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BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC. ispartof: CANCER vol:129 issue:5 pages:697-713 ispartof: location:United States status: published

INTRODUCTION: Serous ovarian carcinomas constitute the largest group of epithelial ovarian cancer (60%-75%) and are further classified into high- and low-grade serous carcinoma. Low-grade serous carcinoma (LGSC) is a relatively rare subtype (approximately 5% of serous carcinomas) and epidemiologic studies of large cohorts are scarce. With the present study we aimed to report trends in stage, primary treatment and relative survival of LGSC of the ovary in a large cohort of patients in an effort to identify opportunities to improve clinical practice and outcome of this relatively rare disease.MATERIAL AND METHODS: Patients diagnosed with LGSC between 2000 and 2019 were identified from the Netherlands Cancer Registry (n = 855). Trends in FIGO stages and primary treatment were analyzed with the Cochran-Armitage trend test, and differences in and trends of 5-year relative survival were analyzed using multivariable Poisson regression.RESULTS: Over time, LGSC was increasingly diagnosed as stage III (39.9%-59.0%) and IV disease (5.7%-14.4%) and less often as stage I (34.6%-13.5%; p 1 cm residual disease in only 15/252 patients (6%), compared with 17/95 patients (17.9%) after interval surgery. Full cohort 5-year survival was 61% and survival after primary debulking surgery was superior to the outcome following interval debulking surgery (60% vs 34%). Survival following primary debulking surgery without macroscopic residual disease (73%) was better compared with ≤1 cm (47%) and >1 cm residual disease (22%). Survival following interval debulking surgery without macroscopic residual disease (51%) was significantly higher than after >1 cm residual disease (24%). Except FIGO stage II (85%-92%), survival did not change significantly over time.CONCLUSIONS: Over the years, LGSC has been diagnosed as FIGO stage III and stage IV disease more often and interval debulking surgery has been increasingly preferred over primary debulking in these patients. Relative survival did not change over time (except for stage II) and worse survival outcomes after interval debulking surgery were observed. The results support the common recommendation to perform primary debulking surgery in patients eligible for primary surgery.

Contains fulltext : 291158.pdf (Publisher’s version ) (Open Access) BACKGROUND: Fifteen percent of patients with endometrial cancer (EC) have advanced stage disease or develop a recurrence. Progestins have been applied as systemic treatment for decades, but there is limited evidence on response prediction with biomarkers and toxicity. OBJECTIVES: To review the response and toxicity of progestin therapy and stratify response to progesterone receptor (PR) expression and tumour grade. SEARCH STRATEGY: We used the search terms 'Endometrial cancer', 'Progestins', 'Disease progression', 'Recurrence' and related terms in Pubmed, Embase and Cochrane databases. SELECTION CRITERIA: Studies on patients with advanced stage or recurrent EC treated with progestin monotherapy were included. Studies on adjuvant therapy, with fewer than ten cases and with sarcoma histology were excluded. DATA COLLECTION AND ANALYSIS: Evaluation for bias was performed with the Revised Cochrane RoB2 tool for randomised studies and the ROBINS-I tool for non-randomised studies. A random effects meta-analysis was performed with the overall response rate (ORR), clinical benefit rate and toxicity as primary outcome measures. MAIN RESULTS: Twenty-six studies (1639 patients) were included. The ORR of progestin therapy was 30% (95% CI 25-36), the clinical benefit rate was 52% (95% CI 42-61). In PR-positive EC, the ORR was 55%, compared with 12% in PR-negative disease (risk difference 43%, 95% CI 15-71). Severe toxicity occurred in 6.5%. CONCLUSIONS: Progestin therapy is a viable treatment option in patients with advanced stage and recurrent EC with low toxicity and high ORR in PR-positive disease. The role of PR expression in relation to progression-free survival and overall survival is unclear. 01 januari 2023

ObjectiveComplication rates after cytoreductive surgery are important quality indicators for hospitals that treat patients with advanced-stage ovarian cancer. Case-mix factors are patient and tumor characteristics that may influence hospital outcomes such as the complication rates. Currently, no case-mix adjustment model exists for complications after cytoreductive surgery; therefore, it is unclear whether hospitals are being compared correctly. This study aims to develop the first case-mix adjustment model for complications after surgery for advanced-stage ovarian cancer, enabling an accurate comparison between hospitals.MethodsThis population-based study included all patients undergoing cytoreductive surgery for advanced-stage ovarian cancer registered in the Netherlands in 2017–2019. Case-mix variables were identified and assessed using logistic regressions. The primary outcome was the composite outcome measure ‘complicated course’. Patients had a complicated course when at least one of the following criteria were met: (1) any complication combined with a prolonged length of hospital stay; (2) complication requiring reintervention; (3) any complication with a prolonged length of stay in the intensive care unit; or (4) 30-day mortality or in-hospital mortality during admission following surgery. Inter-hospital variation was analyzed using univariable and multivariable logistic regressions and visualized using funnel plots.ResultsA total of 1822 patients were included, of which 10.7% (n=195) had a complicated course. Comorbidity and tumor stage had a significant impact on complicated course rates in multivariable logistic regression. Inter-hospital variation was not significant for case-mix factors. Complicated course rates ranged between 2.2% and 29.1%, and case-mix adjusted observed/expected ratios ranged from 0.20 to 2.67 between hospitals. Three hospitals performed outside the confidence intervals for complicated course rates. These hospitals remained outliers after case-mix adjustment.ConclusionThere is variation between hospitals regarding complicated course rates after cytoreductive surgery for ovarian cancer in the Netherlands. While comorbidity and tumor stage significantly affected the complicated course rates, adjusting for case-mix factors did not significantly affect hospital outcomes. The limited impact of case-mix adjustment could be a result of the Dutch centralized healthcare model.

PURPOSE OF REVIEW: Mucinous ovarian cancers (MOCs) are categorized into infiltrative and expansile subtypes. These subtypes have different characteristics and prognoses. Patients with clinical early-stage disease of both subtypes currently undergo surgical staging (peritoneal washing, biopsies, omentectomy). Peritoneal and lymph node metastases of expansile MOC are rare, but whereas lymph node sampling (LNS) is omitted in these patients, peritoneal staging is not. Therefore, we collected all available MOC data to determine whether staging surgeries could safely be omitted in clinical early-stage expansile and infiltrative MOC. RECENT FINDINGS: Current literature confirms that peritoneal metastases are rare in expansile MOC: more than 90% had early-stage disease. Only 3.4% of the patients with clinical early-stage expansile MOC had positive peritoneal washings at surgical staging. Patients with infiltrative MOC were diagnosed more frequently with advanced-stage disease (21-54%). Moreover, upstaging clinical early-stage infiltrative MOC based on positive cytology, peritoneum and omentum metastases occurred in 10.3% of the patients. Therefore, we recommend that patients with early-stage infiltrative MOC undergo peritoneal staging and LNS. However, in addition to omitting LNS, we can also safely recommend omitting peritoneal staging in patients with early-stage expansile MOC. SUMMARY: Peritoneal metastases are rare in clinical early-stage expansile MOC and peritoneal staging can therefore safely be omitted.

How the tumor’s genetic make up (i.e. molecular profiles) is associated with changes in the tumor microenvironment (TME) in high-grade serous ovarian cancer (HGSOC) is incompletely understood, while these factors influence survival. To investigate this we analyzed the TME and molecular profiles (homologous recombination deficiency (HRD) and Cyclin E1 (CCNE1) amplification) of HGSOC and assessed their associations with each other and overall survival (OS). Patients with advanced-stage HGSOC treated in three Dutch hospitals between 2008-2015 were included. Patient, treatment, and outcome data were collected from medical records. BRCA1/2 mutation, BRCA1 promotor methylation analyses, and copy number variations were used to define five molecular profiles. Immunecell densites were assessed with immunohistochemical staining for T- (CD8 and CD103), B- cells (CD20) and macrophages (CD68). This resulted in the assessability of 348 patients who were categorized as; BRCA mutation or promotor methylation (BRCAm) (30%), non-BRCA mutated HRD (19%), CCNE1-amplification (13%), non-BRCAmut HRD and CCNE1-amplification (double classifier) (20%), and no specific molecular profile (NSMP) (18%). BRCAm tumors showed the highest immune cell densities and CCNE1-amplification the lowest. BRCAm showed the most favorable OS (52.5months), compared to non-BRCAmut HRD (41.0months), CCNE1-amplification (28.0months), double classifier (27.8months), and NSMP (35.4months). CCNE1-amplification and double classifier remained to have a significantly worse OS in multivariable analysis. Higher immune cell densities showed a favorable OS compared to lower densities, also within the molecular profiles. CD8+, CD20+, and CD103+ cells remained associated with OS in multivariable analysis. These results depict that both molecular profiles and TME are associated with OS. Immune composition for lymphocytes and macrophages differ per molecular profile, with higher immune cell densities showing a favorable OS, even within the profiles. HGSOC does not reflect one entity but comprises different variants based on molecular profiles and TME, which ideally is translated into tailored treatment approaches.

Computed tomography measurements of total skeletal muscle area can detect changes and predict overall survival (OS) in patients with advanced ovarian cancer. This study investigates whether assessment of psoas muscle area reflects total muscle area and can be used to assess sarcopenia in ovarian cancer patients.Ovarian cancer patients (n = 150) treated with induction chemotherapy and interval debulking were enrolled retrospectively in this longitudinal study. Muscle was measured cross sectionally with computed tomography in three ways: (i) software quantification of total skeletal muscle area (SMA); (ii) software quantification of psoas muscle area (PA); and (iii) manual measurement of length and width of the psoas muscle to derive the psoas surface area (PLW). Pearson correlation between the different methods was studied. Patients were divided into two groups based on the extent of change in muscle area, and agreement was measured with kappa coefficients. Cox-regression was used to test predictors for OS.Correlation between SMA and both psoas muscle area measurements was poor (r = 0.52 and 0.39 for PA and PLW, respectively). After categorizing patients into muscle loss or gain, kappa agreement was also poor for all comparisons (all κ 0.40). In regression analysis, SMA loss was predictive of poor OS (hazard ratio 1.698 (95%CI 1.038-2.778), P = 0.035). No relationship with OS was seen for PA or PLW loss.Change in psoas muscle area is not representative of total muscle area change and should not be used to substitute total skeletal muscle to predict survival in patients with ovarian cancer.

Background Malnutrition, weight loss, and muscle wasting (sarcopenia) are common among women with advanced ovarian cancer and have been associated with adverse clinical outcomes and survival. Our objective is to investigate overall survival (OS) related to changes in skeletal muscle (SM) for patients with advanced ovarian cancer treated with neoadjuvant chemotherapy and interval debulking. Methods Ovarian cancer patients (n = 123) treated with neoadjuvant chemotherapy and interval debulking in the area of Maastricht (the Netherlands) between 2000 and 2014 were included retrospectively. Surface areas of SM and adipose tissue were defined on computed tomography at the level of the third lumbar vertebra. Low SM at baseline and SM changes during chemotherapy were compared with Kaplan Meier curves, and Cox‐regression models were applied to test predictors of OS. Results Median OS for patients who lost SM (n = 83) was 916 ± 99 days, which was significantly different from median OS for patients who maintained or gained SM (n = 40), which was 1431 ± 470 days (P = 0.004). Loss of SM was also a significant predictor of OS in multivariable Cox‐regression analysis (hazard ratio 1.773 (95%CI: 1.018–3.088), P = 0.043). Low baseline SM did not influence survival. Conclusions Patients with ovarian cancer have a worse survival when they lose SM during neoadjuvant chemotherapy. Evaluation of low SM at a specific time point is not prognostic for OS. External and prospective validation of these findings is imperative. Nutritional, pharmacological, and/or physical intervention studies are necessary to establish whether SM impairment can be prevented to prolong ovarian cancer survival.

Current screening methods for uterine cervical cancer such as Papanicolaou smears and/or high risk human Papillomavirus (HR-HPV) detection have a high negative predictive value but a low positive predictive value for the presence of high grade cervical lesions. Therefore, new parameters are needed to reduce the rate of unnecessary referrals for colposcopy. The predictive value of the HPV multiplex ligation-dependent probe amplification (MLPA) assay, which can assess simultaneously HPV16/18 viral load and viral integration, was evaluated. The assay was applied to 170 cervical cytological samples, and the results were correlated with the matching histological follow-up. The GP5+/6+ assay and qPCR were used as a control for HR-HPV typing. The MLPA assay classified a higher percentage of cases as high-risk (high-viral load and/or viral integration) with higher grades of dysplasia. There was a high correlation between the HPV MLPA assay and qPCR for viral load and HPV genotyping, and between the MLPA assay and the GP5+/6+ assay for HPV genotyping. The sensitivity and specificity of the HPV MLPA assay for the detection of high-grade lesions were 44% and 93%, respectively. This study demonstrates that the HPV MLPA assay can reliably detect HPV 16/18, viral load, and viral integration in cytological samples. Also, high-risk classification correlated well with the presence of high-grade dysplasia. However, for the implementation of the MLPA assay into clinical practice, additional HR-HPV types need to be included to increase the sensitivity of the assay, and thereby increase its negative predictive value.