POLE mutation

Prospective studies and registry-based analyses are needed to refine risk assessment, optimize management, and maximize the clinical utility of POLE profiling. This review provides a comprehensive and integrative overview of POLE alterations across human cancers, integrating molecular, clinicopathological, and immunological insights with therapeutic implications.

After three cycles of neoadjuvant carboplatin, pemetrexed, and pembrolizumab, computed tomography (CT) scan revealed a significant response. Incorporating a POLE evaluation could improve the integrated decision-making process for patients with NSCLC in the perioperative setting. Prospective studies are warranted to validate this observation.

Our study supports the prognostic relevance of both sentinel lymph node assessment and molecular classification in early-stage endometrial cancer, with potential implications for post-operative risk stratification and management.

P=N/A, N=50, Not yet recruiting, Peking University Cancer Hospital & Institute

We present a renal transplant recipient with metastatic small bowel adenocarcinoma harboring a POLE mutation who was treated with pembrolizumab and achieved a complete metabolic response on PET-CT with negative circulating tumor DNA. This case suggests that immune checkpoint inhibitors may be considered in carefully selected transplant recipients with high tumor mutational burden, though risks remain.

For early-stage POLE-mutated CRC with favorable prognosis, off-label adjuvant immunotherapy may bring unnecessary toxicity risks. It is necessary to conduct rigorous patient selection, comprehensive risk-benefit evaluation, and close monitoring of organ function during treatment, so as to provide reference for the standardized clinical application of ICIs in this population.

P4, N=80, Not yet recruiting, Hospital Universitari de Bellvitge | Trial completion date: Sep 2028 --> Jan 2035 | Initiation date: Sep 2026 --> Jan 2027 | Trial primary completion date: May 2027 --> Apr 2031

Minimal microsatellite shift is commonly detected in MSI-H cases, and some cases are difficult to interpret due to their classification within the equivocal range. Increasing the number of microsatellite loci, combined with visualization graph comparison and integration of mismatch repair protein immunophenotype and histological features, can effectively improve the accuracy of MSI-H interpretation.

Molecular classification provides clinically meaningful information beyond traditional histopathologic factors and is closely associated with the risk of lymph-node metastasis in endometrial cancer. The consistently low nodal involvement observed in POLEmut and the high risk observed in p53abn support a more tailored approach to surgical staging.

This case underscores the role of immunotherapy in POLE-mutated tumors regardless of the site of origin and highlights the potential usefulness of molecular profiling in rare malignancies. In line with the agnostic approach used for microsatellite instability, molecular-driven clinical trials should be prioritized over histology-based studies to optimize treatment strategies for these orphan diseases.

The complete response to levonorgestrel intra-uterine device therapy was lower than expected for endometrial intra-epithelial neoplasia. Response rates varied by molecular classification, with worse outcomes observed in deficient mismatch repair and p53 abnormal sub-types. Although limited by sample size, these findings suggest that levonorgestrel intra-uterine device therapy may not be sufficient for all molecular sub-groups.