Comprehensive genomic profiling of uterine carcinosarcomas identifies potential targeted therapy opportunities

Background

Uterine carcinosarcomas (UCS) are highly aggressive malignancies that are felt to derive from pluripotent malignant cells in Müllerian tract. Studies of primary chemotherapy for stage III, IV or recurrent disease report median OS ranging from 9-15 mos. No effective therapies are available after progression from front line therapy. Comprehensive genomic profiling (CGP) increases the ability to screen for somatic mutations that may direct therapies. This study characterized CGP results for advanced or recurrent UCS disease and compared results to similar analyses for endometrial adenocarcinomas (EA).

Methods

DNA was extracted from FFPE clinical specimens for 100 UCS and 257 EA (including endometrioid and non-endometrioid subtypes). Hybridization captured libraries of 315 genes, plus select introns frequently rearranged in cancer, were sequenced to high (median 780x), uniform coverage. All classes of genomic alterations (base subs, small indels, rearrangements, and copy number alterations) were evaluated and reported. Clinically relevant genetic alternations (CRGA) were defined as GA associated with on-label targeted therapies and targeted therapies in mechanism-driven clinical trials.

Results

55% of UCS had at least one clinically relevant alteration (not counting TP53). Mutation frequencies for commonly altered genes are displayed below.

Conclusions

Advanced/recurrent UCS are highly malignant neoplasms with poor durable responses to conventional chemotherapy. CGP in this series and others reveals CRGAs also seen in EA, and indicate potential therapeutic sensitivities. More frequent mutation of CCNE1, LYN, and MYC suggest a mechanism for the more aggressive phenotype of UCS. Targeting TP53 GA with WEE-1 inhibitors, KRAS GA with MEK inhibitors, and treating with PARPi when appropriate may benefit patients. Consideration for basket trials based on CGP for patients with UCS may confirm active agents for this disease.

Clinical trial identification

Legal entity responsible for the study

Foundation Medicine, Inc.

Funding

Foundation Medicine, Inc.

Disclosure

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