Real-world characterization and frequency of TSC1 and/or TSC2 alterations collected from tumor tissue and liquid biopsies from the Tempus genomic database in patients with advanced cancer

Background
Tumor suppressor genes tuberous sclerosis complex subunit 1 and 2 (TSC1, TSC2) are critical negative regulators of mTORC1 activity. Patients (pts) harboring inactivating alterations in TSC1 and/or TSC2 (TSC1/2) in the AMPECT PEComa trial (NCT02494570) and in a pan-tumor Expanded Access Program (NCT03817515) demonstrated response to the mTORC1 inhibitor, nab-sirolimus. PRECISION I (NCT05103358), a currently enrolling tumor-agnostic study, will assess the clinical benefit of nab-sirolimus in pts with cancer with inactivating TSC1/2 alterations. To appreciate the potential for TSC1/2 targeted therapy, here we characterize TSC1/2 alterations across a large RW pt population with advanced cancer using data from tissue and liquid biopsies (LBs).

Methods
De-identified RW data for 154965 cancer pts profiled with the Tempus xT tumor DNA sequencing assay were obtained from the Tempus database (accessed 28 Apr 2023). Records included next-generation sequencing (NGS) data from the Tempus xT tumor DNA and/or xF LB sequencing assays. Somatic TSC1/2 variants were categorized as pathogenic/likely pathogenic mutations, deletions (copy number loss), or variants of uncertain significance (VUS). Inactivating TSC1/2 mutations and copy number variants were further characterized including frequency across primary vs metastatic tumor samples.

Results
Of the xT patients, pathogenic/likely pathogenic inactivating TSC1/2 alterations were identified in 2621 (1.7%) pts; TSC1/2 VUS (primarily missense) were identified in 9918 (6.4%) pts. Inactivating TSC1/2 variants consisted of frameshifts (35.9%), stop gains (35.8%), multihits (18.4%), deletions (7.0%), and missense mutations (3.0%), and were most frequently identified in urothelial carcinoma (UC) and pancreatic neuroendocrine tumor (each 8.4%), renal clear cell carcinoma (6.3%), hepatocellular carcinoma (HCC; 5.9%), and endometrial carcinoma (3.9%). Pathogenic TSC1 variants were more common (TSC1 56.6%; TSC2 43.4%), as was their detection among primary (~20380) vs metastatic (~70790) tumors (TSC1 1.1% vs 0.91%; TSC2 0.82% vs 0.60%). Of the 53502 xF pts with LB sequencing, inactivating TSC1/2 mutations were identified in 489 (0.9%) pts; TSC2 variants were slightly more common than TSC1 (TSC2 58.5%; TSC1 41.5%). The most common tumor types harboring inactivating TSC1/2 variants in LBs were HCC (5.2%), UC (3.6%), and gastrointestinal stromal tumor (2.1%).

Conclusion
In a large (N=154965) NGS database of pts with cancer, inactivating TSC1/2 variants occurred in about 1.7% of pts overall and were frequently identified in commonly occurring cancers. The frequency of TSC1/2 alterations and tumor types were generally consistent between tumor tissue samples and LBs. Consistency between primary vs metastatic samples suggests TSC1/2 alterations may not be acquired, although samples were not longitudinal. Additional research is needed to understand the clinical implications of these observations, but these RW observations suggest TSC1/2 alterations in cancer may be a reasonable therapeutic target.