The WHO 2020 classification of endometrial carcinoma introduced a molecularly-driven classification system. A 65-year-old woman with endometrial carcinoma shows POLE (exonuclease domain) mutation on next-generation sequencing. According to the ProMisE/TCGA molecular subgrouping, what is her prognosis and how does it affect adjuvant therapy decisions?

• A POLE mutation indicates the worst prognosis among all molecular subtypes and mandates combination chemoradiation
• B POLE mutated tumours respond specifically to aromatase inhibitors and hormone therapy rather than conventional chemotherapy
• C POLE mutation has no prognostic significance in endometrial cancer and does not modify adjuvant treatment decisions
• D POLE-ultramutated subgroup has excellent prognosis (5-year OS >90%); adjuvant therapy (radiation/chemotherapy) may potentially be omitted even in high-grade histology based on PORTEC-3 molecular analyses ✓

Explanation

The TCGA/ProMisE molecular classification of endometrial carcinoma includes four subgroups: (1) POLE-ultramutated — highest mutation burden, excellent prognosis despite high-grade/advanced-stage histology, likely benefits from immune checkpoint inhibitors; (2) MSI-high (MMR deficient) — intermediate prognosis, responds to immunotherapy (pembrolizumab); (3) Copy number low (p53 wild-type) — good prognosis, predominantly endometrioid; (4) Copy number high/p53-abnormal (serous-like) — worst prognosis. PORTEC-3 molecular analyses (ESMO 2021) showed POLE-ultramutated patients had excellent outcomes regardless of adjuvant treatment, suggesting potential de-escalation of adjuvant chemoradiation — currently under investigation in PORTEC-4a trial.

Reference: Shaw's Textbook of Gynaecology, 17th ed.

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Written and medically reviewed by the StethoPrep medical team.