Stromal cell-associated expression of kallikrein-related peptidase 6 (KLK6) indicates poor prognosis of ovarian cancer patients

Abstract Several members of the human kallikrein-related peptidase family, including KLK6, are up-regulated in ovarian cancer. High KLK6 mRNA or protein expression, measured by quantitative polymerase chain reaction and enzyme-linked immunoassay, respectively, was previously found to be associated with a shortened overall and progression-free survival (OS and PFS, respectively). In the present study, we aimed at analyzing KLK6 protein expression in ovarian cancer tissue by immunohistochemistry. Using a newly developed monospecific polyclonal antibody, KLK6 immunoexpression was initially evaluated in normal tissues. We observed strong staining in the brain and moderate staining in the kidney, liver, and ovary, whereas the pancreas and the skeletal muscle were unreactive, which is in line with previously published results. Next, both tumor cell- and stromal cell-associated KLK6 immunoexpression were analyzed in tumor tissue specimens of 118 ovarian cancer patients. In multivariate Cox regression analysis, only stromal cell-associated expression, besides the established clinical parameters FIGO stage and residual tumor mass, was found to be statistically significant for OS and PFS [high vs. low KLK6 expression; hazard ratio (HR), 1.92; p=0.017; HR, 1.80; p=0.042, respectively]. These results indicate that KLK6 expressed by stromal cells may considerably contribute to the aggressiveness of ovarian cancer.

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Clinical relevance of kallikrein-related peptidase 6 (KLK6) and 8 (KLK8) mRNA expression in advanced serous ovarian cancer

Biological Chemistry ◽

10.1515/hsz-2016-0177 ◽

2016 ◽

Vol 397 (12) ◽

pp. 1265-1276 ◽

Cited By ~ 14

Author(s):

Nancy Ahmed ◽

Julia Dorn ◽

Rudolf Napieralski ◽

Enken Drecoll ◽

Matthias Kotzsch ◽

...

Keyword(s):

Ovarian Cancer ◽

Mrna Expression ◽

Cox Regression ◽

Multivariable Analysis ◽

Progression Free Survival ◽

Predictive Marker ◽

Residual Tumor ◽

Mrna Levels ◽

Serous Ovarian Cancer ◽

Cox Regression Analysis

Abstract Most members of the kallikrein-related peptidase family have been demonstrated to be dysregulated in ovarian cancer and modulate tumor growth, migration, invasion, and resistance to chemotherapy. In the present study, we assessed the mRNA expression levels of KLK6 and KLK8 by quantitative PCR in 100 patients with advanced serous ovarian cancer FIGO stage III/IV. A pronounced correlation between KLK6 and KLK8 mRNA expression (rs = 0.636, p < 0.001) was observed, indicating coordinate expression of both peptidases. No significant associations of clinical parameters with KLK6, KLK8, and a combined score KLK6+KLK8 were found. In univariate Cox regression analysis, elevated mRNA levels of KLK6 were significantly linked with shortened overall survival (OS) (hazard ratio [HR] = 2.07, p = 0.007). While KLK8 values were not associated with patients’ outcome, high KLK6+KLK8 values were significantly associated with shorter progression-free survival (HR = 1.82, p = 0.047) and showed a trend towards significance in the case of OS (HR = 1.82, p = 0.053). Strikingly, in multivariable analysis, elevated KLK6 mRNA values, apart from residual tumor mass, remained an independent predictive marker for poor OS (HR = 2.33, p = 0.005). As KLK6 mRNA and protein levels correlate, KLK6 may represent an attractive therapeutic target for potent and specific inhibitors of its enzymatic activity.

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The Relationship Between Retroperitoneal Lymphadenectomy and Survival in Advanced Ovarian Cancer Patients

10.21203/rs.2.14760/v3 ◽

2020 ◽

Author(s):

Chenyan Fang ◽

Yingli Zhang ◽

Lingqin Zhao ◽

Xi Chen ◽

Liang Xia ◽

...

Keyword(s):

Ovarian Cancer ◽

Postoperative Complications ◽

Lymph Nodes ◽

Cancer Patients ◽

Cox Regression ◽

Advanced Ovarian Cancer ◽

Residual Tumor ◽

Retroperitoneal Lymphadenectomy ◽

Cox Regression Analysis ◽

Significant Difference

Abstract Background Systematic retroperitoneal lymphadenectomy has been widely used in the surgical treatment of advanced ovarian cancer patients. Nevertheless, the corresponding therapeutic may not provide a survival benefit. The aim of this study was to assess the effect of systematic retroperitoneal lymphadenectomy in such patients. Methods Patients with advanced ovarian cancer (stage III-IV, according to the classification presented by the International Federation of Gynecology and Obstetrics) who were admitted and treated in Zhejiang Cancer Hospital from January 2004 to December 2013 were enrolled and reviewed retrospectively. All patients were optimally or suboptimally debulked (absent or residual tumor <1 cm) and divided into two groups. Group A (no-lymphadenectomy group, n =170): patients did not undergo lymph node resection; lymph nodes resection or biopsy were selective. Group B (n=240): patients underwent systematic retroperitoneal lymphadenectomy. Results A total of 410 eligible patients were enrolled in the study. The patients’ median age was 51 years old (range, 28–72 years old). The 5-year overall survival (OS) and 2-year progression-free survival (PFS) rates were 78% and 24% in the no-lymphadenectomy group and 76% and 26% in the lymphadenectomy group (P=0.385 and 0.214, respectively). Subsequently, there was no significant difference in 5-year OS and 2-year PFS between the two groups stratified to histological types (serous type or non-serous type), the clinical evaluation of negative lymph nodes or with macroscopic peritoneal metastasis beyond pelvic (IIIB-IV). Multivariate Cox regression analysis indicated that systematic retroperitoneal lymphadenectomy was not a significant factor influencing the patients’ survival. Patients in the lymphadenectomy group had a higher incidence of postoperative complications (incidence of infection treated with antibiotics was 21.7% vs. 12.9% [P=0.027]; incidence of lymph cysts was 20.8% vs. 2.4% [P < 0.001]). Conclusions Our study showed that systematic retroperitoneal lymphadenectomy did not significantly improve survival of advanced ovarian cancer patients with residual tumor <1 cm or absent after cytoreductive surgery, and were associated with a higher incidence of postoperative complications.

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The Relationship Between Retroperitoneal Lymphadenectomy and Survival in Advanced Ovarian Cancer Patients

10.21203/rs.2.14760/v2 ◽

2020 ◽

Author(s):

Chenyan Fang ◽

Yingli Zhang ◽

Lingqin Zhao ◽

Xi Chen ◽

Liang Xia ◽

...

Keyword(s):

Ovarian Cancer ◽

Postoperative Complications ◽

Lymph Nodes ◽

Cancer Patients ◽

Cox Regression ◽

Advanced Ovarian Cancer ◽

Residual Tumor ◽

Retroperitoneal Lymphadenectomy ◽

Cox Regression Analysis ◽

Significant Difference

Abstract Background Systematic retroperitoneal lymphadenectomy has been widely used in the surgical treatment of advanced ovarian cancer patients. Nevertheless, the corresponding therapeutic may not provide a survival benefit. The aim of this study was to assess the effect of systematic retroperitoneal lymphadenectomy in such patients. Methods Patients with advanced ovarian cancer (stage III-IV, according to the classification presented by the International Federation of Gynecology and Obstetrics) who were admitted and treated in Zhejiang Cancer Hospital from January 2004 to December 2013 were enrolled and reviewed retrospectively. All patients were optimally or suboptimally debulked (absent or residual tumor <1 cm) and divided into two groups. Group A (no-lymphadenectomy group, n =170): patients did not undergo lymph node resection; lymph nodes resection or biopsy were selective. Group B (n=240): patients underwent systematic retroperitoneal lymphadenectomy. Results A total of 410 eligible patients were enrolled in the study. The patients’ median age was 51 years old (range, 28–72 years old). The 5-year overall survival (OS) and 2-year progression-free survival (PFS) rates were 78% and 24% in the no-lymphadenectomy group and 76% and 26% in the lymphadenectomy group (P=0.385 and 0.214, respectively). Subsequently, there was no significant difference in 5-year OS and 2-year PFS between the two groups stratified to histological types (serous type or non-serous type), the clinical evaluation of negative lymph nodes or with macroscopic peritoneal metastasis beyond pelvic (IIIB-IV). Multivariate Cox regression analysis indicated that systematic retroperitoneal lymphadenectomy was not a significant factor influencing the patients’ survival. Patients in the lymphadenectomy group had a higher incidence of postoperative complications (incidence of infection treated with antibiotics was 21.7% vs. 12.9% [P=0.027]; incidence of lymph cysts was 20.8% vs. 2.4% [P < 0.001]). Conclusions Our study showed that systematic retroperitoneal lymphadenectomy did not significantly improve survival in advanced ovarian cancer patients with residual tumor <1 cm or absent after cytoreductive surgery, and were associated with a higher incidence of postoperative complications.

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The Relationship Between Retroperitoneal Lymphadenectomy and Survival in Advanced Ovarian Cancer Patients

10.21203/rs.2.14760/v4 ◽

2020 ◽

Author(s):

Chenyan Fang ◽

Yingli Zhang ◽

Lingqin Zhao ◽

Xi Chen ◽

Liang Xia ◽

...

Keyword(s):

Ovarian Cancer ◽

Postoperative Complications ◽

Lymph Nodes ◽

Cancer Patients ◽

Cox Regression ◽

Advanced Ovarian Cancer ◽

Residual Tumor ◽

Retroperitoneal Lymphadenectomy ◽

Cox Regression Analysis ◽

Significant Difference

Abstract Background Systematic retroperitoneal lymphadenectomy has been widely used in the surgical treatment of advanced ovarian cancer patients. Nevertheless, the corresponding therapeutic may not provide a survival benefit. The aim of this study was to assess the effect of systematic retroperitoneal lymphadenectomy in such patients. Methods Patients with advanced ovarian cancer (stage III-IV, according to the classification presented by the International Federation of Gynecology and Obstetrics) who were admitted and treated in Zhejiang Cancer Hospital from January 2004 to December 2013 were enrolled and reviewed retrospectively. All patients were optimally or suboptimally debulked (absent or residual tumor <1 cm) and divided into two groups. Group A (no-lymphadenectomy group, n =170): patients did not undergo lymph node resection; lymph nodes resection or biopsy were selective. Group B (n=240): patients underwent systematic retroperitoneal lymphadenectomy. Results A total of 410 eligible patients were enrolled in the study. The patients’ median age was 51 years old (range, 28–72 years old). The 5-year overall survival (OS) and 2-year progression-free survival (PFS) rates were 78% and 24% in the no-lymphadenectomy group and 76% and 26% in the lymphadenectomy group (P=0.385 and 0.214, respectively). Subsequently, there was no significant difference in 5-year OS and 2-year PFS between the two groups stratified to histological types (serous type or non-serous type), the clinical evaluation of negative lymph nodes or with macroscopic peritoneal metastasis beyond pelvic (IIIB-IV). Multivariate Cox regression analysis indicated that systematic retroperitoneal lymphadenectomy was not a significant factor influencing the patients’ survival. Patients in the lymphadenectomy group had a higher incidence of postoperative complications (incidence of infection treated with antibiotics was 21.7% vs. 12.9% [P=0.027]; incidence of lymph cysts was 20.8% vs. 2.4% [P < 0.001]). Conclusions Our study showed that systematic retroperitoneal lymphadenectomy did not significantly improve survival of advanced ovarian cancer patients with residual tumor<1 cm or absent after cytoreductive surgery, and were associated with a higher incidence of postoperative complications.

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Alternative splicing acts as an independent prognosticator in ovarian carcinoma

Scientific Reports ◽

10.1038/s41598-021-89778-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yan Ouyang ◽

Kaide Xia ◽

Xue Yang ◽

Shichao Zhang ◽

Li Wang ◽

...

Keyword(s):

Ovarian Cancer ◽

Regression Analysis ◽

Alternative Splicing ◽

Ovarian Carcinoma ◽

Cancer Patients ◽

Cox Regression ◽

Excision Repair ◽

Splicing Factors ◽

Prognostic Signature ◽

Cox Regression Analysis

AbstractAlternative splicing (AS) events associated with oncogenic processes present anomalous perturbations in many cancers, including ovarian carcinoma. There are no reliable features to predict survival outcomes for ovarian cancer patients. In this study, comprehensive profiling of AS events was conducted by integrating AS data and clinical information of ovarian serous cystadenocarcinoma (OV). Survival-related AS events were identified by Univariate Cox regression analysis. Then, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis were used to construct the prognostic signatures within each AS type. Furthermore, we established a splicing-related network to reveal the potential regulatory mechanisms between splicing factors and candidate AS events. A total of 730 AS events were identified as survival-associated splicing events, and the final prognostic signature based on all seven types of AS events could serve as an independent prognostic indicator and had powerful efficiency in distinguishing patient outcomes. In addition, survival-related AS events might be involved in tumor-related pathways including base excision repair and pyrimidine metabolism pathways, and some splicing factors might be correlated with prognosis-related AS events, including SPEN, SF3B5, RNPC3, LUC7L3, SRSF11 and PRPF38B. Our study constructs an independent prognostic signature for predicting ovarian cancer patients’ survival outcome and contributes to elucidating the underlying mechanism of AS in tumor development.

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High expression of fibroblast activation protein (FAP) predicts poor outcome in high-grade serous ovarian cancer

BMC Cancer ◽

10.1186/s12885-020-07541-6 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Min Li ◽

Xue Cheng ◽

Rong Rong ◽

Yan Gao ◽

Xiuwu Tang ◽

...

Keyword(s):

Ovarian Cancer ◽

Cox Regression ◽

Paraffin Section ◽

Progression Free Survival ◽

High Grade ◽

Serous Ovarian Cancer ◽

Systematic Analysis ◽

Cox Regression Analysis ◽

Genes Expression ◽

High Level

Abstract Background High-grade serous ovarian cancer (HGSOC) is a fatal form of ovarian cancer. Previous studies indicated some potential biomarkers for clinical evaluation of HGSOC prognosis. However, there is a lack of systematic analysis of different expression genes (DEGs) to screen and detect significant biomarkers of HGSOC. Methods TCGA database was conducted to analyze relevant genes expression in HGSOC. Outcomes of candidate genes expression, including overall survival (OS) and progression-free survival (PFS), were calculated by Cox regression analysis for hazard rates (HR). Histopathological investigation of the identified genes was carried out in 151 Chinese HGSOC patients to validate gene expression in different stages of HGSOC. Results Of all 57,331 genes that were analyzed, FAP was identified as the only novel gene that significantly contributed to both OS and PFS of HGSOC. In addition, FAP had a consistent expression profile between carcinoma-paracarcinoma and early-advanced stages of HGSOC. Immunological tests in paraffin section also confirmed that up-regulation of FAP was present in advanced stage HGSOC patients. Prediction of FAP network association suggested that FN1 could be a potential downstream gene which further influenced HGSOC survival. Conclusions High-level expression of FAP was associated with poor prognosis of HGSOC via FN1 pathway.

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Homologous recombination deficiency associated with response to poly (ADP-ribose) polymerase inhibitors in ovarian cancer patients: The first real-word data from China.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e17543 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e17543-e17543

Author(s):

Xiaoxiang Chen ◽

Jing Ni ◽

Xia Xu ◽

Wenwen Guo ◽

Xianzhong Cheng ◽

...

Keyword(s):

Ovarian Cancer ◽

Regression Analysis ◽

Homologous Recombination ◽

Cancer Patients ◽

Real World ◽

Cox Regression ◽

Wild Type ◽

Cox Regression Analysis ◽

Homologous Recombination Deficiency ◽

Polymerase Inhibitors

e17543 Background: Homologous recombination deficiency (HRD) is the first phenotypically defined predictive biomarker for Poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer. However, the proportion of HRD positive in real world and the relationship of HRD status with PARPi in Chinese ovarian cancer patients remains unknown. Methods: A total of sixty-four ovarian cancer patients underwent PARPi, both Olaparib and Niraparib, were enrolled from August 2018 to January 2021 in Jiangsu Institute of Cancer Hospital. HRD score which was the sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI) and large-scale state transitions (LST) events were calculated using tumor DNA-based next generation sequencing (NGS) assays. HRD-positive was defined by either BRCA1/2 pathogenic or likely pathogenic mutation or HRD score ≥42. Progression-free survival (PFS) was analyzed with a log-rank test using HRD status and summarized using Kaplan-Meier methodology. Univariate and multiple cox-regression analysis were conducted to investigate all possible clinical factors. Results: 71.9% (46/64) patients were HRD positive and the rest 28.1% (18/64) were HRD negative, which was higher than the HRD positive proportion reported in Western countries. The PFS among HRD positive patients was significantly longer than those HRD negative patients (medium PFS 8.9 m vs 3.6 m, hazard ratio [HR]: 0.22, p < 0.001). Among them, 23 patients who were BRCA wild type but HRD positive had longer PFS than those with BRCA wild type and HRD negative (medium PFS 9.2 m vs 3.6 m, HR: 0.20, p < 0.001). Univariate cox-regression analysis found that HRD status, previous treatment lines, secondary cytoreductive surgery (SCS) were significantly associated with PFS after PARPi treatment. After multiple regression correction, HRD status (HR: 0.39, 95% CI: [0.20-0.76], p = 0.006), ECOG score (HR: 2.53, 95% CI: [1.24-5.17], p = 0.011) and SCS (HR: 2.21, 95% CI: [1.09-4.48], p = 0.028) were the independent factors. Subgroup analysis in ECOG = 0 subgroup (N = 36), HRD positive patients had significant longer PFS than HRD negative patients (medium PFS 10.3 m vs 5.8 m, HR: 0.14, p < 0.001). Also in the subgroup of patients without SCS, PFS in patients with HRD was longer than patients without HRD (medium PFS 10.2 m vs 5.7 m, HR: 0.29, p = 0.003). Conclusions: This is the first real-world data of HRD status in ovarian cancer patients from China and demonstrate that HRD is a valid biomarker for PARP inhibitors in Chinese ovarian cancer patients.

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YB-1 variant and androgen receptor axis-targeted agents in metastatic castration-resistant prostate cancer patients

Pharmacogenomics ◽

10.2217/pgs-2020-0008 ◽

2020 ◽

Vol 21 (13) ◽

pp. 919-928

Author(s):

Ana Afonso ◽

Jani Silva ◽

Ana Rita Lopes ◽

Sara Coelho ◽

Ana Sofia Patrão ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Patients ◽

Cox Regression ◽

Progression Free Survival ◽

Castration Resistant Prostate Cancer ◽

Allelic Discrimination ◽

Cox Regression Analysis ◽

Castration Resistant ◽

Increased Risk

Aim: To evaluate the influence of YB-1 rs10493112 variant as a genetic marker for response to second-generation androgen receptor axis-target agents. Methods: A hospital-based cohort study of 78 patients with metastatic castration-resistant prostate cancer was conducted. Genotyping was performed by TaqMan® allelic discrimination technology. Main results: In abiraterone-treated and high-risk patients, YB-1 rs10493112 AA genotype carriers showed lower progression-free survival than C allele genotype patients (4 vs 17 months; p = 0.009). For carriers of AA genotype, multivariate Cox regression analysis revealed a fivefold increased risk of progression (p = 0.035). Conclusion: The study findings suggest that, for metastatic and castration-resistant prostate cancer patients, this polymorphism might be a putative marker for the clinical outcome.

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A randomized, phase III study (AGO-OVAR-9, GINECO-TCG, NSGO-OC-0102): Gemcitabine-paclitaxel-carboplatin (TCG) versus paclitaxel-carboplatin (TC) as first-line treatment of ovarian cancer (OC): Survival of FIGO stage I-IIA patients

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.18_suppl.lba5510 ◽

2009 ◽

Vol 27 (18_suppl) ◽

pp. LBA5510-LBA5510 ◽

Cited By ~ 2

Author(s):

J. Herrstedt ◽

J. Huober ◽

F. Priou ◽

H. Müller ◽

M. Baekelandt ◽

...

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Cox Regression ◽

Residual Tumor ◽

Figo Stage ◽

Stage I ◽

Phase Iii ◽

Cox Regression Analysis ◽

Phase Iii Study ◽

First Diagnosis

LBA5510 Background: One option to increase the efficacy of TC in pts with first diagnosis of ovarian cancer is to add a not cross-resistant drug. Methods: We conducted a randomized, prospective, stratified, phase III study comparing therapy with TC to TC plus gemcitabine. From 7/02 to 4/04, pts with a histological verified first diagnosis of epithelial OC, FIGO IC-IV were randomized to either TC (paclitaxel [T] 175 mg/m2 3h iv d1 + carboplatin [C] AUC 5 iv d1) or TCG (TC + gemcitabine [G] 800 mg/m2 iv d1+8) for at least 6 cycles every 21 days starting within 6 weeks post-operatively. The randomization was balanced within three strata: 1) FIGO I-IIA, 2) FIGO IIB-IIIC with residual tumor ≤ 10mm, 3) FIGO IIB-IIIC with residual tumor > 10 mm or FIGO IV. Primary endpoint is overall survival. Results: We enrolled 1,742 pts and administered 5,268 cycles TC and 5,129 cycles TCG. All baseline characteristics of the patients in both arms were well balanced. Most pts received 6+ cycles (87.2% TC, 86.2% TCG). Previous interim analyses has shown that TCG was tolerable but induced more hematological toxicity and final analysis has shown that addition of gemcitabine did not improve overall survival in patients with FIGO stage IIB-IV disease. Approximately 11% of the patients (n = 175) had FIGO stage I-IIA disease (stratum I). Most patients received 6+ cycles (93.3% TC, 86.9% TCG). With a median follow-up of 53.8 (range 0 –75) months, and using the log rank test and Cox regression analysis, no relevant differences in progression free survival (first quartile about 57 months and median ≥ 75 months in both groups, HR = 0.90 [95% CI: 0.47–1.72], p = 0.7500) and a negative trend in overall survival (first quartile ≥ 75 months in both groups, HR = 2.19 [95% CI: 0.75–6.41], p = 0.1419) were seen. Conclusions: Addition of G to TC did not improve efficacy in patients with stage I-IIA ovarian cancer. This was also the case for stratum II-III patients (previously reported). The addition of G to TC in patients with first diagnosis of ovarian cancer cannot be recommended. [Table: see text]

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A Novel Prognostic Risk Score Based on Ferroptosis-related LncRNAs Predicting Ovarian Cancer Patient Survival

10.21203/rs.3.rs-1188209/v1 ◽

2021 ◽

Author(s):

Keyu Chen ◽

Xiaohong Li ◽

Caixia Qi

Keyword(s):

Ovarian Cancer ◽

Risk Score ◽

Cox Regression ◽

Characteristic Curve ◽

Therapeutic Targets ◽

Cancer Prognosis ◽

Cancer Tissue ◽

Clinical Implementation ◽

Tumour Immunity ◽

Cox Regression Analysis

Abstract Background: Long non-coding RNAs (lncRNAs) are thought to be associated with several processes during cancer development and have been shown to be involved in the regulation of ferroptosis. Ovarian cancer is highly malignant tumour with a poor prognosis. The identification biomarkers with prognostic value in ovarian cancer may improve patient outcomes and can help to elucidate potential future therapeutic targets.Results: We report differential expression of 187 ferroptosis-related lncRNAs in normal and ovarian cancer tissue. Using univariate and multivariable Cox regression analysis, we identified four lncRNAs that were strongly associated with prognosis. We constructed a prognostic risk score based on these four lncRNAs which was effectively able to distinguish between low- and high-risk OC patients based on survival time. Univariate and multivariable Cox regression analyses and time-related receiver operating characteristic curve analyses revealed that this risk score represented an independent prognostic factor in patients with ovarian cancer. For clinical implementation, we developed a nomogram based on the prognostic feature and patient age. Gene Ontology(GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the four ferroptosis-related lncRNAs were related to tumour immunity.Conclusions: we identify four novel ferroptosis-related lncRNAs as predictors of ovarian cancer prognosis and potential future therapeutic targets for ovarian cancer.

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