TCGA (The Cancer Genome Atlas, 2013) classified endometrial carcinoma into four molecular subgroups. A 58-year-old is found to have a POLEmut (POLE-ultramutated) endometrial carcinoma of grade 3 endometrioid histology. What is the clinical implication of this molecular classification regarding adjuvant treatment?
- A POLE-ultramutated tumours have the worst prognosis and require the most aggressive adjuvant chemoradiation
- B POLE-ultramutated tumours have an excellent prognosis regardless of grade; adjuvant treatment de-escalation is appropriate and supported by ongoing trials ✓
- C POLE mutation confers intermediate prognosis similar to microsatellite-stable tumours
- D POLE mutation indicates benefit from PARP inhibitor maintenance therapy similar to BRCA-mutated ovarian cancer
Explanation
TCGA molecular subgroups of endometrial carcinoma: POLE-ultramutated, MSI-high (hypermutated), copy-number-low (microsatellite-stable/endometrioid), and copy-number-high (serous-like). Paradoxically, POLE-ultramutated tumours — despite often having high grade — carry the best prognosis with near-universal 5-year disease-specific survival >95%. This is attributed to their extreme mutational burden generating neoantigen load driving robust anti-tumour immunity. ESGO/ESTRO/ESP 2021 guidelines and PORTEC-4 trial are investigating de-escalation of adjuvant radiotherapy in POLE-mutated low-to-intermediate risk patients, as their excellent prognosis suggests potential over-treatment with standard adjuvant therapy.
Reference: Shaw's Textbook of Gynaecology, 17th ed.
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