Endometriosis and endometriosis-associated ovarian cancer, possible connection and early diagnosis by evaluation of plasma microRNAs

Introduction

Endometriosis is a chronic condition in which endometrial-like tissue grows outside the uterus. Commonly found on the ovaries, fallopian tubes, or other pelvic structures, this ectopic tissue can lead to symptoms such as chronic pelvic pain, dysmenorrhea, dyspareunia, and infertility [1]. Although endometriosis is considered a benign disorder, several studies have shown a link between this condition and an increased risk of developing certain types of endometriosis-associated ovarian cancer (EAOC), in particular, two histological types: endometrioid- and clear cell-ovarian carcinoma [2].

The ovarian form of endometriosis is more likely to progress into cancer and this evolution can take only 60–120 months in some cases [3]. A significant percentage of endometrioid ovarian carcinomas (10–50 %) arise from endometriosis, with strict anatomopathological criteria defined for this malignant transformation. Similarly, clear-cell ovarian carcinomas are linked to endometriosis in 25–58 % of cases [4], 5].

The exact mechanism by which endometriosis leads to tumor lesions remains still unclear. However, evidence suggests that endometriosis and certain types of ovarian cancer share some genetic alterations that drive malignant transformation. Key driver events in EAOC include the loss-of-function mutations in ARID1A (involved in chromatin remodeling) and PTEN (a tumor suppressor gene), as well as activating mutations in the PIK3CA and KRAS genes. Epigenetic modifications and microRNA (miRNA) alterations further contribute to this process [6]. Moreover, the chronic inflammation, characteristic of endometriosis, and prolonged exposure to estrogen may foster the development of cancerous cells and promote the progression of specific types of ovarian cancer [7].

The diagnosis and management of epithelial ovarian cancer (EOC) are increasingly influenced by the identification of key tumor biomarker mutations, particularly in endometrioid and clear cell subtypes. Recent studies highlight the complex relationship between these biomarkers and chemotherapy response, paving the way for personalized treatment strategies. Given the molecular heterogeneity of EOC, identifying specific biomarkers is crucial for driving targeted therapies, such as PARP inhibitors for BRCA-mutated ovarian cancer [8].

BRCA1/2 mutations and homologous recombination repair deficiency (HRD) play a central role in EOC treatment decisions, while other genetic alterations, including mismatch repair (MMR) deficiencies, also contribute to therapeutic stratification. HRD status is particularly relevant due to its correlation with platinum sensitivity and response to PARP inhibitors; however, the lack of standardized, validated HRD testing remains a significant limitation. Currently, no universal treatment algorithm exists for advanced EOC, underscoring the need for further research to refine biomarker-driven approaches and develop more effective targeted therapies [9]. Integrating comprehensive genomic profiling into clinical practice enables a more precise selection of chemotherapy and targeted treatments, ultimately aiming to improve patient outcomes in EOC.

As regards the therapeutic options, recent advancements in immuno-oncology have led to the development of immune checkpoint inhibitors (ICIs), which hold promise for treating various cancers, including ovarian cancer. While numerous mutations have been identified, and several ICIs are under clinical evaluation, meaningful survival benefits in EOC remain limited, particularly outside of biomarker-selected therapies. The effectiveness of ICI monotherapy in EOC has been modest, in contrast to the significant advantages observed in other solid tumors. A meta-analysis of seven randomized phase III trials [10] found that single-agent PD-L1 inhibitors did not provide substantial benefit in newly diagnosed ovarian cancer. However, in patients without tumor BRCA mutations, maintenance therapy with a combination of bevacizumab, olaparib, and durvalumab improved progression-free survival compared to bevacizumab alone.

In both platinum-sensitive and platinum-resistant EOC, ICIs have shown no significant impact. Ongoing trials are exploring whether integrating ICIs with standard PARP inhibitors and bevacizumab may enhance treatment outcomes. Additionally, combinations of CTLA-4 and PD-1 inhibitors, as well as ICIs combined with other novel therapeutic approaches, are being investigated as potential strategies to boost immunotherapy effectiveness in EOC [10]. However, further research is essential to better define the role of ICIs in ovarian cancer and to identify predictive biomarkers for optimal patient selection.

In light of all the above premises, this perspective paper explores the potential connection between endometriosis and EAOC, emphasizing the role of circulating miRNAs as potential biomarkers for early detection and timely identification of malignant transformation in endometriosis.

Problem to address

Women with endometriosis are at increased risk of developing ovarian cancer, particularly if the endometriosis is long-lasting and involves the ovaries. The key to managing this condition is early and accurate differential diagnosis, which allows for the prompt administration of effective therapies, improving quality of life for patients and slowing disease progression. However, the variability of symptoms and lack of specific diagnostic tests often make early diagnosis of endometriosis challenging. Differential diagnosis, on the other hand, would enable the identification of patients at risk of malignant transformation, allowing for more accurate monitoring and timely surgical intervention if necessary. Nevertheless, distinguishing between benign and malignant endometriosis still represents a difficult diagnostic challenge for clinicians.

Conclusions

The observed dysregulation of miRNAs in endometriosis and EAOC underscores their critical involvement in disease pathogenesis. MiRNAs participate in a range of cellular processes that contribute to both the initiation and progression of these diseases. While further investigation is required to fully elucidate the specific mechanisms through which miRNAs exert their influence, their potential as biomarkers offers significant promise for future research endeavors and clinical applications.