Key considerations for safe de-escalation of therapy for POLE mutated endometrial cancer

Among the 4 molecular subtypes of endometrial carcinoma, POLE mutated carcinomas are notable for excellent clinical outcomes. Pathogenic POLE mutations cause DNA proofreading loss, resulting in the "ultramutated" phenotype, making POLE mutated tumors highly visible to the immune system leading to antitumor immunity. Abundant retrospective studies, meta-analyses, and clinical trials data all confirm the relative indolent course for patients with these tumors; however, until recently, no prospective clinical trials have evaluated the safety of de-escalation of therapy. The recently published PORTEC-4a randomized phase III clinical trial provided prospective data demonstrating that de-escalating therapy by omitting adjuvant treatment is safe for patients with a "favorable" molecular profile, including most stage I and II POLE mutated endometrial carcinomas. POLE mutated tumors often display features considered high risk of recurrence in other molecular subtypes, such as high grade, deep myometrial invasion, and lymphovascular invasion, yet studies consistently find that these features are inconsequential for POLE mutated cancer outcomes. For implementing therapy de-escalation in clinical practice, key factors must be considered to maintain patient safety. Chief among these is to restrict diagnosis of POLE mutated endometrial carcinomas to cancers that contain 1 of 11 validated pathogenic mutations. Further considerations include how best to manage POLE mutated tumors with additional p53 abnormalities and/or mismatch repair deficiencies (so called multiple classifiers) and how to manage rare advanced stage POLE mutated carcinomas. This review evaluates the evidence supporting de-escalated therapy in carefully selected patients with POLE mutated endometrial carcinoma. We highlight the critical considerations to make effective and safe treatment decisions for patients with these tumors.