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Objective: To examine clinical trends in Denmark for younger and older epithelial ovarian cancer (EOC) patients, focusing on incidence, treatment, and survival changes., Methods: We included a nationwide cohort diagnosed with EOC from 2005 to 2018. We described age-standardized incidence, surgical patterns, residual disease trends, and cancer-specific survival stratified by age (<70 and ≥ 70 years), stage, and period (2005-09, 2010-13, 2014-18)., Results: We included 7522 patients. The incidence decreased from 16.3 (2005) to 11.4 (2018) per 100,000 woman-years, driven by the younger cohort. While the proportion of patients with stage IIIC-IV disease undergoing primary debulking surgery (PDS) decreased, the proportion of patients having interval debulking surgery (IDS) and no debulking surgery increased significantly. In 2014-18, 36% and 24% had PDS for younger and older patients, respectively, compared to 72% and 62% in 2005-09. In both age cohorts, the proportion of patients debulked to no residual disease increased significantly among patients with stage IIIC-IV and in the total cohort. Two-year cancer-specific survival increased from 75% (2005-09) to 84% (2014-18) for younger patients and from 53% to 66% for older patients. After adjusting for potential confounders, age ≥ 70 was associated with a 1.4-fold increased risk of cancer-specific death (95% confidence interval: 1.2,1.5)., Conclusions: The proportion of patients with advanced EOC not undergoing PDS or IDS increased significantly. During the same period, patients debulked to no residual disease, and cancer-specific survival increased. However, a survival gap in favor of the younger patients remains after adjusting for potential confounders., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The value of surgical staging of apparent early stage epithelial ovarian carcinoma (EOC) is unclear. The aim of this study was to evaluate the importance of surgical staging on the stage of disease and treatment plan., Material and Methods: All patients with apparent stage I EOC undergoing staging from 01/01/2005 to 30/06/2017 in all Danish hospitals and in the Radboud University Hospital Nijmegen, the Netherlands, were evaluated to identify the pathological findings responsible for upstaging and changes in treatment plans., Results: We included 1234 patients with apparent stage I EOC. The staging steps often missed were the biopsy from the right diaphragmatic surface (missed in 96.9% of all patients) and lymph node (LN) sampling or lymphadenectomy (missed in 65.5% of all patients). Upstaging occurred in 393 patients (31.8%) due to microscopic spread to both ovaries (0.8%); ovarian surface (5.8%); positive cytology (10.0%); fallopian tubes (3.1%), ovary (1.5%) and/or uterus serosa (1.2%); pelvic peritoneum (4.3%); LNs (4.7%); omentum (3.7%); abdominal peritoneum (0.6%) and right diaphragmatic surface (2.6%). Of the 393 upstaged patients, 138 (35.1%) had an altered treatment plan due to metastases found by surgical staging., Conclusion: Staging was incomplete in most patients, mainly because a biopsy of the diaphragm was omitted. However, surgical staging led to adjuvant treatment in 35.1% of the upstaged patients. Peritoneal biopsies (para-colic gutters and right diaphragm) were of little value, since few patients had an adjustment of treatment plan due to these biopsies. Omitting these biopsies, in the absence of peritoneal abnormalities, is justifiable., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370., Methods: Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers)., Results: We found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations., Conclusions: rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aim: To develop and validate a biomarker-based index to optimize referral and diagnosis of patients with suspected ovarian cancer. Furthermore, to compare this new index with the Risk of Malignancy Index (RMI) and Risk of Ovarian Malignancy Algorithm (ROMA)., Patients and Methods: A training study, consisting of patients with benign ovarian disease (n=809) and ovarian cancer (n=246), was used to develop the Copenhagen Index (CPH-I) utilizing the variables serum HE4, serum CA125 and patient age. Eight international studies provided the validation population; comprising 1060 patients with benign ovarian masses and 550 patients with ovarian cancer., Results: Overall, 2665 patients were included. CPH-I was highly significant in discriminating benign from malignant ovarian disease. At the defined cut-off of 0.070 for CPH-I the sensitivity and specificity were 95.0% and 78.4% respectively in the training cohort and 82.0% and 88.4% in the validation cohort. Comparison of CPH-I, ROMA and RMI demonstrated area-under-curve (AUC) at 0.960, 0.954 and 0.959 respectively in the training study and 0.951, 0.953 and 0.935 respectively in the validation study. Using a sensitivity of 95.0%, the specificities for CPH-I, ROMA and RMI in the training cohort were 78.4%, 71.7% and 81.5% respectively, and in the validation cohort 67.3%, 70.7% and 69.5% respectively., Conclusion: All three indices perform well at the clinically relevant sensitivity of 95%, but CPH-I, unlike RMI and ROMA, is independent of ultrasound and menopausal status, and may provide a simple index to optimize referral of women with suspected ovarian cancer., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: The aim of this systematic review is to analyze data on risk factors, epidemiology, clinicopathology and molecular biology from studies comparing primary peritoneal cancer, fallopian tube cancer and ovarian cancer of serous histology, in order to achieve a greater understanding of whether or not these disorders should be considered as separate entities., Methods: A systematic literature search was conducted in PubMed and MEDLINE. Case-control studies comparing primary serous peritoneal or fallopian tube carcinomas with primary serous ovarian carcinomas or a control group were included., Results: Twenty-eight studies were found eligible. Primary peritoneal cancer patients were older, had higher parity, were more often obese and had poorer survival compared to ovarian cancer patients. Differences in protein expression patterns of Her2/neu, estrogen and progestin receptors and frequency of loss of heterozygosity differed between primary peritoneal cancer and primary ovarian cancer patients. No major differences were found between primary fallopian tube cancer and primary ovarian cancer. The proportion of serous tubal intraepithelial carcinomas (STIC) was lower in primary peritoneal cancer and primary ovarian cancer compared to primary fallopian tube cancer., Conclusion: Except from differences in the proportion of STIC only few differences between primary fallopian tube cancer and primary ovarian cancer have been found. In contrast, observed differences in risk factor profile, clinicopathologic and prognostic factors, as well as in the molecular patterns, indicate that peritoneal cancer and ovarian cancer may be linked to different carcinogenic pathways., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: To determine the WT1 expression level in tumor tissues from 774 women with an epithelial ovarian tumor. Secondly, to evaluate whether WT1 tissue expression levels correlate with clinico-pathological parameters and finally to investigate the prognostic value of WT1 expression levels in ovarian cancer (OC) patients., Methods: Using tissue array we analyzed the WT1 expression level in tissues from 186 women with Low Malignant Potential tumors (LMP) (160 stage I, 5 stage II and 21 stage III) and 560 OC patients (160 stage I, 60 stage II, 289 stage III and 51 stage IV)., Results: Using 10% as cut-off level for WT1 overexpression an overall of 19% LMPs and 17% carcinomas, respectively, were found positive. For both, a higher proportion of positive tumors was found in the serous subtype compared to other histological subtypes (p<0.0001). Kaplan-Meier survival analysis stratified by FIGO stage performed on cases using a 10% cut-off showed a shorter disease specific survival in patients with a positive WT1 expression in the tumor tissue. In a Cox survival analysis including 559 stage I to IV OC prognostic factors included FIGO stage (II vs. I: HR=2.74, 95% CI: 1.42-5.29; III vs. II: HR=2.23, 95% CI: 1.49-3.36; IV vs. III: HR=1.75, 95% CI: 1.25-2.44), residual tumor after primary surgery (HR=2.82, 95% CI: 1.87-4.26), age at diagnosis (HR=1.02, 95% CI: 1.01-1.03), histological grade 3 of tumor versus grade 1 (grade 2 vs. grade 1: HR=1.31, 95% CI: 0.95-1.81; grade 3 vs. grade 1: HR=1.51, 95% CI: 1.08-2.09) and other histological tumor types vs. serous (mucinous vs. serous: HR=0.91, 95% CI: 0.53-1.56; endometrioid vs. serous: HR=1.02, 95% CI: 0.69-1.50; other histological types vs. serous: HR=1.40, 95% CI: 1.01-1.95). WT1 expression (HR=1.22, 95% CI: 0.94-1.59) had statistically no significant independent impact on survival., Conclusion: In conclusion, based on our analyses we found that WT1 expression in clinical settings may be of limited prognostic value in Danish OC patients.

Objectives: To determine the CA125 tissue expression levels in borderline and invasive epithelial ovarian tumor tissues. Secondly, to evaluate whether CA125 tissue expression levels correlate with clinico-pathological parameters and serum CA125 levels and finally to investigate the prognostic value of tissue CA125 expression levels in ovarian cancer (OC) patients., Methods: We designed tissue arrays (TA) and analyzed the CA125 expression in tissues from 778 Danish women with an ovarian tumor. Furthermore, corresponding preoperative blood samples obtained before surgery were collected from 382 women with OC., Results: Significantly more CA125 expression positive tumors (no expression vs. expression) were found in the serous subtype compared to the percentage of positive tumors in mucinous, endometroid and other subtypes for patients both with borderline ovarian tumors and with OC (p<0.00001, p<0.00001). Similarly, a positive significant correlation was found between elevated serum CA125 levels and elevated levels of CA125 tissue expression (N=382 stage I-IV OC, Spearman rho=0.31, p<0.0001) (N=206 stage III OC, Spearman rho=0.30, p<0.0001). We found a significantly shorter survival for stage III/IV OC patients with no CA125 tissue expression compared to stage III/IV OC patients with positive CA125 tissue expression (p=0.0003)., Conclusion: Our finding that tissue CA125 expression was lacking in late stage primary OC tumor of Danish women with poor survival may be of value in selecting patients as eligible candidates for individually based treatments.

Objectives: The p53 gene, a tumor suppressor gene located on the short arm of chromosome 17 (17p13), has been found mutated in 30-80% of epithelial ovarian cancers (OC), with the most frequently detected mutations in the conserved regions of the gene. A small number of studies investigated the survival of patients with p53 mutations in OC, but their conclusions are not in agreement., Methods: We analyzed the frequency of p53 mutations in 124 Danish women with OC, using Single-Stranded Conformation Polymorphism analysis in addition with DNA sequencing and evaluated if mutations correlated with clinicopathological parameters and with patient survival., Results: Thirty-five (28%) ovarian tumors were found to contain one or more p53 variations, two of which were considered polymorphisms. Twenty-seven (82%) mutations were single nucleotide substitutions of which 23 (85%) were missense mutations and therefore led to amino acid substitutions. Significantly shorter survival was found for stage III/IV patients with a p53 missense mutation compared to stage III/IV OC patients with wild type p53 (P = 0.0018). Multivariate Cox regression analysis restricted to 107 OC patients with a p53 missense mutation or p53 wild type in the tumor tissue and with information on radicality of primary surgery showed that missense p53 mutation (HR = 2.5, 95% CI: 1.21-4.98), radicality after primary surgery (HR = 1.7, 95% CI: 1.04-2.88), tetranectin (mg/l: HR = 0.78, 95% CI: 0.67-0.91) and stage (I vs. III: HR = 0.30, 95% CI: 0.10-0.92, II vs. III: HR = 0.24, 95% CI: 0.05-1.05, IV vs. III: HR = 2.70, 95% CI: 1.22-5.98) were independent prognostic factors., Conclusion: Missense mutations in the conserved regions of p53 may be of prognostic value in Danish OC patients.

Objective: Activation of ras oncogenes has been demonstrated in ovarian tumours. All the reported studies are based on a relatively small number of patients and the results therefore remain a subject of debate., Methods: In this study, we analyzed the presence of mutations at codons 12 and 13 of the K-ras gene in 165 Danish women with ovarian tumours, including 138 invasive ovarian cancers and 27 borderline ovarian tumours, using a restriction fragment length polymorphism-polymerase chain reaction technique and evaluated whether such alterations were associated with the clinicopathological parameters of the patients and survival., Results: K-ras codon 12 gene mutations were found in 8.7% of ovarian cancer patients and in 14.8% of the borderline ovarian tumour patients. A K-ras codon 13 gene mutation was found in 1.5% of ovarian cancer patients. K-ras mutations were found with a significantly higher frequency in mucinous tumours compared to serous tumours (P = 0.011)., Conclusions: Mutation frequency was correlated with the histological type of tumour, but not with stage, radicality of operation, and age. Furthermore, no significant difference in survival was demonstrated between patients with or without K-ras mutation, neither in the univariate nor in the multivariate survival analyses.

Objective: The aim of the study was to examine the prognostic values of, respectively, tetranectin (TN) and CA-125 measured in serum from patients presenting with relapse of ovarian cancer (OC)., Methods: TN and CA-125 were measured in serum samples from 75 patients with relapse of OC before the start of second-line chemotherapy. The endpoint used was death of OC. The variables were analyzed by univariate life table analysis and multivariate Cox analysis., Results: A significantly shortened survival was found for patients with low serum TN values compared to patients with serum TN levels above one of the cutoff levels. The survivals are illustrated by life tables. No prognostic function was found for CA-125. TN and relapse

Serum tetranectin (Se-TN) and CA-125 were measured in 315 patients with a pelvic tumor and 458 healthy females. At a false-positive rate of 0.7% the sensitivity for ovarian cancer stage 1 and 2 was 33% for Se-TN and 76% for both CA 125 and an index based on Se-TN and CA 125 (Index 1). At a false-positive rate of 0.4% the sensitivity was 29% for Se-TN, 62% for CA 125 (35 U/ml), and 76% for Index 1. A negative correlation was found between the Se-TN level and the stage of cancer. The sensitivity for benign tumors was 6% for Se-TN, 17% for CA 125, and 21% for Index 1 at a false-positive rate of 0.4%. In the present study the sensitivity and specificity levels of Se-TN were not sufficiently high to warrant the use of Se-TN as an individual marker for ovarian cancer. The sensitivity rose with the index-based Se-TN and CA 125 without causing a concomitant increase in the rate of false-positive results. None of the markers rose to levels that would allow their use in clinical diagnosis to discriminate between localized cancer and benign tumors.

Plasma tetranectin was measured in 67 controls, 121 patients with a benign or malignant ovarian tumor, and 24 patients with another benign gynecologic disease to evaluate the predictive value of plasma tetranectin. A significant reduction of plasma tetranectin was found in every malignant tumor type except for mucinous tumors. Further a significant correlation was found between stage of tumors and plasma tetranectin. Depending on the cutoff level the sensitivity for stage 1 cancer ranged from 52 to 71%. In stage 1 + 2 the sensitivity ranged from 58 to 75% and for advanced cancer (stage 3 + 4) from 80 to 95%. The corresponding specificities ranged from 97 to 84%. Plasma tetranectin may be a useful tool for detecting early stages of ovarian cancer.