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Comprehensive molecular profiling of adult ovarian granulosa cell tumors (GCT) identifies candidate actionable targets

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ESGO State of the Art 2018 Conference

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Abstract

Ovarian sex cord stromal tumors (SCST) are rare and heterogeneous group of neoplasms among which GCTs are the most common. Hot-spot mutations in FOXL2, a gene encoding a transcription factor critical for granulosa-cell development, characterize the majority of adult type granulosa cell tumors. The prevalence of other mutations and targetable alterations in GCT is not well described. We aimed to conduct a comprehensive genomic and proteomic characterization of a large series of GCTs in an effort to identify actionable targets. Methods and Patients: A total of 305 adult ovarian GCTs were available. Diagnosis was confirmed on central review by expert gynecology pathologists prior to molecular profiling. Next generation sequencing (NGS) was performed using a 592 gene panel on 112 cases. Total mutational burden (TMB) and DNA microsatellite instability (MSI) were calculated from NGS data. Additionally, IHC for estrogen (ER), progesterone (PR) and androgen (AR) receptors as well as PD-L1 (SP142) was performed (for all 305 cases). Biomarker analyses performed by Caris Life Sciences’ (Phoenix, AZ) Results As expected, the most common alteration was a FOXL2 p.C134W mutation (93%; 98/105). In addition, 37% (37/105) of adult GCTs demonstrated at least one other pathogenic mutation: 17% (17/105) of GCT harbored a PI3K pathway alteration, a further 11% had a mutation in MLL2, a histone methyl-transferase gene, 9% showed a TP53 mutation, and 5% had alterations in DNA repair genes, such as BRIP1 or CHEK2. All cases were microsatellite stable. TMB was low (Mean: 6.1mutations/Mb; range:3-12)with only 6 cases exhibiting ≥10 mutations/Mb. PD-L1 was expressed on tumor cells in 37/232 cases (16%). No gene fusions were identified in the entire cohort. Among the 300 GCTs tested for hormone receptor expression, 96% (284/296) were PR-positive, 83% were AR-positive and 67% ER-positive. Conclusion: To our knowledge, we present the first integrated molecular description of such a large cohort of GCTs suggesting possible biomarker-driven treatment options for this rare tumor. In line with previous studies, FOXL2 mutations were present in 93% of GCTs. In addition, oncogenic, potentially actionable mutations were frequent, detected in 40% of cases suggesting GCTs may be eligible to molecular-guided treatment strategies such as mTOR/Akt inhibitors, epigenetic agents or PARP inhibitors in the case of alterations in PIK3CA, MLL2 or DNA repair genes, respectively. PDL1 overexpression or high TMB was only detected in a small subset (15%). Of note, 83% of GCTs were androgen receptor-positive, providing the rationale for ongoing studies of AR inhibitors in metastatic GCT (NCT03464201).

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© Copyright 2020 Morressier GmbH.
All rights reserved.