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Introduction: The clinical role of the molecular endometrial cancer (EC) classification has not been fully explored in patients staged with lymphadenectomy or without adjuvant treatment, conditions that could potentially moderate the prognostic value of the classification. We aimed to evaluate the clinical outcome of the molecular subgroups in patients with high-grade EC staged by lymphadenectomy and those without adjuvant treatment.Methods: DNA-sequencing for the detection of pathogenic POLE-exonuclease domain mutations and immunohistochemistry for mismatch repair (MMR) proteins and p53 expression were performed on 412 high-grade EC from the Danish Gynaecological Cancer Database (2005-2012) to classify them as POLE-ultramutated (POLEmut), MMR-deficient (MMRd), p53-mutant (p53abn), or no specific molecular profile (NSMP). Patients with stage IV or residual disease after surgery were excluded. Kaplan-Meier method, log-rank test and Cox proportional hazard models were used for analysis.Results: Molecular analysis was successful in 367 EC; 251 patients had undergone lymphadenectomy. Five-year recurrence rates in this subgroup of patients was 36.7% for women with p53abn EC, 0.0% for POLEmut EC, 13.4% for MMRd EC and 42.9% for NSMP EC (p < 0.001). Similar results were observed among stage IA-IB patients. Among patients without adjuvant treatment (n = 264), none with POLEmut EC (n = 26) had a recurrence.Conclusion: The molecular EC classification has strong prognostic value, independent of clinicopathological factors, also among high-grade EC patients staged by lymphadenectomy and those without adjuvant treatment. The unfavourable prognosis of early-stage p53abn EC is not due to undetected lymph node metastasis, and the indolent behaviour of POLEmut EC is independent of adjuvant treatment.

Cervical cancer is the fourth most common cancer in women worldwide. Squamous cell carcinoma (SCC) and adenocarcinoma (AC) are the most common histological types, with AC patients having worse prognosis. Over the last two decades, incidence rates of AC have increased, highlighting the importance of further understanding AC tumorigenesis, and the need to investigate new treatment options. The cytokine TGF-beta functions as a tumour suppressor in healthy tissue. However, in tumour cells this suppressive function can be overcome. Therefore there is an increasing interest in using TGF-beta inhibitors in the treatment of cancer. Here, we hypothesize that TGF-beta plays a different role in SCC and AC. Analysis of RNA-seq data from the TCGA, using a TGF-beta response signature, resulted in separate clustering of the two subtypes. We further investigated the expression of TGF-beta-signalling related proteins (T beta R1/2, SMAD4, pSMAD2, PAI-1, alpha v beta 6 and MMP2/9) in a cohort of 62 AC patients. Low T beta R2 and SMAD4 expression was associated with worse survival in AC patients and interestingly, high PAI-1 and alpha v beta 6 expression was also correlated with worse survival. Similar correlations of T beta R2, PAI-1 and alpha v beta 6 with clinical parameters were found in previously reported SCC analyses. However, when comparing expression levels between SCC and AC patient samples, pSMAD2, SMAD4, PAI-1 and alpha v beta 6 showed lower expression in AC compared to SCC. Because of the low expression of core T beta R1/2, (p-)SMAD2 and SMAD4 proteins and the correlation with worse prognosis, TGF-beta pathway most likely leads to tumour inhibitory effects in AC and therefore the use of TGF-beta inhibitors would not be recommended. However, given the correlation of PAI-1 and alpha v beta 6 with poor prognosis, the use of TGF- beta inhibitors might be of interest in SCC and in the subsets of AC patients with high expression of these TGF-beta associated proteins.

Objectives: We have developed two Dutch questionnaires to assess the shared decision-making (SDM) process in oncology; the iSHAREpatient and iSHAREphysician. In this study, we aimed to determine: scores, construct validity, test-retest agreement (iSHAREpatient), and inter-rater (iSHAREpatient-iSHAREphysician) agreement.Methods: Physicians from seven Dutch hospitals recruited cancer patients, and completed the iSHAREphysician and SDM-Questionnaire-physician version. Their patients completed the: iSHAREpatient, nine-item SDM-Questionnaire, Decisional Conflict Scale, Combined Outcome Measure for Risk communication And treatment Decision-making Effectiveness, and five-item Perceived Efficacy in Patient-Physician Interactions. We formulated, respectively, one (iSHAREphysician) and 10 (iSHAREpatient) a priori hypotheses regarding correlations between the iSHARE questionnaires and questionnaires assessing related constructs. To assess test-retest agreement patients completed the iSHAREpatient again 1-2 weeks later.Results: In total, 151 treatment decision-making processes with unique patients were rated. Dimension and total iSHARE scores were high both in patients and physicians. The hypothesis on the iSHAREphysician and 9/10 hypotheses on the iSHAREpatient were confirmed. Test-retest and inter-rater agreement were >.60 for most items.Conclusions: The iSHARE questionnaires show high scores, have good construct validity, substantial test-retest agreement, and moderate inter-rater agreement.Practice implications: Results from the iSHARE questionnaires can inform both physician- and patient-directed efforts to improve SDM in clinical practice. (C) 2021 The Author(s). Published by Elsevier B.V. CC_BY_4.0

Background Endometrial cancer (EC) risk in BReast CAncer gene 1/2 (BRCA1/2) mutation carriers is uncertain; therefore, we assessed this in a large Dutch nationwide cohort study. Methods We selected 5980 BRCA1/2 (3788 BRCA1, 2151 gBRCA2, 41 both BRCA1/BRCA2) and 8451 non-BRCA1/2 mutation carriers from the Hereditary Breast and Ovarian cancer study, the Netherlands cohort. Follow-up started at the date of the nationwide Dutch Pathology Registry coverage (January 1, 1989) or at the age of 25 years (whichever came last) and ended at date of EC diagnosis, last follow-up, or death (whichever came first). EC risk in BRCA1/2 mutation carriers was compared with 1) the general population, estimating standardized incidence ratios (SIRs) based on Dutch population-based incidence rates; and 2) non-BRCA1/2 mutation carriers, using Cox-regression analyses, expressed as hazard ratio (HR). Statistical tests were 2-sided. Results Fifty-eight BRCA1/2 and 33 non-BRCA1/2 mutation carriers developed EC over 119 296 and 160 841 person-years, respectively (SIR = 2.83, 95% confidence interval [CI] = 2.18 to 3.65; and HR = 2.37, 95% CI = 1.53 to 3.69, respectively). gBRCA1 mutation carriers showed increased risks for EC overall (SIR = 3.51, 95% CI = 2.61 to 4.72; HR = 2.91, 95% CI = 1.83 to 4.66), serous-like EC (SIR = 12.64, 95% CI = 7.62 to 20.96; HR = 10.48, 95% CI = 2.95 to 37.20), endometrioid EC (SIR = 2.63, 95% CI = 1.80 to 3.83; HR = 2.01, 95% CI = 1.18 to 3.45), and TP53-mutated EC (HR = 15.71, 95% CI = 4.62 to 53.40). For BRCA2 mutation carriers, overall (SIR = 1.70, 95% CI = 1.01 to 2.87) and serous-like EC risks (SIR = 5.11, 95% CI = 1.92 to 13.63) were increased compared with the general population. Absolute risks by 75 years remained low (overall EC = 3.0%; serous-like EC = 1.1%). Conclusions BRCA1/2 mutation carriers have a two- to threefold increased risk for EC, with highest risk observed for the rare subgroups of serous-like and p53-abnormal EC in BRCA1 mutation carriers.

Purpose: Whether endometrial carcinoma (EC) should be considered part of the gBRCA1/2-associated hereditary breast and ovarian cancer (HBOC) syndrome is topic of debate. We sought to assess whether ECs occurring in gBRCA carriers are enriched for clinicopathologic and molecular characteristics, thereby supporting a causal relationship. Experimental Design: Thirty-eight gBRCA carriers that developed EC were selected from the nationwide cohort study on hereditary breast and ovarian cancer in the Netherlands (HEBON), and these were supplemented with four institutional cases. Tumor tissue was retrieved via PALGA (Dutch Pathology Registry). Nineteen morphologic features were scored and histotype was determined by three expert gynecologic pathologists, blinded for molecular analyses (UCM-OncoPlus Assay including 1213 genes). ECs with LOH of the gBRCA-wild-type allele (gBRCA/LOHpos) were defined “gBRCA-associated,” those without LOH (gBRCA/LOHneg) were defined “sporadic.” Results: LOH could be assessed for 40 ECs (30 gBRCA1, 10 gBRCA2), of which 60% were gBRCA/LOHpos. gBRCA/LOHpos ECs were more frequently of nonendometrioid (58%, P = 0.001) and grade 3 histology (79%, P < 0.001). All but two were in the TP53-mutated TCGA-subgroup (91.7%, P < 0.001). In contrast, gBRCA/LOHneg ECs were mainly grade 1 endometrioid EC (94%) and showed a more heterogeneous distribution of TCGA-molecular subgroups: POLE-mutated (6.3%), MSI-high (25%), NSMP (62.5%), and TP53-mutated (6.3%). Conclusions: We provide novel evidence in favor of EC being part of the gBRCA-associated HBOC-syndrome. gBRCA-associated ECs are enriched for EC subtypes associated with unfavorable clinical outcome. These findings have profound therapeutic consequences as these patients may benefit from treatment strategies such as PARP inhibitors. In addition, it should influence counseling and surveillance of gBRCA carriers.

Objectives: Completeness of staging is an independent prognostic factor for survival in surgical staging procedures for early ovarian cancer. Near-infrared (NIR) fluorescence imaging has the potential to improve the intraoperative assessment of metastatic spread and thus completeness of staging. Feasibility of folate receptor alpha (FR alpha) targeted fluorescence imaging using OTL-38, a folate analogue conjugated to an NIR fluorescent dye, has been previously demonstrated in advanced ovarian cancer. The present authors hypothesized that in early ovarian cancer, fluorescence imaging using OTL-38 could lead to more accurate detection of (occult) ovarian cancer metastases, allowing gynecologic surgeons to take targeted rather than blind biopsy samples. Materials and Methods: Six patients scheduled to undergo a staging procedure for suspected early stage ovarian cancer, received an intravenous infusion of 0.0125 mg/kg OTL38 2-3 hours prior to surgery. The authors assessed tolerability, pharmacokinetics, and the feasibility of intraoperative NIR fluorescence detection of ovarian cancer lesions. Feasibility was evaluated using histopathological analysis, tumor-to-background ratio, and number of false positive and negative lesions. Results: Distinction between a malignant and benign primary tumor was possible with OTL-38 based fluorescence imaging. In addition, nine fluorescent lesions, all lymph node (LN) clusters, were detected intraoperatively. Tumor cells were not demonstrated in any of the biopsy samples taken during staging procedures, including the fluorescent lesions. Therefore all fluorescent LNs were false positives. Conclusions: Metastatic lesions were not present in the patients with confirmed early ovarian cancer; hence the anticipated added value of NIR fluorescence imaging could not be demonstrated in this study. Fluorescence imaging led to resection of non-malignant LNs, as comprehensive lymph node dissection should be pursued in surgical staging procedures, this should not impede application of OTL38. Importantly, fluorescence imaging allowed distinction between a malignant and benign primary tumor and had no false negatives.

In dit proefschrift worden verschillende methodes onderzocht en uitgevoerd om de ovariële functie te sparen bij vrouwen die een behandeling moeten ondergaan als chemotherapie en/ of radiotherapie, die de ovaria kunnen aantasten.Een behandeling is het invriezen van ovariumweefsel en indien een vrouw daadwerkelijk in de overgang is geraakt kan dit weefsel weer in haar eigen lichaam terug geplaatst worden. Het percentage vrouwen dat na ovarium cryopreservatie vervroegd in de overgang komt, is laag. Wij adviseren daarom enkel ovarium cryopreservatie aan te bieden aan vrouwen die door een gonadotoxische behandeling een hoog risico hebben op het ontwikkelen van vervroegde overgang. De autotransplantatie zelf is een effectieve methode met 86% herstel van ovariele functie en 57% levendgeborenen. Het risico van uitzaaiingen van de primaire ziekte in de ovaria bij patiënten met kanker is in onze studie zeer klein gebleken en is deze techniek dus een veilige methode.Ovariumtranspositie voorafgaand aan radiotherapie op het bekken is een veilige en zinvolle behandeling ter preventie van vervroegde overgang en zou standaard aangeboden moeten worden bij vrouwen tot 35 jaar.Met betrekking tot de reeds geaccepteerde techniek van vitrificatie dient men zicht te realiseren, dat alvorens deze techniek te implementeren, er een steile leercurve is.

The thesis is on tailoring therapy in endometrial and cervical cancer. The standard treatment for endometrial cancer is a hysterectomy with bilateral salpingo-oophorectomy. This means definitive sterilisation for women in their fertile age. Treatment with progesterones is widely used, but the treatment needs evaluation and improvement since recurrences are frequent after response. This thesis gives an overview of the literature on this topic in chapter 2. Chapter 3 describes a study on molecular and histopathological changes is women on progesterone treatment to predict responders to therapy. Standard treatment of cervical cancer is a radical hysterectomy. Conventional radical hysterectomy damages nerves in het pelvic area and this results in therapy induced morbidity: urinary, bowel and sexual dysfunction. Chapter 4 is a systematic review and meta-analysis on nerve sparing radical hysterectomy versus non-nerve sparing radical hysterectomy, evaluating survival outcomes and quality of life. In chapter 5 the long term oncological outcomes of the conventional radical hysterectomy, the former Leiden nerve sparing hysterectomy and the nerve sparing Swift procedure, all performed at the LUMC are compared. In chapter 6 fertility and nerve sparing treatment are combined and the results of the abdominal trachelectomy performed at the LUMC is analysed.

Background: The tumour microenvironment comprises a network of immune response and vascularization factors. From this network, we identified immunological and vascularization gene expression clusters and the correlations between the clusters. We subsequently determined which factors were correlated with patient survival in cervical carcinoma. Methods: The expression of 42 genes was investigated in 52 fresh frozen squamous cervical cancer samples by qRT-PCR. Weighted gene co-expression network analysis and mixed-model analyses were performed to identify gene expression clusters. Correlations and survival analyses were further studied at expression cluster and single gene level. Results: We identified four immune response clusters: 'T cells' (CD3E/CD8A/TBX21/IFNG/FOXP3/IDO1), 'Macrophages' (CD4/CD14/CD163), 'Th2' (IL4/IL5/IL13/IL12) and 'Inflammation' (IL6/IL1B/IL8/IL23/IL10/ARG1) and two vascularization clusters: 'Angiogenesis' (VEGFA/FLT1/ANGPT2/ PGF/ICAM1) and 'Vessel maturation' (PECAM1/VCAM1/ANGPT1/SELE/KDR/LGALS9). The 'T cells' module was correlated with all modules except for 'Inflammation', while 'Inflammation' was most significantly correlated with 'Angiogenesis' (p < 0.001). High expression of the 'T cells' cluster was correlated with earlier TNM stage (p = 0.007). High CD3E expression was correlated with improved disease-specific survival (p = 0.022), while high VEGFA expression was correlated with poor disease-specific survival (p = 0.032). Independent predictors of poor disease-specific survival were IL6 (hazard ratio = 2.3, p = 0.011) and a high IL6/IL17 ratio combined with low IL5 expression (hazard ratio = 4.2, p = 0.010). Conclusions: 'Inflammation' marker IL6, especially in combination with low levels of IL5 and IL17, was correlated with poor survival. This suggests that IL6 promotes tumour growth, which may be suppressed by a Th17 and Th2 response. Measuring IL6, IL5 and IL17 expression may improve the accuracy of predicting prognosis in cervical cancer.