Endometrial cancer (EC) is usually diagnosed at an early stage, and patients generally have a good prognosis with the prospect of curative surgery. However, about 15-20% of patients present with high-risk disease with increased incidence of distant metastases and death. The standard of care for patients with high-risk EC is adjuvant pelvic external beam radiotherapy (EBRT), with or without chemotherapy (CT). The randomized Adjuvant Chemoradiotherapy (CTRT) Versus Radiotherapy (RT) Alone in Women with High-Risk Endometrial Cancer PORTEC-3 trial showed a significant benefit with adjuvant CTRT in both overall survival (OS) and failure-free survival (FFS), although the absolute benefit was limited (5% for 5-year OS and 7% for 5-year FFS), with significantly more adverse events occurring with CTRT. Selecting patients who may experience better outcomes with adjuvant CTRT is challenging, given the added toxicity of CT and impact on quality of life. Recent findings from The Cancer Genome Atlas (TCGA) have been important in understanding the molecular pathways involved in EC development and has defined four molecular subgroups of EC that have a clear prognostic value, and may potentially impact patient management: p53-abnormal (p53abn), POLE-ultramutated (POLEmut), mismatch-repair deficient (MMRd) or no specific molecular profile (NSMP).

In a recently published study, tissue samples obtained from 423 patients involved in the PORTEC-3 trial were used to determine the prognostic and predictive value of the molecular classification in high-risk EC. Immunohistochemistry was performed to determine p53 and MMR status, and next generation sequencing for assessment of POLE mutations. Molecular analysis was successful in 410 patients (97%): 22.7% of tumors were classified as p53abn, 12.4% as POLEmut, 33.4% as MMRd, and 31.5% as NSMP. The primary endpoint of the study was recurrence-free survival (RFS) and the secondary endpoint was OS. Median follow-up was 6.1 years. The data showed that patients with p53abn EC had the poorest prognosis with 5-year RFS of 48% and OS of 54%. For women with POLEmut EC, the 5-year RFS and OS were both 98%; those with MMRd had 5-year RFS of 71.7% and OS of 81.3%, and patients with NSMP had 5-year RFS of 74.4% and OS of 88.5%. Molecular subtypes also predict benefit of adjuvant treatment. Patients with p53abn EC experienced a statistically significant benefit from CTRT combination versus RT alone: 5-year RFS was 58.6% versus 36.2%, respectively (hazard ratio [HR] 0.52; P = 0.021) and OS was 64.9% versus 41.8% (HR, 0.55; P=0.049). In patients with POLEmut EC, the 5-year RFS and OS was 100% with CTRT versus 96.6% with RT alone. Women with MMRd EC had 5-year RFS of 68.0% with CTRT versus 75.5% with RT alone and OS was 78.6% versus 84.0%, respectively. Among patients with NSMP EC, a trend towards clinical benefit was seen, with 5-year RFS of 79.7% with CTRT versus 67.7% with RT alone, and OS of 89.3% versus 87.6%, respectively; however, statistical significance was not reached.

The results from this study indicate that the molecular classification of high-risk EC has a strong prognostic value, providing an opportunity to optimize treatment approach for each individual patient and prevent over- and undertreatment. For example, in women with p53abn EC, the clinical benefit of adjuvant CTRT was significant and those patients should be considered for CTRT combination, whereas addition of CT to RT did not provide additional benefit in patients with POLE mutations, thus de-escalation of adjuvant therapy may be an appropriate strategy in this molecular subgroup. The apparent lack of benefit with CTRT in patients with MMRd EC suggests that further research into therapeutic options other than adjuvant CT is warranted. In addition, the trend towards a clinical benefit with CTRT seen in patients with NSMP EC justifies further exploration. The authors conclude that EC molecular classification should be incorporated in standard clinical diagnostics, treatment decision making and future precision medicine studies.

Reference

Leon-Castillo A, et al. J Clin Oncol. 2020 Aug 4. [Epub ahead of print]