A study by Creutzberg et al investigated the survival outcome of combined adjuvant chemotherapy and radiotherapy vs radiotherapy alone in women with endometrial cancer with high-risk features. The researchers found that 5-year recurrence-free survival varied according to a patient’s specific molecular tumor classification. Patients with the POLE-ultramutated subtype had a 5-year recurrence-free survival of 98%, regardless of whether they received combined adjuvant chemotherapy and radiotherapy or radiotherapy alone. The study was presented at the European Society for Medical Oncology (ESMO) Congress 2019 (Abstract LBA63).

Methodology

The researchers evaluated the survival outcomes and impact of chemotherapy for each of the four molecular subgroups of endometrial cancer defined by The Cancer Genome Atlas, including POLE-ultramutated, microsatellite instability–hypermutated, copy number–low, and copy number–high. They collected tissue samples from 423 patients with stage I to III endometrial cancer with high-risk features enrolled in the PORTEC-3 trial to determine the benefit of combined adjuvant chemotherapy and radiotherapy compared to radiotherapy alone.

Immunohistochemistry for p53 and mismatch repair (MMR) proteins and DNA sequencing for POLE pathogenic exonuclease domain mutations were done to classify tumors as p53 abnormal, based on mutant-like immunostaining (p53abn), POLE-ultramutated (POLEmut), mismatch repair–deficient (MMRd), or no specific molecular profile (NSMP). The Kaplan-Meier method, log-rank test, and Cox model were used for the analysis.

Study Results

The molecular classification according to the four subgroups was possible in 410 (97%) samples of patients with high-risk endometrial cancer; 92 (22%) of the samples were p53abn; 52 (13%) were POLEmut; 137 (33%) were MMRd; and 129 (32%) were NSMP. Patient outcome per molecular subgroup was evaluated by 5-year recurrence-free survival. The researchers found that the 5-year recurrence-free survival for patients with high-risk endometrial cancer was 98% for patients with POLEmut disease; 50% for patients with p53abn disease; 74% for MMRd disease; and 76% for NSMP disease (P < .0001).

Regarding outcome following each treatment, patients with p53abn tumors benefited from combined chemotherapy and radiotherapy, with a 5-year recurrence-free survival of 61.1% vs 37.2% with radiotherapy alone (hazard ratio [HR] = 0.50; 95% confidence interval [CI] = 0.28–0.88; P = .017). In contrast, patients in the POLEmut category had a clinical benefit regardless of the treatment group: the 5-year recurrence-free survival was 100% in patients who had received the combination therapy vs 96.6% in patients who received radiotherapy alone (HR = 0.02; 95% CI = < 0.01–> 10⁴; P = .632).

Patients with MMRd disease in both treatment arms had similar 5-year recurrence-free survival results: 75.8% with chemotherapy plus radiotherapy compared to 72.4% with radiotherapy alone (HR = 1.15; 95% CI = 0.59–2.22; P = .687). The rates for patients in the NSMP subgroup were 68.9% vs 81.2%, respectively (HR = 0.71; 95% CI = 0.37–1.37; P = .311).

Clinical Relevance

The molecular endometrial cancer classification system offers a strong prognostic value in patients with high-risk endometrial cancer, and better identifies patients who benefit from adjuvant chemoradiotherapy than clinicopathologic factors, according to the researchers. “Patients with p53abn high-risk endometrial cancer had significantly improved [recurrence-free survival] with adjuvant chemoradiotherapy while those with MMRd [disease] did not seem to benefit from chemotherapy. Patients with POLEmut high-risk endometrial cancer had an excellent [recurrence-free survival] in both arms. Future trials should incorporate the molecular classification and target specific subgroups,” concluded the study authors.

Disclosure: Funding for this study was provided by the Dutch Cancer Society. For full disclosures of the study authors, visit esmo.org.