771P - Genomic characterization of advanced endometrial carcinosarcoma: Identification of potentially actionable targets

Background

Endometrial carcinosarcoma is an aggressive variant of high-grade endometrial carcinoma, whose genomic landscape is poorly studied due to the low disease prevalence and the lack of known druggable molecular drivers. In this study, we explored the genomic profiles of this tumor to assess new targeted therapy and immunotherapy options for this uncommon and challenging disease.

Methods

We retrospectively analyzed 2,177 cases of endometrial carcinosarcoma from the Foundation Medicine database containing results from comprehensive genomic profiling (CGP) performed by next generation sequencing, to detect genomic alterations (GA), microsatellite instability (MSI), tumor mutational burden (TMB), and genomic loss of heterozygosity (gLOH,) as a surrogate for homologous recombination deficiency (HRD). PD-L1 was evaluated using DAKO 22C3.

Results

The median age in the cohort was 67y (interquartile range: 61-72y). TP53 was the most common GA, found in 83.7% of cases. Additionally, samples harbored GAs in PIK3CA (34.2%), PTEN (23.5%), KRAS (16.0%), ARID1A (14.8%) ERBB2 (8.5%), BRCA2 (2.7%) and BRCA1 (2.0%). Immune checkpoint biomarkers were also prevalent; 171/2177 (7.9%) of assessable samples were TMB-high (≥10 mutations/megabase), 141/2170 (6.5%) were MSI-high, 795/1382 (30.7%) had PD-L1 positivity (TPS≥1%). HRD (gLOH≥16%) was observed in 351/1727 (20.3%) cases. A co-occurrence analysis revealed unique molecular subsets. TP53 was mutually exclusive with GAs in PTEN and ARID1A (OR = 0.2, p<1E-4). PTEN and ARID1A were highly co-occurrent (OR = 9.2, p<1E-4) and strongly overlapped the MSI-High subset (OR>40, p<1E-4). ERBB2 GAs, while co-occurrent with TP53 (OR = 2.2, p = 0.01), showed mutually exclusivity with PTEN (OR 0.4, p<1E-4) and TMB-high status (OR 0.3, p = 0.02).

Conclusions

To our knowledge, this is the largest reported series of endometrial carcinosarcoma, which could open new avenues for personalized approaches based on the identified targets including PIK3CA, HRD/gLOH, MSI, TMB, ERBB2 and ARID1A.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Ugo De Giorgi.

Funding

Has not received any funding.

Disclosure

U.F.F. De Giorgi: Financial Interests, Personal, Advisory Board: Pfizer, BMS, MSD, PharmaMar, Astellas, Bayer, Ipsen, Novartis, EISAI, Janssen; Financial Interests, Personal, Invited Speaker: Roche, BMS, Clovis Oncology, AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca, Sanofi, Roche. Z. Kuang, N.A. Danziger, J.A. Moore, D.I. Lin, E.S. Sokol, S. Sivakumar: Financial Interests, Personal, Stocks/Shares: Roche; Financial Interests, Personal, Full or part-time Employment: Foundation Medicine, Inc. All other authors have declared no conflicts of interest.