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    GENE:

    POLE (DNA Polymerase Epsilon)

    i
    Other names: POLE1, DNA Polymerase Epsilon Catalytic Subunit, DNA Polymerase Epsilon Catalytic Subunit A, Polymerase (DNA) Epsilon Catalytic Subunit, DNA Polymerase II Subunit A, Polymerase (DNA Directed) Epsilon Catalytic Subunit, DNA Polymerase Epsilon Catalytic Subunit Protein, Polymerase (DNA Directed) Epsilon
    16h
    Investigating somatic variants and pathways in mismatch repair-deficient (dMMR) colorectal carcinoma in South Africa. (PubMed, J Clin Pathol)
    The spectrum of disease-causing MMR gene variants in our population necessitates NGS testing for LS screening. This study also highlights the role of somatic testing on readily available FFPE samples to generate data on the epidemiology of CRC in different settings.
    Journal • Mismatch repair
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    POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2) • POLD1 (DNA Polymerase Delta 1)
    |
    MSI-H/dMMR • MSH2 mutation
    7d
    POLE-END REAL LIFE: Endometrial Cancer Early Stages I-II and Advanced Stages III and IV Evaluation of POLE as a Prognostic Factor. Participants Are Women >= 18 Years Old, With the Pole Mutation (clinicaltrials.gov)
    P=N/A, N=80, Enrolling by invitation, Azienda Ulss 2 Marca Trevigiana
    New trial • Metastases
    |
    POLE (DNA Polymerase Epsilon)
    11d
    MITO END-3: Efficacy of Avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy. (PubMed, Ann Oncol)
    The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced endometrial cancer.
    Journal • Tumor mutational burden • BRCA Biomarker • MSi-H Biomarker • PD(L)-1 Biomarker • IO biomarker
    |
    TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • PTEN (Phosphatase and tensin homolog) • ARID1A (AT-rich interaction domain 1A) • POLE (DNA Polymerase Epsilon)
    |
    TP53 mutation • BRCA2 mutation • BRCA1 mutation • TMB-H • MSI-H/dMMR • PIK3CA mutation • TP53 wild-type • PTEN mutation • ARID1A mutation • POLE mutation
    |
    carboplatin • paclitaxel • Bavencio (avelumab)
    22d
    Prognostic value of molecular classification in stage IV endometrial cancer. (PubMed, Int J Gynecol Cancer)
    The distribution of the molecular subclasses in stage IV endometrial cancer patients differed substantially from the distribution in stage I-III endometrial cancer patients, with the unfavorable subclasses being more frequently present. Although the molecular classification was not prognostic in stage IV endometrial cancer, it could guide adjuvant treatment decisions.
    Journal • Metastases
    |
    ER (Estrogen receptor) • POLE (DNA Polymerase Epsilon)
    |
    ER positive • MSI-H/dMMR • POLE mutation • ER negative
    22d
    Predicting the Risk of nOdal disease with histological and Molecular features in Endometrial cancer: the prospective PROME trial. (PubMed, Int J Gynecol Cancer)
    Our data suggest that molecular classification does not seem useful to tailor the need of nodal dissection in apparent early-stage endometrial cancer. p53 abnormality predicts the risk of having advanced disease at presentation. Further external validation is needed.
    Journal • MSi-H Biomarker
    |
    TP53 (Tumor protein P53) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon)
    |
    TP53 mutation • MSI-H/dMMR • POLE mutation
    1m
    Pembrolizumab (MK-3475) in Patients With Recurrent Malignant Glioma With a Hypermutator Phenotype (clinicaltrials.gov)
    P=N/A; Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025
    Trial completion date • Trial primary completion date
    |
    MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • POLD1 (DNA Polymerase Delta 1)
    |
    MSK-IMPACT
    |
    Keytruda (pembrolizumab)
    1m
    Pembrolizumab in Ultramutated and Hypermutated Endometrial Cancer (clinicaltrials.gov)
    P2, N=25, Active, not recruiting, Yale University | Trial completion date: Jun 2024 --> Oct 2025 | Trial primary completion date: Jun 2024 --> Oct 2025
    Trial completion date • Trial primary completion date • IO biomarker
    |
    MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1)
    |
    POLE mutation • POLD1 mutation • POLE mutation + POLD1 mutation
    |
    Keytruda (pembrolizumab)
    1m
    Molecular profile in endometrial carcinoma: can we predict the lymph node status? A systematic review and meta-analysis. (PubMed, Clin Transl Oncol)
    The presence of LNM seems to be influenced by molecular classification. P53-abnormal group presents the highest rate of nodal involvement, and POLE-mutated the lowest.
    Retrospective data • Review • Journal
    |
    POLE (DNA Polymerase Epsilon)
    |
    POLE mutation
    1m
    An Intervention to Increase Genetic Testing in Families Who May Share a Gene Mutation Related to Cancer Risk (clinicaltrials.gov)
    P=N/A, N=2590, Recruiting, Memorial Sloan Kettering Cancer Center | N=896 --> 2590
    Enrollment change
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • SMAD4 (SMAD family member 4) • CHEK2 (Checkpoint kinase 2) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • POLD1 (DNA Polymerase Delta 1) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • EPCAM (Epithelial cell adhesion molecule) • BARD1 (BRCA1 Associated RING Domain 1) • BMPR1A (Bone Morphogenetic Protein Receptor Type 1A)
    1m
    High prevalence of "non-pathogenic" POLE mutation with poor prognosis in a cohort of endometrial cancer from South India. (PubMed, Int J Gynaecol Obstet)
    This study identified a unique set of POLE mutations in Indian EC patients associated with poor prognosis, which were particularly pronounced in advanced stages. Advanced stage of presentation, type of POLE mutations, and possibly ethnicity are predictors of adverse outcomes in POLE-mutated EC. The present study highlights ethnicity as a determinant of phenotypic expression of genetic change.
    Journal
    |
    POLE (DNA Polymerase Epsilon)
    |
    POLE mutation
    2ms
    Morules and β-catenin predict POLE mutation status in endometrial cancer: A pathway to more cost-effective diagnostic procedures. (PubMed, Am J Clin Pathol)
    Our findings suggest that the presence of either morules or nuclear β-catenin expression in EEC could practically rule out the presence of POLE mutations. These morphologic and immunohistochemical features can be used as preliminary screening tools for POLE mutations, offering significant savings in time and resources and potentially enhancing clinical decision-making and patient management strategies. However, further validation in larger, multi-institutional studies is required to fully understand the implications of these findings on clinical practice.
    Journal • HEOR • Cost-effectiveness • Cost effectiveness
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    POLE (DNA Polymerase Epsilon) • CTNNB1 (Catenin (cadherin-associated protein), beta 1)
    |
    POLE mutation
    2ms
    Pembrolizumab in Ultramutated and Hypermutated Endometrial Cancer (clinicaltrials.gov)
    P2, N=25, Active, not recruiting, Yale University | Trial completion date: Dec 2028 --> Jun 2024 | Trial primary completion date: Dec 2023 --> Jun 2024
    Trial completion date • Trial primary completion date • IO biomarker
    |
    MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1)
    |
    POLE mutation • POLD1 mutation • POLE mutation + POLD1 mutation
    |
    Keytruda (pembrolizumab)
    2ms
    Genetic mutation profiling reveals biomarkers for targeted therapy efficacy and prognosis in non-small cell lung cancer. (PubMed, Heliyon)
    In first-generation EGFR-TKIs treatment, gefitinib showed favorable efficacy compared to icotinib and erlotinib, particularly in patients with EGFR L858R mutations...In third-line treatments, the combination of osimertinib and anlotinib demonstrated superior efficacy compared to other regimens. Glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) mutation was an independent risk indicator of shorter OS following third-line treatments. Comprehending the tumor evolution in NSCLC is advantageous for assessing the efficacy and prognosis at each stage of treatment, providing valuable insights to guide personalized treatment decisions for patients.
    Journal
    |
    POLE (DNA Polymerase Epsilon) • IKZF1 (IKAROS Family Zinc Finger 1) • RBM10 (RNA Binding Motif Protein 10) • RAC1 (Rac Family Small GTPase 1) • EPHA3 (EPH receptor A3) • RAD21 (RAD21 Cohesin Complex Component) • GRIN2A (Glutamate Ionotropic Receptor NMDA Type Subunit 2A) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • PAK1 (p21 (RAC1) activated kinase 1) • PAK5 (P21 (RAC1) Activated Kinase 5)
    |
    EGFR mutation • EGFR L858R • GRIN2A mutation • RBM10 mutation
    |
    Tagrisso (osimertinib) • erlotinib • gefitinib • Focus V (anlotinib) • Conmana (icotinib)
    2ms
    SYNERGY-AI: Artificial Intelligence Based Precision Oncology Clinical Trial Matching and Registry (clinicaltrials.gov)
    P=N/A, N=50000, Recruiting, Massive Bio, Inc. | Trial completion date: Jun 2025 --> Jun 2027 | Trial primary completion date: Dec 2024 --> Dec 2026
    Trial completion date • Trial primary completion date
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    EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ER (Estrogen receptor) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • FGFR2 (Fibroblast growth factor receptor 2) • PTEN (Phosphatase and tensin homolog) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • BCL2 (B-cell CLL/lymphoma 2) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • STK11 (Serine/threonine kinase 11) • NPM1 (Nucleophosmin 1) • HRAS (Harvey rat sarcoma viral oncogene homolog) • DNMT3A (DNA methyltransferase 1) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • RB1 (RB Transcriptional Corepressor 1) • CLDN18 (Claudin 18) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1) • JAK2 (Janus kinase 2) • NRG1 (Neuregulin 1) • POLE (DNA Polymerase Epsilon) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • PD-1 (Programmed cell death 1) • CCND1 (Cyclin D1) • MCL1 (Myeloid cell leukemia 1) • KDR (Kinase insert domain receptor) • PBRM1 (Polybromo 1) • BAP1 (BRCA1 Associated Protein 1) • VEGFA (Vascular endothelial growth factor A) • BCL6 (B-cell CLL/lymphoma 6) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • PTCH1 (Patched 1) • FGFR4 (Fibroblast growth factor receptor 4) • MSH6 (MutS homolog 6) • CDK4 (Cyclin-dependent kinase 4) • MSH2 (MutS Homolog 2) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • MAP2K2 (Mitogen-activated protein kinase kinase 2) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • WT1 (WT1 Transcription Factor) • ATRX (ATRX Chromatin Remodeler) • BRCA (Breast cancer early onset) • RAF1 (Raf-1 Proto-Oncogene Serine/Threonine Kinase) • TSC2 (TSC complex subunit 2) • CHEK2 (Checkpoint kinase 2) • PD-L2 (Programmed Cell Death 1 Ligand 2) • ERBB4 (erb-b2 receptor tyrosine kinase 4) • JAK1 (Janus Kinase 1) • FANCA (FA Complementation Group A) • TSC1 (TSC complex subunit 1) • MDM4 (The mouse double minute 4) • POLD1 (DNA Polymerase Delta 1) • CDK6 (Cyclin-dependent kinase 6) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • PARP1 (Poly(ADP-Ribose) Polymerase 1) • AURKA (Aurora kinase A) • JAK3 (Janus Kinase 3) • RICTOR (RPTOR Independent Companion Of MTOR Complex 2) • CHEK1 (Checkpoint kinase 1) • GATA6 (GATA Binding Protein 6) • MSH3 (MutS Homolog 3) • TGFBR2 (Transforming Growth Factor Beta Receptor 2) • GNAS (GNAS Complex Locus) • MYCL (MYCL Proto-Oncogene BHLH Transcription Factor) • AKT2 (V-akt murine thymoma viral oncogene homolog 2) • CCND2 (Cyclin D2) • CCND3 (Cyclin D3) • CSF1R (Colony stimulating factor 1 receptor) • MAP3K1 (Mitogen-Activated Protein Kinase Kinase Kinase 1) • ERCC4 (ERCC Excision Repair 4, Endonuclease Catalytic Subunit) • HDAC1 (Histone Deacetylase 1) • PRDM1 (PR/SET Domain 1) • ZNF217 (Zinc Finger Protein 217) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • GATA3 (GATA binding protein 3) • PARP2 (Poly(ADP-Ribose) Polymerase 2) • PARP3 (Poly(ADP-Ribose) Polymerase Family Member 3) • SDHA (Succinate Dehydrogenase Complex Flavoprotein Subunit A) • ACVR1B (Activin A Receptor Type 1B) • ZNF703 (Zinc Finger Protein 703)
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    HER-2 mutation • BAP1 mutation • AKT1 mutation • FGFR3 fusion • JAK3 mutation
    2ms
    Assessing the New 2020 ESGO/ESTRO/ESP Endometrial Cancer Risk Molecular Categorization System for Predicting Survival and Recurrence. (PubMed, Cancers (Basel))
    The 2020 ESGO molecular classification system demonstrated practical utility and significantly influenced survival outcomes. Immunohistochemistry for TP53 and MMR, along with POLE sequencing, facilitated substantial patient reclassification, underscoring the clinical relevance of molecular risk categories in EC management.
    Journal
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    TP53 (Tumor protein P53) • POLE (DNA Polymerase Epsilon)
    |
    TP53 mutation • MSI-H/dMMR • POLE mutation
    2ms
    The Clinical and Pathological Characteristics of POLE-Mutated Endometrial Cancer: A Comprehensive Review. (PubMed, Cancer Manag Res)
    This subtype exhibits a high tumor mutation burden, abundant lymphocyte infiltration, and a favorable prognosis, making it a promising candidate for immune checkpoint inhibitor therapy. This paper presents a comprehensive review of the clinical and pathological characteristics, outcomes, treatment advancements, pathogenic POLE gene detection, and alternative testing methods for POLE-mutated endometrial cancer.
    Review • Journal • Tumor mutational burden • IO biomarker
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    TMB (Tumor Mutational Burden) • POLE (DNA Polymerase Epsilon)
    |
    TMB-H • POLE mutation
    3ms
    GC 2nd Line Durvalumab(MEDI4736)/Tremelimumab Plus Paclitaxel Study (clinicaltrials.gov)
    P1/2, N=58, Completed, Asan Medical Center | Active, not recruiting --> Completed
    Trial completion
    |
    PD-L1 (Programmed death ligand 1) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • POLD1 (DNA Polymerase Delta 1) • MSH3 (MutS Homolog 3) • PMS1 (PMS1 protein homolog 1) • POLD2 (DNA Polymerase Delta 2)
    |
    MSI-H/dMMR • MSH2 mutation • MLH1 mutation • PD-L1 amplification • POLD1 mutation • MSH3 mutation • PMS2 mutation • MLH3 mutation • PMS1 mutation • POLD2 mutation
    |
    Imfinzi (durvalumab) • paclitaxel • Imjudo (tremelimumab)
    3ms
    AcSé: Secured Access to Nivolumab for Adult Patients With Selected Rare Cancer Types (clinicaltrials.gov)
    P2, N=269, Completed, UNICANCER | Active, not recruiting --> Completed
    Trial completion
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    MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon)
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    POLE mutation
    |
    Opdivo (nivolumab)
    3ms
    Potential of molecular classification to guide fertility-sparing management among young patients with endometrial cancer. (PubMed, Gynecol Oncol)
    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.
    Journal
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    TP53 (Tumor protein P53) • POLE (DNA Polymerase Epsilon)
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    TP53 mutation • MSI-H/dMMR • TP53 wild-type • POLE mutation • TP53 expression • POLE EDM
    3ms
    Tumor mutational burden assessment and standardized bioinformatics approach using custom NGS panels in clinical routine. (PubMed, BMC Biol)
    We herein propose a TMB calculation method and a bioinformatics tool that is customizable to different NGS panels and sample types. We were not able to retrieve TMB values from FO algorithm using our own algorithm and NGS panel.
    Journal • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker • Next-generation sequencing
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    TMB (Tumor Mutational Burden) • POLE (DNA Polymerase Epsilon)
    |
    TMB-H • POLE mutation
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    FoundationOne® CDx
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    Keytruda (pembrolizumab)
    3ms
    Multiple duodenal epithelial tumors in a patient with polymerase proofreading-associated polyposis in POLE variant. (PubMed, Clin J Gastroenterol)
    In addition, duodenal tumors frequently coexist in patients with PPAP-carrying POLE variants, while the endoscopic treatment for duodenal tumors becomes safe and useful with several new approaches. Therefore, surveillance EGD is necessary in such patients for the early detection and treatment of duodenal tumors.
    Journal
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    POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1)
    |
    POLE mutation
    3ms
    Nivolumab Ipilimumab in Patients With hyperMutated Cancers Detected in Blood (NIMBLe) (clinicaltrials.gov)
    P2, N=4, Terminated, Canadian Cancer Trials Group | Active, not recruiting --> Terminated; cfDNA screening data found that the prevalence of POLE/POLD1 mutations was lower than expected. It was determined that there are no feasible options to amend this study in a fashion that would not be duplicative of other currently accruing trials.
    Trial termination
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    POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1)
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    POLE mutation • POLD1 mutation • POLE mutation + POLD1 mutation
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    Opdivo (nivolumab) • Yervoy (ipilimumab)
    3ms
    Molecular profile is a strong predictor of the pattern of recurrence in patients with endometrial cancer. (PubMed, Int J Gynecol Cancer)
    Endometrial cancer featured different patterns of recurrence depending on the molecular profile. p53-abnormal molecular profiling was the only independent risk factor for peritoneal relapse, while non-specific molecular profile showed a strong association with distant failures.
    Journal
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    POLE (DNA Polymerase Epsilon)
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    TP53 mutation • MSI-H/dMMR • POLE mutation
    3ms
    Correlation of PTEN Alterations with Immunohistochemistry in POLE-Mutated and Mismatch Repair-Deficient Endometrial Carcinoma (USCAP 2024)
    In summary, PTEN IHC expression was retained in the majority of PTEN- and POLE-mutated ECs with frequent missense mutations in codon 130. Some codon 130 mutations (e.g., R130Q) are known to be associated with protein stability. Nearly half of PTEN-mutated MMR-d ECs were associated with PTEN expression (retained, reduced or subclonal loss).
    Mismatch repair
    |
    MSI (Microsatellite instability) • PTEN (Phosphatase and tensin homolog) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • PMS2 (PMS1 protein homolog 2)
    |
    MSI-H/dMMR • PTEN mutation • POLE mutation • PTEN expression • PMS2 mutation
    |
    Oncomine™ Comprehensive Assay v3M
    3ms
    Dominant Negative PTEN Alterations in Endometrial Carcinomas Are Associated with Positive (Retained or Reduced) Immunohistochemical PTEN Expression (USCAP 2024)
    In summary, our results indicate that PTEN IHC staining is present in majority of ECs with four common dominant-negative PTEN mutations (retained or less commonly reduced). While recent literature suggests complementary use of PTEN IHC and sequencing to assess PTEN status in EC, these results further highlight that IHC may not be helpful in assessment of PTEN abnormality in cases with dominant-negative PTEN mutations.
    PTEN (Phosphatase and tensin homolog) • POLE (DNA Polymerase Epsilon) • ARG1 (Arginase 1)
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    TP53 mutation • PTEN mutation • POLE mutation • PTEN expression • PTEN negative
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    Oncomine™ Comprehensive Assay v3M
    3ms
    Endometrial Cancers with Low Level Microsatellite Instability: Classification Pitfalls and Practical Recommendations for Assigning Mismatch Repair Status by Next Generation Sequencing with MSIsensor and Ancillary Tests (USCAP 2024)
    MSIsensor scores as low as 3.5% may represent true MMRd in EC tested by NGS. Further testing for MMRd is advised for MSIsensor scores between 3% and 30%, particularly if there is low tumor content or associated high TMB. In this setting, MMR IHC may have superior sensitivity for detection of MMRd compared to DNA-based assays.
    Microsatellite instability • Tumor mutational burden • IO biomarker • Next-generation sequencing • Mismatch repair
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    TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2)
    |
    TMB-H • POLE mutation • MSH6 mutation • MSH2 mutation • PMS2 mutation
    |
    Idylla™ MSI Test
    3ms
    A Study of Pembrolizumab and Olaparib in People With Endometrial Cancer or Endometrial Carcinosarcoma (clinicaltrials.gov)
    P2, N=25, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025
    Trial completion date • Trial primary completion date
    |
    TP53 (Tumor protein P53) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon)
    |
    TP53 mutation • MSI-H/dMMR • TP53 expression
    |
    Keytruda (pembrolizumab) • Lynparza (olaparib)
    3ms
    Homologous Recombination Deficiency (HRD) In Primary Advanced Stage And Recurrent P53 Abnormal Endometrial Carcinoma (ESGO 2024)
    Further investigation of HRD and EC-specific GIS cut-off value are highly warranted and may help to improve outcome in this specific EC subgroup. Patients with p53abn tumors may benefit from PARP inhibition and HRD testing may provide key information for patient selection.
    Tumor mutational burden • PARP Biomarker • BRCA Biomarker • Metastases
    |
    TMB (Tumor Mutational Burden) • HRD (Homologous Recombination Deficiency) • POLE (DNA Polymerase Epsilon) • BRCA (Breast cancer early onset)
    |
    TP53 mutation • HRD • POLE mutation • TMB-L • BRCA mutation
    |
    Myriad myChoice® CDx
    3ms
    Multiomic molecular characterization of the response to combination immunotherapy in MSS/pMMR metastatic colorectal cancer. (PubMed, J Immunother Cancer)
    We identified molecular features associated with the response to the REGONIVO and TASNIVO, particularly those related to tumor microenvironmental factors. These findings are likely to contribute to the development of biomarkers to predict treatment efficacy for MSS/pMMR CRC and future immunotherapy combinations for treatment.
    Journal • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker • Metastases
    |
    TMB (Tumor Mutational Burden) • POLE (DNA Polymerase Epsilon) • CD8 (cluster of differentiation 8)
    |
    Opdivo (nivolumab) • Stivarga (regorafenib) • Jeselhy (pimitespib)
    3ms
    Impact of molecular profile on prognosis and relapse pattern in low and intermediate risk endometrial cancer. (PubMed, Eur J Cancer)
    The differences in outcome by molecular groups are driven by differences in relapse frequency and -patterns and demand a higher precision in diagnostics, also in patients with low/intermediate risk EC. Tailored adjuvant treatment strategies need to consider systemic treatment for patients with p53 abnormal tumors and de-escalated treatment for patients with POLE mutated tumors.
    Journal
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    POLE (DNA Polymerase Epsilon) • L1CAM (L1 cell adhesion molecule)
    |
    TP53 mutation • MSI-H/dMMR • POLE mutation
    3ms
    New therapeutic targets for endometrial cancer: a glimpse into the preclinical sphere. (PubMed, Expert Opin Ther Targets)
    Moreover, the expression of specific molecular signatures offers the possibility to employ novel target therapies, such as immune-checkpoint inhibitors that have demonstrated a significant benefit on prognosis. New treatment guidelines are still being established, and ongoing studies are exploring the potential prognostic role of further sub-stratifications of the four molecular classes and treatment options.
    Preclinical • Review • Journal
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    TP53 (Tumor protein P53) • POLE (DNA Polymerase Epsilon)
    |
    TP53 mutation • POLE mutation
    3ms
    Exploring Co-occurring POLE Exonuclease and Non-exonuclease Domain Mutations and Their Impact on Tumor Mutagenicity. (PubMed, Cancer Res Commun)
    This study suggests a novel modifier role for POLE variants in POLE ExoD-driven tumors, associated with ultra-high TMB. These data, in addition to future functional studies, may inform tumor classification, therapeutic response, and patient outcomes.
    Journal • Tumor mutational burden
    |
    TMB (Tumor Mutational Burden) • POLE (DNA Polymerase Epsilon)
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    TMB-H • POLE mutation • TMB-L
    3ms
    The new 2023 FIGO staging system for endometrial cancer: what is different from the previous 2009 FIGO staging system? (PubMed, J Gynecol Oncol)
    The 2023 staging system for EC subdivided stages I and II compared to the 2009 system. The 2023 system with molecular classification is a good predictor of survival.
    Journal
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    POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • PMS2 (PMS1 protein homolog 2)
    |
    TP53 mutation • POLE mutation • PMS2 mutation
    4ms
    Tumor characteristics of dissociated response to immune checkpoint inhibition in advanced melanoma. (PubMed, Cancer Immunol Immunother)
    Intrapatient comparison of progressive versus regressive lesions indicates no defect in tumor T cell infiltration, and in general no tumor immune exclusion were observed.
    Journal • Checkpoint inhibition • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker • Metastases
    |
    PD-L1 (Programmed death ligand 1) • TMB (Tumor Mutational Burden) • PTEN (Phosphatase and tensin homolog) • POLE (DNA Polymerase Epsilon) • CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • B2M (Beta-2-microglobulin)
    |
    PD-L1 expression • PTEN mutation • POLE mutation • CD8-H
    4ms
    Prognosis of polymerase epsilon (POLE) mutation in high-grade endometrioid endometrial cancer: Systematic review and meta-analysis. (PubMed, Gynecol Oncol)
    POLE mutations in high-grade endometrioid EC are associated with a more favorable prognosis with increased OS and PFS.
    Retrospective data • Review • Journal
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    POLE (DNA Polymerase Epsilon)
    |
    POLE mutation
    4ms
    The P286R mutation of DNA polymerase ε activates cancer-cell-intrinsic immunity and suppresses endometrial tumorigenesis via the cGAS-STING pathway. (PubMed, Cell Death Dis)
    Furthermore, the POLE P286R mutation inhibits tumor growth and facilitates the infiltration of cytotoxic T cells in human endometrial cancers. These findings uncover a novel mechanism of POLE mutations in antagonizing tumorigenesis and provide a promising direction for effective cancer therapy.
    Journal • PD(L)-1 Biomarker • IO biomarker
    |
    POLE (DNA Polymerase Epsilon)
    |
    POLE mutation
    4ms
    Somatic POLE Mutation and Ultra-Hypermutated Genotype in a De Novo High-Grade, Isocitrate Dehydrogenase Wild-Type Glioma: Treatment Implications. (PubMed, JCO Precis Oncol)
    Pembrolizumab leads to a durable response in ultra-hypermutated, high-grade, glioma.
    Journal • PD(L)-1 Biomarker
    |
    POLE (DNA Polymerase Epsilon)
    |
    POLE mutation • IDH wild-type
    |
    Keytruda (pembrolizumab)
    4ms
    Loss-Of-Heterozygosity As A Biomarker For Genomic Instability And Poor Outcomes In Endometrial Cancer (ESGO 2024)
    Higher LOH was correlated with hormone-receptor-negative tumors and poorer survival rates. LOH may serve as a valuable tool for identifying EC cases with high genomic instability that could potentially benefit from PARP inhibitors.
    PARP Biomarker • MSi-H Biomarker • BRCA Biomarker
    |
    ER (Estrogen receptor) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PGR (Progesterone receptor) • BRCA1 (Breast cancer 1, early onset) • PTEN (Phosphatase and tensin homolog) • ARID1A (AT-rich interaction domain 1A) • POLE (DNA Polymerase Epsilon) • CTNNB1 (Catenin (cadherin-associated protein), beta 1)
    |
    TP53 mutation • BRCA1 mutation • MSI-H/dMMR • PIK3CA mutation • PTEN mutation • ARID1A mutation • POLE mutation • HR negative • PGR negative
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    FoundationOne® CDx
    4ms
    Homologous Recombination Deficiency (HRD) In Primary Advanced Stage And Recurrent P53 Abnormal Endometrial Carcinoma (ESGO 2024)
    Further investigation of HRD and EC-specific GIS cut-off value are highly warranted and may help to improve outcome in this specific EC subgroup. Patients with p53abn tumors may benefit from PARP inhibition and HRD testing may provide key information for patient selection.
    Tumor mutational burden • PARP Biomarker • BRCA Biomarker • Metastases
    |
    TMB (Tumor Mutational Burden) • HRD (Homologous Recombination Deficiency) • POLE (DNA Polymerase Epsilon) • BRCA (Breast cancer early onset)
    |
    TP53 mutation • HRD • POLE mutation • TMB-L • BRCA mutation
    |
    Myriad myChoice® CDx
    4ms
    OPTIMUM: Olaparib With or Without Durvalumab for DDR Gene Mutated Biliary Tract Cancer Following Platinum-based Chemotherapy (clinicaltrials.gov)
    P2, N=62, Recruiting, Asan Medical Center | Trial completion date: Oct 2024 --> Dec 2025 | Trial primary completion date: Oct 2023 --> Dec 2024
    Trial completion date • Trial primary completion date • Metastases
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ATM (ATM serine/threonine kinase) • POLE (DNA Polymerase Epsilon) • BAP1 (BRCA1 Associated Protein 1) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • BRCA (Breast cancer early onset) • CHEK2 (Checkpoint kinase 2) • RAD51 (RAD51 Homolog A) • FANCA (FA Complementation Group A) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • RAD50 (RAD50 Double Strand Break Repair Protein) • RAD51D (RAD51 paralog D) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • XRCC2 (X-Ray Repair Cross Complementing 2) • FANCD2 (FA Complementation Group D2) • GEN1 (GEN1 Holliday junction 5' flap endonuclease)
    |
    ATM mutation • BAP1 mutation • CHEK2 mutation • BRIP1 mutation • FANCA mutation • RAD50 mutation • BARD1 mutation • BLM mutation • NBN mutation
    |
    Lynparza (olaparib) • Imfinzi (durvalumab)
    4ms
    Molecular Classification in Mexican Patients With Endometrial Cancer and Its Impact on Prognosis (clinicaltrials.gov)
    P=N/A, N=64, Recruiting, National Institute of Cancerología
    New trial
    |
    TP53 (Tumor protein P53) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2)
    |
    POLE mutation • MLH1 mutation
    4ms
    Efficacy of fertility-sparing treatment with LNG-IUS is associated with different ProMisE subtypes of endometrial carcinoma or atypical endometrial hyperplasia. (PubMed, J Gynecol Oncol)
    Patients with early-stage EC or AEH who are more likely to benefit from fertility-sparing treatment can be identified using ProMisE classifier. Patients with POLE-mutated are suitable for fertility-sparing treatment with LNG-IUS.
    Journal • PD(L)-1 Biomarker
    |
    PD-L1 (Programmed death ligand 1) • POLE (DNA Polymerase Epsilon) • PD-1 (Programmed cell death 1)
    |
    TP53 mutation • MSI-H/dMMR • TP53 wild-type • POLE mutation