We now know that there are distinct molecular classes of endometrial cancer with very different risks of recurrence. PORTEC 4a was a randomized non-inferiority trial that enrolled 564 patients with resected, high-intermediate risk endometrial cancer. They were randomized to either molecular risk-guided adjuvant therapy or standard vaginal brachytherapy (21 Gy in 3 fractions). In the molecular group, those with POLEmut or no specific molecular profile (NSMP-CTNNB1wt) were observed (46%), those with dMMR or NSMP-CTNNB1mut received vaginal brachytherapy (40%), and those with p53abn, substantial LVI, or L1 cell adhesion molecule overexpression received pelvic radiation (14%). The rate of vaginal recurrence was deemed non-inferior with molecular-based adjuvant therapy, however the rate at 5 years was 4.5% compared to 1.6% with VBT across the board. In the most favorable group, vaginal recurrence rates were 4.1% v 0.9%. While noninferior, one could ask whether the small benefit is still worth the relatively benign 3 VBT treatments? | van den Heerik, Lancet Oncol 2025
