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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
    4d
    Prognostic and therapeutic implication of molecular classification including L1CAM expression in high-risk endometrial cancer. (PubMed, Gynecol Oncol)
    L1CAM is an additional adverse factor in the p53 abnormal and NSMP groups. These groups need special attention in studies intensifying adjuvant treatment.
    Journal
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    POLE (DNA Polymerase Epsilon) • L1CAM (L1 cell adhesion molecule)
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    TP53 mutation • POLE mutation
    4d
    Molecular classification and adjuvant treatment in endometrioid endometrial cancer with microcystic elongated and fragmented (MELF) invasion pattern. (PubMed, BMC Womens Health)
    The presence of the MELF pattern in EEC should be incorporated into decision-making regarding adjuvant therapy. The use of adjuvant treatment should be tailored based on histology and molecular type.
    Retrospective data • Journal
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    TP53 (Tumor protein P53) • POLE (DNA Polymerase Epsilon)
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    TP53 mutation • MSI-H/dMMR • POLE mutation
    5d
    Molecular characterization of adult non-glioblastoma central nervous system (CNS) tumors to identify potential targettable alterations (AIOM 2024)
    4 pts received TT at recurrence, within clinical trials: one with grade 3 meningioma and ALK rearrangement treated with alectinib, one with PTCH1 mutant medulloblastoma treated with vismodegib, and two with high TMB treated with nivolumab/ipilumumab. The incidence of targettable molecular alterations in adult CNS tumor patients was lower than in GBM. Nevertheless, in a few selected cases TT have the potential to increase treatment options at recurrence and improve outcomes.
    Clinical • Tumor mutational burden • BRCA Biomarker • PD(L)-1 Biomarker • IO biomarker
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    BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • MET (MET proto-oncogene, receptor tyrosine kinase) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • FGFR1 (Fibroblast growth factor receptor 1) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1) • POLE (DNA Polymerase Epsilon) • MDM2 (E3 ubiquitin protein ligase) • PTCH1 (Patched 1) • NF2 (Neurofibromin 2) • BRCA (Breast cancer early onset) • NTRK (Neurotrophic receptor tyrosine kinase)
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    BRAF V600E • BRCA2 mutation • BRCA1 mutation • TMB-H • PIK3CA mutation • MET amplification • ALK rearrangement • FGFR1 amplification • POLE mutation • NF1 mutation • MDM2 amplification • RET mutation • PTCH1 mutation • NF2 mutation • ROS1 mutation • BRCA mutation • ALK rearrangement + PIK3CA mutation • PTCH1 rearrangement • NTRK fusion
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    FoundationOne® CDx
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    Opdivo (nivolumab) • Yervoy (ipilimumab) • Alecensa (alectinib) • Erivedge (vismodegib)
    5d
    PIK3CA mutations in endometrial cancer: a pre-planned biomarker analysis from the phase II MITO END-3 study of carboplatin and paclitaxel with or without avelumab in advanced or recurrent endometrial cancer (AIOM 2024)
    The frequent alterations of the PI3K pathway in gynecological cancers could emerge as new treatment target. Our data confirm the high frequency of PIK3CA mutations establishing EC as an ideal candidate for testing of PI3K inhibitors regardless of the TCGA classification. Moreover, these data confirm that other targetable mutations are present also in MSS EC group thus suggesting that new target agents should be explored.
    P2 data • MSi-H Biomarker • PD(L)-1 Biomarker • IO biomarker • Metastases
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    TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MSI (Microsatellite instability) • PTEN (Phosphatase and tensin homolog) • ARID1A (AT-rich interaction domain 1A) • POLE (DNA Polymerase Epsilon)
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    TP53 mutation • MSI-H/dMMR • PIK3CA mutation • TP53 wild-type • PIK3CA H1047R • PTEN mutation • ARID1A mutation • POLE mutation • PIK3CA E545K • PIK3CA E545 • PIK3CA E542 • PIK3CA H1047L • PIK3CA mutation + PTEN mutation • PIK3CA C420R • PIK3CA E545A • PIK3CA E545G • PIK3CA Q546 • PIK3CA Q546R
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    FoundationOne® CDx
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    carboplatin • paclitaxel • Bavencio (avelumab)
    6d
    Advantages of next-generation sequencing (NGS) in the molecular classifi cation of endometrial carcinomas - our experience with 270 cases. (PubMed, Ceska Gynekol)
    In comparison with recommended diagnostic algorithms, NGS provides a more reliable classification of EC into particular molecular subgroups. Furthermore, NGS reveals the complex molecular genetic background in individual ECs, which is especially significant within ECs with no specific molecular profile. These data can serve as a springboard for the research of therapeutic programs committed to targeted therapy in this type of tumor.
    Journal • Next-generation sequencing • BRCA Biomarker
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    HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • ARID1A (AT-rich interaction domain 1A) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • PMS2 (PMS1 protein homolog 2) • BCOR (BCL6 Corepressor) • PIK3R1 (Phosphoinositide-3-Kinase Regulatory Subunit 1) • POLD1 (DNA Polymerase Delta 1)
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    TP53 mutation • PIK3CA mutation • PTEN mutation • POLE mutation
    10d
    Radiation and TSR-042 (Dostarlimab) in People With Endometrial Cancer After They Receive Surgery (clinicaltrials.gov)
    P2, N=62, Recruiting, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Recruiting | N=31 --> 62 | Trial completion date: Feb 2025 --> Feb 2026 | Trial primary completion date: Feb 2025 --> Feb 2026
    Enrollment open • Enrollment change • Trial completion date • Trial primary completion date • Checkpoint inhibition • Mismatch repair • Surgery • Checkpoint block • Metastases
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    MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2)
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    MSI-H/dMMR • POLE mutation
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    Jemperli (dostarlimab-gxly)
    12d
    A retrospective study on the prognosis and influencing factors of patients with advanced endometrial cancer with POLE mutations (ChiCTR2400089579)
    P=N/A, N=30, Not yet recruiting, Sun Yat-sen University Cancer Center; Sun Yat-sen University Cancer Center
    New trial • Metastases
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    POLE (DNA Polymerase Epsilon)
    1m
    Durvalumab for MSI-H or POLE Mutated Metastatic Colorectal Cancer (clinicaltrials.gov)
    P2, N=33, Completed, Asan Medical Center | Active, not recruiting --> Completed
    Trial completion • Mismatch repair • Tumor mutational burden • Metastases
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    POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2)
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    MSI-H/dMMR • POLE mutation
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    Imfinzi (durvalumab) • oxaliplatin • irinotecan
    2ms
    Effect of hemoglobin, albumin, lymphocyte, and platelet score on prognosis in intermediate-risk endometrial cancer according to molecular-based classification. (PubMed, J Obstet Gynaecol Res)
    MMR deficiency and NSMP have been considered intermediate-risk groups for endometrial cancer and are a heterogeneous group. Although the use of the HALP score to reduce this heterogeneity is successful in predicting OS, it is not sufficient for PFS.
    Journal
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    TP53 (Tumor protein P53) • POLE (DNA Polymerase Epsilon)
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    TP53 mutation • POLE mutation
    2ms
    A Phase 1 Trial of Trebananib, an Angiopoietin 1 and 2 Neutralizing Peptibody, Combined with Pembrolizumab in Patients with Advanced Ovarian and Colorectal Cancer. (PubMed, Cancer Immunol Res)
    After development of acquired resistance, biopsy of one patient's KRAS wild-type, ERBB2 amplified tumor showed a substantial decline in tumor-associated T cells and an increase in immunosuppressive intratumoral macrophages. Future studies are needed to carefully assess whether clinicogenomic features, such as lack of liver metastases, ERBB2 amplification, and left-sided tumors, can predict increased sensitivity to PD1 immunotherapy combinations.
    P1 data • Journal • PD(L)-1 Biomarker • IO biomarker • Metastases
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    HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • POLE (DNA Polymerase Epsilon)
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    HER-2 amplification • POLE mutation • KRAS wild-type • RAS wild-type
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    Keytruda (pembrolizumab) • trebananib (AMG 386)
    2ms
    Predictors of Node Positivity in Endometrial Cancer (clinicaltrials.gov)
    P=N/A, N=200, Recruiting, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano | Not yet recruiting --> Recruiting | N=100 --> 200 | Trial completion date: Dec 2023 --> Jan 2025 | Trial primary completion date: Dec 2023 --> Dec 2024
    Enrollment open • Enrollment change • Trial completion date • Trial primary completion date
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    TP53 (Tumor protein P53) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon)
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    TP53 mutation • MSI-H/dMMR • POLE mutation
    2ms
    POD1UM-204: Safety and Efficacy of Retifanlimab (INCMGA00012) Alone or in Combination With Other Therapies in Participants With Advanced or Metastatic Endometrial Cancer Who Have Progressed on or After Platinum-based Chemotherapy. (clinicaltrials.gov)
    P2, N=206, Active, not recruiting, Incyte Corporation | Recruiting --> Active, not recruiting | N=300 --> 206
    Enrollment closed • Enrollment change • Combination therapy • Metastases
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    PD-L1 (Programmed death ligand 1) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon)
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    PD-L1 expression • MSI-H/dMMR • FGFR mutation • FGFR1 mutation
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    Pemazyre (pemigatinib) • Zynyz (retifanlimab-dlwr) • epacadostat (INCB024360) • tuparstobart (INCAGN2385) • verzistobart (INCAGN2390)
    2ms
    Clinical implications of next generation sequencing for the classification of endometrial carcinoma (ECP 2024)
    Molecular characterization of endometrial carcinoma into subgroups has important implications for prognosis and treatment. Next-generation sequencing is a powerful tool that provides reliable results consistent with surrogate immunohistochemical markers. By performing a molecular profile of patients, NGS can identify important genetic mutations such as p53, POLE and MSI, as well as variants like CTNNB1 that have prognostic value.
    Clinical • Next-generation sequencing
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    TP53 (Tumor protein P53) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • CTNNB1 (Catenin (cadherin-associated protein), beta 1)
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    TP53 mutation • POLE mutation • TP53 expression
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    OncoKitDx
    2ms
    High tumour mutation burden assessed by comprehensive molecular genetic profiling as a targeted therapeutic option for solid tumours (ECP 2024)
    Eight patients received immune checkpoint inhibitor therapy (7 pembrolizumab and 1 atezolizumab). TMB status determined by CGP was found to be an effective method for predicting the response to immune checkpoint inhibitors; both PFS and OS improved markedly for patients who received therapy. In our experience, TMB status, along with microsatellite instability and POLE mutation status, can be used as a predictive biomarker for therapeutic response in a wide range of histologies.
    Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker
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    TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon)
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    TMB-H • POLE mutation
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    Oncomine™ Comprehensive Assay Plus
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    Keytruda (pembrolizumab) • Tecentriq (atezolizumab)
    2ms
    Deciphering the immune landscape of gastro-entero-pancreatic high-grade neuroendocrine neoplasms could help in tailoring medical treatment? (ECP 2024)
    Immunotherapy has shown poor efficacy in the unselected population of HG-GEP-NENs because the immune microenvironment landscape was scant in HG-GEP-NENs at transcriptomic analysis and PD-L1 expression was absent. Thus, there is a great need to identify subsets of HG-GEP-NENs responsive to immunotherapy approaches. The present results addressed GEP-NECs with high proliferation index as sensible candidates to immunotherapy due to the enrichment in TMB-high and MSI coupled with higher CD4+ and CD8+ T cell expression.
    Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker
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    PD-L1 (Programmed death ligand 1) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • CD8 (cluster of differentiation 8) • MSH2 (MutS Homolog 2) • CD4 (CD4 Molecule)
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    PD-L1 expression • TMB-H • PD-L1 negative • POLE mutation
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    TruSight Oncology 500 Assay
    2ms
    Concurrent POLE hotspot mutations and mismatch repair deficiency/microsatellite instability in endometrial cancer: A challenge in molecular classification. (PubMed, Gynecol Oncol)
    POLEmut/MMRd ECs may be genetically distinct. Further studies are needed to assess the impact on outcomes and treatment response within this population.
    Journal • Mismatch repair • Tumor mutational burden • Microsatellite instability • MSi-H Biomarker
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    TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon)
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    TMB-H • MSI-H/dMMR • POLE mutation
    2ms
    Exceptional Evolution of a Squamous Odontogenic Tumor in the Jaw: Molecular Approach. (PubMed, Int J Mol Sci)
    The case presented contributes to the better understanding of this SOT tumor entity and to indicates its malignant evolution, together with its biological behavior and its histologic, clinical, and radiographic features. Also, it aims to stress the importance of deeper genetic analyses in rare diseases to uncover mutations that help to select a personalized treatment.
    Journal
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    ALK (Anaplastic lymphoma kinase) • RET (Ret Proto-Oncogene) • POLE (DNA Polymerase Epsilon) • CDKN1B (Cyclin dependent kinase inhibitor 1B)
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    RET mutation
    2ms
    Rare Germline Variants in DNA Repair Genes Detected in BRCA-Negative Finnish Patients with Early-Onset Breast Cancer. (PubMed, Cancers (Basel))
    Taken together, whole-exome sequencing yielded 72 deleterious variants, including 8 novel variants that may play a pivotal role in the development of early-onset breast cancer. Although more studies are warranted, we demonstrate that young breast cancer patients tend to carry multiple deleterious variants in one or more DNA repair genes.
    Journal • BRCA Biomarker
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    POLE (DNA Polymerase Epsilon) • ERCC2 (Excision repair cross-complementation group 2) • BRCA (Breast cancer early onset) • WRN (WRN RecQ Like Helicase) • RNF8 (Ring Finger Protein 8)
    3ms
    The game-changing impact of POLE mutations in oncology-a review from a gynecologic oncology perspective. (PubMed, Front Oncol)
    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.
    Review • Journal • Tumor mutational burden
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    TMB (Tumor Mutational Burden) • POLE (DNA Polymerase Epsilon)
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    TMB-H • POLE mutation • POLE EDM
    3ms
    Endometrial carcinomas with ambiguous histology often harbor TP53 mutations. (PubMed, Virchows Arch)
    In conclusion, based on this series, the molecular landscape of endometrial carcinomas with ambiguous histology is dominated by TP53 mutations and the absence of POLE mutations, with heterogeneous molecular profile with respect to other genes. A high proportion of these tumors is clinically aggressive.
    Journal • BRCA Biomarker
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    HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • PTEN (Phosphatase and tensin homolog) • ARID1A (AT-rich interaction domain 1A) • POLE (DNA Polymerase Epsilon) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • MUC16 (Mucin 16, Cell Surface Associated) • FAT1 (FAT atypical cadherin 1) • JAK1 (Janus Kinase 1) • FAT4 (FAT Atypical Cadherin 4) • CSMD3 (CUB And Sushi Multiple Domains 3) • PPP2R1A (Protein Phosphatase 2 Scaffold Subunit Aalpha)
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    TP53 mutation • PIK3CA mutation • POLE mutation
    3ms
    Molecular classification of endometrial cancer: preliminary experience from a single Portuguese academic center. (PubMed, Pathol Oncol Res)
    Despite the small sample size, we were able to show that molecular classification is feasible. To our knowledge this is the first cohort of endometroid endometrial carcinomas fully characterized according to the TCGA classification in Portugal, from one single center.
    Retrospective data • Journal
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    POLE (DNA Polymerase Epsilon)
    3ms
    A phase II clinical trial of toripalimab in advanced solid tumors with polymerase epsilon/polymerase delta (POLE/POLD1) mutation. (PubMed, Signal Transduct Target Ther)
    Notably, patients with PBRM1 gene mutations exhibited a high response rate to toripalimab at 75.0% (3/4). This study showed that neither the exonuclease domain mutations nor non-exonuclease domain mutations could fully predict the efficacy of immunotherapy, urging the need for more investigations to clarify potential immune sensitization differences within polymerase epsilon/polymerase delta mutation variants.
    P2 data • Journal • MSi-H Biomarker • PD(L)-1 Biomarker • IO biomarker • Metastases
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    MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • PBRM1 (Polybromo 1) • POLD1 (DNA Polymerase Delta 1)
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    Loqtorzi (toripalimab-tpzi)
    3ms
    Prognostic performance of FIGO 2023 endometrial carcinoma staging: a comparison to FIGO 2009 staging in the setting of known and unknown molecular classification. (PubMed, Histopathology)
    Downstaging based on POLE mutation more accurately represents patient outcomes. However, in the absence of known POLE status, applying molecular-agnostic FIGO 2023 criteria for stage I/II disease should be conducted with caution. For aggressive histotypes, additionally reporting FIGO 2009 stage should be considered. Upstaging based on substantial lymphovascular space invasion, aggressive histotype with any myometrial invasion and abnormal p53 improves prognostic discernment. Further subdivisions within stage I/II provide minimal additional prognostic information.
    Journal
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    POLE (DNA Polymerase Epsilon)
    3ms
    Excellent concordance of the molecular classification between preoperative biopsy and final hysterectomy in endometrial carcinoma. (PubMed, Gynecol Oncol)
    Molecular subtypes were completely consistent with those derived from surgical specimens, demonstrating high concordance between preoperative and postoperative molecular classifications. This suggests that endometrial biopsies could reliably predict prognosis. Future studies should investigate how biopsy-based molecular profiling influences treatment planning and patient outcomes.
    Journal • Biopsy • Discordant
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    TP53 (Tumor protein P53) • POLE (DNA Polymerase Epsilon)
    3ms
    NCI-2017-02296: Testing Olaparib in Patients With Advanced or Metastatic (Cancer That Has Spread) Bladder Cancer and Other Genitourinary Tumors With DNA-Repair Genetic Changes (clinicaltrials.gov)
    P2; Trial completion date: Aug 2024 --> Dec 2025 | Trial primary completion date: Aug 2024 --> Dec 2025
    Trial completion date • Trial primary completion date • Tumor mutational burden • Metastases
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    TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • ABL1 (ABL proto-oncogene 1) • MSI (Microsatellite instability) • STK11 (Serine/threonine kinase 11) • NPM1 (Nucleophosmin 1) • POLE (DNA Polymerase Epsilon) • CCND1 (Cyclin D1) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • ATRX (ATRX Chromatin Remodeler) • CHEK2 (Checkpoint kinase 2) • SMARCB1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1) • RAD51 (RAD51 Homolog A) • POLD1 (DNA Polymerase Delta 1) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • FANCL (FA Complementation Group L) • BRD4 (Bromodomain Containing 4) • DOT1L (DOT1 Like Histone Lysine Methyltransferase) • FANCE (FA Complementation Group E) • FANCG (FA Complementation Group G) • IKBKE (Inhibitor Of Nuclear Factor Kappa B Kinase Subunit Epsilon) • FANCC (FA Complementation Group C)
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    FoundationOne® CDx • FoundationOne® Liquid CDx
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    Lynparza (olaparib)
    3ms
    p53 Abnormal (Copy Number High) Endometrioid Endometrial Carcinoma Has a Prognosis Indistinguishable From Serous Carcinoma. (PubMed, Int J Gynecol Pathol)
    In conclusion, the findings of our study suggest that low-grade p53 abnormal endometrioid endometrial carcinomas (especially FIGO 2 tumors) have an aggressive course, with a prognosis similar to high-grade tumors. Furthermore, our study suggests that patients who had early-stage low-grade p53 abnormal disease might have been undertreated because of the "low-grade" histotype.
    Journal
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    TP53 (Tumor protein P53) • POLE (DNA Polymerase Epsilon)
    3ms
    SENECA study: staging endometrial cancer based on molecular classification. (PubMed, Int J Gynecol Cancer)
    Our study reveals significant differences in SLN involvement among patients with early-stage endometrial cancer based on molecular subtypes. This underscores the importance of considering molecular characteristics for accurate staging and optimal management decisions.
    Journal
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    POLE (DNA Polymerase Epsilon)
    3ms
    Impact of molecular classification on recurrence risk in endometrial cancer patients with lymph node metastasis: multicenter retrospective study. (PubMed, Int J Gynecol Cancer)
    Among patients with stage IIIC endometrial cancer, POLE mutated tumors exhibited an extremely low prevalence, with no specific molecular profile emerging as the largest molecular subgroup. Despite the significant difference in recurrence-free survival between molecular classes, conventional histopathologic parameters retained crucial prognostic value. Our findings highlight the necessity of integrating molecular classes with pathological characteristics, rather than considering them in isolation as crucial prognostic factors in stage IIIC endometrial cancer.
    Retrospective data • Journal
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    POLE (DNA Polymerase Epsilon)
    3ms
    Comprehensive molecular characterization of early stage grade 3 endometrioid endometrial adenocarcinoma. (PubMed, Gynecol Oncol)
    This comprehensive evaluation found a molecularly diverse cohort of tumors, despite the same histology, stage and grade. Mutational signature SBS5 correlated with a high risk of recurrence. Further refining of endometrial cancer classification may enable more precise patient stratification and personalized treatment approaches.
    Journal
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    PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog) • ARID1A (AT-rich interaction domain 1A) • POLE (DNA Polymerase Epsilon) • MUC16 (Mucin 16, Cell Surface Associated)
    4ms
    FOLFOX and Bevacizumab in Combination With Botensilimab and Balstilimab (3B-FOLFOX) for the Treatment of Microsatellite Stable (MSS) Metastatic Colorectal Cancer (clinicaltrials.gov)
    P1/2, N=86, Recruiting, City of Hope Medical Center | Trial completion date: Apr 2025 --> Oct 2025 | Trial primary completion date: Apr 2025 --> Oct 2025
    Trial completion date • Trial primary completion date • Combination therapy • Metastases
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    POLE (DNA Polymerase Epsilon)
    |
    Avastin (bevacizumab) • oxaliplatin • leucovorin calcium • balstilimab (AGEN2034) • botensilimab (AGEN1181) • fluorouracil topical
    4ms
    Neoadjuvant Immunotherapy for Patients With Microsatellite Instability-High or POLE-Mutated Locally Advanced Colorectal Cancer With Bulky Tumors: New Optimization Strategy. (PubMed, Clin Colorectal Cancer)
    Two-year event-free and overall survival for the whole cohort was both 100%.  Preoperative immunotherapy is the optimal option for MSI-H or POLE-mutated LACRC with bulky tumors, especially cT4b. Preoperative immunotherapy in patients with T4b CRC can reduce multivisceral resection and achieve high CR rate.
    Journal • Microsatellite instability • MSi-H Biomarker • IO biomarker • Metastases
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    MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon)
    4ms
    Tailoring Endometrial Cancer Treatment Based on Molecular Pathology: Current Status and Possible Impacts on Systemic and Local Treatment. (PubMed, Int J Mol Sci)
    However, the incorporation of molecular aspects into treatment decision-making is challenging. This review explores the available data and future directions on tailoring treatment based on molecular subtypes, alongside the challenges associated with their testing.
    Review • Journal
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    TP53 (Tumor protein P53) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon)
    4ms
    An uncommon case of POLE mutated uterine carcinosarcoma - complemented by a review of literature. (PubMed, Gynecol Oncol Rep)
    This finding hints to a clonal origin of both histologic components of this tumor and supports conversion theory as mechanism of carcinosarcoma emergence. The cancer was correctly staged as FIGO 2023 Stage IAmPOLEmut and according to ESGO-ESTRO-ESP guidelines adjuvant chemotherapy no longer considered and our patient entered follow-up after a detailed discussion.
    Review • Journal
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    TP53 (Tumor protein P53) • POLE (DNA Polymerase Epsilon)
    4ms
    ERBB2 mutations define a subgroup of endometrial carcinomas associated with high tumor mutational burden and the microsatellite instability-high (MSI-H) molecular subtype. (PubMed, Mol Oncol)
    Survival outcomes were similar between patients with ERBB2-mutated/non-amplified versus wildtype EC, whereas ERBB2 amplification was associated with worse prognosis on univariate, but not multivariate, analyses. In conclusion, ERBB2 mutation defines a rare subgroup of ECs that is pathogenically distinct from ERBB2-wildtype and ERBB2-amplified ECs.
    Journal • Tumor mutational burden • Microsatellite instability • MSi-H Biomarker
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    HER-2 (Human epidermal growth factor receptor 2) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • TYK2 (Tyrosine Kinase 2)
    4ms
    Morphomolecular Correlation and Clinicopathologic Analysis in Endometrial Carcinoma. (PubMed, Int J Gynecol Pathol)
    Using the new algorithm we designed, after narrowing down the number of patients, the microcystic, elongated, and fragmented pattern of invasion was revealed as an independent prognostic factor that reduces overall survival time (hazard ratio: 16.395, 95% CI: 2.140-125.606, P=0.007). In conclusion, using the new algorithm we have designed, and by identifying patients for whom molecular classification could alter risk groups, we observed that molecular tests can be utilized more efficiently in populations with limited economic resources and, in doing so, we discovered a new morphologic marker with prognostic significance.
    Journal
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    TP53 (Tumor protein P53) • POLE (DNA Polymerase Epsilon)
    4ms
    Molecular classification improves preoperative risk assessment of endometrial cancer. (PubMed, Gynecol Oncol)
    EC molecular classification is more accurate than histotype or grade in preoperative biopsy to predict advanced disease, and together with imaging tests are the most reliable preoperative information. This work provides an initial framework for using molecular information preoperatively to tailor surgical treatment.
    Journal
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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)
    4ms
    Accelerated clinical response achieved by combining short-term tumor-directed photodynamic therapy with immunotherapy-based systemic therapies in synchronous colorectal cancer with MSI-H and POLE mutation: a case report. (PubMed, Front Immunol)
    Here we reported a synchronous colorectal cancer patient with MSI-High and POLE mutation who had accelerated response in less than 2 cycles (42 days) of immunotherapy-based systemic therapies after tumor-directed PDT and has remained progression-free by far. This case enlightened the synergetic effect of PDT in immunotherapy-treated CRC patients, with the MSI and POLE-mutation status as predictors of survival benefits.
    Journal • MSi-H Biomarker • IO biomarker
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    MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon)
    4ms
    Introducing Neoadjuvant Immunotherapy for Colorectal Cancer: Advancing the Frontier. (PubMed, Ann Surg)
    Establishing mismatch repair status at the time of diagnosis is central to the potential use of neoadjuvant immunotherapy, in particular immune checkpoint inhibitors, in localized colorectal cancer. To date, efficacy is primarily seen in patients with deficient mismatch repair status and POLE mutations, although a small group of patients with proficient mismatch repair does respond. In conclusion, neoadjuvant immunotherapy shows promising complete response rates, which may open a future avenue of an organ-sparing watch-and-wait approach for a group of patients.
    Journal • IO biomarker
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    POLE (DNA Polymerase Epsilon)
    4ms
    Unsolved Issues in the Integrated Histo-Molecular Classification of Endometrial Carcinoma and Therapeutic Implications. (PubMed, Cancers (Basel))
    Hopefully, the numerous ongoing clinical trials in the adjuvant and metastatic settings of EC will likely produce evidence to refine the histo-molecular classification and therapeutic guidelines. Our review aims to retrace the origin and evolution of the molecular classification for EC, reveal its strengths and limitations, show clinical relevance, and uncover the desired future developments.
    Review • Journal
    |
    POLE (DNA Polymerase Epsilon)
    5ms
    Cohort of Tumors With POLE/D1 Mutation (clinicaltrials.gov)
    P=N/A, N=100, Recruiting, Federation Francophone de Cancerologie Digestive | Trial completion date: Oct 2027 --> Oct 2025 | Trial primary completion date: Oct 2027 --> Oct 2025
    Trial completion date • Trial primary completion date
    |
    POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1)
    5ms
    Tumoral programmed cell death 1 (PD1) expression in endometrial carcinoma is a prognostic marker for patient outcome. (PubMed, Int J Gynecol Cancer)
    Tumoral gene expression controlling the PD1 immune checkpoint, particularly expressed in "hot tumors", predicted recurrence-free, disease-specific, and overall survival in patients with endometrial carcinoma in two independent cohorts. Evaluation of these genes could be used to stratify patients who qualify for immune checkpoint inhibitors, which warrants prospective clinical trials.
    Journal • PD(L)-1 Biomarker • IO biomarker
    |
    PD-L1 (Programmed death ligand 1) • POLE (DNA Polymerase Epsilon) • PD-1 (Programmed cell death 1) • IFNG (Interferon, gamma)
    5ms
    Avelumab in Patients With MSS, MSI-H and POLE-mutated Recurrent or Persistent Endometrial Cancer and of Avelumab/Talazoparib and Avelumab/Axitinib in Patients With MSS Recurrent or Persistent Endometrial Cancer (clinicaltrials.gov)
    P2, N=106, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Mar 2027 --> Nov 2026 | Trial primary completion date: Mar 2025 --> Nov 2023
    Trial completion date • Trial primary completion date
    |
    MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2)
    |
    Bavencio (avelumab) • Talzenna (talazoparib) • Inlyta (axitinib)