methods: 3,540 NEN tumors were profiled for DNA (592-gene panel/whole exome sequencing) at Caris Life Sciences. Patients were stratified by the presence or absence of pathogenic or likely pathogenic mutations in mTOR pathway-related genes (PIK3CA, PTEN, AKT1, AKT2, AKT3, TSC1, TSC2, and MTOR: mTORMUT vs mTORWT). Survival outcomes obtained from insurance claims and calculated from the date of tumor biopsy to last clinical contact OS or from start to end of eve treatment (TOT) using Kaplan Meier estimates and Cox proportional hazards models. Statistical significance was calculated using Chi-square, Wald test and adjusted for multiple hypothesis testing where applicable (P < 0.05). Results: Overall, 13.4% of cases harbored mTORMUT ; prevalence varied by tissue site, including GI (13%, n = 62), pancreatic (22.9%, n = 109), lung (5.5%, n = 26), and other sites (58.6%, n = 279). Patients with mTORMUT were similar in age and race/ethnicity but were more likely to be female (55.3% vs 44.7%) and of pancreatic origin (22.9% vs 15.2%, both P < 0.05). These tumors were enriched for mutations in ASXL1, CTNNB1, ARID1A, FBXW7, ATRX, KMT2D, MEN1, RB1, TP53 and APC (ORs: 1.5-5.6, all P < 0.05). Additionally, in mTORMUT tumors, deletions in PTEN and AURKB were more frequent (ORs:1.6-3.5), while those in MTAP were less frequent (OR: 0.7, all P < 0.05). Overall, the mTORMUT group exhibited shorter OS (HR: 1.5, 95% CI:1.34–1.68, p < 0.00001) across all non-pancreatic NENs (Table). Among eve-treated patients (n = 347), while OS did not differ between the two groups (43.8m vs 39.6m, p > 0.05), mTORMUT exhibited a longer TOT (HR = 0.6, 95% CI:0.41-0.87, p = 0.0069). Conclusions: This study supports prioritizing the use of eve in patients with mTORMUT and suggests that it may negate the deleterious effect of the mutations on overall survival. This also supports early utilization of genomic sequencing in patients with advanced and metastatic NENs. Future prospective studies can determine when eve should be incorporated into treatment sequencing for patients with mTORMUT NENs. Median survival outcomes (95% CI, months) stratified by mTOR mutation status and disease cohort. Cohorts mTOR MUT mTOR WT overall (OS) 13.9 (11.1-15.9) 24.2 (22.5-26.1) GI (OS) 7.4 (5.7-15.4) 29.6 (23.9-37.7) Lung (OS) 12.2 (8.0-32.3) 36.1 (29.6-42.5) Pancreas (OS) 39.0 (24.6-62.3) 30.1 (23.4-36.6) overall (TOT) 8.0 (3.4-20.1) 4.7 (3.8-6.3)