Anlotinib in patients with recurrent platinum resistant/refractory ovarian cancer: a prospective, single arm, phase II study.

OBJECTIVE: This study aimed to prospectively evaluate the efficacy and safety of anlotinib in patients with platinum resistant/refractory ovarian cancer. METHODS: In this prospective, single arm, phase II study, patients with platinum resistant/refractory ovarian cancer received anlotinib (12 mg once daily; days 1-14; 21 days per cycle) until disease progression, unacceptable toxicity, or study withdrawal. The study was conducted between May 2019 and May 2021. The primary endpoint was objective response rate. Secondary endpoints were disease control rate, progression free survival, overall survival, and safety. An exploratory biomarker analysis was performed to evaluate the correlation of baseline TP53 mutation status with outcomes. RESULTS: 33 of 34 enrolled patients received at least one dose of anlotinib. The objective response rate was 31.2% (95% confidence interval (CI) 16.1% to 50.0%), with 2 (6.3%) complete and 8 (25.0%) partial responses. In total, 14 (43.8%) patients achieved stable disease, resulting in a disease control rate of 75.0% (95% CI 56.6% to 88.5%). With a median follow-up of 4.6 months (range 0.5-17.2) at data cut-off (September 16, 2022), median progression free survival was 5.3 months (95% CI 4.04 to 6.56) and median overall survival was not reached. In a subgroup analysis, patients with a TP53 mutation showed a trend towards worse progression free survival than those with the wild-type TP53 (4.4 months vs 8.4 months; hazard ratio 2.48 (95% CI 0.91 to 6.76), p=0.067). Common adverse events were hypertension (42.4%), hand-foot syndrome (27.3%), and fatigue (24.2%). Grade 3 events were reported in 3 (9.1%) patients and no grade 4-5 events or deaths were observed. CONCLUSION: Anlotinib showed antitumor activity with an acceptable safety profile in patients with platinum resistant/refractory ovarian cancer, and it might be a potential treatment in this population.

Genomic profiling of ovarian clear cell carcinoma in Chinese patients reveals potential prognostic biomarkers for survival.

INTRODUCTION: Ovarian clear cell carcinoma (OCCC) has distinct clinical and molecular features and heterogeneous prognosis. Insights into the somatic genomic abnormalities of OCCC provide the basis for deeper understanding and potential therapeutic avenues. Herein, we performed extensive genomic profiling in Chinese patients to illustrate the mutation landscape and genetic prognostic biomarkers of OCCC. PATIENTS AND METHODS: We used targeted DNA sequencing on 61 OCCC cases with a panel of 520 cancer-related genes. Correlations between clinicopathological features and survival were evaluated. Nomogram-based models were constructed to predict progress-free survival (PFS). RESULTS: We detected 763 somatic mutations spanning 286 genes. The most frequent genetic alterations, ARID1A (49%) and PIK3CA (48%), were concurrently mutated. Comprehensive copy number alterations (CNAs) were identified in chromosomes 20q13.2 and 8q. Most (73.7%) patients harboured potentially targetable driver mutations. The mean and median tumour mutational burden were 7.0 and 3.0 mutations/Mb, respectively. Microsatellite instability (high) was identified in 8.2% of patients. Mutation of the base-excision repair pathway was significantly higher in patients of stage II/III/IV. ATM mutation was associated with platinum sensitivity (p < .05). Survival analysis identified chr8q CNAs in all patients, PIK3CA mutations in stage I patients and SWI/SNF complex (ARID1A and SMARCA4) mutations in stage II/III/IV patients as potential prognosticators (p < .05). Integration of genetic alterations (SWI/SNF complex mutations, ATM mutations and chr8q CNAs) improved the performance of a nomogram based on tumour stage and residual disease (concordance index 0.75 vs. 0.70, p < .05). CONCLUSIONS: We described somatic genomic alterations in Chinese OCCC patients and observed different genomic alterations between stage I and stage II/III/IV tumours. Genetic factors may supplement clinical factors in nomogram modelling for PFS prediction.Key MessagesWe performed extensive genomic profiling in a well-annotated cohort of 61 Chinese ovarian clear cell carcinoma (OCCC) patients.PIK3CA mutations were associated with worse overall survival (OS) in stage I OCCC, and SWI/SNF gene mutations were associated with improved OS in stage II/III/IV disease.We propose an easy-to-use nomogram using clinical factors (tumour stage and residual disease) and genetic alterations (SWI/SNF complex mutations, ATM mutations and chr8q CNAs) to predict the progress-free survival (PFS) of OCCC.

A NOTCH1 Mutation Found in a Newly Established Ovarian Cancer Cell Line (FDOVL) Promotes Lymph Node Metastasis in Ovarian Cancer.

Peritoneal implantation and lymph node metastasis have different driving mechanisms in ovarian cancer. Elucidating the underlying mechanism of lymph node metastasis is important for treatment outcomes. A new cell line, FDOVL, was established from a metastatic lymph node of a patient with primary platinum-resistant ovarian cancer and was then characterized. The effect of NOTCH1-p.C702fs mutation and NOTCH1 inhibitor on migration was evaluated in vitro and in vivo. Ten paired primary sites and metastatic lymph nodes were analyzed by RNA sequencing. The FDOVL cell line with serious karyotype abnormalities could be stably passaged and could be used to generated xenografts. NOTCH1-p.C702fs mutation was found exclusively in the FDOVL cell line and the metastatic lymph node. The mutation promoted migration and invasion in cell and animal models, and these effects were markedly repressed by the NOTCH inhibitor LY3039478. RNA sequencing confirmed CSF3 as the downstream effector of NOTCH1 mutation. Furthermore, the mutation was significantly more common in metastatic lymph nodes than in other peritoneal metastases in 10 paired samples (60% vs. 20%). The study revealed that NOTCH1 mutation is probably a driver of lymph node metastasis in ovarian cancer, which offers new ideas for the treatment of ovarian cancer lymph node metastasis with NOTCH inhibitors.

Characterization of hotspot exonuclease domain mutations in the DNA polymerase ϵ gene in endometrial cancer.

Objective: This study was aimed to profile hotspot exonuclease domain mutations (EDMs) of the DNA polymerase ϵ gene (POLE) in endometrial cancer (EC) and to investigate the effects of EDMs on tumor cell behavior and catalytic activities of Polϵ. Methods: POLE sequencing was performed in tumor tissue samples from patients with EC to identify hotspot EDMs. Bioinformatics tools were used to select the potential pathogenic EDMs. The association of EDMs with the clinical outcomes of patients was assessed. EC cells were transfected with wildtype POLE or POLE variants to examine the effects of the EDMs on EC cell behavior, including cell cycle, migration, and invasion. Co-immunoprecipitation was employed to obtain FLAG-tagged wildtype and mutant catalytic subunits of Polϵ, followed by the assessment of polymerase and exonuclease activities. Results: In addition to previously reported P286R and V411L, R375Q and P452L were identified as novel, and deleterious POLE hotspot EDMs of EC. Patients in EDM group had significantly better clinical outcomes than the rest of the cohort. Compared with wildtype POLE, overexpression of POLE variants promoted cisplatin resistance, G0/G1 cell cycle arrest, and cell migration and invasion in EC cells. Overexpression of POLE variants significantly increased the abundance of 3'-OH and upregulated the expression of DNA mismatch repair genes in HEK293T cells. Compared with wildtype Polϵ, Pol ϵ mutants exhibited undermined polymerase and exonuclease abilities in the presence of mismatched nucleotides in HEK293 cells. Conclusion: We characterized the of hotspot exonuclease domain mutations in the DNA polymerase ϵ gene and identified P286R, V411L, R375Q, and P452L as pathogenic POLE hotspot EDMs in endometrial cancer. These hotspot EDMs are associated with the malignant behavior of endometrial cancer cells in vitro and favorable prognosis in patients, suggesting that POLE affects a wide range of cellular processes beyond DNA replication and proofreading.

Hysteroscopic Curettage Followed by Megestrol Acetate Plus Metformin as a Fertility-Sparing Treatment for Women with Atypical Endometrial Hyperplasia or Well-Differentiated Endometrioid Endometrial Carcinoma.

Background: In reproductive-aged women, the incidence of atypical endometrial hyperplasia (AEH) or endometrioid endometrial carcinoma (EEC) is rising globally. The study aimed to investigate the effectiveness of hysteroscopic curettage followed by megestrol acetate (MA) plus metformin as conservative treatment in AEH and early EEC. Methods: We retrospectively studied AEH and stage IA, grade 1 EEC patients treated with hysteroscopic curettage followed by MA (160 mg/d) plus metformin (1500 mg/d) from January 2010 to December 2020 at Fudan University Shanghai Cancer Center. Treatment outcomes were assessed by complete response (CR) rate, recurrence rate, and pregnancy outcomes. Univariate and multivariate analyses were performed via the logistic regression model. Results: The study included 79 patients, 31 (39.2%) with AEH and 48 (60.8%) with EEC. The medians of age (years) and follow-up time (months) were 30 and 39.5, respectively. Seventy-six patients (96.2%) finally achieved CR. The median time to CR was 3.6 (3.0-20.6) months. The CR rate after 3 months, 6 months, and 1 year was 55 (69.6%), 67 (84.8%), and 72 (91.1%), respectively. Recurrence occurred in 26 (34.2%) patients. Treatment duration ⩾9 months was associated with a lower recurrence rate after CR (P = .012). Fourteen (93.3%) of the 15 recurrent patients who received progestin re-treatment achieved CR again. Finally, 29 patients delivered live births. Conclusions: Hysteroscopy followed by MA plus metformin can achieve CR in short time and is overall safe. Consolidation treatment should be prolonged to decrease the recurrence rate, despite a shorter time to CR.

The frequency and clinical implication of mismatch repair protein deficiency in Chinese patients with ovarian clear cell carcinoma.

BACKGROUND: The aim of the present study was to assess the prevalence of deficient mismatch repair (MMR) in Chinese ovarian clear cell carcinoma (CCC) patients and its association with clinicopathologic features. METHODS: Immunohistochemistry with four antibodies against MLH1, PMS2, MSH2 and MSH6 was performed on whole section slides, and the results were correlated with clinicopathologic variables. RESULTS: A total of 108 cases were included in the present study with a median age of 52 years at first diagnosis. Early-stage disease and platinum-sensitive recurrence accounted for 62.3 and 69.6%, respectively, of the total cases. Overall, the estimated 5-year overall survival was 70.3 and 20.7% in patients with early- and late-stage tumors, respectively. Deficient MMR was identified in 5.6% (6/108) of the cohort and included MSH2/MSH6 (n = 4) and MLH1/PMS2 (n = 2). The average age of the six patients with deficient MMR was 45.6 years, and the rate of MMR-deficient tumors in women ≤50 years was relatively higher than that in women over 50 years (10.0% vs. 2.9%; P = 0.266). Half of the patients with deficient MMR were diagnosed with synchronous (endometrial or colorectal) and metachronous (endometrial) cancer, which was significantly more than their intact counterparts (P = 0.002). All six patients with deficient MMR had early-stage tumors, and the majority (83.3%) were platinum sensitive. The median progression-free survival was slightly higher in patients with defective MMR expression than in their intact counterparts (30 months vs. 27 months), but significance was not achieved (P = 0.471). CONCLUSIONS: Young ovarian CCC patients with concurrent diagnosis of endometrial and colorectal cancer are more likely to have MMR-deficient tumors, thereby warranting additional studies to determine whether patients harboring MMR abnormalities have a favorable prognosis.

Identification of epigenetic genes for predicting prognosis and immunotherapy response of ovarian cancer.

BACKGROUND: Epigenetic factors play a critical role in tumour development and progression. The aim of this study was to construct and validate a robust epigenetic gene set-based signature for predicting prognosis of ovarian cancer. METHODS: By using LASSO Cox regression model, we screened out the most useful prognostic epigenetic factors and a prognostic signature was developed based on them. Survival receiver operating characteristic was used to test the prognostic accuracy of signature in training and validation sets. The associations between the risk scores and immune cell infiltration, tumour purity, immune checkpoint inhibitor genes expression were also assessed in ovarian cancer . RESULTS: A total of 26 epigenetic factors were identified to develop the prognostic signature. In the training set, the prognosis of high-risk patients was strikingly poorer than that of low-risk patients (hazard ratio: 2.11, 95% confidence interval: 1.65-2.72, P < 0.001). Similar results were further observed in the internal validation set (hazard ratio: 1.69, 95% confidence interval: 1.07-2.63, P = 0.020) and external validation set (hazard ratio:1.95, 95% confidence interval: 1.41-2.69; P < 0.001). Survival receiver operating characteristic at 5 year showed the epigenetic signature (area under the curve = 0.700) performed better than other clinical features in predicting prognosis. Distinct difference in immune activation related pathways, immune cells infiltration, tumour purity reflected by immune and stromal score and immune checkpoint inhibitor genes gene expression was observed between high- and low-risk samples. CONCLUSIONS: This study constructed an epigenetic signature that was capable of predicting postoperative outcomes and may also serve as potential biomarker for immunotherapy responses for ovarian cancer.

Integrative genomic and transcriptomic analysis reveals immune subtypes and prognostic markers in ovarian clear cell carcinoma.

BACKGROUND: We performed an integrative genomic and transcriptomic profiling to identify molecular subtypes and prognostic markers with special focus on immune-related pathways. METHODS: Totally, 50 Chinese patients were subjected to targeted next-generation sequencing and transcriptomic sequencing. RESULTS: Two distinct subgroups were identified as immune (22.0%) and non-immune (78.0%) based on the immune-pathway related hierarchical clustering. Surprisingly, patients with immune subtype had a significantly worse survival. The prognostic capacity was validated in external cohorts. The immune group had higher expression of genes involved in pro-inflammation and checkpoints. PD-1 signalling pathway was enriched in the immune subtype. Besides, the immune cluster presented enriched expression of genes involved in epithelial-mesenchymal transition, angiogenesis and PI3K-AKT-mTOR signalling, while the non-immune subtype had higher expression of metabolic pathways. The immune subtype had a higher mutation rate of PIK3CA though significance was not achieved. Lastly, we established a prognostic immune signature for overall survival. Interestingly, the immune signature could also be applied to renal clear cell carcinoma, but not to other histologic subtype of ovarian cancer. CONCLUSIONS: An immune subtype of OCCC was identified with poor survival and enrichment of PD-1 and PI3K-AKT-mTOR signalling. We constructed and validated a robust prognostic immune signature of OCCC patients.

Fibrinogen/albumin ratio as a promising predictor of platinum response and survival in ovarian clear cell carcinoma.

BACKGROUND: This study aims to evaluate the role of the fibrinogen/albumin ratio (FAR) in predicting platinum resistance and survival outcomes of patients with ovarian clear cell carcinoma (OCCC). METHODS: Coagulation function and D-dimer, serum albumin, CA125 and HE4 levels were measured before surgery in OCCC patients undergoing initial surgery in our institution. FAR was calculated as fibrinogen/albumin level. The correlation between these indicators and clinicopathological features, platinum response, and survival outcomes was further analyzed. The Kaplan-Meier method and multivariable Cox regression model were used to assess the effects of FAR on progression-free survival (PFS) and overall survival (OS). RESULTS: Advanced stage patients accounted for 42.1% of the 114 participants. Optimal cytoreductive surgery was achieved in 105 patients, and the complete resection rate was 78.1%. FAR was associated with tumor stage, residual tumor and platinum response. A receiver operating characteristic curve for predicting platinum response showed that the optimal cutoff point of the FAR was 12%. The sensitivity was 73.3% and the specificity was 68.2%. In multivariate analysis, FAR ≥12% (HR = 4.963, P = 0.002) was an independent risk factor for platinum resistance. In addition, FAR and D-dimer proved to be independent negative factors for outcomes including both PFS and OS. The median follow-up time was 52 months. A high FAR (≥ 12%) showed a stronger correlation with poor OS and PFS in the subgroup analysis of advanced and completely resected patients. CONCLUSIONS: The FAR might be a potential preoperative biochemical marker for predicting treatment response and oncological outcomes in OCCC patients.

Exploration of Potential Diagnostic Value of Protein Content in Serum Small Extracellular Vesicles for Early-Stage Epithelial Ovarian Carcinoma.

Epithelial ovarian carcinoma (EOC) is one of the most common gynecologic malignancies with a high mortality rate. Serum biomarkers and imaging approaches are insufficient in identifying EOC patients at an early stage. This study is to set up a combination of proteins from serum small extracellular vesicles (sEVs) for the diagnosis of early-stage EOC and to determine its performance. A biomarker for early-stage ovarian cancer (BESOC) cohort was used as a Chinese multi-center population-based biomarker study and registered as a Chinese Clinical Trial ChiCTR2000040136. The sEV protein levels of CA125, HE4, and C5a were measured in 299 subjects. Logistic regression was exploited to calculate the odds ratio and to create the sEV protein model for the predicted probability and subsequently receiver-operating characteristic (ROC) analysis. The combined sEV marker panel of CA125, HE4, and C5a as a sEV model obtained an area under curve (AUC) of 0.912, which was greater than the serum model (0.809), by ROC analysis to identify EOC patients from the whole cohort. With the cutoff of 0.370, the sensitivity and specificity of the sEV model were 0.80 and 0.89, which were much better performance than the serum markers (sensitivity: 0.55~0.66; specificity: 0.59~0.68) and the risk of ovarian malignancy algorithm (ROMA) index approved by the U.S. Food and Drug Administration (sensitivity: 0.65; specificity: 0.61), to identify EOC patients from patients with benign ovarian diseases or other controls. The sEV levels of CA125 significantly differed among early-stage and late-stage EOC (p < 0.001). Moreover, the AUC of ROC to identify early-stage EOC patients was 0.888. Further investigation revealed that the sEV levels of these 3 proteins significantly decreased after cytoreductive surgery (CA125, p = 0.008; HE4, p = 0.025; C5a, p = 0.044). In summary, our study showed that CA125, HE4, and C5a levels in serum sEVs can identify EOC patients at the early stage, elucidating the possibility of using a sEV model for the diagnosis of early-stage EOC.

Changes in peripheral lymphocyte populations in patients with advanced/recurrent ovarian cancer undergoing splenectomy during cytoreductive surgery.

BACKGROUND: To investigate changes in peripheral lymphocyte subsets after splenectomy during cytoreductive surgery for advanced or recurrent ovarian cancers. METHODS: We enrolled 83 patients with advanced or recurrent ovarian cancer who underwent cytoreductive surgery. Twenty patients who also underwent splenectomy were assigned to the splenectomy cohort and the rest were assigned to the non-splenectomy cohort. Flow cytometry was used to measure peripheral lymphocyte subsets consisting of T cells, regulatory T cells, natural killer cells, B cells, and activation antigens before and after surgery. RESULTS: There was no difference in the number and distribution of peripheral lymphocyte subsets between the two cohorts before surgery. After surgery, we observed elevated levels of T cells (CD3+, CD3+CD8+) in the splenectomy cohort compared to those in the non-splenectomy cohort, and the difference was statistically significant. CD8+CD28+ T cells had a significant decreasing tendency (P = 0.011) while CD3+/HLA-DR+ T cells showed the opposite trend (P = 0.001) in the splenectomy cohort. The proportion of Tregs (P = 0.005) and B cells (P < 0.001) including CD3-/HLA-DR+ B cells (P = 0.007) increased after surgery, and the absolute number of T cells and NK cells decreased to different extents (P < 0.001) in the non-splenectomy cohort. The post-operative percentage of CD8+CD28+ T cells was less than the pre-operative percentage (P = 0.022), which was similar to the splenectomy cohort. There was no significant difference in progression-free survival or overall survival between the groups after a median follow-up time of 41 months. CONCLUSIONS: The changes in peripheral lymphocyte populations were different between patients with and those without splenectomy during cytoreductive surgery for ovarian cancers. T cells were increased and activated in the splenectomy cohort, whereas, B cells were increased and activated in the non-splenectomy cohort.

Hybrid Capture-based Genomic Profiling of Circulating Tumor DNA From Patients With Advanced Ovarian Cancer.

Objective: We conducted this study to characterize somatic genomic alterations in circulating tumor DNA (ctDNA) from patients with ovarian cancer and compare GAs detected in ctDNA with tissue databases. Methods: Hybrid capture-next generation sequencing genomic profiling of 150 genes was performed on ctDNA from 138 patients with ovarian cancer with 1,500× sequencing depth. The GAs detected in ctDNA were compared with those in our ovarian cancer tissue database (N = 488) and the Cancer Genome Atlas (TCGA) database (N = 489). Results: 115 patients (83%) had at least 1 GA detected in ctDNA. The most frequently altered genes detected in ctDNA were TP53 (72%), KRAS (11%), LRP1B (10%), ZNF703 (9%) and NF1 (8%). Comparative analysis with our tissue database showed similar frequencies of GAs per gene, although PIK3CA and KRAS mutations were more frequent in tissue and ctDNA, respectively (p < 0.05). Gene amplification and rearrangement were more frequent in ctDNA samples. The mutation frequency of homologous recombination repair associated-genes, VEGF signal/angiogenesis pathways, RAS pathways, NOTCH pathways and MSI-H ratio was not statistically different either in ctDNA or in tissue database. However, the mutation frequency of AKT, PIK3CA, PTEN and STK11 in PI3K/AKT/mTOR pathway was significantly lower than that in tissue samples (p < 0.05). Conclusions: Our results suggest that genomic profiling of ctDNA could detect somatic GAs in a significant subset of patients with ovarian cancer. Hybrid capture-NGS based on liquid biopsy has the potential capability to serve as a substitute to tissue biopsy and further studies are warranted.

A preoperative prediction model for predicting coexisting adnexa malignancy of patients with G1/G2 endometrioid endometrial cancer.

OBJECTIVE: To identify the predictors of coexisting adnexa malignancy (CAM) before surgery for patients with G1/G2 endometrioid endometrial cancer (EEC). METHODS: Patients with G1/G2 EEC who received surgery in Fudan University Shanghai Cancer Center from 1996 to 2017 were enrolled. Univariate and multivariate logistic regression were performed to identify the predictors for CAM, and the nomogram was constructed and evaluated the discrimination and calibration. RESULTS: Among the 1511 patients in the study cohort, 66 (4.4%) coexisted adnexa malignancy (51 metastatic and 15 synchronous primaries). In the univariate logistic regression analysis, CA125 level (>35 U/ml), histologic grades, myometrial invasion depth in magnetic resonance imaging (MRI), adnexal involvement in MRI/surgical exploration (SEP) were found to be significant predictors for CAM (P < .001, 0.047, 0.011, <0.001, respectively). The multivariate analysis demonstrated that high CA125 level (P < .001; OR: 2.945; 95%CI: 1.700-5.101), deep myometrial invasion (P = .011; OR: 2.194; 95%CI: 1.200-4.011), and suspected adnexal involvement in MRI/SEP (P < .001; OR: 11.524; 95%CI: 6.726-19.744) were independent predictors for CAM (AUC = 0.786). In 338 patients with MMR results, eighty-seven (25.7%) were detected MSI-high. There were 5.7% (5/87) patients diagnosed with CAM in the MSI-high group compared with 4.4% (11/251) in the MSS group. CONCLUSIONS: A nomogram with pre- and intra-operative factors was constructed to predict CAM in G1/G2 EEC patients, which may help clinicians in decision-making for ovarian preservation for these patients.

Serum D-dimer, albumin and systemic inflammatory response markers in ovarian clear cell carcinoma and their prognostic implications.

BACKGROUND: This study attempts to evaluate whether preoperative systemic inflammatory response (SIR) markers or other hematological variables, such as albumin, D-dimer, and carbohydrate antigen 125, play roles in predicting chemotherapy response and survival outcome in patients with ovarian clear cell carcinoma (OCCC). METHODS: Preoperative leukocyte differential counts, as well as platelet, serum albumin, plasma D-dimer and CA-125 levels, were measured in patients with FIGO IC-IV ovarian clear cell cancer. The correlations of these hematological biomarkers with clinicopathological features, chemotherapy response, and survival outcomes were further analyzed. Survival time was estimated using the Kaplan-Meier model, whereas Cox regression was conducted for multivariate analysis. RESULTS: Among the 84 patients, 28.6% were classified as platinum resistant, and 69.0% were platinum sensitive. Preoperative CA125, albumin, and D-dimer levels; neutrophil to lymphocyte ratios (NLR); and monocyte to lymphocyte ratios were significantly correlated with FIGO stage, residual tumor, and platinum response. Platelet to lymphocyte ratio was not related to platinum response (P = 0.060). The median follow-up time was 28 months (range, 1 to 128 months). Preoperative CA125, albumin, and D-dimer levels were significant prognostic factors for overall survival (OS) and progression-free survival (PFS). In the univariate analysis, only NLR exhibited prognostic significance for PFS (P = 0.007). Multivariate analysis indicated that D-dimer > 3.27 (P = 0.001 for OS; P = 0.040 for PFS) and albumin < 39.6 (P = 0.005 for OS and P = 0.041 for PFS) retained significance. CONCLUSIONS: Preoperative NLR has some predictive value for platinum resistance in patients with IC-IV stage OCCC but has little predictive effect on prognosis. Elevated D-dimer and reduced albumin might be potential biomarkers for worse response to first-line platinum-based chemotherapy and poor clinical outcomes.

Nomogram for Predicting Recurrence-Free Survival in Chinese Women with Endometrial Cancer after Initial Therapy: External Validation.

This study aimed at developing an available recurrence-free survival (RFS) model of endometrial cancer (EC) for accurate and individualized prognosis assessment. A training cohort of 520 women with EC who underwent initial surgical treatment and an external validation cohort of 445 eligible EC patients from 2006 to 2016 were analyzed retrospectively. Multivariable Cox proportional hazards regression models were used to develop nomograms for predicting recurrence. The concordance index (C-index) and the area under the receiver operating characteristic curve (AUC) were calculated to determine the discrimination of RFS prognostic scoring systems. Calibration plots were generated to examine the performance characteristics of the predictive nomograms. Regression analysis revealed that an advanced International Federation of Gynecology and Obstetrics (FIGO) stage, histological grade 3, primary tumor diameter ≥2 cm, and positive peritoneal cytology were independent prognostic factors for RFS in EC in the training set. The nomograms estimated RFS according to these four variables, with a C-index of 0.860, which was superior to that of FIGO stage (2009 criteria), at 0.809 (P=0.034), in the training cohort. Encouragingly, consistent results were observed in the validation set, with a C-index of 0.875 for the nomogram and a C-index of 0.833 for the FIGO staging (P=0.0137). Furthermore, the calibrations of the nomograms predicting 3- and 5-year RFS strongly corresponded to the actual survival outcome. In conclusion, this study developed an available nomogram with effective external validation and relatively appreciable discrimination and conformity for the accurate assessment of 3- and 5-year RFS in Chinese women with EC.

Plasma omega-3 polyunsaturated fatty acids and recurrence of endometrial cancer.

BACKGROUND: Omega-3 polyunsaturated fatty acids (PUFAs) were proposed to have potential effects against inflammation and cancer. However, results from epidemiology studies remain inconsistent. We aimed to explore the associations of plasma PUFAs with EC recurrence and all-cause mortality. METHOD: Women diagnosed with endometrial cancer (EC) between 2008 and 2013 and underwent surgery at Fudan University Shanghai Cancer Center of China were recruited. Survival status was followed up through September 2017. EC recurrence and total cause deaths were identified through medical record and telephone interview. In total, 202 patients with enough plasma samples at time of surgery were included. There were 195 patients who provided baseline plasma and survival information included in the current study. Plasma omega-3 PUFAs were measured by GC-FID. Cox Proportional Hazard model adjusted for potential cofounders was used to estimate HRs and 95% CIs. RESULTS: Median follow-up time for patients was 58 months after surgery. A total of 13 recurrences and 11 all-cause deaths, of which, 2 deaths from EC, were identified. Level of plasma EPA was higher in recurrent patients than total patients (0.78% vs 0.51%, P = 0.015). Higher plasma eicosapentaenoic acid (EPA) level trended to have positive association with EC recurrence (P-trend = 0.04), although comparing to the lowest tertile, the highest tertile of EPA level was not significantly associated with increased risk of EC recurrence (HRT3vsT1 = 6.02; 95%CI = 0.7-52.06). The association between total omega-3 PUFA and EC recurrence tended to be stronger among patients with deeper myometrial invasion (OR = 3.41; 95%CI = 1.06-10.95; P-interaction = 0.04). CONCLUSIONS: Higher plasma EPA level was significantly associated with EC recurrence. Further studies are warranted to confirm these findings. TRIAL REGISTRATION: ChiCTR1900025418; Retrospectively registered (26 August 2019); Chinses Clinical Trial Registry.

Methylation­associated silencing of miR­638 promotes endometrial carcinoma progression by targeting MEF2C.

Promoter methylation­associated silencing of cancer­associated microRNAs (miRNAs) is a common epigenetic mechanism during tumorigenesis in various types of human cancer. However, this has not been comprehensively examined in endometrial carcinoma (EC). In the present study, an miRNA microarray consisting of 1,347 common human miRNAs was used to select potential tumor suppressive miRNAs that were hyper­methylated in EC. This led to the identification of miR­638, miR­210 and miR­3665. The methylation status of miR­638 was examined by bisulfite sequencing polymerase chain reaction and miR­638 expression was measured by TaqMan miRNA assays. EC cell lines transfected with vectors overexpressing miR­638, its target gene myocyte enhancer factor 2C (MEF2C) or both, were constructed. Dual­luciferase reporter assays, a xenograft mouse model and rescue experiments were designed to study miR­638 and its target gene MEF2C. The results indicated that the promoter region of miR­638 was highly methylated and the expression of miR­638 was significantly downregulated in cancerous tissues from 42 patients with EC who underwent surgical resection. Additionally, a low expression of miR­638 was significantly associated with advanced Federation of Gynecology and Obstetrics stage and was demonstrated to indicate shorter disease­free survival. Functional studies indicated that the overexpression of miR­638 in EC cell lines inhibited in vitro tumor progression and in vivo tumorigenicity. MEF2C was verified as a direct target of miR­638 and was demonstrated to mediate the tumor­suppressive function of miR­638 in EC.

Association between DNA damage repair gene somatic mutations and immune-related gene expression in ovarian cancer.

BACKGROUND: Defects in DNA damage repair (DDR) system may lead to genomic instability and manifest as increased immunogenicity. DDR deficiency is prevalent in ovarian cancer (OvCa); however, the association of DDR mutation with immune profiles in OvCa remains largely unknown. This knowledge will provide an essential basis to the rational design of biomarker-guided immune combination therapy of OvCa in the future. METHODS: Whole-exome sequencing data of 587 OvCa from The Cancer Genome Atlas (TCGA) were used to determine the expression profiles of 47 immune-related genes and the abundance of tumor-infiltrating immune cells. A Chinese OvCa cohort (n = 220) tested by next-generation sequencing (NGS) was used to validate the association between DDR status and tumor mutation burden (TMB). RESULTS: A total of 19.3% in TCGA cohort and 25.9% in Chinese cohort harbored at least one DDR somatic mutation. DDR deficiency exhibited a distinct immune profile with significant higher expression levels of PTPRCAP, CCL5, IFI16, LAG3, IL15RA, and GBP1 in OvCa in the TCGA cohort. Different DDR pathway deficiency displayed various immune profiles. Increased levels of Th1 cells, TMB, and neoantigen were also observed in DDR-deficient tumors. CONCLUSIONS: DDR deficiency was associated with specific immune signatures in OvCa. Our findings emphasize the urgent need for biomarker-guided rational immune combination therapy to maximize the OvCa patients who could benefit from immunotherapy.

An Externally Validated Nomogram for Predicting Lymph Node Metastasis of Presumed Stage I and II Endometrial Cancer.

Background: Optimal management for endometrial cancer in patients with clinically negative lymph nodes is still under debate. Several prediction models for lymphatic dissemination of early-stage endometrial cancer have been developed. However, external validation is rare, and decision curve analysis has hardly been applied for these models. Objective: To develop and validate a nomogram to predict lymph node metastasis of presumed stage I and II endometrial cancer. Study Design: The prediction nomogram was developed by using multivariable logistic regression with data for 700 EC patients who underwent initial surgery from 2006 to 2017 at Peking University People's Hospital (training dataset), Beijing. External validation was performed in 727 eligible patients from Fudan University Shanghai Cancer Center (validation dataset), Shanghai. Results: For the 700 women in the training dataset, the lymph node metastasis rate was 8.0% (56/700). Lymphovascular space invasion, histological grade, cervical stromal invasion, and myometrial invasion were independent prognostic factors in the training dataset. We generated a nomogram based on these pathological factors. To determine the clinical usefulness of our nomogram, we compared it with the Mayo criteria. For our nomogram, the area under the receiver operating characteristic curve (AUC) was 0.85 as compared with 0.63 for the Mayo criteria. In the validation dataset, the AUC was 0.78 as compared with 0.57 for the Mayo criteria. The nomogram was well-calibrated in both the training and validation datasets. At a 10% probability threshold, our nomogram decreased almost 29 unnecessary lymphadenectomies per 100 patients than the Mayo criteria without missing more metastatic disease. Conclusion: We developed a nomogram to predict lymph node metastasis in patients with early-stage endometrial cancer in China. This prediction model may help clinicians in decision-making for patients with early-stage endometrial cancer, especially for the patient with incomplete surgery, reducing overtreatment, and medical costs.

Screening for hereditary cancers in patients with endometrial cancer reveals a high frequency of germline mutations in cancer predisposition genes.

As inherited genetic alterations are important etiological factors causing endometrial cancer (EC), our study aimed to outline the ethnic-related prevalence and the associated clinical and biological characteristics of germline mutations in cancer predisposition genes in Chinese EC patients. One hundred ninety-eight Chinese EC patients were screened for germline mutations in a panel of cancer susceptibility genes using next-generation sequencing combined with multiplex ligation-dependent probe amplification. First, we found that among patients under 50 years of age, 26% (18/69) carried germline genetic mutations, all involving mismatch repair (MMR) genes except for one mutation affecting BRCA1. Second, when we focused on Lynch syndrome (LS) with additional selected patients, 45 were identified to carry pathogenic mutations in MMR genes, with a higher frequency found in MSH2 and MSH6. We found that age at onset, personal and familial history together with immunohistochemical assay results were the most useful criteria for the diagnosis of LS although limitations in routine practice and the sensitivity and specificity of each parameter should be taken into account. One pathogenic mutation in the PALB2 gene was detected in a patient with no breast cancer in her family. Interestingly, we identified a family carrying pathogenic variant in both PMS2 and BRCA1 genes with distinct clinical phenotypes. Multigene panel testing should be recommended to patients based on their clinical information and tumor phenotype. Our study also showed the genetic complexity in EC, which requires further investigations.