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Targeting m6A-Modified lncRNAs for EC Therapy

KEY TAKEAWAYS

  • The study aimed to investigate the role of m6A-modified lncRNAs in ferroptosis and cuproptosis during EC progression.
  • Researchers noted that 5 hub lncRNAs could serve as potential biomarkers for targeted therapy and prognosis in EC.

Endometrial cancer (EC) is the leading gynecological malignancy affecting the female reproductive system globally. N6-methyladenosine, along with cuproptosis- and ferroptosis-related biomarkers, plays a beneficial role in the prognosis of tumor patients.

However, the relationship between m6A-modified lncRNAs and ferroptosis, specifically copper-induced apoptosis in the initiation and progression of EC, has yet to be explored in the existing literature.

Yongkang Qian and the team aimed to employ a bioinformatics approach to identify lncRNAs that co-express with cuproptosis-, ferroptosis-, and m6A-related lncRNAs from expression data in EC. By constructing a prognosis model for EC, they screened hub lncRNA signatures that influence the prognosis of patients with EC.

Additionally, they evaluated the guiding significance of m6A-modified ferroptosis-related lncRNA (mfrlncRNA) features concerning prognosis, the immune microenvironment, and drug sensitivity.

They performed an inclusive analysis using gene expression data combined with clinical insights derived from The Cancer Genome Atlas (TCGA) collection. To develop prognostic models, five machine learning approaches were adopted, with their efficacy assessed through C-index and time-independent ROC analysis.

Prognostic indicators were identified using the LASSO Cox regression approach. Furthermore, the biological and immunological implications of the discovered lncRNA prognostic signatures were explored in patients.

About the survival analysis, the survival rate for the low-risk group was significantly higher than that for the high-risk group, as demonstrated by a significant log-rank test (P < 0.001). The LASSO Cox regression model produced concordance indices of 0.76 for the training set and 0.77 for the validation set, indicating reliable prognostic accuracy.

Enrichment analysis of gene functions associated with the identified signature predominantly with endopeptidase inhibitor activity, underscoring the signature’s potential implications. Furthermore, immune function and drug sensitivity highlighted the critical importance of early diagnosis in EC.

The study concluded that five hub lncRNAs in EC were identified through the construction of the prognosis model. These genes may serve as potential biomarkers, offering valuable references for targeted therapy and prognostic assessment of EC.

The study received no funds.

Source: https://pubmed.ncbi.nlm.nih.gov/39324703/

Qian Y, Chen H, Miao P, et al. (2024). “Integrated Identification and Immunotherapy Response Analysis of the Prognostic Signature Associated With m6A, Cuproptosis-Related, Ferroptosis-Related lncRNA in Endometrial Cancer.” Cancer Rep (Hoboken). 2024;7(9):e70009. doi:10.1002/cnr2.70009

Chemotherapy Enhances Antigen Presentation in Ovarian Cancer

KEY TAKEAWAYS

  • The study aimed to investigate how chemotherapy and tumor factors impact monocytes in patients with HGSOC.
  • Chemotherapy boosts antigen presentation in monocytes by increasing MHC class II expression, enhancing immunotherapy potential in HGSOC.

Ovarian cancer, particularly high-grade serous ovarian cancer (HGSOC), presents significant clinical challenges due to late diagnosis and high relapse rates following standard platinum-based chemotherapy. Immunotherapy offers a promising avenue for treatment, but its efficacy depends on effective antigen presentation, a crucial process for triggering cytotoxic immune responses.

Irina Larionova and the team aimed to investigate tumor-specific transcriptional and epigenetic changes in peripheral blood monocytes of patients with HGSOC and determine how chemotherapy influences these monocytes and other immune subpopulations in the blood.

Researchers performed single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) obtained from patients with HGSOC who underwent neoadjuvant chemotherapy (NACT) and treatment-naïve patients.

About 3 distinct monocyte subpopulations (CD14.Mn.S100A8.9hi, CD14.Mn.MHC2hi, and CD16.Mn) were identified based on gene expression profiles. Notably, NACT significantly impacted monocytes by transcriptionally upregulating MHC class II molecules, crucial for antigen presentation.

This upregulation was observed across all 3 monocyte subpopulations post-chemotherapy. Furthermore, chemotherapy was found to inhibit interferon-dependent signalling pathways while activating certain TGFb-related genes.

The study demonstrated that chemotherapy enhances antigen presentation in monocytes of patients with HGSOC by increasing MHC class II molecule expression. These findings suggested that chemotherapy could potentially prime the immune response in ovarian cancer, improving the efficacy of immunotherapy either as a combination therapy or a monotherapy regimen.

This work was supported by the Russian Science Foundation, grant RSF 21-75-10021 (to IL), a state contract of the Ministry of Science and Higher Education of the Russian Federation “Genetic and epigenetic editing of tumor cells and microenvironment in order to block metastasis” no. 075-15-2021-1073 (to JK), and BSMU Strategic Academic Leadership Program PRIORITY-2030 (to VP).

Source: https://pubmed.ncbi.nlm.nih.gov/39315092/

Larionova I, Iamshchikov P, Kazakova A, et al. (2024). “Platinum-based chemotherapy promotes antigen presenting potential in monocytes of patients with high-grade serous ovarian carcinoma.” Front Immunol. 2024;15:1414716. Published 2024 Sep 9. doi:10.3389/fimmu.2024.1414716

CYP7B1 Expression as a Prognostic Marker in EC

KEY TAKEAWAYS

  • The study aimed to investigate the relationship between CYP7B1 expression levels in EC tissues and patient prognosis.
  • Researchers noticed that high CYP7B1 protein expression is associated with improved OS.

Endometrial cancer (EC) is among the most common gynecological malignancies, with rising incidence rates linked to increasing obesity levels. Significant advancements have been made in the treatment of EC through immunotherapy, particularly with immune checkpoint inhibitors. Despite the expression of CYP7B1 in EC tissues, its prognostic association necessitates further investigation.

Xiao-Fang Lu and the team aimed to evaluate the relationship between CYP7B1 expression levels in EC and patient outcomes.

They performed an inclusive analysis to assess CYP7B1 protein expression in paraffin-embedded endometrial tumor sections using immunohistochemistry and image analysis software. Associations between CYP7B1 and clinical factors were evaluated with the Wilcoxon rank-sum test.

Survival was described using Kaplan-Meier curves, with differences analyzed through the log-rank test. Cox regression analysis was utilized to determine the association between CYP7B1 expression and the prognosis of patients with EC.

About 307 patients were enrolled with an average age of 52.6 ± 8.0 years at diagnosis. During the follow-up period, 46 patients (15.0%) died, and 29 (9.4%) experienced recurrence. The expression of CYP7B1 protein was found to be significantly higher in the cytoplasm than in the nucleus (P < 0.001). Patients aged < 55 years (P = 0.040), those who were ER-positive (P = 0.028), and PR-positive patients (P < 0.001) reported higher levels of CYP7B1 protein.

Both univariate (HR = 0.41, 95% CI: 0.18-0.90, P = 0.025) and multivariate (HR = 0.35, 95% CI: 0.16-0.79, P = 0.011) Cox regression analyses demonstrated that high CYP7B1 protein expression predicts longer overall survival (OS).

In the subset of ER-positive patients (n = 265), CYP7B1 protein expression showed a stronger association with OS (HR = 0.20, 95% CI: 0.08-0.52, P = 0.001). The 3-year OS and 5-year OS in the low-CYP7B1 subgroup were 81.6% and 76.8%, respectively, while in the high-CYP7B1 subgroup, these rates were 93.0% and 92.0%, respectively (P = 0.021).

The study concluded that high CYP7B1 protein expression is associated with longer OS, indicating its potential role as an important molecular marker for the prognosis of EC.

This study was funded by the National Natural Science Foundation of China.

Source: https://pubmed.ncbi.nlm.nih.gov/39289693/

Lu XF, Huang T, Chen C, et al. (2024). “Association of CYP7B1 expression with the prognosis of endometrial cancer: a retrospective study.” World J Surg Oncol. 2024;22(1):251. Published 2024 Sep 17. doi:10.1186/s12957-024-03504-4

Dose-Response Meta-Analysis of Folate Intake on EC Risk

Dose-Response Meta-Analysis of Folate Intake on EC Risk

KEY TAKEAWAYS

  • The study aimed to investigate the association between folate intake and the risk of EC through a dose-response meta-analysis.
  • Researchers noticed that increased folate intake reduces the risk of EC.

A common cancer in the female reproductive system is endometrial cancer (EC), which ranks second and third in terms of new cases and deaths among gynecological malignancies. Respectively, the folate intake and the risk of EC relation remain controversial.

Jiaye Long and the team aimed to explore the connection between folate consumption and EC, followed by a dose-response analysis.

They performed an inclusive analysis up until February 1, 2024, utilizing PubMed, EMBASE, the Cochrane Library, and Web of Science for a comprehensive literature search. Stata 14 software was employed to analyze the findings of the articles.

The study protocol was registered in PROSPERO (CRD42024505943), and the meta-analysis was conducted in accordance with PRISMA guidelines, focusing on patients with relevant data on folate intake and EC risk.

About 9 case-control studies and 6 cohort studies were included, comprising 379,570 participants and 8,660 EC cases. The highest level of folate consumption was linked to a 10% reduction in the occurrence of EC (relative risk [RR] = 0.90, 95% confidence intervals [CIs]: 0.78-1.05, I² = 63.2%) when compared to the lowest level of intake. The association demonstrated a statistically significant linear trend (P = .231), with a combined RR of 0.974 (95% CI: 0.968-0.981) for each daily intake of 50 µg folate.

The study concluded that higher folate intake may be associated with a reduced risk of EC.

No funding information was given for this source.

Source: https://pubmed.ncbi.nlm.nih.gov/39312350/

Long J, Wang D, Yang M, et al. (2024). “Folate intake and the risk of endometrial cancer: A dose-response meta-analysis. Medicine (Baltimore).” 2024;103(38):e39775. doi:10.1097/MD.0000000000039775

MINS Predicts Lymph Node Metastasis in Endometrial Cancer

KEY TAKEAWAYS

  • The study aimed to create a personalized model predicting LNM and survival in Lynch-associated cancers.
  • Researchers showed preoperative MINS was linked to LNM risk, aiding prognosis in Lynch-associated EC.

Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. Lymph node metastasis (LNM) is a significant prognostic factor in EC. Therefore, accurate prediction of LNM is crucial for treatment planning and improving patient outcomes.

Xite Lin and the team aimed to develop a personalized cancer prediction model using metabolic-inflammatory-nutritional score (MINS) to predict LNM in EC and validate its prediction of survival probability in patients with a family history of Lynch syndrome-associated cancers (LSAC).

The study included 676 patients with EC. Researchers used restricted cubic splines (RCS) analysis to determine the optimal cut-off value for MINS. The LASSO regression model aided in feature selection for constructing the MINS. Logistic regression analysis evaluated the association between MINS and LNM. Kaplan-Meier method with a log-rank test assessed the prognostic value of MINS on survival.

A nomogram, validated using the concordance index (C-index) and calibration plot, was constructed to assess the prognostic significance of MINS.

The results demonstrated that LNM risk was linked to both a family history of Lynch syndrome-associated cancers and the MINS group (all adjusted P<0.05). Individuals in the high-risk MINS group or those with a family history of LSAC had poorer overall survival (P=0.038, P=0.001, respectively). Additionally, a nomogram showed effective predictive performance with a C-index of 0.778 (95% CI: 0.725-0.832).

This research indicated that a pre-operative MINS is associated with the risk of LNM in patients with EC. A prognostic nomogram based on MINS may be an effective tool for risk stratification in clinical settings, especially among patients with EC having a family history of LSAC.

This study was funded by the National Natural Science Foundation of China (Grant number: 82203739); the National Key Research and Development Program of China (Grant number: 2022YFC2704303); the Fujian Clinical Medical Research Center for Gynecologic Oncology (Grant no. 2021Y2013); Joint Funds for the Innovation of Science and Technology, Fujian Province (Grant number: 2020Y9160); and Joint Funds for the Innovation of Science and Technology, Fujian Province (Grant number: 2021Y9157).

Source: https://pubmed.ncbi.nlm.nih.gov/39310257

Lin X, Chen T, Wang L, et al. (2024). “A metabolic-inflammatory-nutritional score (MINS) is associated with lymph node metastasis and prognostic stratification for endometrial cancer patients.” Int J Med Sci. 2024;21(12):2379-2389. Published 2024 Sep 9. doi:10.7150/ijms.96179

Enhancing EC Management With cfDNA/ctDNA Monitoring

KEY TAKEAWAYS

  • The study aimed to investigate the role of cfDNA and ctDNA monitoring in anticipating disease relapse in patients with EC.
  • Researchers noticed that cfDNA and ctDNA monitoring improve risk stratification and relapse prediction in EC.

Carlos Casas-Arozamena and the team aimed to evaluate the effectiveness of cfDNA and ctDNA monitoring in enhancing the clinical management of patients with localized and recurrent endometrial cancer (EC).

Given the increasing incidence and mortality rates associated with EC, it is crucial to refine post-surgery recurrence risk stratification and predict disease relapse and treatment resistance. Liquid biopsy analyses present a promising solution to these clinical challenges, yet the optimal application strategies for these tools in EC remain to be established.

They performed an inclusive analysis of plasma samples and uterine aspirates (UA) from 198 patients with EC collected at surgery and during follow-up. The genetic landscape of the UA was characterized using targeted sequencing, and total cfDNA was analyzed for the presence of ctDNA based on the mutational profile identified in the UA.

About high cfDNA levels and detectable ctDNA at baseline correlated with poor prognosis for disease-free survival (DFS) (P-value < 0.0001; HR = 9.25) and disease-specific survival (DSS) (P-value < 0.0001; HR = 11.20).

This correlation remained clinically significant when stratifying tumors by histopathological risk factors. Notably, cfDNA/ctDNA analyses distinguished patients with early post-surgery relapse, and ctDNA kinetics identified patients experiencing relapse before any clinical evidence became apparent.

The study concluded that this is the most comprehensive analysis of cfDNA/ctDNA characterization in EC, highlighting its effectiveness in enhancing risk stratification and predicting disease relapse in patients with localized disease.

The assessment of ctDNA kinetics complements existing strategies for monitoring disease progression and treatment response. Consequently, the implementation of cfDNA/ctDNA monitoring in clinical practice presents a unique opportunity to advance the management of EC.

The study was funded by the Instituto de Salud Carlos III (ISCIII) (PI20/00969, PI21/00990 and PI20/01566)/Co-fund by the European Union for A.G-M, M.A and L.M-R; the Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación (PID2022-136854OB-I00) for G.M-B, the CIBERONC CB16/12/00328 for L.M-R, EC, A.G-M and MA) and CB16/12/00295 for G.M-B) and the Fundación científica AECC, Proyectos de Excelencia (IN607D2021/05) for L.M-R and ERA PerMed ERA-NET cofunded by the European Union, NextGeneration-EU through ISCIII and FCAECC (AC21_2/00020) for G.M-B and L.M-R. L.M-R and EC are supported by a contract “Miguel Servet” from ISCIII (CP20/00119, CP22/00147, respectively). SO is funded by an FCAECC-postdoctoral grant (PI21/00990). C.C-A is funded by an IDIS-predoctoral grant (2020). J.R-B is supported by a Juan Rodés contract (JR21/00019) from ISCIII.

Source: https://pubmed.ncbi.nlm.nih.gov/39304963/

Casas-Arozamena C, Vilar A, Cueva J, et al. (2024). “Role of cfDNA and ctDNA to improve the risk stratification and the disease follow-up in patients with endometrial cancer: towards the clinical application.” J Exp Clin Cancer Res. 2024;43(1):264. Published 2024 Sep 20. doi:10.1186/s13046-024-03158-w

Survival Impact of R2 Resection vs. No Surgery in EOC

KEY TAKEAWAYS

  • The study aimed to compare survival outcomes between patients with advanced EOC having R2 resection and those with no surgery.
  • The primary endpoints were to determine PFS and OS.
  • Researchers noticed that despite the uniformly unfavorable prognosis, R2 resection may still offer a survival advantage over no surgery.

Cytoreductive surgery is essential for effective tumor clearance in advanced epithelial ovarian cancer (EOC). However, some patients may only achieve R2 resection (with residual tumor >1 cm), while others might not undergo any surgical intervention.

Konstantinos Pitsikakis and the team aimed to compare the outcomes between patients with advanced EOC who received R2 resection and those who did not have surgery.

They performed an inclusive analysis of retrospective data from 51 patients with R2 resection and 122 patients with no surgery. Progression-free survival (PFS) and overall survival (OS) were the primary endpoints. Principal Component Analysis and Term Frequency – Inverse Document Frequency scores were employed to differentiate and predict R>2 cm from pre-operative computed tomography reports.

No statistical significance was found, except for age (73 years in the no-surgery group vs. 67 years in the R2 group, P: .001). Principal Components analysis accounted for 34% of the data variance. Reasons for not undergoing surgery included age, co-morbidities, patient preference, refractory disease, patient deterioration or disease progression, and lack of measurable intra-abdominal disease.

The median PFS and OS were 12 and 14 months for the no-surgery group, compared to 14 and 26 months for the R2 group (P: .138 and P: .001, respectively). Serous histology and performance status independently predicted PFS in both groups.

In the no-surgery group, serous histology independently predicted OS, whereas in the R2 group, both serous histology and adjuvant chemotherapy were independent predictors of OS. The bi-grams “abdominopelvic ascites” and “solid omental” were among the most effective in distinguishing between R>2 cm and R1-2 cm.

The study concluded that both R2 resection and no-surgery cohorts exhibited unfavorable prognosis with a notable degree of uniformity. However, even when cytoreduction results in suboptimal outcomes, the survival benefit may still be higher compared to those who did not undergo surgery.

The study received no funds.

Source: https://pubmed.ncbi.nlm.nih.gov/39283489/

Pitsikakis K, DeJong D, Kitsos-Kalyvianakis K, et al. (2024). “Survival Dynamics in Advanced Ovarian Cancer: R2 Resection Versus No-Surgery Paths Explored.” Cancer Control. 2024;31:10732748241285480. doi:10.1177/10732748241285480

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