Gloria Ravegnini

Can miRNAs be useful biomarkers in improving prognostic stratification in endometrial cancer patients? An update review

AbstractEndometrial cancer (EC) is the most common gynecological cancer, with annual incidence rates in Western countries ranging between 15 and 25 per 100 000 women. About 15% to 20% of patients with EC have high‐risk disease and follow an aggressive clinical course. Unfortunately, the assessment of histologic parameters is poorly reproducible and conventional clinicopathological and molecular features do not reliably predict either the patient's response to the available treatments or the definition of personalized therapeutic approaches. In this context, the identification of novel diagnostic and prognostic biomarkers, which can be integrated in the current classification schemes, represents an unmet clinical need and an important challenge. miRNAs are key players in cancer by regulating the expression of specific target genes. Their role in EC, in association with clinical and prognostic tumor biomarkers, has been investigated but, so far, with little consensus among the studies. The present review aims to describe the recent advances in miRNAs research in EC taking into consideration the current classification schemes and to highlight the most promising miRNAs. Finally, a perspective point of view sheds light on the challenges ahead in the landscape of EC.

Endometrial carcinoma and immune escape: prognostic relevance of HLA class I loss in NSMP subtype

Aims This study aims to define and characterize human leukocyte antigen class I (HLA‐I) expression in a consecutive series of molecularly classified endometrial carcinomas (ECs), and to evaluate its association with clinicopathologic features, spatial cancer–immune phenotypes and patient prognosis, with a focus on the NSMP (no specific molecular profile) subtype. Methods and results HLA‐I expression was assessed by immunohistochemistry on whole tissue sections from 208 ECs, classified into POLE ‐mutated, MMR‐deficient (MMRd), p53‐abnormal (p53abn) and NSMP subtypes. Loss of HLA‐I was identified in 31% of cases and was associated with adverse features including high‐grade, aggressive histotypes, deep myometrial invasion, substantial lymphovascular space invasion (LVSI), extensive tumour necrosis and an ‘excluded’ immune phenotype. While HLA‐I loss showed no significant prognostic impact in POLE , MMRd or p53abn tumours, it significantly correlated with worse disease‐free survival in NSMP tumours ( P  < 0.001). Multivariate analysis confirmed HLA‐I loss as an independent prognostic factor in early‐stage NSMP ECs, in addition to substantial LVSI, presence of lymph node metastases and spatial cancer–immune phenotypes. Integration of HLA‐I status improved the performance of predictive models over time. Conclusions HLA‐I loss defines a biologically aggressive subgroup within NSMP ECs and is associated with adverse clinicopathologic and immune features. Assessment of HLA‐I expression could refine risk stratification in NSMP ECs, a group traditionally lacking robust prognostic markers and may help identify patients who could benefit from intensified clinical surveillance and future immunomodulatory treatment strategies.

miRNA levels are associated with body mass index in endometrial cancer and may have implications for therapy

AbstractEndometrial cancer (EC) is the most prevalent gynecological cancer in high‐income countries. Its incidence is skyrocketing due to the increase in risk factors such as obesity, which represents a true pandemic. This study aimed to evaluate microRNA (miRNA) expression in obesity‐related EC to identify potential associations between this specific cancer type and obesity. miRNA levels were analyzed in 84 EC patients stratified based on body mass index (BMI; ≥30 or <30) and nine noncancer women with obesity. The data were further tested in The Cancer Genome Atlas (TCGA) cohort, including 384 EC patients, 235 with BMI ≥30 and 149 with BMI <30. Prediction of miRNA targets and analysis of their expression were also performed to identify the potential epigenetic networks involved in obesity modulation. In the EC cohort, BMI ≥30 was significantly associated with 11 deregulated miRNAs. The topmost deregulated miRNAs were first analyzed in 84 EC samples by single miRNA assay and then tested in the TCGA dataset. This independent validation provided further confirmation about the significant difference of three miRNAs (miR‐199a‐5p, miR‐449a, miR‐449b‐5p) in normal‐weight EC patients versus EC patients with obesity, resulting significantly higher expressed in the latter. Moreover, the three miRNAs were significantly correlated with grade, histological type, and overall survival. Analysis of their target genes revealed that these miRNAs may regulate obesity‐related pathways. In conclusion, we identified specific miRNAs associated with BMI that are potentially involved in modulating obesity‐related pathways and that may provide novel implications for the clinical management of obese EC patients.

Optimal number of neoadjuvant chemotherapy cycles prior to interval debulking surgery in advanced epithelial ovarian cancer: a systematic review and meta-analysis of progression-free survival and overall survival

Neoadjuvant chemotherapy (NACT) represents a treatment option in patients with advanced epithelial ovarian cancer (AEOC) who are not good candidates for primary debulking surgery. Usually, 3 cycles of chemotherapy before surgery have been considered the best option for patient survival, although quite often some patients receive more than 3 cycles. The aim of this systematic review and meta-analysis was to identify the optimal number of NACT cycles reporting better survival in AEOC patients. PubMed, Cochrane Library, and Scopus were searched for original articles that analyzed the relationship between the number of chemotherapy cycles and clinical outcomes in AEOC patients before interval debulking surgery (IDS). The main outcomes were progression-free survival (PFS) and overall survival (OS). A total of 22 studies comprising 7,005 patients diagnosed with AEOC were included in our analysis. In terms of survival, the reviewed studies dividing the patients in ≤3 NACT cycles vs. >3, showed a trend for a decrease in PFS and a significant reduction in OS with an increasing number of cycles, while a difference in both PFS and OS was revealed if early IDS included patients with 4 NACT cycles. These results should be interpreted with caution due to the complex characteristics of AEOC patients. In conclusion, our review and meta-analysis revealed that there is not enough evidence to determine the optimal number of NACT treatments before surgery. Further research in the form of well-designed randomized controlled trials is necessary to address this issue. PROSPERO Identifier: CRD42022334959.