Gynaecological cancers represent a unique group of cancers associated with the endocrine physiological regulations in the body. Standard
management of these cancers often has a significant impact on the hormonal balance in women and can lead to significant debilitating
consequences due to early menopause or loss of reproductive function. Endometrial cancer is the most common gynaecological malignancy in the
developed world and in women younger than 40 years represent up to 5% of cases and around 20% of women are diagnosed before menopause.
Although most endometrial cancers are diagnosed early, up to 20% progress to high-stage carcinoma. Current diagnostic approaches fail to identify
high-risk disease that is apparently early stage at presentation. This indicates the need for improvement in risk assessment and subsequent
management of these women.

Current risk assessment is based on clinical or integrated molecular group classifications endorsed by the ESGO/ESTRO/ESP guidelines. These
classify endometrial cancer into 4 distinct groups. These groups are POLEmut, MMRd, p53abn and NSMP (no specific mutational profile). The NSMP
represents the largest group. Considering the heterogeneity in prognosis, there is a great need for additional specific biomarkers. Improved risk
assessment will enable therapy de-escalation and a safer approach to non-standard, fertility sparing therapy (FST). This will ultimately enable
individualised counselling and patient focused treatment. Following this path, we should be able to shift the focus from oncological outcomes to
improvement of long-term patient reported outcomes (PROs).

In the project, we will address the current unmet needs in women with endometrial cancer by i) identifying new biomarkers (WP1) to improve risk stratification, de-escalating therapy, identifying candidates for non-standard therapy, such as FST or hormone replacement therapy, ii) developing
conventional and smart risk stratification algorithms (WP3) to incorporate these biomarkers, iii) developing minimally invasive methods of
diagnostics and screening (WP2) that would allow accurate risk stratification, early diagnostics and possible screening in high-risk populations.
Finally, following the results of our research, our ultimate goal is to improve PROs (WP4).

We will first recruit patients at both national tertiary centres to obtain the necessary biological samples and precise tumour imaging data. Through
sample analysis, we will determine the established molecular classification and analyse for the presence of new biomarkers. In addition to
evaluating biomarkers in standard therapy, UMC Maribor will lead research of the molecular classification and biomarkers role in FST. This will
provide fresh insight on the impact of tumour biology on reproductive and oncological outcomes of FST.
Furthermore, we will focus on the possibility of obtaining the diagnosis and the biomarker-based risk assessment non-invasively. The project will
focus on developing liquid biopsy methods and analysis of cell-free DNA and cell-free RNA in women with endometrial cancer to enhance
individualised management.

The main purpose of introducing novel biomarkers to clinical practice is to improve patient tailored management and possibly use less aggressive
management in low risk patients. Hence, we have designed “in-vitro” studies of standard and unconventional therapeutic approaches to molecularly
characterised endometrial cancer. For this purpose, we will for the first time characterise our own and commercially available endometrial cancer
cell lines. The findings of these studies will have major implications for the design of subsequent clinical trials. All the knowledge gained through our
project will be integrated to design a better, clinically applicable risk stratification model. The findings will culminate in better possibilities for tailored
management and precision medicine, especially in young, low-risk women with endometrial cancer.