(P 422) CLINICAL UTILITY OF WHOLE GENOME SEQUENCING IN SARCOMA FOR THE IDENTIFICATION OF ACTIONABLE MUTATIONS: A RETROSPECTIVE COHORT ANALYSIS

Objective: Sarcomas are rare, mesenchymal tumours exhibiting significant heterogeneity, with more than 100 subtypes recognised by the WHO classification (1). Following the 100,000 genomes project, across England, all patients diagnosed with sarcoma are entitled to whole genome sequencing (WGS), which is approved and funded by NHSE since 2018. WGS is a useful tool for refining diagnoses and identifying novel genomic alterations (2). There are ongoing challenges of optimising uptake of testing, delivery of the service within the NHS and utilising results to enhance patient care including access to personalised therapies and clinical trials. The clinical utility of WGS at diagnosis for paediatric, teenage and young adult (TYA) and adult sarcoma patients as well as its impact on outcomes requires further elucidation.

Methods: We retrospectively analysed clinical data for all new or relapsed sarcoma diagnoses in paediatric, TYA and adult patients consented for WGS from May 2021 to September 2022 within the London Sarcoma Service (LSS). Patients were identified using a local electronic healthcare record system. Timing from consent and sample collection to acquisition of results and patients being informed was analysed, along with genetic findings and genomic tumour advisory board (GTAB) outcomes.

Results: Clinical records of 45 paediatric/TYA and 43 adult sarcoma patients that had consented to WGS were identified. From these, WGS was completed and results available for 25 paediatric/TYA and 5 adult patients. 24 patients were informed of their results (paediatric/TYA 22, adult 2). Median time from patient consent to being informed of results was 13 weeks (range 6 – 67).
In our paediatric/TYA cohort, the histological subtypes were osteosarcoma (OS) (n=18), Ewing sarcoma (n= 5), rhabdomyosarcoma (n=1) and malignant peripheral nerve sheath tumour (n=1). The median age was 15 years (range 6-22). WGS identified two patients with germline variants – MLH1 variant and TP53 variant (both OS). Both patients were referred to clinical genetics services and Lynch syndrome and Li-Fraumeni syndrome were confirmed. The patient with Lynch syndrome subsequently received compassionate access immunotherapy, based on this result. The most frequent somatic genetic variants were TP53 (n=12), RB1 (n=8), gain of 8q (n=8), gain of MYC (n=6), gain of 17p (n=5), CDKN2A (n=4) and aneuploidy (n=4). In one paediatric patient with high grade osteoblastic osteosarcoma, a novel fusion gene, PSMC1::NFATC2 was identified.
In the adult cohort, the histological subtypes were chordoma (n=1), OS (n=1), small round cell sarcoma (n=1), myxofibrosarcoma (n=1) and pleomorphic liposarcoma (PLS) (n=1). The median age was 72 years (range 35-75). WGS for one patient with PLS was resulted after they had died. The most frequent somatic genetic variants were FGF14, TP53, RB1, CDKN2A, ATRX and PTEN.
Overall, 47% of patients had at least one AMP tier IA variant, 3% AMP tier IIC, 16% AMP tier IID and 16% tier 3 variants. None of these variants were actionable for referral to clinical trials.

Conclusion: WGS has shown clinical utility in identifying pathogenic germline variants. Based on germline MLH1 variant confirmation, one patient received compassionate access immunotherapy. Although almost 50% of patients had a clinically relevant tumour genetic alteration (eg. TP53 variant), these remain non-actionable for sarcoma patients and therefore no patients were referred to clinical trials based on these results. One novel somatic gene fusion was identified.
Long intervals from sampling to issuing of results remain a challenge. Documentation being held across different trusts created gaps in patient data and limited our analysis. To enhance understanding and communication, in October 2022 our local pathway protocol formalized that all WGS results are discussed at the LSS genomic tumour advisory board meeting (GTAB).
Our next steps involve - optimisation of pathways to capture all eligible patients; reduction of timescales for results; utilisation of electronic healthcare records to streamline documentation; establishing a WGS database with the future aim of collaborating with national and international centres to facilitate improved access to clinical trials for sarcoma patients