Karen A. Cadoo

Modifiable Risk Factors and Risk of Colorectal and Endometrial Cancers in Lynch Syndrome: A Systematic Review and Meta-Analysis

PURPOSE Lynch syndrome is the most common hereditary cause of colorectal and endometrial cancers. Modifiable risk factors, including obesity, physical activity, alcohol intake, and smoking, are well-established in sporadic cancers but are less studied in Lynch syndrome. METHODS Searches were conducted on MEDLINE, Embase, and Web of Science for cohort studies that investigated the association between modifiable risk factors and the risk of colorectal or endometrial cancer in people with Lynch syndrome. Adjusted hazard ratios (HRs) and 95% CIs for colorectal and endometrial cancers were pooled using a random effects model. The protocol was prospectively registered on PROSPERO (CRD 42022378462), and the meta-analysis was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-Analysis of Observational Studies in Epidemiology reporting guidelines. RESULTS A total of 770 citations were reviewed. Eighteen studies were identified for qualitative synthesis, with seven colorectal cancer (CRC) studies eligible for meta-analysis. Obesity (HR, 2.38 [95% CI, 1.52 to 3.73]) was associated with increased CRC risk. There was no increased CRC risk associated with smoking (HR, 1.04 [95% CI, 0.82 to 1.32]) or alcohol intake (HR, 1.32 [95% CI, 0.97 to 1.81]). Type 2 diabetes mellitus (T2DM) and some dietary factors might increase risk of CRC although more studies are needed. In a qualitative synthesis of three endometrial cancer cohort studies, female hormonal risk factors and T2DM may affect the risk of endometrial cancer, but obesity was not associated with an increased risk. CONCLUSION Lifestyle recommendations related to weight and physical activity may also be relevant to cancer prevention for individuals with Lynch syndrome. Further high-quality prospective cohort studies, in particular, including endometrial cancer as an end point, are needed to inform evidence-based cancer prevention strategies in this high-risk population.

High-Sensitivity Mutation Analysis of Cell-Free DNA for Disease Monitoring in Endometrial Cancer

Abstract Purpose: We sought to determine whether sequencing analysis of circulating cell-free DNA (cfDNA) in patients with prospectively accrued endometrial cancer captures the mutational repertoire of the primary lesion and allows for disease monitoring. Experimental Design: Peripheral blood was prospectively collected from 44 newly diagnosed patients with endometrial cancer over a 24-month period (i.e., baseline, postsurgery, every 6 months after). DNA from the primary endometrial cancers was subjected to targeted next-generation sequencing (NGS) of 468 cancer-related genes, and cfDNA to a high-depth NGS assay of 129 genes with molecular barcoding. Sequencing data were analyzed using validated bioinformatics methods. Results: cfDNA levels correlated with surgical stage in endometrial cancers, with higher levels of cfDNA being present in advanced-stage disease. Mutations in cfDNA at baseline were detected preoperatively in 8 of 36 (22%) patients with sequencing data, all of whom were diagnosed with advanced-stage disease, high tumor volume, and/or aggressive histologic type. Of the 38 somatic mutations identified in the primary tumors also present in the cfDNA assay, 35 (92%) and 38 (100%) were detected at baseline and follow-up, respectively. In 6 patients with recurrent disease, changes in circulating tumor DNA (ctDNA) fraction/variant allele fractions in cfDNA during follow-up closely mirrored disease progression and therapy response, with a lead time over clinically detected recurrence in two cases. The presence of ctDNA at baseline (P < 0.001) or postsurgery (P = 0.014) was significantly associated with reduced progression-free survival. Conclusions: cfDNA sequencing analysis in patients with endometrial cancer at diagnosis has prognostic value, and serial postsurgery cfDNA analysis enables disease and treatment response monitoring. See related commentary by Grant et al., p. 305

A pilot study evaluating the feasibility of enriching and detecting circulating tumour cells from peripheral and ovarian veins in rare epithelial ovarian carcinomas.

Studies on circulating tumour cells (CTCs) in rare epithelial ovarian carcinomas (EOC) are limited, despite their potential as a minimally invasive biomarker for monitoring cancer progression and predicting outcomes. This pilot study aimed to assess the feasibility of enriching and detecting CTCs from both peripheral and ovarian vein blood samples in rare EOC subtypes. Blood samples were collected from the peripheral and ovarian veins of 20 patients with rare EOC. Among the 20 patients, 12 had early-stage disease (I-II), while 8 had advanced disease (III-IV). CTCs were enriched using the Parsortix® system and immunophenotyped via immunofluorescence targeting epithelial markers (EpCAM/pan-cytokeratin) and Hoechst for positive selection, and CD45 for negative selection. CTC status (positive versus negative) was correlated with clinicopathological data. CTCs were successfully detected in 45 % (1-19 CTCs) of baseline peripheral samples and 55 % (1-4776 CTCs) of ovarian vein samples. CTC doublets and clusters were detected in ovarian vein samples (3/11), but not in peripheral samples (0/20). A higher proportion of deaths were observed in CTC+ patients compared to CTC- patients (p = 0.0088). Here we demonstrate the feasibility of enriching and detecting CTCs from both peripheral and ovarian vein blood in patients with rare EOC. The higher CTC yield in ovarian vein blood suggests that tumour-draining blood may play a role in improving CTC detection. This pilot study paves the way for larger studies to investigate the prognostic utility of CTCs and refine their clinical value in these rare understudied EOC.

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.