# POLE-ultramutated endometrial cancer

Source: https://onco.cc/cancers/endometrial-pole-ultramutated/  
OnCo record `endometrial-pole-ultramutated` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

POLE-ultramutated endometrial cancer carries a fault in the proofreading part of a DNA-copying enzyme, so its cells pile up enormous numbers of mutations. It looks aggressive under the microscope yet almost never comes back after surgery, so trials are testing whether radiotherapy and chemotherapy can be dropped altogether.

## Summary

The Cancer Genome Atlas defined the POLE-ultramutated class in 2013: tumours with a hotspot mutation in the exonuclease domain of DNA polymerase epsilon, most often P286R or V411L, which carry more than a hundred mutations per megabase, far more even than mismatch-repair-deficient tumours. About seven percent of endometrial cancers fall into this class. They are more often high grade, endometrioid, with prominent lymphocyte infiltration and ambiguous histology, and they occur in younger, thinner women than the average endometrial cancer patient. Because the pathogenic hotspots are few, a targeted sequencing test settles the class, and the ProMisE algorithm and the WHO 2020 classification both place POLE testing first because a POLE mutation overrides an abnormal p53 or mismatch-repair result.

The defining clinical fact is an excellent outcome regardless of grade or stage. In the molecular analysis of PORTEC-3, women with POLE-ultramutated tumours had almost no recurrences in either arm, so chemotherapy added nothing; the same pattern appeared in PORTEC-1 and PORTEC-2 and in the TransPORTEC pooled cohorts. The ESGO/ESTRO/ESP 2021 guideline therefore lets clinicians omit adjuvant therapy for stage I and II POLE-ultramutated disease, and the RAINBO programme's POLEmut-BLUE trial is testing de-escalation prospectively: no adjuvant treatment for stage I and II tumours and radiotherapy alone for stage III. The rationale is that the ultramutated tumour is intensely immunogenic and any residual cells are cleared by the immune system after surgery.

Open questions are practical rather than therapeutic. Not every POLE variant is pathogenic, and misclassifying a passenger variant as a driver would deny a woman treatment she needs, so laboratories use a curated list of hotspots and a scoring scheme for other variants. The rare advanced or recurrent POLE-ultramutated tumour is expected to respond to checkpoint inhibitors because of its mutational load, but numbers are too small for trials. Universal molecular classification, now routine in the Netherlands, Canada and the United Kingdom, is the step that makes any of this possible, and it is still uneven elsewhere.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: POLEmut endometrial cancer; POLE exonuclease domain mutant endometrial carcinoma; Ultramutated endometrial cancer
- Tags: subtype-page
- Group: gynaecologic
- Burden: Roughly one in fourteen endometrial cancers, typically in younger women with high-grade endometrioid tumours; almost none recur after surgery, so the class matters mainly because it identifies women who can safely be spared adjuvant treatment.
- Subtypes: POLE exonuclease domain hotspot mutation (P286R, V411L, S297F, A456P, S459F); POLE-ultramutated with secondary p53 or MMR abnormality (multiple classifier, treated as POLE); Stage I to II POLE-ultramutated (adjuvant therapy can be omitted); Stage III POLE-ultramutated (RAINBO POLEmut-BLUE, radiotherapy alone); High-grade endometrioid histology with ultramutated profile
- Biomarkers: POLE exonuclease domain sequencing (first step of the ProMisE classifier); Tumour mutational burden above 100 mutations per megabase; p53 and MMR immunohistochemistry (interpreted after POLE); Tumour-infiltrating lymphocytes; Stage and lymphovascular space invasion

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/endometrial-pole-ultramutated/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/endometrial-pole-ultramutated/#overview [3 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/endometrial-pole-ultramutated/#what-it-is [5 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/endometrial-pole-ultramutated/#finding-it [5 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/endometrial-pole-ultramutated/#treating-it [4 settings, 3 decisions with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/endometrial-pole-ultramutated/#evidence [4 trials, 5 key papers, 5 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/endometrial-pole-ultramutated/#science [1 target]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/endometrial-pole-ultramutated/where-you-are/
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/endometrial-pole-ultramutated/#living-with-it [17 questions, 6 red cards]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/endometrial-pole-ultramutated/coming/ [4 medicines, 3 trials, 1 idea, 3 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/endometrial-pole-ultramutated/data/ [31 connected records]

## Standard of care

- Diagnosis and classification: Hysterectomy with bilateral salpingo-oophorectomy and sentinel node mapping; molecular classification of every endometrial cancer with POLE sequencing, MMR and p53 immunohistochemistry. ([Endometrial cancer molecular classes (POLEmut, MMRd, p53abn, NSMP)](https://onco.cc/terms/endometrial-molecular-classes/), [Histopathology & immunohistochemistry](https://onco.cc/technologies/histopathology-ihc/), [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/), [Sentinel lymph node biopsy](https://onco.cc/technologies/sentinel-node/), [FIRES & SENTOR (sentinel node mapping)](https://onco.cc/trials/fires-sentor/), [Hysterectomy](https://onco.cc/terms/hysterectomy/))
- Stage I to II after surgery: Observation without adjuvant treatment is acceptable under the ESGO/ESTRO/ESP guideline; vaginal brachytherapy where local protocol still requires it. ([Brachytherapy](https://onco.cc/technologies/brachytherapy/), [Endometrial cancer molecular classes (POLEmut, MMRd, p53abn, NSMP)](https://onco.cc/terms/endometrial-molecular-classes/), [Molecular-class-directed adjuvant therapy in endometrial cancer](https://onco.cc/ideas/idea-molecular-class-adjuvant-endometrial/))
- Stage III after surgery: Pelvic radiotherapy without chemotherapy, as in RAINBO POLEmut-BLUE; chemoradiation with chemotherapy remains an option outside trials. ([IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [PORTEC-3](https://onco.cc/trials/portec-3/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [RAINBO](https://onco.cc/trials/rainbo/))
- Advanced or recurrent (rare): Checkpoint inhibitor with or without chemotherapy by extrapolation from the mismatch-repair-deficient class. ([Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Dostarlimab](https://onco.cc/drugs/dostarlimab/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/))

## State of the art

- POLE testing is the first branch of every molecular classifier because it overrides the other classes.
- PORTEC-3's molecular analysis showed that POLE-ultramutated tumours do not need chemotherapy.
- RAINBO POLEmut-BLUE is the first prospective trial to omit adjuvant treatment on a molecular basis.

## Open problems

- Deciding which non-hotspot POLE variants are pathogenic.
- Whether stage III and IV disease can also be de-escalated.
- Making molecular classification universal outside a few countries.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Endometrial_cancer
- Wikipedia: https://en.wikipedia.org/wiki/Endometrial_cancer

## Connected records

- cancers: [Advanced or recurrent endometrial cancer](https://onco.cc/cancers/advanced-recurrent-endometrial-cancer/), [Endometrial cancer](https://onco.cc/cancers/endometrial/), [Endometrial cancer with no specific molecular profile](https://onco.cc/cancers/endometrial-nsmp/), [Mismatch-repair-deficient endometrial cancer](https://onco.cc/cancers/endometrial-mmr-deficient/), [p53-abnormal endometrial cancer, including uterine serous carcinoma](https://onco.cc/cancers/endometrial-p53-abnormal/), [Uterine carcinosarcoma](https://onco.cc/cancers/uterine-carcinosarcoma/)
- terms: [Endometrial cancer molecular classes (POLEmut, MMRd, p53abn, NSMP)](https://onco.cc/terms/endometrial-molecular-classes/), [Hysterectomy](https://onco.cc/terms/hysterectomy/), [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/), [POLE ultramutation (POLEmut)](https://onco.cc/terms/pole-ultramutation/)
- trials: [FIRES & SENTOR (sentinel node mapping)](https://onco.cc/trials/fires-sentor/), [PORTEC-2](https://onco.cc/trials/portec-2/), [PORTEC-3](https://onco.cc/trials/portec-3/), [RAINBO](https://onco.cc/trials/rainbo/)
- key papers: [Confirmation of ProMisE: a genomics-based clinical classifier for endometrial cancer](https://onco.cc/key-papers/paper-promise-talhouk-cancer-2017/), [ESGO/ESTRO/ESP guidelines for the management of endometrial carcinoma (2021)](https://onco.cc/key-papers/paper-esgo-estro-esp-endometrial-concin-ijgc-2021/), [Integrated genomic characterisation of endometrial carcinoma (The Cancer Genome Atlas)](https://onco.cc/key-papers/paper-tcga-endometrial-nature-2013/), [Molecular classification of the PORTEC-3 trial: prognosis and benefit from adjuvant chemotherapy by molecular group](https://onco.cc/key-papers/paper-portec-3-molecular-leon-castillo-jco-2020/), [Prognostic significance of POLE proofreading mutations in endometrial cancer](https://onco.cc/key-papers/paper-church-pole-endometrial-jnci-2015/)
- ideas: [Molecular-class-directed adjuvant therapy in endometrial cancer](https://onco.cc/ideas/idea-molecular-class-adjuvant-endometrial/)
- technologies: [Brachytherapy](https://onco.cc/technologies/brachytherapy/), [Histopathology & immunohistochemistry](https://onco.cc/technologies/histopathology-ihc/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [MRD / molecular residual disease testing](https://onco.cc/technologies/mrd-testing/), [Sentinel lymph node biopsy](https://onco.cc/technologies/sentinel-node/)
- drugs: [Carboplatin](https://onco.cc/drugs/carboplatin/), [Dostarlimab](https://onco.cc/drugs/dostarlimab/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)

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JSON: https://onco.cc/api/v1/entities/endometrial-pole-ultramutated.json