Comprehensive genomic profiling of uterine leiomyosarcomas identifies opportunities for personalized therapies

Background

Uterine leiomyosarcoma (uLMS) respond poorly to conventional chemotherapeutic agents, and personalized therapies have not yet been systematically explored. We hypothesize that comprehensive genomic profiling (CGP) of uLMS will identify therapeutic targets and provide insight into the biology of this highly aggressive tumor.

Methods

CGP of 232 FFPE uLMS and 138 male LMS clinical specimens by hybridization-capture of up to 405 cancer-related genes provided genomic alterations (GA; SV, indels, CNA, rearrangements) and tumor mutational burden (TMB). TMB was calculated by counting mutations across a 1.25Mb region encompassing these genes.

Results

Analysis of clinically advanced/recurrent uLMS from women with a median age 54 years (range 23-76 years) revealed that 96.5% harbor at least one GA (mean 3.5; range 0-17), most frequently in one or both of the TP53 (66%) and RB1 (50%) genes. Mutation frequencies in uLMS were compared to those in a cohort of 138 LMS cases from male patients. GA significantly more frequent in uLMS were PTEN (17.6% vs. 8%; p = .009) and MED12 (12% vs. 2.9%; p = 0.0019) while TP53 was enriched in male LMS (77.5% vs. 66%; p= 0.019). GA predicted to activate the PI3K/AKT/mTOR pathway were identified in 33% of uLMS versus 25% of male LMS samples, including loss of function in negative regulators (PTEN, NF1, TSC1, STK11, TSC2, PIK3R1) and gain of function in positive regulators (RICTOR, IGF1R, AKT2, AKT1, PIK3CA). 34% of uLMS and 26% of male LMS harbored inactivation of the chromatin remodeling regulator ATRX. Potentially targetable fusions were identified in 4% of patients (NTRK1, ALK, BRAF, ROS1, MET), with several responses to TKIs. The median TMB for uLMS was 2.9 mut/Mb (range 0-55) and 2.6% of cases had > 10 mut/Mb, suggesting a limited role for single agent immune checkpoint inhibitors.

Conclusions

Two therapies commonly used to treat soft tissue sarcomas (STS), pazopanib and trabectedin, demonstrate limited efficacy for uLMS (RR 6-10%; median PFI 4.5 mo), highlighting the need for other treatment options. In contrast, case reports of responses to CGP-matched targeted therapy support systematic genomic characterization of uLMS to drive molecularly informed clinical trials for this rare and deadly malignancy.

Clinical trial identification

Legal entity responsible for the study

Foundation Medicine, Inc.

Funding

Foundation Medicine, Inc.

Disclosure

S. Ramkissoon, S. Ali, C. McMahon, L.M. Gay, J.S. Ross, J.A. Elvin: Employee of and shareholder in Foundation Medicine, Inc. All other authors have declared no conflicts of interest.