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

Обзор

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.

Подробное описание

The main goal of the project is to define specific mutational signatures of endometrial cancer (EC) patients using whole-exome sequencing technology. The relationship between mutational profiles and molecular classification of endometrial cancer will be analyzed in order to improve the stratification of these patients, especially those classified as having a non-specific molecular profile or p53 mutations. At the same time, the association between the dominant mutational profiles of EC patients with the prevalence of lifestyle risk factors such as obesity/BMI, hypertension and diabetes mellitus will be investigated and their incidence is becoming more prevalent in the modern population. Associations between the occurrence of specific mutation profiles with risk factors will be sought and their role in influencing the genetic profile of EC patients will be analyzed. Another aim of the project is to find relationships between specific mutational profiles of patients with the extent of staging lymphadenectomy, which could help to decide the extent of this surgery, which subsequently affects the quality of life of patients, especially in patients with high BMI. The final aim of the project is to establish a methodology to detect mutations arising from dominant specific mutational profiles in circulating tumor DNA (ctDNA) to monitor potential recurrence in patients at high risk of developing and recurrent disease. Overall, the main contribution of the project will be a detailed understanding of the relationship of the genetic profile of EC patients with their molecular subtype, the extent of staging lymphadenectomy and, most importantly, their impact related to the presence of lifestyle risk factors. These factors may be related to the presence of specific dominant mutational profiles subsequently serving as a tool for prognosis, prevention, risk of recurrence but also potential therapeutic targets in women with the presence of any of the lifestyle risk factors.

Первичные конечные точки

• Genetic variants/mutation signatures [Срок оценки: Sampled during surgery]
• Quality of life of EC patients using the EORTC QLQ-C30 questionnaire [Срок оценки: Questionnaires filled before surgery, then after 6,12,24 months]
• Quality of life of EC patients using the EORTC QLQ-EN24 questionnaire [Срок оценки: Questionnaires filled before surgery, then after 6,12,24 months]
• Physical activity of EC patients [Срок оценки: Questionnaires filled before surgery, then after 6,12,24 months]
• Introduction of methodology of ctDNA detection by digital PCR of consecutive follow-up samples. [Срок оценки: Collection of blood samples at the day of surgery, then after 6,12 and 24 months]

Критерии участия

Критерии включения

• Clinical diagnosis of endometrial cancer.
• Treated with uterine removal with adequate staging.

Критерии исключения

• There are no exclusion criteria in this study.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Чехия · 1 центр

• Faculty Hospital Královské Vinohrady — Prague

Публикации

• Akesson A, Wolmesjo N, Adok C, Milsom I, Dahm-Kahler P. Lymphadenectomy, obesity and open surgery are associated with surgical complications in endometrial cancer. Eur J Surg Oncol. 2021 Nov;47(11):2907-2914. doi: 10.1016/j.ejso.2021.06.034. Epub 2021 Jul 1. PMID 34238643
• Alexandrov LB, Kim J, Haradhvala NJ, Huang MN, Tian Ng AW, Wu Y, Boot A, Covington KR, Gordenin DA, Bergstrom EN, Islam SMA, Lopez-Bigas N, Klimczak LJ, McPherson JR, Morganella S, Sabarinathan R, Wheeler DA, Mustonen V; PCAWG Mutational Signatures Working Group; Getz G, Rozen SG, Stratton MR; PCAWG Consortium. The repertoire of mutational signatures in human cancer. Nature. 2020 Feb;578(7793):94- PMID 32025018
• Ashley CW, Da Cruz Paula A, Kumar R, Mandelker D, Pei X, Riaz N, Reis-Filho JS, Weigelt B. Analysis of mutational signatures in primary and metastatic endometrial cancer reveals distinct patterns of DNA repair defects and shifts during tumor progression. Gynecol Oncol. 2019 Jan;152(1):11-19. doi: 10.1016/j.ygyno.2018.10.032. Epub 2018 Nov 8. PMID 30415991
• Ashley CW, Selenica P, Patel J, Wu M, Nincevic J, Lakhman Y, Zhou Q, Shah RH, Berger MF, Da Cruz Paula A, Brown DN, Marra A, Iasonos A, Momeni-Boroujeni A, Alektiar KM, Long Roche K, Zivanovic O, Mueller JJ, Zamarin D, Broach VA, Sonoda Y, Leitao MM, Friedman CF, Jewell E, Reis-Filho JS, Ellenson LH, Aghajanian C, Abu-Rustum NR, Cadoo K, Weigelt B. High-Sensitivity Mutation Analysis of Cell-Free D PMID 36007103
• Barry JA, Azizia MM, Hardiman PJ. Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2014 Sep-Oct;20(5):748-58. doi: 10.1093/humupd/dmu012. Epub 2014 Mar 30. PMID 24688118
• Bhaskaran K, Douglas I, Forbes H, dos-Santos-Silva I, Leon DA, Smeeth L. Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5.24 million UK adults. Lancet. 2014 Aug 30;384(9945):755-65. doi: 10.1016/S0140-6736(14)60892-8. Epub 2014 Aug 13. PMID 25129328
• Bolivar AM, Luthra R, Mehrotra M, Chen W, Barkoh BA, Hu P, Zhang W, Broaddus RR. Targeted next-generation sequencing of endometrial cancer and matched circulating tumor DNA: identification of plasma-based, tumor-associated mutations in early stage patients. Mod Pathol. 2019 Mar;32(3):405-414. doi: 10.1038/s41379-018-0158-8. Epub 2018 Oct 12. PMID 30315273
• Crosbie EJ, Zwahlen M, Kitchener HC, Egger M, Renehan AG. Body mass index, hormone replacement therapy, and endometrial cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev. 2010 Dec;19(12):3119-30. doi: 10.1158/1055-9965.EPI-10-0832. Epub 2010 Oct 28. PMID 21030602

Идентификаторы

NCT: NCT06680791 · NW24-09-00505

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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