Molecular Classification Predicts Radiotherapy Benefit in Early-Stage Endometrioid Endometrial Cancer

According to a study using data from the PORTEC-1 and PORTEC-2 trials, molecular classification predicts response to radiotherapy in early-stage endometrioid endometrial cancer, potentially guiding adjuvant treatment decision making.

Nanda Horewig, MD, PhD, Leiden University Medical Center, Leiden, Netherlands, and coauthors wrote, “Endometrial cancer is currently classified into four molecular groups with a distinct tumor biology and prognosis.” Molecular classification has previously “proven to have prognostic value and is predictive of response to adjuvant chemotherapy…the molecular class might also have clinically relevant implications in (high-) intermediate-risk [endometrial cancer], for which adjuvant radiotherapy is often recommended.”

In the multi-center PORTEC-1 trial, patients with early-stage, intermediate-risk endometrial cancer were treated with either pelvic external beam radiotherapy (EBRT) or no adjuvant therapy. In the PORTEC-2 trial, patients were randomized to receive treatment with either vaginal brachytherapy (VBT) or EBRT. The primary analysis of the current study evaluated the locoregional recurrence-free survival by treatment across molecular classes in PORTEC-1, and the pelvic recurrence-free survival by treatment across molecular classes in PORTEC-2. For the secondary analysis, data from both PORTEC-1 and PORTEC-2 were pooled and locoregional recurrence-free survival by treatment across the molecular classes was determined.

At a median follow-up of 11.3 years in both PORTEC-1 and PORTEC-2, a total of 880 cases of endometrial cancers were molecularly classified from PORTEC-1 (n = 484) and PORTEC-2 (n = 396). The most common molecular class was no specific molecular profile (NSMP), followed by mismatch-repair deficient (MMRd). Pathogenic mutations of DNA polymerase-ε (POLEmut) and p53 abnormalities (p53abn) were relatively rare.

In PORTEC-1, patients treated with EBRT had a significantly longer 5-year locoregional recurrence-free survival compared to patients treated with no adjuvant therapy (97.4% vs 88.3%; P = .0006). When broken down by molecular classification, patients with POLEmut did not experience locoregional recurrence regardless of adjuvant therapy. Patients with MMRd disease experienced a non-significant benefit when treated with EBRT. Patients with a p53abn had a substantial but non-significant benefit when treated with EBRT. Among patients with NSMP, there was a significant benefit with EBRT.

In PORTEC-2, results indicated no difference in 5-year vaginal recurrence-free survival between patients treated with VBT and EBRT (97.8% vs 97.9; P = .98), But pelvic recurrence-free survival was significantly better in the EBRT arm compared with the VBT arm (98.9% vs 94.6%; P = .010). No patients with POLEmut experienced a pelvic recurrence, regardless of therapy. Patients with MMRd disease had a low risk of pelvic recurrence (EBRT, 96.2% vs VBT, 100%; P = .20). No patients with p53abn disease in the EBRT arm experienced recurrence but 68.6% of patients in the VBT arm experienced locoregional recurrence (P = .055). In patients with NSMP, there was no differences in pelvic recurrence-free survival between treatment groups (EBRT, 98.2% vs VBT, 97.2%; P = .38).

In the secondary analysis of pooled data from PORTEC-1 and PORTEC-2, no locoregional recurrences were observed in patients with POLEmut endometrial cancer. Among patients with MMRd disease, locoregional recurrence-free survival was achieved at similar rates after treatment with EBRT (94.2%), VBT (94.2%), and no adjuvant therapy (90.3%; P = .74). Among patients with p53abn endometrial cancer, EBRT (96.9%) displayed substantial benefit over VBT (94.2%) and no adjuvant therapy (72.2%; P = .048). Cases with NSMP had better locoregional control with EBRT (98.3%) and VBT (96.2%) compared to no adjuvant therapy (87.7%; P < .0001).

Dr Horewig and coauthors concluded, “the molecular classification is predictive of benefit from radiotherapy in women with stage-I [endometrioid endometrial cancer].” They added, “results of this study support decisions on adjuvant therapy.”

“Systemic therapy for [endometrial cancer] is being adapted for different TCGA groups, and this report adds to our knowledge about also adapting radiotherapy for biologic subsets,” added associate editor of Journal of Clinical Oncology, Gini F. Fleming, MD, University of Chicago Medicine, Chicago, Illinois. 

Source:

Horeweg N, Nout RA, Jürgenliemk-Schulz IM, et al. Molecular classification predicts response to radiotherapy in the randomized PORTEC-1 and PORTEC-2 trials for early-stage endometrioid endometrial cancer. J Clin Oncol. Published online: July 24,2023. doi: 10.1200/JCO.23.00062