Top Line: Should molecular classification be used to determine the benefit of adjuvant radiation for stage I endometrial cancer?
The Study: Molecular classification plays an increasingly important role in the management of endometrial cancer. There are 4 molecular subgroups of endometrial cancer: tumors with mutated DNA polymerase-epsilon (POLEmut, good prognosis), DNA mismatch repair deficient tumors (MMRd, intermediate prognosis), p53 mutated tumors (p53abn, poor prognosis), and finally those with no specific molecular profile (NSMP, stage-dependent prognosis). In this study, 880 patients from PORTEC-1 and PORTEC-2 were categorized into molecular subgroups to determine if the benefit of adjuvant radiation varied among groups. PORTEC-1 compared EBRT to no further therapy for intermediate risk endometrial cancer, and PORTEC-2 compared adjuvant EBRT to VBT for high-intermediate risk disease. Important baseline characteristics were that 97.2% had stage I disease, 97.7% had endometrioid histology, and only 4.4% had LVI. Most were categorized as NSMP (56.5%), 28.1% were MMRd, 8% were p53abn, and 7.5% were POLEmut. Rates of vaginal and pelvic recurrences were 0%/0% for POLEmut, 6.4%/4.9% for MMRd, 10%/2.2% for NSMP, and 24%/6.2% for p53abn. In the overall PORTEC-1 cohort, EBRT significantly improved locoregional RFS (97.4% v 88.3%). This improvement was most notable for the p53abn (96.2% v 72.2%) and NSMP (98.3% v 87.7%) subgroups. There was a 5.4% absolute difference in LR-PFS for MMRd (95.7% v 90.3%), but this wasn’t statistically significant. In the overall PORTEC-2 cohort, there was no difference in 5-year vaginal RFS with EBRT v VBT (97.9% v 97.8%), but there was a higher rate of pelvic RFS (98.9% v 94.6%). Only in the p53abn subgroup was there a significantly higher rate of locoregional RFS with EBRT compared to VBT (100% v 68.6%). A similar analysis of high risk patients in PORTEC-3 (RT v chemo-RT) found that mainly the p53abn group benefits from chemo.
TBL: In patients with intermediate risk, stage I, endometrioid endometrial cancer, over half have no specific molecular alterations. Patients with NSMP benefit from adjuvant therapy with either VBT or EBRT. Those with POLEmut tumors have excellent locoregional control without adjuvant radiation. Those with MMRd tumors have a small magnitude RFS benefit with either VBT or EBRT. And those with p53abn tumors benefit most from pelvic EBRT. | Horeweg, J Clin Oncol 2023
The Study: Molecular classification plays an increasingly important role in the management of endometrial cancer. There are 4 molecular subgroups of endometrial cancer: tumors with mutated DNA polymerase-epsilon (POLEmut, good prognosis), DNA mismatch repair deficient tumors (MMRd, intermediate prognosis), p53 mutated tumors (p53abn, poor prognosis), and finally those with no specific molecular profile (NSMP, stage-dependent prognosis). In this study, 880 patients from PORTEC-1 and PORTEC-2 were categorized into molecular subgroups to determine if the benefit of adjuvant radiation varied among groups. PORTEC-1 compared EBRT to no further therapy for intermediate risk endometrial cancer, and PORTEC-2 compared adjuvant EBRT to VBT for high-intermediate risk disease. Important baseline characteristics were that 97.2% had stage I disease, 97.7% had endometrioid histology, and only 4.4% had LVI. Most were categorized as NSMP (56.5%), 28.1% were MMRd, 8% were p53abn, and 7.5% were POLEmut. Rates of vaginal and pelvic recurrences were 0%/0% for POLEmut, 6.4%/4.9% for MMRd, 10%/2.2% for NSMP, and 24%/6.2% for p53abn. In the overall PORTEC-1 cohort, EBRT significantly improved locoregional RFS (97.4% v 88.3%). This improvement was most notable for the p53abn (96.2% v 72.2%) and NSMP (98.3% v 87.7%) subgroups. There was a 5.4% absolute difference in LR-PFS for MMRd (95.7% v 90.3%), but this wasn’t statistically significant. In the overall PORTEC-2 cohort, there was no difference in 5-year vaginal RFS with EBRT v VBT (97.9% v 97.8%), but there was a higher rate of pelvic RFS (98.9% v 94.6%). Only in the p53abn subgroup was there a significantly higher rate of locoregional RFS with EBRT compared to VBT (100% v 68.6%). A similar analysis of high risk patients in PORTEC-3 (RT v chemo-RT) found that mainly the p53abn group benefits from chemo.
TBL: In patients with intermediate risk, stage I, endometrioid endometrial cancer, over half have no specific molecular alterations. Patients with NSMP benefit from adjuvant therapy with either VBT or EBRT. Those with POLEmut tumors have excellent locoregional control without adjuvant radiation. Those with MMRd tumors have a small magnitude RFS benefit with either VBT or EBRT. And those with p53abn tumors benefit most from pelvic EBRT. | Horeweg, J Clin Oncol 2023