Endometrial cancer with no specific molecular profile

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.