# Endometrial cancer with no specific molecular profile

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

## TL;DR

Endometrial cancer with no specific molecular profile is the default class: no POLE mutation, intact mismatch repair and normal p53. Most are low-grade, oestrogen-driven tumours cured by hysterectomy, and hormone-blocking drugs are their most natural treatment when they do recur.

## Summary

The class is defined by exclusion: POLE wild-type, mismatch-repair proficient and p53 wild-type. It corresponds to the copy-number-low class of the TCGA and holds about half of endometrial cancers, dominated by grade 1 and 2 endometrioid carcinoma with PTEN, PIK3CA, ARID1A and CTNNB1 mutations and strong oestrogen and progesterone receptor expression. Outcome depends on the classical factors, grade, depth of invasion, lymphovascular space invasion and stage, and two markers refine risk within the class: L1CAM expression and loss of oestrogen receptor mark a worse group, and CTNNB1 mutation raises recurrence risk in otherwise low-risk tumours. The WHO 2020 classification and the ESGO/ESTRO/ESP guideline place low-grade, receptor-positive disease in the favourable group and high-grade or receptor-negative disease closer to p53-abnormal risk.

Treatment follows stage and risk. Stage IA grade 1 to 2 disease without lymphovascular invasion is cured by hysterectomy alone; intermediate risk receives vaginal brachytherapy after PORTEC-2 showed it equivalent to pelvic radiotherapy for vaginal control; high-intermediate risk receives pelvic radiotherapy. PORTEC-3 found no meaningful benefit from adding chemotherapy in this class, and RAINBO's NSMP-ORANGE trial is testing whether adjuvant progestin therapy can replace chemotherapy for receptor-positive stage II to III disease. Young women with grade 1 tumours confined to the endometrium can be treated with a levonorgestrel intrauterine device or oral progestins to preserve fertility, with hysterectomy once childbearing is complete.

Recurrent and advanced disease is treated as mismatch-repair-proficient endometrial cancer: carboplatin-paclitaxel with pembrolizumab or dostarlimab in the first line, where the immunotherapy gain is smaller than in deficient tumours, then lenvatinib with pembrolizumab, which extended median survival from 11.4 to 18.3 months in KEYNOTE-775. Endocrine therapy with letrozole, megestrol or fulvestrant gives durable control in low-grade receptor-positive disease with little toxicity, and adding a CDK4/6 inhibitor to letrozole improved progression-free survival in the randomised phase 2 PALEO trial. The XPORT-EC-042 trial of maintenance selinexor in TP53-wild-type disease, which is mostly this class, missed its primary endpoint in 2026.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: NSMP endometrial cancer; p53-wild-type, MMR-proficient, POLE-wild-type endometrial cancer; Copy-number-low endometrial cancer
- Tags: subtype-page
- Group: gynaecologic
- Burden: About half of all endometrial cancers, mostly low-grade endometrioid tumours in postmenopausal women with obesity or oestrogen excess; the great majority are cured by surgery alone, and the challenge is finding the minority that will recur.
- Subtypes: Low-grade endometrioid, oestrogen receptor-positive NSMP (favourable); CTNNB1-mutant low-grade NSMP (higher recurrence risk); L1CAM-positive or oestrogen receptor-negative NSMP (unfavourable); High-grade endometrioid NSMP; Stage II to III receptor-positive NSMP (RAINBO NSMP-ORANGE, progestin versus chemotherapy); Grade 1 stage IA NSMP in young women (fertility-sparing progestin therapy)
- Biomarkers: Negative POLE, MMR and p53 results (diagnosis by exclusion); Oestrogen and progesterone receptor expression; L1CAM expression; CTNNB1 exon 3 mutation; Grade, depth of invasion and lymphovascular space invasion; PTEN, PIK3CA and ARID1A mutations

## 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-nsmp/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-nsmp/#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-nsmp/#what-it-is [6 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-nsmp/#finding-it [6 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-nsmp/#treating-it [5 settings, 5 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-nsmp/#evidence [7 trials, 4 key papers, 6 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-nsmp/#science [9 targets]
- 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-nsmp/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-nsmp/#living-with-it [21 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-nsmp/coming/ [10 medicines, 5 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-nsmp/data/ [63 connected records]

## Standard of care

- Low risk (stage IA grade 1 to 2, no substantial LVSI): Hysterectomy with bilateral salpingo-oophorectomy and sentinel node mapping; no adjuvant treatment. ([Hysterectomy](https://onco.cc/terms/hysterectomy/), [Sentinel lymph node biopsy](https://onco.cc/technologies/sentinel-node/), [FIRES & SENTOR (sentinel node mapping)](https://onco.cc/trials/fires-sentor/), [Robotic & minimally invasive surgery](https://onco.cc/technologies/robotic-surgery/), [Endometrial cancer molecular classes (POLEmut, MMRd, p53abn, NSMP)](https://onco.cc/terms/endometrial-molecular-classes/))
- Intermediate and high-intermediate risk: Vaginal brachytherapy (PORTEC-2) or pelvic radiotherapy; chemotherapy adds little in this class. ([Brachytherapy](https://onco.cc/technologies/brachytherapy/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [PORTEC-3](https://onco.cc/trials/portec-3/))
- Fertility-sparing (grade 1, stage IA, no invasion): Levonorgestrel intrauterine device or oral progestin with hysteroscopic sampling every three to six months; hysterectomy after childbearing. ([Fertility-sparing hormonal treatment of early endometrial cancer](https://onco.cc/technologies/fertility-sparing-endometrial/), [Progestins (megestrol acetate, medroxyprogesterone, levonorgestrel IUD)](https://onco.cc/drugs/megestrol-progestins/))
- Advanced or recurrent, first line: Carboplatin-paclitaxel with pembrolizumab or dostarlimab (smaller benefit than in dMMR); endocrine therapy for low-grade receptor-positive disease. ([Carboplatin](https://onco.cc/drugs/carboplatin/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Dostarlimab](https://onco.cc/drugs/dostarlimab/), [NRG-GY018 / KEYNOTE-868](https://onco.cc/trials/nrg-gy018-keynote-868/), [RUBY / ENGOT-EN6 / GOG-3031](https://onco.cc/trials/ruby/), [Letrozole (and other aromatase inhibitors)](https://onco.cc/drugs/letrozole/), [Progestins (megestrol acetate, medroxyprogesterone, levonorgestrel IUD)](https://onco.cc/drugs/megestrol-progestins/), [Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR)](https://onco.cc/terms/mss-pmmr/))
- After platinum: Lenvatinib with pembrolizumab (KEYNOTE-775); aromatase inhibitor with or without a CDK4/6 inhibitor in receptor-positive disease. ([Lenvatinib](https://onco.cc/drugs/lenvatinib/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [KEYNOTE-775 / Study 309](https://onco.cc/trials/keynote-775/), [Letrozole (and other aromatase inhibitors)](https://onco.cc/drugs/letrozole/), [Abemaciclib](https://onco.cc/drugs/abemaciclib/))

## State of the art

- Molecular classification identifies NSMP as the class where classical pathology still decides treatment.
- RAINBO NSMP-ORANGE is the first trial to test hormone therapy instead of chemotherapy after surgery.
- CDK4/6 inhibitors with letrozole are extending the endocrine option from breast to endometrial cancer.

## Open problems

- Splitting the class into truly low-risk and higher-risk tumours with L1CAM, CTNNB1 and receptor status.
- Whether progestins can replace chemotherapy after surgery.
- Small immunotherapy benefit in proficient tumours.

## 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/), [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/), [POLE-ultramutated endometrial cancer](https://onco.cc/cancers/endometrial-pole-ultramutated/), [Uterine carcinosarcoma](https://onco.cc/cancers/uterine-carcinosarcoma/)
- terms: [Depth of invasion (DOI)](https://onco.cc/terms/depth-of-invasion/), [Endometrial cancer molecular classes (POLEmut, MMRd, p53abn, NSMP)](https://onco.cc/terms/endometrial-molecular-classes/), [Hysterectomy](https://onco.cc/terms/hysterectomy/), [Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR)](https://onco.cc/terms/mss-pmmr/), [MLH1 promoter methylation (sporadic versus Lynch mismatch repair loss)](https://onco.cc/terms/mlh1-promoter-methylation/), [No specific molecular profile (NSMP) endometrial cancer](https://onco.cc/terms/nsmp/), [PTEN loss](https://onco.cc/terms/pten-loss/)
- trials: [FIRES & SENTOR (sentinel node mapping)](https://onco.cc/trials/fires-sentor/), [KEYNOTE-775 / Study 309](https://onco.cc/trials/keynote-775/), [NRG-GY018 / KEYNOTE-868](https://onco.cc/trials/nrg-gy018-keynote-868/), [PORTEC-2](https://onco.cc/trials/portec-2/), [PORTEC-3](https://onco.cc/trials/portec-3/), [RUBY / ENGOT-EN6 / GOG-3031](https://onco.cc/trials/ruby/), [XPORT-EC-042 / ENGOT-EN20 / GOG-3083](https://onco.cc/trials/xport-ec-042/)
- 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/), [NRG-GY018: pembrolizumab plus chemotherapy in advanced or recurrent endometrial cancer](https://onco.cc/key-papers/paper-nrg-gy018-nejm-2023/), [PORTEC-2: vaginal brachytherapy versus pelvic external beam radiotherapy for high-intermediate-risk endometrial cancer](https://onco.cc/key-papers/paper-portec-2-lancet-2010/)
- technologies: [Brachytherapy](https://onco.cc/technologies/brachytherapy/), [Fertility-sparing hormonal treatment of early endometrial cancer](https://onco.cc/technologies/fertility-sparing-endometrial/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Robotic & minimally invasive surgery](https://onco.cc/technologies/robotic-surgery/), [Sentinel lymph node biopsy](https://onco.cc/technologies/sentinel-node/)
- drugs: [Abemaciclib](https://onco.cc/drugs/abemaciclib/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Dostarlimab](https://onco.cc/drugs/dostarlimab/), [Lenvatinib](https://onco.cc/drugs/lenvatinib/), [Letrozole (and other aromatase inhibitors)](https://onco.cc/drugs/letrozole/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Progestins (megestrol acetate, medroxyprogesterone, levonorgestrel IUD)](https://onco.cc/drugs/megestrol-progestins/), [Sacituzumab tirumotecan](https://onco.cc/drugs/sacituzumab-tirumotecan/), [Selinexor](https://onco.cc/drugs/selinexor/)
- ideas: [Molecular-class-directed adjuvant therapy in endometrial cancer](https://onco.cc/ideas/idea-molecular-class-adjuvant-endometrial/)
- people: [Remi A. Nout](https://onco.cc/people/remi-nout/)

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