Qin Xu

Early detection of uterine corpus endometrial carcinoma utilizing plasma cfDNA fragmentomics

Abstract Background Uterine corpus endometrial carcinoma (UCEC) is a prevalent gynecologic malignancy with a favorable prognosis if detected early. However, there is a lack of accurate and reliable early detection tests for UCEC. This study aims to develop a precise and non-invasive diagnostic method for UCEC using circulating cell-free DNA (cfDNA) fragmentomics. Methods Peripheral blood samples were collected from all participants, and cfDNA was extracted for analysis. Low-coverage whole-genome sequencing was performed to obtain cfDNA fragmentomics data. A robust machine learning model was developed using these features to differentiate between UCEC and healthy conditions. Results The cfDNA fragmentomics-based model showed high predictive power for UCEC detection in training (n = 133; AUC 0.991) and validation cohorts (n = 89; AUC 0.994). The model manifested a specificity of 95.5% and a sensitivity of 98.5% in the training cohort, and a specificity of 95.5% and a sensitivity of 97.8% in the validation cohort. Physiological variables and preanalytical procedures had no significant impact on the classifier’s outcomes. In terms of clinical benefit, our model would identify 99% of Chinese UCEC patients at stage I, compared to 21% under standard care, potentially raising the 5-year survival rate from 84 to 95%. Conclusion This study presents a novel approach for the early detection of UCEC using cfDNA fragmentomics and machine learning showing promising sensitivity and specificity. Using this model in clinical practice could significantly improve UCEC management and control, enabling early intervention and better patient outcomes. Further optimization and validation of this approach are warranted to establish its clinical utility.

Molecular and Immune Correlates of Response to First-Line De-escalated Chemotherapy plus Penpulimab and Anlotinib in Advanced Cervical Cancer

Abstract The standard of care for advanced cervical cancer includes chemotherapy, antiangiogenic, and/or immune checkpoint blockade regimens. Although effective, it leads to pleiotropic side effects. Deescalation chemotherapy together with immunotargeted therapies has been proven effective and less toxic in other cancers. In this study, we conducted a multicenter, single-arm, phase II study of first-line deescalated platinum-based chemotherapy plus anlotinib and penpulimab, followed by maintenance therapy solely with anlotinib and penpulimab in patients with PD-L1–positive, persistent, recurrent, or metastatic cervical cancer. Of 32 efficacy-evaluable patients, 30 (93.8%, 95% confidence interval, 79.2%–99.2%) had an investigator-confirmed objective response. Single-nucleus RNA sequencing implied enhanced chemotaxis and proliferative activity of tumor-infiltrating T cells, and activated germinal center B cells portended optimal treatment response. Patients with a high tertiary lymphoid structure-to-tumor area ratio exhibited better survival. Our findings lay the groundwork for the feasibility of first-line de-escalated chemotherapy plus anlotinib and penpulimab in patients with metastatic, persistent, or recurrent cervical cancer. Significance: We recruited 34 patients with advanced cervical cancer receiving two cycles of platinum-based chemotherapy plus anlotinib and penpulimab, followed by maintenance therapy solely with anlotinib and penpulimab, and showed safety and efficacy of this deescalation regimen. This work highlights the potential for personalized treatment strategies and feasibility of reduced-toxicity regimens.

Comprehensive clinical analysis of gastric-type endocervical adenocarcinoma: a real-world multicenter study

Gastric-type endocervical adenocarcinoma (G-EAC) is a rare malignancy, and its clinicopathological characteristics remain poorly defined. This study aimed to evaluate the real-world features, treatment patterns, and outcomes of patients with G-EAC. Clinical data from 124 patients diagnosed with G-EAC between 2012 and 2024 across four tertiary hospitals in China were retrospectively analyzed. Clinicopathological features, therapeutic approaches, and survival outcomes were assessed. Overall survival (OS) was the primary endpoint. Kaplan-Meier and Cox regression analyses were performed to identify prognostic factors. The median diagnostic age was 55 years (range, 33-82). At presentation, 62.1% of patients had invasion or metastasis, most commonly lymphovascular (47.6%). Surgery was performed in 81.5% of cases, and 84.7% received chemotherapy, primarily platinum-based (81.5%). Radiotherapy was administered to 69.4%. The 1-, 3-, and 5-year OS rates were 78.6%, 54.8%, and 46.1%, respectively. Older age (≥65 years; HR, 4.71; 95% CI, 1.52-14.58; G-EAC exhibits aggressive behavior and unfavorable prognosis, with a 5-year OS of 46.1%. Multimodal treatment, particularly surgery combined with chemotherapy, remains the cornerstone of management and may improve survival. Prospective multicenter studies are warranted to further define optimal therapeutic strategies for this rare entity.

Prognostic Differences and Survival Predictive Models for Mucinous Versus Usual‐Type Adenocarcinoma of the Uterine Cervix

ABSTRACT Background There is significant histological heterogeneity between the endocervical adenocarcinoma (EA) subtypes. Usual‐type carcinoma (adenocarcinoma) and mucinous carcinoma (mucinous adenocarcinoma, MA) are the most common types of EA. Methods Demographic and clinical variables were collected from the SEER database for selected patients between 2004 and 2021. The effect of confounding variables was reduced by propensity score matching (PSM). Survival data were analyzed using the Kaplan–Meier method and Cox regression models. A risk prediction model nomogram for MA was developed and validated. Results The median age for MA patients was 46 years compared to 45 years for adenocarcinoma ( p  = 0.021). The 1‐, 3‐, and 5‐year overall survival (OS) rates for MA were 88.2%, 74.5%, and 68.4%, respectively, significantly lower than those for adenocarcinoma (89.0%, 79.0%, and 74.9%, p  < 0.0001). Cancer‐specific survival (CSS) showed a similar trend ( p  < 0.0001). Seven variables, including age, primary site, T, N, combined stage, surgery, and chemotherapy, were selected to create the nomograms for predicting OS, while age, primary site, tumor size, T, N, combined stage, and surgery were selected for CSS. The validations of all predictive models were satisfactory. Conclusion This study revealed MA's poorer prognosis compared to adenocarcinoma using the SEER database. It developed predictive models for OS and CSS of MA, offering a more accurate prognosis assessment tool for clinical practice.

Efficacy and Safety of the Anti–PD-L1 mAb Socazolimab for Recurrent or Metastatic Cervical Cancer: a Phase I Dose-Escalation and Expansion Study

Abstract Purpose: This study (ClinicalTrials.gov identifier, NCT03676959) is an open, phase I dose-escalation and expansion study investigating the safety and efficacy of the recombinant, fully human anti–programmed death ligand 1 (PD-L1) mAb socazolimab in patients diagnosed with recurrent or metastatic cervical cancer. Patients and Methods: Patients received socazolimab every 2 weeks until disease progression. The study was divided into a dose-escalation phase and a dose-expansion phase. Safety and tolerability were primary endpoints of the dose-escalation phase. The primary endpoints of the dose-expansion phase were safety and the objective response rate (ORR) of the 5 mg/kg dose. Efficacy was assessed by the third-party independent review committee (IRC) using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Results: 104 patients were successfully enrolled into the study. Twelve patients were included in the dose-escalation phase, with one complete response and two partial responses in the 5 mg/kg treatment group. Ninety-two patients (5 mg/kg) were enrolled in the dose-expansion phase. Fifty-four patients (59.3%) had baseline PD-L1–positive tumor expression (combined positive score ≥1). ORR was 15.4% [95% confidence interval (CI), 8.7%–24.5%]. Median PFS was 4.44 months (95% CI, 2.37–5.75 months), and the median OS was 14.72 months (95% CI, 9.59–NE months). ORR of PD-L1–positive patients was 16.7%, and the ORR of PD-L1–negative patients was 17.9%. No treatment-related deaths occurred. Conclusions: Our study demonstrates that socazolimab has durable safety and efficacy for the treatment of recurrent or metastatic cervical cancer and exhibits a safety profile similar to other anti–PD-1/PD-L1 mAbs.

N6-methyladenosine modification of CENPK mRNA by ZC3H13 promotes cervical cancer stemness and chemoresistance

Abstract Background Stemness and chemoresistance contribute to cervical cancer recurrence and metastasis. In the current study, we determined the relevant players and role of N 6 -methyladenine (m 6 A) RNA methylation in cervical cancer progression. Methods The roles of m 6 A RNA methylation and centromere protein K (CENPK) in cervical cancer were analyzed using bioinformatics analysis. Methylated RNA immunoprecipitation was adopted to detect m 6 A modification of CENPK mRNA. Human cervical cancer clinical samples, cell lines, and xenografts were used for analyzing gene expression and function. Immunofluorescence staining and the tumorsphere formation, clonogenic, MTT, and EdU assays were performed to determine cell stemness, chemoresistance, migration, invasion, and proliferation in HeLa and SiHa cells, respectively. Western blot analysis, co-immunoprecipitation, chromatin immunoprecipitation, and luciferase reporter, cycloheximide chase, and cell fractionation assays were performed to elucidate the underlying mechanism. Results Bioinformatics analysis of public cancer datasets revealed firm links between m 6 A modification patterns and cervical cancer prognosis, especially through ZC3H13-mediated m 6 A modification of CENPK mRNA. CENPK expression was elevated in cervical cancer, associated with cancer recurrence, and independently predicts poor patient prognosis [hazard ratio = 1.413, 95% confidence interval = 1.078 − 1.853, P  = 0.012]. Silencing of CENPK prolonged the overall survival time of cervical cancer-bearing mice and improved the response of cervical cancer tumors to chemotherapy in vivo ( P  < 0.001). We also showed that CENPK was directly bound to SOX6 and disrupted the interactions of CENPK with β-catenin, which promoted β-catenin expression and nuclear translocation, facilitated p53 ubiquitination, and led to activation of Wnt/β-catenin signaling, but suppression of the p53 pathway. This dysregulation ultimately enhanced the tumorigenic pathways required for cell stemness, DNA damage repair pathways necessary for cisplatin/carboplatin resistance, epithelial-mesenchymal transition involved in metastasis, and DNA replication that drove tumor cell proliferation. Conclusions CENPK was shown to have an oncogenic role in cervical cancer and can thus serve as a prognostic indicator and novel target for cervical cancer treatment.

A Clinical Study of PD-L1 Antibody ZKAB001（Drug Code） in Recurrent or Metastatic Cervical Cancer

This is a Phase 1, open-label, dose-escalation, and multidose study, aiming to investigate the safety, tolerability and pharmacokinetics(PK) of ZKAB001 (a fully human monoclonal antibody targeting the Programmed Death - Ligand 1 (PD-L1) membrane receptor on T lymphocytes and other cells of the immune system) administered every 14 days in subjects with recurrent or metastatic cervical cancer.