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    BIOMARKER:

    POLE mutation + POLD1 mutation

    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, POLD1, DNA Polymerase Delta 1 Catalytic Subunit, Polymerase (DNA) Delta 1 Catalytic Subunit, DNA Polymerase Delta Catalytic Subunit, DNA Polymerase Subunit Delta P125, Polymerase (DNA Directed) Delta 1 Catalytic Subunit (125kD), Polymerase (DNA Directed) Delta 1 Catalytic Subunit 125kDa, CDC2 Homolog (S. Cerevisiae), CDC2 Homolog
    Entrez ID:
    5426; 5424
    Related biomarkers:
    Mutation
    Others
    3ms
    Glioma oncogenesis in the Constitutional mismatch repair deficiency (CMMRD) syndrome. (PubMed, Neurooncol Adv)
    CMMRD-associated gliomas have a specific oncogenesis that does not involve usual pathways and mutations seen in sporadic pediatric or adult glioblastomas. Frequent alterations in other pathways such as MAPK may suggest the use of other targeted therapies along with PD1 inhibitors.
    Journal • Mismatch repair • PD(L)-1 Biomarker • IO biomarker
    |
    PD-L1 (Programmed death ligand 1) • TP53 (Tumor protein P53) • NF1 (Neurofibromin 1) • POLD1 (DNA Polymerase Delta 1) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) • DICER1 (Dicer 1 Ribonuclease III) • EPHB2 (EPH Receptor B2) • PRKDC (Protein Kinase, DNA-Activated, Catalytic Subunit)
    |
    PD-L1 expression • POLD1 mutation • SETD2 mutation • POLE mutation + POLD1 mutation
    6ms
    A comprehensive analysis of POLE/POLD1 genomic alterations in colorectal cancer. (PubMed, Oncologist)
    Patients with POLE/POLD1 mutations exhibited significant differences across immunological markers (ie, TMB, MMR, and MSI-H) and molecular co-alterations. Those with short variant mutations represented 18% of the POLE/POLD1 cohort and 0.4% of the total cohort examined. This group of patients had a median TMB of 159 mut/Mb (range 34-488), representing the ultra-hypermutated phenotype. This group of patients is important to identify given the potential for exceptional response to immune checkpoint inhibitors.
    Journal • Tumor mutational burden • MSi-H Biomarker • BRCA Biomarker • IO biomarker
    |
    ALK (Anaplastic lymphoma kinase) • TMB (Tumor Mutational Burden) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • RET (Ret Proto-Oncogene) • POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1)
    |
    TMB-H • MSI-H/dMMR • ATM mutation • POLE mutation • ALK mutation • RET mutation • POLD1 mutation • POLE mutation + POLD1 mutation
    |
    Tempus xT Assay
    8ms
    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)
    8ms
    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)
    9ms
    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
    |
    POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1)
    |
    POLE mutation • POLD1 mutation • POLE mutation + POLD1 mutation
    |
    Opdivo (nivolumab) • Yervoy (ipilimumab)
    12ms
    Molecular and clinical characteristics of POLE/POLD1 alterations among patients with colorectal cancer. (ASCO-GI 2024)
    POLE/POLD1 mutations frequently co-exist with MSI-H disease in CRC. Patients with MSS-CRC harboring POLE/POLD1 mutations represent a smaller subgroup of CRC (~1%). The incidence of POLE/POLD1 somatic mutations was more common among patients with colon cancer than those with rectal cancer.
    Clinical • MSi-H Biomarker
    |
    MSI (Microsatellite instability) • 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 • POLE mutation • MSH6 mutation • MSH2 mutation • MLH1 mutation • POLD1 mutation • PMS2 mutation • POLE mutation + POLD1 mutation
    12ms
    Rare germline variants in POLE and POLD1 encoding the catalytic subunits of DNA polymerases ε and δ in glioma families. (PubMed, Acta Neuropathol Commun)
    Our data provide evidence that rare POLE/POLD1 germline variants predispose to gliomas that may be susceptible to ICIs. Data compiled here suggest that glioma patients carrying POLE/POLD1 variants may be recognized by cutaneous manifestations, e.g. café-au-lait macules, and benefit from surveillance colonoscopy.
    Journal • IO biomarker
    |
    POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1)
    |
    POLD1 mutation • POLE mutation + POLD1 mutation
    over1year
    The role of immune checkpoint inhibitors for patients with advanced stage microsatellite stable colorectal cancer and high tumor mutation burden: quantity or quality? (PubMed, Expert Opin Biol Ther)
    The US Food and Drug Administration (FDA) approved pembrolizumab for patients with unresectable or metastatic solid tumors with tumor mutational burden (TMB) of ≥ 10 mutations/megabase...Predetermined cutoff TMB ≥ 10 mutation per MB does not seem to define a universal cutoff for the benefit of disease-agnostic ICI therapy, particularly for patients with MSS CRC. Patients with POLE/POLD1 mutations with MSS CRC represent a unique biological subgroup of MSS CRC with favorable responses to ICI therapy.
    Journal • Checkpoint inhibition • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker • Metastases
    |
    TMB (Tumor Mutational Burden) • POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1)
    |
    TMB-H • POLE mutation • POLD1 mutation • POLE mutation + POLD1 mutation
    |
    Keytruda (pembrolizumab)
    over1year
    Pre-operative Targeted Treatments in Molecularly Selected Resectable Colorectal Cancer (UNICORN) (clinicaltrials.gov)
    P2, N=98, Recruiting, Gruppo Oncologico del Nord-Ovest | Active, not recruiting --> Recruiting
    Enrollment open
    |
    HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • CD8 (cluster of differentiation 8) • POLD1 (DNA Polymerase Delta 1) • CD4 (CD4 Molecule)
    |
    HER-2 positive • MSI-H/dMMR • HER-2 amplification • POLE mutation • POLD1 mutation • POLE mutation + POLD1 mutation
    |
    Imfinzi (durvalumab) • Vectibix (panitumumab) • Enhertu (fam-trastuzumab deruxtecan-nxki) • balstilimab (AGEN2034) • botensilimab (AGEN1181)
    over1year
    Integrating POLE/POLD1 mutated for immunotherapy treatment planning of advanced stage non-small cell lung cancer. (PubMed, Thorac Cancer)
    Current smokers have a five-fold increased risk of having POLE mutations than never-smokers. POLE/POLD1 mutation status and TMB > 18 can be a composite biomarker for selecting NSCLC patients with survival benefits to ICI treatment.
    Journal • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker • Metastases
    |
    PD-L1 (Programmed death ligand 1) • TMB (Tumor Mutational Burden) • POLE (DNA Polymerase Epsilon) • POLD1 (DNA Polymerase Delta 1)
    |
    POLE mutation • POLD1 mutation • POLE mutation + POLD1 mutation
    |
    MSK-IMPACT
    over1year
    Pre-operative Targeted Treatments in Molecularly Selected Resectable Colorectal Cancer (UNICORN) (clinicaltrials.gov)
    P2, N=98, Active, not recruiting, Gruppo Oncologico del Nord-Ovest
    New P2 trial
    |
    HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon) • CD8 (cluster of differentiation 8) • POLD1 (DNA Polymerase Delta 1) • CD4 (CD4 Molecule)
    |
    HER-2 positive • MSI-H/dMMR • HER-2 amplification • POLE mutation • POLD1 mutation • POLE mutation + POLD1 mutation
    |
    Imfinzi (durvalumab) • Vectibix (panitumumab) • Enhertu (fam-trastuzumab deruxtecan-nxki) • balstilimab (AGEN2034) • botensilimab (AGEN1181)