Brooke M. Grant

Molecular Monitoring in Endometrial Cancer—Ready for Prime Time?

Summary Efforts are under way to define the role of minimally invasive strategies for molecular monitoring and risk stratification in endometrial cancer. A recent publication aims to define the association between circulating tumor DNA level and disease stage in patients with newly diagnosed endometrial cancer and determine whether sequencing of longitudinal cell-free DNA samples can be used for disease monitoring and detection of progression or recurrence. These results accelerate the current knowledge of molecular follow-up in endometrial cancer. See related article by Ashley et al., p. 410

Genomic Landscape of ctDNA and Real-World Outcomes in Advanced Endometrial Cancer

Abstract Purpose: ctDNA is a novel technique extensively studied in solid tumors, although not currently well defined in endometrial cancer. Experimental Design: A de-identified retrospective analysis of 1,988 patients with advanced/recurrent endometrial cancer was performed. In addition, an analysis of a real-world evidence cohort was completed (n = 1,266). Patients underwent ctDNA testing using Guardant360 during routine clinical care. The objective was to describe and assess molecular landscape using ctDNA. Results: Among 1,988 ctDNA samples, at least one somatic alteration was detected in 91.6% (n = 1,821). Most frequently altered genes were TP53 (64%), PIK3CA (29%), PTEN (25%), ARID1A (20%), and KRAS (14%). Overall, 18.5% had amplifications, with the majority identified in CCNE1 (40.9%), PIK3CA (22%), and EGFR (19.3%). From the real-world evidence cohort, those with TP53 mutations had a worse overall survival (OS) versus those without TP53 mutations (P = 0.02) and those with TP53 comutations had an inferior OS in comparison with TP53-mutated only (P = 0.016). Amongst these, patients with a PIK3CA comutation (P = 0.012) and CCNE1 amplification (P = 0.01) had an inferior OS compared with those with only TP53 mutations. Fifty-seven patients with newly diagnosed endometrial cancer had at least two serial ctDNA samples showing evolution in detected variants compared with baseline samples, with TP53 being the most frequent change. Conclusions: This study is one of the largest cohorts of ctDNA currently reported in endometrial cancer. The presence of TP53 mutation and other comutations detected by ctDNA have a negative effect on outcomes. This report suggests that ctDNA analysis is feasible and could become a useful biomarker for endometrial cancer.

Molecular Classification in Relation to Prevention of Endometrial Cancer Recurrence and Lifestyle Factors

Endometrial cancer (EC) is one of the most prevalent cancers in women worldwide with a significantly increasing incidence, especially in developed countries. One of the reasons for the increase in the incidence of this disease is the rising incidence of obesity as the biggest risk factor for the development of this disease. Other important risk factors are hypertension, diabetes mellitus and the general ageing of the population. These risk factors are not only associated with a higher risk of developing the disease, but also, for example, with post-operative complications affecting the quality of life of patients after surgery. The molecular classification of endometrial cancer, which has been introduced into clinical practice in recent years, is currently helping physicians to make treatment decisions for individual patients and predict prognosis. In this project, we would like to focus on the relationship of this molecular classification with genomic mutational signatures detected by whole-exome sequencing and their association with lifestyle risk factors for endometrial cancer (obesity - BMI, hypertension, diabetes mellitus), including the extent of staging lymphadenectomy. Identification and detailed analysis of dominant mutational profiles associated with a specific molecular subtype of EC and their influence on the presence of lifestyle risk factors may have a major impact on both disease development and prevention of disease recurrence. The possible relationship of the mutational profile with the extent of staging lymphadenectomy may help in deciding the extent of this surgical procedure, which subsequently affects the quality of life of patients, especially in patients with high BMI. Given the widespread prevalence of lifestyle risk factors in the developed world, a detailed understanding of the relationship between the genetic profile, its alterations and the prevalence of these risk factors, with potentially major implications for treatment success, is crutial.