Adjuvant therapy for endometrial cancer in the era of molecular classification: radiotherapy, chemoradiation and novel targets for therapy

Abstract

Endometrial cancer is primarily treated with surgery. Adjuvant treatment strategies for endometrial cancer, such as external beam pelvic radiotherapy, vaginal brachytherapy, chemotherapy, and combined chemotherapy and radiotherapy, have been studied in several randomized trials. Adjuvant treatment is currently based on the presence of clinico-pathological risk factors. Low-risk disease is adequately managed with surgery alone. In high-intermediate risk endometrial cancer, adjuvant vaginal brachytherapy is recommended to maximize local control, with only mild side effects and without impact on quality of life. For high-risk endometrial cancer, recent large randomized trials support the use of pelvic radiotherapy, especially in stage I–II endometrial cancer with risk factors. For women with serous cancers and those with stage III disease, chemoradiation increased both recurrence-free and overall survival, while GOG-258 showed similar recurrence-free survival compared with six cycles of chemotherapy alone, but with better pelvic and para-aortic nodal control with combined chemotherapy and radiotherapy. Recent molecular studies, most notably the work from The Cancer Genome Atlas (TCGA) project, have shown that four endometrial cancer molecular classes can be distinguished; POLE ultra-mutated, microsatellite instable hypermutated, copy-number-low, and copy-number-high. Subsequent studies, using surrogate markers to identify groups analogous to TCGA sub-classes, showed that all four endometrial cancer sub-types are found across all stages, histological types, and grades. Moreover, the molecular sub-groups have proved to have a stronger prognostic impact than histo-pathological tumor characteristics. This introduces an new era of molecular classification based diagnostics and treatment approaches. Integration of the molecular factors and new therapeutic targets will lead to molecular-integrated adjuvant treatment including targeted treatments, which are the rationale of new and ongoing trials. This review presents an overview of current adjuvant treatment strategies in endometrial cancer, highlights the development and evaluation of a molecular-integrated risk profile, and briefly discusses ongoing developments in targeted treatment.

Pre-treatment risk assessment of women with endometrial cancer: differences in outcomes of molecular and clinical classifications in the Slovenian patient cohort

“…Without appropriate adjuvant therapy, these patients were found to be at a approximately 30% higher risk than if adjuvant therapy was offered. 21 One of our patients was downgraded from high risk to the HIR risk group. While this individual has received radiotherapy and chemotherapy, this is also a valid strategy of treatment in the HIR risk group 4 and the decision process most likely would have not changed for her.…”

Ultrasonography-integrated risk profile for determining the need for radiotherapy after phase I surgery

“…Previous studies had attempts to predict the need for radiotherapy based on the molecular characteristics of the tumor. Unfavorable profile of endometrial cancer which needs external beam pelvic radiotherapy was defined by van den et al (14) . Molecular-integrated risk profile was suggested by Wortman et al also confirmed the worse condition of the patient and the need for the radiotherapy.…”

Contemporary Fertility-Sparing Management Options of Early Stage Endometrioid Endometrial Cancer in Young Nulliparous Patients

“…Histopathological evaluation including subtyping and grading allows clinicians to create appropriate treatment recommendations and predict outcomes [ 83 ]. However, patients with histologically similar EC may have different outcomes [ 82 , 83 , 84 , 85 ]. Four molecular subgroups of EC have undergone extensive studies during the past decades: POLE ultramutated ( POLE mut), mismatch repair-deficient (MMRd), p53 mutant (p53abn), and those EC lacking any of these alterations, referred to as nonspecific molecular profile (NSMP) [ 83 , 84 , 86 ].…”