(P 386) GENOMIC PROFILING OF GYNAECOLOGICAL SARCOMAS: REPORT FROM THE AUSTRALIA-WIDE PRECISION ONCOLOGY PROGRAM

Objective: Metastatic gynaecological sarcomas (GS) have a poor prognosis with limited therapeutic options. We evaluated genomic profiling of GS to identify potentially actionable alterations /biomarkers to guide therapy and to investigate any prognostic implications.

Methods: The Cancer Molecular Screening and Therapeutics Program (MoST, ACTRN12616000908437) is an Australia-wide precision oncology platform for adult patients (pts) with advanced cancers, prioritising rare cancers, to gain access to comprehensive genomic profiling (CGP). Archival tumour specimens were sequenced using a panel-based assay (Illumina TST170 or TSO500, FoundationOne CDX). Variant interpretation was conducted at a weekly molecular tumour board (MTB). Genomic results were tiered using TOPOGRAPH strength of recommendation framework to indicate actionability (https://topograph.info). Pts were followed for subsequent treatment and clinical outcomes. Overall survival (OS) from the date of MTB report issue was estimated by using the Kaplan-Meier method.

Results: Between Sept 2016 and Oct 2022, 108 GS underwent CGP, and were followed for a minimum of 6 months (mo). The majority were ages 45-54 years (n=43, 40%). The overall survival was 17.3 mo (95% CI: 12.8—23.2) The majority received 1 prior line of therapy (range: 0-5) before CGP. Key histologies included uterine leiomyosarcoma (uLMS; n=78, 72%), endometrial stromal sarcoma (n=8, 7%), PEComa (n=6, 6%), and undifferentiated uterine sarcoma and adenosarcoma (n=5 each, 5%). The median number of reported variants was 2.5 (IQR 1-4) and tumour mutational burden (TMB) was 2.6 mut/Mb (maximum 27). Shown in Figure 1, the identified gene alterations include loss-of-function alterations in the TP53 (n=59, 55%), RB1 (n=43, 40%), ATRX (n=26, 24%), PTEN (n=19, 18%), CDKN2A (n=11,10%), BRCA2 (n=6, 6%), and TSC2 (n=5, 5%) genes. In pts with uLMS, TP53 mutation was associated with poorer prognosis (mutated vs wild type, 14.0 vs 28.6 mo; HR 1.92, p=0.045). Overall, 69 (64%) pts received further therapy after CGP, including 16 biomarker-linked therapies and 53 standard of care therapies. Further stratification by actionability tier identified only 11 patients (10%) had biomarker-linked therapies belonging to a clinically active tier group (TOPOGRAPH tier 1-3A). Notable alterations include 2 ALK fusion (1 uLMS harbouring TIMP3-ALK fusion, and 1 inflammatory myofibroblastic tumour harbouring TNS1-ALK fusion), 1 microsatellite unstable (uLMS), 1 EML4-NTRK3 fusion, and 2 TSC2 mutations (2 PEComa); high TMB was observed in 1 each of PEComa and uLMS, but were microsatellite stable. Only 2 pts received biomarker-linked therapies after CGP. Pt with PEComa harbouring a BRCA2 mutation and high TMB (20.3 mut/Mb) was treated on a matched MoST trial of olaparib and durvalumab (ACTRN12617001000392), achieving a complete radiological response and remained progression free at 22.6 mo. Pt with endometrial stromal sarcoma harbouring EML4-NTRK3 fusion received larotrectinib and had stable disease at 35 mo.

Conclusion: Molecular characterization of GS through CGP may be prognostic and can also identify actionable alterations in small subsets of patients that can help delineate this heterogeneous group.