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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.
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.
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.
Most high-grade ovarian cancers begin at the tip of the fallopian tube; endometrial cancer lines the uterus, cervical cancer starts at the transformation zone; each drains to a different node group.
Same organ: Adenosquamous carcinoma of the cervix, Small cell neuroendocrine carcinoma of the cervix, Bartholin gland carcinoma, Vulvar melanoma, Vaginal melanoma, High-grade serous ovarian cancer, Low-grade serous ovarian cancer, Clear cell ovarian cancer, Mucinous ovarian cancer, Adult granulosa cell tumour of the ovary, Ovarian cancer, Endometrial cancer, Cervical cancer, Vulvar cancer, Gestational trophoblastic neoplasia, Uterine sarcoma, Vaginal cancer, POLE-ultramutated endometrial cancer, Mismatch-repair-deficient endometrial cancer, p53-abnormal endometrial cancer, including uterine serous carcinoma, Advanced or recurrent endometrial cancer, Uterine carcinosarcoma, Early cervical cancer and fertility-sparing surgery, Locally advanced cervical cancer, Recurrent or metastatic cervical cancer, Platinum-sensitive ovarian cancer, Platinum-resistant ovarian cancer, HPV-associated vulvar squamous cell carcinoma, HPV-independent vulvar squamous cell carcinoma (p53-mutant), Vaginal squamous cell carcinoma (HPV-associated), Vaginal adenocarcinoma (including DES-associated clear cell adenocarcinoma), Low-risk gestational trophoblastic neoplasia (FIGO score 0 to 6), High-risk gestational trophoblastic neoplasia (FIGO score 7 or more, including ultra-high-risk), Placental-site trophoblastic tumour and epithelioid trophoblastic tumour
Hysterectomy with bilateral salpingo-oophorectomy and sentinel node mapping; no adjuvant treatment.
Vaginal brachytherapy (PORTEC-2) or pelvic radiotherapy; chemotherapy adds little in this class.
Levonorgestrel intrauterine device or oral progestin with hysteroscopic sampling every three to six months; hysterectomy after childbearing.
Carboplatin-paclitaxel with pembrolizumab or dostarlimab (smaller benefit than in dMMR); endocrine therapy for low-grade receptor-positive disease.
Lenvatinib with pembrolizumab (KEYNOTE-775); aromatase inhibitor with or without a CDK4/6 inhibitor in receptor-positive disease.
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Together with RUBY, this trial made chemo-immunotherapy the first-line standard for advanced endometrial cancer in both molecular groups, with the largest effect in mismatch repair-deficient tumours.
The adjuvant recommendations on this site's endometrial subtype pages (observation for stage I to II POLE-mutated disease, chemotherapy for p53-abnormal tumours with myometrial invasion, brachytherapy for intermediate risk) follow this guideline.
Molecular classification of every endometrial cancer, now embedded in the WHO classification and the ESGO/ESTRO/ESP guideline, rests on ProMisE; it decides adjuvant therapy and identifies candidates for immunotherapy.
Vaginal brachytherapy is the standard adjuvant treatment for high-intermediate-risk endometrial cancer, with pelvic radiotherapy reserved for higher-risk features such as substantial lymphovascular invasion or p53 abnormality.
Query for this cancer: (TITLE:"Endometrial cancer with no specific molecular profile" OR ABSTRACT:"Endometrial cancer with no specific molecular profile" OR TITLE:"NSMP endometrial cancer" OR ABSTRACT:"NSMP endometrial cancer" OR TITLE:"p53-wild-type, MMR-proficient, POLE-wild-type endometrial cancer" OR ABSTRACT:"p53-wild-type, MMR-proficient, POLE-wild-type endometrial cancer" OR TITLE:"Copy-number-low endometrial cancer" OR ABSTRACT:"Copy-number-low endometrial cancer") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Endometrial cancer with no specific molecular profile, not a curated reading list.
The targets of this cancer's medicines and the ones linked to it directly.
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.
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Bleeding that does not stop by itself, bleeding from more than one site, or new bruising in several places or one large area.
A swollen painful calf, or sudden breathlessness with chest pain; the tamoxifen boxed warning covers pulmonary embolism and stroke.
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
Sudden severe abdominal pain, a hard or very tender abdomen, or abdominal pain with vomiting and fever. Boxed warning for gastrointestinal perforation on bevacizumab.
Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
Fainting, dizziness or an irregular heartbeat; QT prolongation is a labelled warning and ECGs are checked in the first cycles.
See all on the product pages:AbemaciclibCarboplatinDostarlimabLenvatinibLetrozole (and other aromatase inhibitors)Paclitaxel / nab-paclitaxelPembrolizumabProgestins (megestrol acetate, medroxyprogesterone, levonorgestrel IUD)·Printable cards in the navigator
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