Pole mutated endometrial carcinoma: Clinical and genomic characteristics from a real-world UK cohort.

e17600 Background: Pathogenic mutations within the DNA polymerase epsilon (POLE) exonuclease domain characterise the POLE/ultra-mutated molecular subgroup as defined by the Cancer Genome Atlas (TCGA) Research Network. Our study aimed to evaluate clinical and genomic characteristics of POLE mutated endometrial carcinoma (EC) from a real-world cohort. Methods: 246 tumour samples from patients diagnosed with primary endometrial cancer (EC) between September 2007 and June 2022 were sequenced using the Royal Marsden RMH200 Solid panel which includes 233 genes and evaluates microsatellite instability (MSI) and tumour mutational burden (TMB). Droplet Digital PCR (ddPCR) was used for MLH1 promoter methylation status in each case. Mismatch repair proteins (MMR) and P53 were tested by immunohistochemistry (IHC). Patients’ characteristics were documented from our electronic records. Results: POLE mutations were identified in 21 patients (8.5%). Mean age at diagnosis was 63 years old (52-92). Mean BMI was 28.5 (21.1-48) and 38.1% of patients had hypertension (n=8). 20 cases were stage I (95%) and 1 case was stage III (5%). Predominant histological subtype was endometrioid in 17 cases (81%). The other histological subtypes comprised clear cell (n=1), mixed (n=1) and carcinosarcoma (n=2). All patients had surgery and 15 (71.4%) received adjuvant therapy which included chemotherapy in 4 (19%) cases. Mean TMB was 125.11 mut/Mb (25.77-345.82). 8 (38%) cases demonstrated MMR deficiency with MLH1 promoter hypermethylation detected in 7/8 cases. P53 was wild type (WT) in 17 (81%) and subclonal mutant in 4 (19%) of cases. 13 (61.9%) cases were microsatellite stable and 8 (38.1%) MSI-high. Recognised pathogenic POLE variants were identified in 16 (76.2%) cases: V411L* c.1231G (n=7), P286R c.857C>G (n=4), A456P c.1366G>C (n=2), A465V c.1394C>T (n=1), P436R c.1307C>G (n=1), M444K c.1331T>A (n=1).After a median follow-up of 21 months, one patient developed distant recurrence and died of progressive brain metastases following surgery for stage IA grade 1 endometrioid carcinoma, however recurrence was not biopsied. Conclusions: In this real-world cohort, POLE mutated EC cases were associated with a favourable prognosis. One distant recurrence was observed in initially uterine-confined case but was not histologically proven. Further research is needed to prognosticate POLE mutated EC and define appropriate adjuvant treatment recommendation.