Abstract C019: Inactivating TSC1 and TSC2 alterations, co-mutations, and genomic instability in advanced cancers: Analysis of a real-world (RW) patient (pt) population using the Foundation Medicine genomic database
Authors: Kwiatkowski David J. , Palma Norma A. , Navarro Willis H. , Iyer Gopa 
Published: December 2023

Abstract
Background Tumor suppressor genes tuberous sclerosis complex subunit 1 and 2 (TSC1, TSC2) are critical negative regulators of mTOR activity. In the exploratory biomarker analysis (AMPECT, NCT02494570) and an Expanded Access Program (NCT03817515), pts with inactivating alterations in TSC1 or TSC2 demonstrated responses with the mTOR inhibitor, nab-sirolimus. While these alterations are observed in most cancer histologies, characterization and distribution of TSC1 and TSC2 alterations across tumor types are not well understood. PRECISION I (NCT05103358), a currently enrolling tumor-agnostic study, will assess the clinical benefit of nab-sirolimus in pts with cancer who harbor inactivating TSC1 and TSC2 alterations. To appreciate the potential for TSC1 and TSC2 as therapeutic biomarkers, we analyzed TSC1 and TSC2 mutational data from a RW genomic database.
Methods Next-generation sequencing (NGS) data from Foundation Medicine’s genomic database of pts primarily with advanced cancer were analyzed using the FoundationInsights™ web-based platform. Frequency and actionability of TSC1 and TSC2 alterations were assessed. Known or likely pathogenic inactivating TSC1 and TSC2 alterations (ie, indel, rearrangement, frameshift, biallelic loss, nonsense, and some missense mutations) were further characterized for co-mutations, tumor mutational burden (TMB), and microsatellite instability status.
Results As of 29 Mar 2022, 438,974 pts with advanced cancer in the Foundation Medicine genomic database had tumor tissue NGS data available. Known/likely inactivating alterations in TSC1 and TSC2 were identified in 8464 (1.9%) pts; 4.3% had variants of unknown significance, primarily missense (~89%), that were not known to be inactivating. Of the inactivating alterations, 52.1% were TSC1 and 48.6% TSC2, including short variants, defined as base substitutions and short indels (85.0%), rearrangements (10.8%), and copy number deletions (17.9%). Alterations were most frequently identified in urinary bladder (8.6%), kidney and renal pelvis (5.8%), corpus and uterus (3.4%), soft tissue (including heart; 2.4%), and liver and intrahepatic bile duct (2.3%) cancers. The most frequently co-occurring mutations included TP53 (62.2%), CDKN2A (26.2%), and TERT (22.2%). TMB was low (&lt;6 mutations per megabase) in 51.6% of pts with inactivating alterations in TSC1 and TSC2. Samples were mostly microsatellite stable (MSS; 82.2%) across tumor types.
Conclusion In a large RW database of pts with advanced cancer, inactivating TSC1 and TSC2 variants occurred in 1.9% of pts. These occurred across common tumor types at rates as high as 8.6% (urinary bladder tumors). A majority of pts had low TMB and/or MSS status, suggesting that these are actionable alterations and not passenger events (Bennett et al, Mod Pathol 2022). Common co-mutations also have limited clinical actionability. These observations suggest cancers with TSC1 and TSC2 alterations may be candidates for targeted therapy; this hypothesis is being tested in the currently enrolling PRECISION I (NCT05103358) study.
Citation Format: David J. Kwiatkowski, Norma A. Palma, Willis H. Navarro, Gopa Iyer. Inactivating TSC1 and TSC2 alterations, co-mutations, and genomic instability in advanced cancers: Analysis of a real-world (RW) patient (pt) population using the Foundation Medicine genomic database [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C019.