Wenjun Cheng

Chemotherapy‐Induced Myelosuppression in Patients With gBRCA ‐m Epithelial Ovarian Cancer: A Retrospective Study

ABSTRACT Background Existing evidence indicates that germline BRCA mutation (gBRCA‐m) may increase chemotherapy sensitivity and toxicity. However, its role in chemotherapy‐induced myelosuppression (CIM) remains unclear. We conducted this study to investigate the influence of gBRCA‐m on CIM incidence and severity in patients with epithelial ovarian carcinoma (EOC). Methods Patients with EOC treated at the First Affiliated Hospital of Nanjing Medical University from January 2018 to August 2023 were classified into two groups: gBRCA‐m and gBRCA wild‐type. Chemotherapy regimen and myelosuppression data were retrospectively reviewed. Multivariate analysis assessed the association between gBRCA‐m and CIM incidence and severity in patients with EOC receiving first‐line chemotherapy. Results Sixty six (27%) of 242 included patients were gBRCA‐m carriers. The median times to myelosuppression onset and the most severe occurrence were significantly shorter for patients with gBRCA‐m (6.0 vs. 27.0 days, p  < 0.001; 73.5 vs. 121.0 days, p  < 0.001). Patients with gBRCA‐m had a greater likelihood of Grade IV (GIV) myelosuppression at onset (aOR = 5.585, 95% CI = 1.621–19.241). During the most severe myelosuppression, patients with gBRCA‐m experienced more pronounced decreases in white blood cells (1.83 × 10 9 vs. 2.33*10 9  cells/L, p  = 0.002), neutrophils (0.73 × 10 9 vs. 1.08 × 10 9  cells/L, p  = 0.001), haemoglobin levels (90.41 vs. 94.14 g/L, p  = 0.017) and platelets (81.62 × 10 9 vs. 97.63 × 10 9  cells/L, p  = 0.001) and were more prone to febrile GIV myelosuppression (aOR = 2.882, 95% CI = 1.071–7.754). The incidences of chemotherapy dose reduction (aOR = 4.322, 95% CI = 2.048–9.124) and delay (aOR = 6.045, 95% CI = 2.266–16.126) were significantly greater in patients with gBRCA‐m. An analysis across all chemotherapy cycles indicated that patients with gBRCA‐m had greater risks of GIII (aOR = 2.356, 95% CI = 1.770–3.137), GIV (aOR = 2.324, 95% CI = 1.685–3.207) myelosuppression and GIV myelosuppression with fever (aOR = 2.097, 95% CI = 1.077–4.083), as well as a greater incidence of chemotherapy dose reduction (aOR = 2.606, 95% CI = 1.785–3.805) and delay (aOR = 4.118, 95% CI = 2.213–7.663). Conclusions EOC patients with gBRCA‐m experienced earlier and more severe CIM, highlighting the need for careful monitoring and tailored management.

Preoperative hysteroscopy shortened progression‐free survival in advanced FIGO stage in endometrial cancer: Ten year analysis

AbstractObjectiveTo investigate the impact of preoperative hysteroscopy on progression‐free survival (PFS) and disease‐specific survival (DFS), and to explore the factors which contribute to poor clinical outcomes between hysteroscopy and dilation and curettage (D&C) in endometrial cancer (EC).MethodsA retrospective study was designed by collecting data from women diagnosed with EC through hysteroscopy or D&C from January 2010 to December 2019 in a tertiary hospital in China. A propensity score was used for 1:1 matching of advanced stage patients. Univariate and multivariate analysis were conducted to determine whether hysteroscopy was a prognostic factor in EC and to identify factors associated with its impact on PFS and DFS in different subgroups.ResultsOverall, 543 and 272 women who underwent D&C and hysteroscopy, respectively were included. Compared to D&C, preoperative hysteroscopy was related to reduced PFS and DFS, with a hazard ratio (HR) of 1.904 and 3.905, respectively. Hysteroscopy contributed to an increased risk of positive wash cytology (48.27% vs 24.13%), recurrence (48.28% vs 20.69%) and shorter PFS after matching in FIGO Stage I–IV EC, while there was no significance in positive ascites cytology (14.04% vs 13.45%), PFS and DFS in FIGO Stage I EC.ConclusionsHysteroscopy was an independent predictive factor for poor prognosis in EC. Hysteroscopy appeared to be a safe diagnostic method as D&C in FIGO Stage I EC but was a risk factor for increased recurrence and reduced PFS in advanced stage disease. Its impact on DFS is uncertain.

Identification of aberrantly methylated differentially expressed genes and associated pathways in endometrial cancer using integrated bioinformatic analysis

AbstractEndometrial cancer (EC) is a fatal female reproductive tumor. Bioinformatic tools are increasingly developed to screen out molecular targets related to EC. In this study, GSE17025 and GSE40032 were obtained from Gene Expression Omnibus (GEO). “limma” package and Venn diagram tool were used to identify hub genes. FunRich was used for functional analysis. Retrieval of Interacting Genes Database (STRING) was used to analyze protein‐protein interaction (PPI) complex. Cancer Genome Atlas (TCGA), GEPIA, immunohistochemistry staining, and ROC curve analysis were carried out for validation. Univariate and multivariate regression analyses were performed to predict the risk score. Compound muscle action potential (CMap) was used to find potential drugs. GSEA was also done. We retrieved seven oncogenes which were upregulated and hypomethylated and 12 tumor suppressor genes (TSGs) which were downregulated and hypermethylated. The upregulated and hypomethylated genes were strikingly enriched in term “immune response” while the downregulated and hypermethylated genes were mainly focused on term “aromatic compound catabolic process.” TCGA and GEPIA were used to screen out EDNRB, CDO1, NDN, PLCD1, ROR2, ESPL1, PRAME, and PTTG1. Among them, ESPL1 and ROR2 were identified by Cox regression analysis and were used to construct prognostic risk model. The result showed that ESPL1 was a negative independent prognostic factor. Cmap identified aminoglutethimide, luteolin, sulfadimethoxine, and maprotiline had correlation with EC. GSEA results showed that “hedgehog signaling pathway” was enriched. This research inferred potential aberrantly methylated DEGs and dysregulated pathways may participate in EC development and firstly reported eight hub genes, including EDNRB, CDO1, NDN, PLCD1, ROR2, ESPL1, PRAME, and PTTG1 that could be used to predict EC prognosis. Aminoglutethimide and luteolin may be used to fight against EC.

IL7R remodels immunosuppression tumor microenvironment and promotes macrophage polarization by regulating NF-κB/CXCL1 axis in ovarian cancer

Abstract In the ovarian cancer microenvironment, the polarization of tumor-associated macrophages (TAMs) is closely associated with immunosuppressive phenotypes. Although elevated levels of circulating interleukin-7 (IL-7) have been linked to a poor prognosis, the regulatory mechanisms underlying this association remain incompletely understood. This study demonstrated that increased IL7R expression in ovarian cancer is correlated with the polarization of CD206 + macrophages, the remodeling of the immunosuppressive microenvironment, and unfavorable patient prognosis. By employing 3D bioprinted co-culture systems and mouse models, we showed that the knockdown or knockout of IL7R inhibits tumor progression and intraperitoneal dissemination. Mechanistically, IL7R signaling promotes the polarization of macrophages toward an immunosuppressive phenotype through the NF-κB/CXCL1 axis. This is supported by the upregulated expression of Arg1 and IL-10, as well as the downregulated expression of pro-inflammatory markers. These polarized macrophages further enhance tumor cell proliferation and invasion, thereby forming a tumor-immune feedback loop. In conclusion, this study clarifies how IL7R signaling mediates crosstalk between ovarian cancer cells and macrophages to maintain the homeostasis of the immunosuppressive tumor microenvironment (TME).

Causal effect between breast cancer and ovarian cancer: a two-sample mendelian randomization study

Improved breast cancer (BC) outcomes highlight the importance of secondary primary cancers (SPCs) on survivor prognosis. The objective of this study was to investigate the potential genetic association between primary BC and ovarian cancer (OC), laying the groundwork for the development of preventive strategies for SPC-OC following BC surgery. This study aimed to assess the connection between BC and OC using a two sample Mendelian randomization (MR) approach, exclusively employing aggregate level data from publicly available genome wide association studies (GWASs). Finally, the Genetic Risk Scores (GRS) method was used for secondary analysis to verify the results robustness further. The IVW method revealed a genetic correlation between Overall BC and ER + BC with Serous borderline tumors, while ER-BC exhibited genetic correlation with Mucinous borderline tumors and high-grade serous ovarian cancer. The findings from the GRS method aligned with those of the primary analysis, reinforcing the study's robustness. Our MR Study identifies an association between BC and OC, highlighting the importance of increased vigilance in clinical practice for individuals with a history of BC. Timely intervention and treatment measures should be taken when necessary.

FSP1 inhibition enhances olaparib sensitivity in BRCA-proficient ovarian cancer patients via a nonferroptosis mechanism

AbstractPoly ADP-ribose polymerase inhibitors (PARPis) exhibit promising efficacy in patients with BRCA mutations or homologous repair deficiency (HRD) in ovarian cancer (OC). However, less than 40% of patients have HRD, it is vital to expand the indications for PARPis in BRCA-proficient patients. Ferroptosis suppressor protein 1 (FSP1) is a key protein in a newly identified ferroptosis-protective mechanism that occurs in parallel with the GPX4-mediated pathway and is associated with chemoresistance in several cancers. Herein, FSP1 is reported to be negatively correlated with the prognosis in OC patients. Combination therapy comprising olaparib and iFSP1 (a FSP1 inhibitor) strongly inhibited tumour proliferation in BRCA-proficient OC cell lines, patient-derived organoids (PDOs) and xenograft mouse models. Surprisingly, the synergistic killing effect could not be reversed by ferroptosis inhibitors, indicating that mechanisms other than ferroptosis were responsible for the synergistic lethality. In addition, cotreatment was shown to induce increased γH2A.X foci and to impair nonhomologous end joining (NHEJ) activity to a greater extent than did any single drug. Mass spectrometry and immunoprecipitation analyses revealed that FSP1 interacted with Ku70, a classical component recruited to and occupying the end of double-strand breaks (DSBs) in the NHEJ process. FSP1 inhibition decreased Ku70 PARylation, impaired subsequent DNA-PKcs recruitment to the Ku complex at DSB sites and was rescued by restoring PARylation. These findings unprecedentedly reveal a novel role of FSP1 in DNA damage repair and provide new insights into how to sensitize OC patients to PARPi treatment.

Comparative prognosis analysis of ovarian squamous cell carcinoma versus serous carcinoma: Insights from the SEER database

Abstract Objective The aim of this study was to identify survival rates and potential prognostic factors of ovarian squamous cell carcinoma (OSCC), offering valuable insights for clinical decision making. Methods Leveraging the Surveillance, Epidemiology, and End Results (SEER) database, we selected 11 078 serous carcinoma (SC) patients and 198 OSCC patients based on predetermined criteria diagnosed from 2000 to 2020. We compared the overall survival (OS) and cancer‐specific survival (CSS) before and after propensity score matching (PSM) in two groups. Prognostic differences were also compared between OSCC and SC groups at different stages. Univariate and multivariate Cox regression analyses were performed to investigate the impact of clinical and pathologic variables on the survival of patients with OSCC. Finally, we developed and validated a nomogram predictive model. Results OSCC tumors exhibited distinct characteristics, being relatively larger, more frequently unilateral, and better differentiated than SC tumors. After PSM, Kaplan–Meier analysis revealed significantly lower survival rates for OSCC patients in Stages IIB–IV, while Stages IA–IC displayed comparable survival. Independent risk factors for OSCC patients included advanced age, single marital status, higher tumor stage, and increased tumor size. Conversely, higher median household income and chemotherapy emerged as independent protective factors. Our predictive model and nomogram accurately forecasted patient survival rates in both SEER and internal validation datasets. Conclusion OSCC patients face significantly poorer prognosis than their SC counterparts, except in the very early stages. Higher median household income was associated with better OSCC survival.

The serum LDH level and KELIM scores are potential predictors of a benefit from bevacizumab first-line therapy for patients with advanced ovarian cancer

The survival benefit of first-line treatment with bevacizumab in advanced ovarian cancer patients are multifaceted. In our study, we aimed to identify potential markers of bevacizumab efficacy to help predict which patients would experience survival benefits. This was a retrospective analysis of 114 patients examined from January 1, 2015, to March 1, 2023, and data on clinical, biological, and imaging variables, such as ascites, serum LDH, and CA125, were extracted from electronic medical records. We performed a correlation analysis and principal component analysis to investigate correlations among variables and reduce their dimensionality. Then, univariate and multivariate Cox proportional hazards regression analyses were used to identify the predictors of progression-free survival. Favorable KELIM score (≥ 1, HR 0.376, 95% CI [0.202-0.700], p = 0.002), which indicated better chemosensitivity, and lower LDH levels (≤ 210 U/L, HR 38.73, 95% CI [6.108-245.6], p < 0.001) were found to be independent predictors of a treatment benefit with bevacizumab in patients with advanced ovarian cancer. Regardless of LDH level, patients with favorable KELIM scores had a higher progression-free survival (PFS) benefit (p = 0.18). Among patients with unfavorable KELIM scores, those with higher LDH levels had the lowest PFS benefit (median: 11.5 months, p = 0.0059). Patients with poor chemosensitivity and low LDH levels are more likely to benefit from first-line bevacizumab treatment. The combination of the two markers can be a helpful predictor of patients who are most likely to benefit from treatment and a guide for treatment decisions-making. Retrospectively registered: 2020-MD-371, 2020.10.12.

YBX1 promotes homologous recombination and resistance to platinum-induced stress in ovarian cancer by recognizing m5C modification

Platinum-based chemotherapy causes genetic damage and induces apoptosis in ovarian cancer cells. Enhancing the ability to resist platinum drug-induced DNA damage and apoptotic stress is critical for tumor cells to acquire drug resistance. Here, we found that Y-box binding protein 1 (YBX1) was highly expressed in cisplatin-resistant patient-derived organoids (PDOs) and was a crucial gene for alleviating platinum-induced stress and maintaining drug resistance characteristics in ovarian cancer cells. Mechanistically, YBX1 recognized m5C modifications in CHD3 mRNA and maintained mRNA stability by recruiting PABPC1 protein. This regulatory process enhanced chromatin accessibility and improved the efficiency of homologous recombination (HR) repair, facilitating tumor cells to withstand platinum-induced apoptotic stress. In addition, SU056, an inhibitor of YBX1, exhibited the potential to reverse platinum resistance in subcutaneous and PDO orthotopic xenograft models. In conclusion, YBX1 is critical for ovarian cancer cells to alleviate the platinum-induced stress and may be a potential target for reversing drug-resistant therapies.

The Gustave Roussy immune score as a novel scoring system for predicting platinum resistance in advanced high-grade serous ovarian cancer

This study was designed to investigate the relationship between the Gustave-Roussy immune score (GRIm-score) and platinum resistance in patients with advanced high-grade serous ovarian cancer (HGSOC). We conducted a retrospective study of patients diagnosed with advanced HGSOC between January 2017 and December 2020. A nomogram was developed to predict the risk of platinum resistance. Receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) were used to validate the nomogram. Bootstrap analysis was utilized for internal validation. Additionally, we analyzed the risk factors for platinum resistance in patients who received neoadjuvant chemotherapy (NACT). A total of 232 patients with advanced HGSOC were included, 52 (22.4 %) of whom experienced relapse with platinum resistance. Multivariate logistic regression analysis revealed that high GRIm-score (OR = 4.174, P  260 (OR = 2.233, P = 0.037) and non-R0 (OR = 2.526, P = 0.012) were independent risk factors for platinum resistance. The area under the curve (AUC) of the model was 0.802 (95 % CI 0.736-0.868), and the internally validated AUC of 1000 bootstrap samples was 0.798 (95 % CI 0.725-0.862). In NACT-treated patients, univariate and multivariate logistic regression analyses revealed that a low KELIM score (OR = 10.405, P = 0.001) and PLT > 260 (OR = 4.611, P = 0.014) were independent risk factors for platinum resistance. The GRIm-score and PLT count are important prognostic factors in patients with HGSOC. For precision treatment, the status of partially platinum-sensitive patients should also be considered.

Identification of prognostic factors and construction of nomogram to predict cancer‐specific survival for patients with ovarian granulosa cell tumors

AbstractBackgroundOvarian granulosa cell tumors (OGCTs) feature low incidence, indolent growth and late recurrence. Treatment for recurrent OGCTs is challenging.MethodsThe present study was designed to explore the prognostic factors and establish a nomogram to predict cancer‐specific survival (CSS) for OGCTs patients. Enrolled in the study were 1459 eligible patients in the Surveillance, Epidemiology, and End Results (SEER) database, who were randomized to the training (n = 1021) or testing set (n = 438) at a ratio of 7:3. Univariate and multivariate Cox regression analyses were employed to screen the prognostic factors. The predictors were determined by using the Least absolute shrinkage and selection operator (LASSO) regression analysis. The model was constructed via the Cox proportional hazards risk regression analysis. The performance and clinical value of the nomograms was assessed with C‐index, calibration plots, and decision curve analysis.ResultsAge, pTNM stage, tumor size, surgery of the primary tumor, surgery of regional lymph nodes (LNs), residual disease after surgery, and chemotherapy were considered as significant predictive factors for CSS in OGCTs patients. After screening, the prognostic factors except surgery of regional LNs and chemotherapy were employed to build the nomogram. With desirable discrimination and calibration, the nomogram was more powerful in predicting CSS than the American Joint Committee on Cancer staging system in clinical use.ConclusionThis novel prognostic nomogram, which comprises a stationary nomogram and a web‐based calculator, offers convenience for clinicians in personalized decision‐making including optimal treatment plans and prognosis assessments for OGCTs patients.

Visceral obesity determined by CT as a predictor of short-term postoperative complications in patients with ovarian cancer

To explore the association between visceral obesity and short-term postoperative complications in patients with advanced ovarian cancer undergoing cytoreductive surgery. The medical records of patients with advanced epithelial ovarian cancer were reviewed. The visceral fat area, subcutaneous fat area and total fat area at the L3/4 level were measured on a preoperative single-slice CT scan. The receiver operating characteristic (ROC) curve was used to calculate the optimal cutoff value for the visceral fat area. The relationship between the visceral fat area and the characteristics of ovarian cancer patients were analyzed. Univariable and multivariable logistic regression analyses were performed to investigate relationship between perioperative characteristics and short-term complications. According to the ROC curve, the best cutoff value of the VFA was 93 cm Visceral obesity is an important risk factor for short-term postoperative complications in patients with advanced ovarian cancer undergoing cytoreductive surgery.

CT-based radiomics nomogram analysis for assessing BRCA mutation status in patients with high-grade serous ovarian cancer

Background Radiomics nomogram analysis is widely preoperatively used to assess gene mutations in various tumors. Purpose To explore the value of computed tomography (CT)-based radiomics nomogram analysis for assessing BRCA gene mutation status of patients with high-grade serous ovarian cancer (HGSOC). Material and Methods In total, 96 patients with HGSOC were retrospectively screened and randomly divided into primary (n = 68) and validation cohorts (n = 28). The clinical model was constructed based on clinical features and CT morphological features using univariate and multivariate logistic analyses. Maximum-relevance and minimum-redundancy (mRMR) and least absolute shrinkage and selection operator (LASSO) were performed for feature dimensionality reduction and radiomics score was calculated. The nomogram model combining the clinical model and the radiomics score was constructed using multivariate logistic regression. Receiver operating characteristic (ROC) curves were generated to assess models’ performance. The calibration analysis and decision curve analysis (DCA) were also performed. Results The clinical model consisted of CA125 level and supradiaphragmatic lymphadenopathy and yielded an area under the curve (AUC) of 0.69 (primary cohort) and 0.81 (validation cohort). The radiomics model was built with seven selected features and showed an AUC of 0.87 (primary cohort) and 0.81 (validation cohort). The nomogram finally showed the highest AUC of 0.89 (primary cohort) and 0.87 (validation cohort). The nomogram presented favorable calibrations in both the primary and validation cohorts. DCA further confirmed the clinical benefits of the constructed nomogram. Conclusion CT-based radiomics nomogram provides a non-invasive method to discriminate BRCA gene mutation status of HGSOC and potentially helps develop precise medical strategies.

Analysis of adverse events and quality of life in high-grade serous ovarian cancer patients with Olaparib maintenance therapy: A single-center study in China

Olaparib showed good efficacy and tolerability in the maintenance treatment of patients with initial therapy or high-grade serous recurrent ovarian cancer patients. This study aimed to analyze adverse events (AEs) of patients taking Olaparib and the quality of life (QoL) with Olaparib in 1 center of China. The study included 98 patients who received Olaparib and 210 patients without Olaparib from July 2018 to October 2021 for high-grade serous ovarian cancer in the Gynecology Oncology Department of Jiangsu Provincial Hospital. Information of clinicopathologic characteristics was collected from medical records. Then, we used the QLQ-C30 and Quality of Life Ovarian Cancer 28 Questionnaire (QLQ-OV28) to determine the QoL of 98 patients with and 210 patients without Olaparib. Among all 98 patients with Olaparib, 66 patients in first-line and 32 patients in more than second-line treatment. Regarding the best objective response with Olaparib maintenance in 78 patients with partial remission from most recent chemotherapy, 3 (3.84%) patients showed complete response (CR) and 6 (7.69%) showed as partial response (PR), whereas stable disease was observed in 42 patients (53.84%) and 27 patients (34.6%) showed as progression disease. AEs of Grade 3 and more were: anemia in 16 patients (16.32%), neutropenia in 20 patients (20.40%), thrombocytopenia in 4 patients (4.08%), and headache in 4 patients (4.08%). Dose reduction and drug discontinuation accounted for 73.40% and 20.40%, respectively. Olaparib as maintenance therapy increased QoL on all functioning domains and several symptom domains. Consistent with previous clinical trials, Olaparib maintenance therapy was proved safe and effective. Most patients may experience Grade 1 and 2 AEs. Olaparib maintenance therapy can increase QoL in several domains.

Ovarian clear cell cancer associated with Trousseau syndrome: A case report and literature review

Rationale: Trousseau syndrome is known as patients with tumors have a combination of multiple thrombi with systemic organ infarction. The incidence of ovarian clear cell cancer associated with Trousseau syndrome is relatively low. We report the case of a 41-year-old woman diagnosed with ovarian clear cell cancer with deep vein thrombosis and cerebral infarction who had a poor prognosis. Patient concerns: A 41-year-old woman was brought to our hospital with abdominal pain. Abdominal computerized tomography scan suggested large mass of ovarian origin which was considered an ovarian tumor with pelvic metastasis and peritoneal metastasis. Laboratory analyses indicated an elevated levels of serum tumor marker carbohydrate antigen 125 was 321.9 U/mL and the level of D-dimer was 16.71 mg/L. Diagnosis: The patient underwent pelvic mass aspiration was diagnosed with ovarian clear cell cancer. B-ultrasound revealed thrombosis of the lower limbs. Interventions: She underwent 2 neoadjuvant chemotherapies, along with anticoagulation therapy. However, it had a poor therapeutic effect, and the patient suffered from acute cerebral infarction that worsened. Outcomes: Chemotherapy and anticoagulation failed to stop the tumor and blood clot progression. The patient died 2 months after cerebral infarction without surgical treatment. Lessons: Gynecologists should be aware of the need for clinical suspicion of the risk of thrombosis during the treatment period of ovarian cancer and make careful decisions

Bractoppin, a BRCA1 carboxy-terminal domain (BRCT) inhibitor, suppresses tumor progression in ovarian borderline tumor organoids

Borderline ovarian tumors are a special class of ovarian tumors between benign and malignant, which are not sensitive to traditional chemotherapy regimens, and the development of target drugs is limited due to the lack of cell lines. Tumor organoids can well preserve the genetic characteristics of the primary tumor, but there are only a few reports of application in borderline tumors. In this study, we successfully generated 13 ovarian borderline tumor organoids and tested the antitumor activity of Bractoppin, a BRCA1 carboxy-terminal domain (BRCT) inhibitor. Bractoppin promotes organoid apoptosis. Mechanistically, Bractoppin can inhibit organoid cell cycle progression, inhibit the repair of DSB damage and promote tumor cell apoptosis. In addition, Bractoppin can also promote the apoptosis of ovarian cancer cell lines and inhibit the HR and NHEJ repair ability of tumor cells. We demonstrate the value of ovarian borderline tumor organoids in the exploration of molecular therapy drugs, and Bractoppin may be a valuable small molecule drug in the treatment of BOT.

Multiomics profiling and experiments in preclinical models revealed RAD51-IN-1 as a synergistic potentiator of anlotinib sensitivity

Anlotinib has demonstrated preliminary efficacy as a first-line maintenance therapy for ovarian cancer. However, clinical responses vary widely. To investigate resistance mechanisms and explore rational combinations, pretreatment tumors from 18 patients in clinical trial NCT04807166 underwent whole-exome and RNA sequencing and stratified into sensitive and resistant groups based on progression-free survival. VEGFR-related mutations were enriched in sensitive tumors, whereas resistant tumors showed increased activity of DNA repair pathways and Notch signaling. In vitro screening identified strong synergy between anlotinib and the RAD51 inhibitor RAD51-IN-1, which outperformed the Notch inhibitor FLI-06 in resistant patient-derived organoids. Mechanistic studies revealed that RAD51 inhibition was associated with impaired HRR and increased sensitivity to anlotinib. In vivo, combined treatment with anlotinib and RAD51-IN-1 significantly reduced tumor burden without notable toxicity. These findings suggest that RAD51-mediated HRR may contribute to anlotinib resistance and support RAD51 inhibition as a promising approach to overcome therapeutic resistance in ovarian cancer.