POLE EDM

Our study demonstrates that the concise NGS panel is an effective 'one-stop' strategy for precisely classifying EC with high clinical availability.

Therapeutic modalities for these hypermutated tumors are also an important consideration, including the need for or de-escalation of adjuvant treatments and the response to immune therapy. This review addresses the critical role of POLE mutations in gynecologic oncology and oncology in general, focusing on definitions, variants, underlying pathogenic mechanisms, upcoming developments in the field, and the clinic behavior associated with such mutations.

Recently, TCGA molecular subgroups have been integrated into the 2023 International Federation of Gynecology and Obstetrics (FIGO) staging classification which incorporates other non-anatomic parameters like histotype, tumor grade, and lymphovascular space invasion. The result is a complicated and non-intuitive classification that makes its clinical application difficult and does not facilitate correspondence with the 2009 FIGO staging.

P=N/A, N=1000, Recruiting, University Hospital, Gasthuisberg

Lastly, the no specific molecular profile (or p53 wild-type) tumors, while having a relatively good prognosis, are heterogeneous and require more precise biomarkers to effectively guide therapy for those with poorer prognoses. Addressing these research gaps will lead to more precise guidelines to ensure optimal selection for fertility-sparing treatment.

These findings emphasize the need for integrating tumor sequencing into LS diagnostics, along with clear interpretation guidelines, to improve clinical management. While not impacting prognosis, confirmation of DS-MMRd EC may release patients and relatives from burdensome LS-surveillance.

P1, N=10, Completed, University Medical Center Groningen | Recruiting --> Completed | N=20 --> 10 | Trial completion date: Nov 2022 --> Nov 2023 | Trial primary completion date: May 2022 --> Apr 2023

Our findings highlighted the importance of accurately interpreting heterogeneous MMR protein staining patterns for developing a more efficient personalized genetic investigation strategy.

TP53mut prediction model (TPMM) had good diagnostic accuracy, and survival analysis showed the model can identify patients with different prognostic risk.

Conclusions Our study demonstrates that the concise NGS panel is an effective "one-stop" strategy to precisely classify EC with high clinical availability. Further follow-up data are needed to testify to the effect of the classification on the prognosis of different adjuvant therapies or rare pathological subtypes.

Identification of 'POLE-like' groups may facilitate therapeutic de-escalation in some TP53-mutated cases - a novel option. Instead of 5% (POLE-EDM), potential beneficiary would then comprise 10% (POLE-like) of TCGA-UCEC.

Patients with EOCRC were less likely to have a MMR deficient signature, but more likely to have mutational signatures consistent with damage by ROS, POLE exonuclease domain mutations. Expectedly, more AOCRC cases harbored clock-like signatures related to age. While EOCRC and AOCRC often do not differ significantly on the single gene variant level, this genomic clustering data suggests that EOCRC may be caused by uniquely different mutagenic processes compared to AOCRC.

pPOLE were seen in both TB and LB across cancer types. The high rate of passenger mutations underscores the utility of this POLE-specific variant classification model. Because TMB can be underestimated when tumor purity is near the limit of detection for the assay, accurate detection and classification of pPOLE is critical for identifying patients who may benefit from immunotherapy.

We report an endometrial cancer patient harbored a novel somatic POLE T278K mutation. This mutation was a novel pathogenic POLE EDM should be considered as "POLE (ultramutated)" in clinical practice for the molecular classification of EC.

We also report one CRC patient harboring a germline POLE mutation who received camrelizumab and exhibited long-term stable disease...A significant association between POLE EDMs and improved PFS and OS may exist, but future studies with larger sample sizes are needed. Entire coding region of the POLE gene should be screened.

The four CRLM patients received toripalimab or sintilimab plus chemotherapy (FOLFOX or FOLFIRI or XELOX) with or without bevacizumab after POLE EDM were detected...Despite being a rare phenotype, CRLM patients with POLE EDM exhibit ultra-high TMB and, more importantly, significant clinical response to ICI-based combination therapy. Therefore, the complete sequencing of POLE exonuclease domains is recommended in CRLM patients clinically.

The tendency for recurrence-free survival in the POLE exonuclease domain mutation group was better than that in the TP53 mutation and mismatch repair-deficient groups (P = 0.08 and P = 0.07, respectively), consistent with the Proactive Molecular Risk Classifier for Endometrial Cancer risk classifier definition. The CTNNB1 mutation is a potential novel biomarker for the prognosis of patients with grade 3 endometrial endometrioid carcinoma, and prognosis classification using Proactive Molecular Risk Classifier for Endometrial Cancer may help screen Japanese patients with the disease.

In conclusion, durvalumab showed promising clinical activity with encouraging response rates and satisfactory survival outcomes in mCRC patients with MSI-H/dMMR or POLE EDM. In patients with POLE-mutated mCRC, clinical response to durvalumab may be restricted to those with EDM.

POLE mutations serve as an important biomarker of favorable prognosis in EC. The tumors are characteristically high grade, early stage, and remain localized in the endometrium with reduced likelihood of lymph node metastasis for improved survival prospects and the lowest risk classification. These findings have implications for medical management of EC.