The identification of causal BRCA1/2 pathogenic variants (PVs) in epithelial ovarian carcinoma (EOC) aids the selection of patients for genetic counselling and treatment decision-making. Current... Show moreThe identification of causal BRCA1/2 pathogenic variants (PVs) in epithelial ovarian carcinoma (EOC) aids the selection of patients for genetic counselling and treatment decision-making. Current recommendations therefore stress sequencing of all EOCs, regardless of histotype. Although it is recognised that BRCA1/2 PVs cluster in high-grade serous ovarian carcinomas (HGSOC), this view is largely unsubstantiated by detailed analysis. Here, we aimed to analyse the results of BRCA1/2 tumour sequencing in a centrally revised, consecutive, prospective series including all EOC histotypes. Sequencing of n = 946 EOCs revealed BRCA1/2 PVs in 125 samples (13%), only eight of which were found in non-HGSOC histotypes. Specifically, BRCA1/2 PVs were identified in high-grade endometrioid (3/20; 15%), low-grade endometrioid (1/40; 2.5%), low-grade serous (3/67; 4.5%), and clear cell (1/64; 1.6%) EOCs. No PVs were identified in any mucinous ovarian carcinomas tested. By re-evaluation and using loss of heterozygosity and homologous recombination deficiency analyses, we then assessed: (1) whether the eight ‘anomalous’ cases were potentially histologically misclassified and (2) whether the identified variants were likely causal in carcinogenesis. The first ‘anomalous’ non-HGSOC with a BRCA1/2 PV proved to be a misdiagnosed HGSOC. Next, germline BRCA2 variants, found in two p53-abnormal high-grade endometrioid tumours, showed substantial evidence supporting causality. One additional, likely causal variant, found in a p53-wildtype low-grade serous ovarian carcinoma, was of somatic origin. The remaining cases showed retention of the BRCA1/2 wildtype allele, suggestive of non-causal secondary passenger variants. We conclude that likely causal BRCA1/2 variants are present in high-grade endometrioid tumours but are absent from the other EOC histotypes tested. Although the findings require validation, these results seem to justify a transition from universal to histotype-directed sequencing. Furthermore, in-depth functional analysis of tumours harbouring BRCA1/2 variants combined with detailed revision of cancer histotypes can serve as a model in other BRCA1/2-related cancers. Show less
Objective: To study the impact of premenopausal risk-reducing salpingo-oophorectomy (RRSO), compared with postmenopausal RRSO, on urinary incontinence (UI) >= 10 years later.Design: Cross... Show moreObjective: To study the impact of premenopausal risk-reducing salpingo-oophorectomy (RRSO), compared with postmenopausal RRSO, on urinary incontinence (UI) >= 10 years later.Design: Cross-sectional study, nested in a nationwide cohort.Setting: Multicentre in the Netherlands.Population: 750 women (68% BRCA1/2 pathogenic variant carriers) who underwent either premenopausal RRSO (<= 45 years, n = 496) or postmenopausal RRSO (>= 54 years, n = 254). All participants were >= 55 years at the time of the study.Methods: Urinary incontinence was assessed by the urinary distress inventory-6 (UDI-6); a score >= 33.3 indicated symptomatic UI. The incontinence impact questionnaire short form (IIQ-SF) was used to assess the impact on women's health-related quality of life (HR-QoL). Differences between groups were analysed using regression analyses adjusting for current age and other confounders.Main outcome measures: Differences in UDI-6 scores and IIQ-SF scores between women with a premenopausal and a postmenopausal RRSO.Results: Women in the premenopausal RRSO group had slightly higher UDI-6 scores compared with women in the postmenopausal RRSO group (P = 0.053), and their risk of symptomatic UI was non-significantly increased (odds ratio [OR] 2.1, 95% confidence interval [95% CI] 0.93-4.78). A premenopausal RRSO was associated with a higher risk of stress UI (OR 3.5, 95% CI 1.2-10.0) but not with urge UI. The proportions of women with a significant impact of UI on HR-QoL were similar in the premenopausal and postmenopausal RRSO groups (10.4% and 13.0%, respectively; P = 0.46).Conclusions: More than 15 years after premenopausal RRSO, there were no significant differences in overall symptomatic UI between women with a premenopausal and those with a postmenopausal RRSO. Show less
PURPOSETo investigate the prevalence of and clinical factors associated with high-grade serous carcinoma (HGSC) at risk-reducing salpingo-oophorectomy (RRSO) in asymptomatic BRCA1/2-pathogenic... Show morePURPOSETo investigate the prevalence of and clinical factors associated with high-grade serous carcinoma (HGSC) at risk-reducing salpingo-oophorectomy (RRSO) in asymptomatic BRCA1/2-pathogenic variant (PV) carriers.PATIENTS AND METHODSWe included BRCA1/2-PV carriers who underwent RRSO between 1995 and 2018 from the Hereditary Breast and Ovarian cancer in the Netherlands study. All pathology reports were screened, and histopathology reviews were performed for RRSO specimens with epithelial abnormalities or where HGSC developed after normal RRSO. We then compared clinical characteristics, including parity and oral contraceptive pill (OCP) use, for women with and without HGSC at RRSO.RESULTSOf the 2,557 included women, 1,624 had BRCA1, 930 had BRCA2, and three had both BRCA1/2-PV. The median age at RRSO was 43.0 years (range: 25.3-73.8) for BRCA1-PV and 46.8 years (27.6-77.9) for BRCA2-PV carriers. Histopathologic review confirmed 28 of 29 HGSCs and two further HGSCs from among 20 apparently normal RRSO specimens. Thus, 24 (1.5%) BRCA1-PV and 6 (0.6%) BRCA2-PV carriers had HGSC at RRSO, with the fallopian tube identified as the primary site in 73%. The prevalence of HGSC in women who underwent RRSO at the recommended age was 0.4%. Among BRCA1/2-PV carriers, older age at RRSO increased the risk of HGSC and long-term OCP use was protective.CONCLUSIONWe detected HGSC in 1.5% (BRCA1-PV) and 0.6% (BRCA2-PV) of RRSO specimens from asymptomatic BRCA1/2-PV carriers. Consistent with the fallopian tube hypothesis, we found most lesions in the fallopian tube. Our results highlight the importance of timely RRSO with total removal and assessment of the fallopian tubes and show the protective effects of long-term OCP. Show less
Terra, L.; Beekman, M.J.; Engelhardt, E.G.; Heemskerk-Gerritsen, B.A.M.; Beurden, M. van; Lennep, J.E.R. van; ... ; Leeuwen, F.E. van 2023
BACKGROUND: Women with a BRCA1/2 pathogenic variant are advised to undergo premenopausal risk-reducing salpingo-oophorectomy after completion of childbearing, to reduce their risk of ovarian cancer... Show moreBACKGROUND: Women with a BRCA1/2 pathogenic variant are advised to undergo premenopausal risk-reducing salpingo-oophorectomy after completion of childbearing, to reduce their risk of ovarian cancer. Several studies reported less sexual pleasure 1 to 3 years after a pre-menopausal oophorectomy. However, the long-term effects of premeno-pausal oophorectomy on sexual functioning are unknown.OBJECTIVE: This study aimed to study long-term sexual functioning in women at increased familial risk of breast or ovarian cancer who under-went a risk-reducing salpingo-oophorectomy either before the age of 46 years (premenopausal group) or after the age of 54 years (postmenopausal group). Subgroup analyses were performed in the premenopausal group, comparing early (before the age of 41 years) and later (at ages 41-45 years) premenopausal risk-reducing salpingo-oophorectomy.STUDY DESIGN: Between 2018 and 2021, 817 women with a high familial risk of breast or ovarian cancer from an ongoing cohort study were invited to participate in our study. Because of a large difference in age in the study between the premenopausal and postmenopausal salpingo-oophorectomy groups, we restricted the comparison of sexual func-tioning between the groups to 368 women who were 60 to 70 years old at completion of the questionnaire (226 in the premenopausal group and 142 in the postmenopausal group). In 496 women with a premenopausal risk -reducing salpingo-oophorectomy, we compared the sexual functioning between women in the early premenopausal group (n=151) and women in the later premenopausal group (n=345). Differences between groups were analyzed using multiple regression analyses, adjusting for current age, breast cancer history, use of hormone replacement therapy, body mass index, chronic medication use (yes or no), and body image. RESULTS: Mean times since risk-reducing salpingo-oophorectomy were 20.6 years in the premenopausal group and 10.6 years in the postmenopausal group (P<.001). The mean age at questionnaire completion was 62.7 years in the premenopausal group, compared with 67.0 years in the postmenopausal group (P<.001). Compared with 48.9% of women in the postmenopausal group, 47.4% of women in the pre-menopausal group were still sexually active (P=.80). Current sexual pleasure scores were the same for women in the premenopausal group and women in the postmenopausal group (mean pleasure score, 8.6; P=.99). However, women in the premenopausal group more often re-ported substantial discomfort than women in the postmenopausal group (35.6% vs 20.9%; P=.04). After adjusting for confounders, premeno-pausal risk-reducing salpingo-oophorectomy was associated with sub-stantially more discomfort during sexual intercourse than postmenopausal risk-reducing salpingo-oophorectomy (odds ratio, 3.1; 95% confidence interval, 1.04-9.4). Moreover, after premenopausal risk-reducing sal-pingo-oophorectomy, more severe complaints of vaginal dryness were observed (odds ratio, 2.6; 95% confidence interval, 1.4-4.7). Women with a risk-reducing salpingo-oophorectomy before the age of 41 years reported similar pleasure and discomfort scores as women with a risk -reducing salpingo-oophorectomy between ages 41 and 45 years.CONCLUSION: More than 15 years after premenopausal risk-reducing salpingo-oophorectomy, the proportion of sexually active women was com-parable with the proportion of sexually active women with a postmenopausal risk-reducing salpingo-oophorectomy.However, after a premenopausal risk -reducing salpingo-oophorectomy, women experienced more vaginal dryness and more often had substantial sexual discomfort during sexual intercourse. This did not lead to less pleasure with sexual activity. Show less
Objective: To examine the effect of a premenopausal risk-reducing salpingo-oophorectomy (RRSO) in women at increased risk of ovarian cancer on objective and subjective cognition at least 10 years... Show moreObjective: To examine the effect of a premenopausal risk-reducing salpingo-oophorectomy (RRSO) in women at increased risk of ovarian cancer on objective and subjective cognition at least 10 years after RRSO.Design: A cross-sectional study with prospective follow-up, nested in a nationwide cohort.Setting: Multicentre in the Netherlands.Population or Sample: 641 women (66% BRCA1/2 pathogenic variant carriers) who underwent either a premenopausal RRSO <= age 45 (n = 436) or a postmenopausal RRSO >= age 54 (n = 205). All participants were older than 55 years at recruitment.Methods: Participants completed an online cognitive test battery and a questionnaire on subjective cognition. We used multivariable regression analyses, adjusting for age, education, breast cancer, hormone replacement therapy, cardiovascular risk factors and depression.Main Outcome Measures: The influence of RRSO on objective and subjective cognition of women with a premenopausal RRSO compared with women with a postmenopausal RRSO.Results: After adjustment, women with a premenopausal RRSO (mean time since RRSO 18.2 years) performed similarly on objective cognitive tests compared with women with a postmenopausal RRSO (mean time since RRSO 11.9 years). However, they more frequently reported problems with reasoning (odds ratio [OR] 1.8, 95% confidence interval [95% CI] 1.1-3.1) and multitasking (OR 1.9, 95% CI 1.1-3.4) than women with a postmenopausal RRSO. This difference between groups disappeared in an analysis restricted to women of comparable ages (60-70 years).Conclusions: Reassuringly, approximately 18 years after RRSO, we found no association between premenopausal RRSO and objective cognition. Show less
Heemskerk-Gerritsen, B.A.M.; Hollestelle, A.; Asperen, C.J. van; Beek, I. van den; Driel, W.J. van; Engelen, K. van; ... ; Boere, I.A. 2022
IntroductionGermline BRCA1/2-associated epithelial ovarian cancer has been associated with better progression-free survival and overall survival than sporadic epithelial ovarian cancer, but... Show moreIntroductionGermline BRCA1/2-associated epithelial ovarian cancer has been associated with better progression-free survival and overall survival than sporadic epithelial ovarian cancer, but conclusive data are lacking.MethodsWe matched 389 BRCA1-associated and 123 BRCA2-associated epithelial ovarian cancer patients 1:1 to sporadic epithelial ovarian cancer patients on year of birth, year of diagnosis, and FIGO stage (< = IIA/> = IIB). Germline DNA test was performed before or after epithelial ovarian cancer diagnosis. All patients received chemotherapy. We used Cox proportional hazards models to estimate the associations between mutation status (BRCA1 or BRCA2 versus sporadic) and progression-free survival and overall survival. To investigate whether DNA testing after epithelial ovarian cancer diagnosis resulted in survival bias, we performed additional analyses limited to BRCA1/2-associated epithelial ovarian cancer patients with a DNA test result before cancer diagnosis (n = 73 BRCA1; n = 9 BRCA2 and their matched sporadic controls.ResultsThe median follow-up was 4.4 years (range 0.1-30.1). During the first three years after epithelial ovarian cancer diagnosis, progression-free survival was better for BRCA1 (HR 0.88, 95% CI 0.74-1.04) and BRCA2 (HR 0.58, 95% CI 0.41-0.81) patients than for sporadic patients. Overall survival was better during the first six years after epithelial ovarian cancer for BRCA1 (HR 0.7, 95% CI 0.58-0.84) and BRCA2 (HR 0.41, 95% CI 0.29-0.59) patients. After surviving these years, survival benefits disappeared or were in favor of the sporadic patients.ConclusionFor epithelial ovarian cancer patients who received chemotherapy, we confirmed survival benefit for BRCA1 and BRCA2 germline pathogenic variant carriers. This may indicate higher sensitivity to chemotherapy, both in first line treatment and in the recurrent setting. The observed benefit appears to be limited to a relatively short period after epithelial ovarian cancer diagnosis. Show less
Steenbeek, M.P.; Bommel, M.H.D. van; Bulten, J.; Hulsmann, J.A.; Bogaerts, J.; Garcia, C.; ... ; Hullu, J.A. de 2022
PURPOSE After risk-reducing salpingo-oophorectomy (RRSO), BRCA1/2 pathogenic variant (PV) carriers have a residual risk to develop peritoneal carcinomatosis (PC). The etiology of PC is not yet... Show morePURPOSE After risk-reducing salpingo-oophorectomy (RRSO), BRCA1/2 pathogenic variant (PV) carriers have a residual risk to develop peritoneal carcinomatosis (PC). The etiology of PC is not yet clarified, but may be related to serous tubal intraepithelial carcinoma (STIC), the postulated origin for high-grade serous cancer. In this systematic review and individual patient data meta-analysis, we investigate the risk of PC in women with and without STIC at RRSO.METHODS Unpublished data from three centers were supplemented by studies identified in a systematic review of EMBASE, MEDLINE, and the Cochrane library describing women with a BRCA-PV with and without STIC at RRSO until September 2020. Primary outcome was the hazard ratio for the risk of PC between BRCA-PV carriers with and without STIC at RRSO, and the corresponding 5- and 10-year risks. Primary analysis was based on a one-stage Cox proportional-hazards regression with a frailty term for study.RESULTS From 17 studies, individual patient data were available for 3,121 women, of whom 115 had a STIC at RRSO. The estimated hazard ratio to develop PC during follow-up in women with STIC was 33.9 (95% CI, 15.6 to 73.9), P < .001) compared with women without STIC. For women with STIC, the five- and ten-year risks to develop PC were 10.5% (95% CI, 6.2 to 17.2) and 27.5% (95% CI, 15.6 to 43.9), respectively, whereas the corresponding risks were 0.3% (95% CI, 0.2 to 0.6) and 0.9% (95% CI, 0.6 to 1.4) for women without STIC at RRSO.CONCLUSION BRCA-PV carriers with STIC at RRSO have a strongly increased risk to develop PC which increases over time, although current data are limited by small numbers of events. Show less
Zanden, V. van der; Soolingen, N.J. van; Viddeleer, A.R.; Trum, J.W.; Amant, F.; Mourits, M.J.E.; ... ; Munster, B.C. van 2022
Objective: To assess the association between loss of lumbar skeletal muscle mass and density during neoadjuvant chemotherapy (NACT) and postoperative complications after interval cytoreductive... Show moreObjective: To assess the association between loss of lumbar skeletal muscle mass and density during neoadjuvant chemotherapy (NACT) and postoperative complications after interval cytoreductive surgery (CRS) in older patients with ovarian cancer. Materials and methods: This multicenter, retrospective cohort study included patients aged 70 years and older with primary advanced stage ovarian cancer (International Federation of Gynecology and Ob-stetrics stage III-IV), treated with NACT and interval CRS. Skeletal muscle mass and density were retrospectively assessed using Skeletal Muscle Index (SMI) and Muscle Attenuation (MA) on routinely made Computed Tomography scans before and after NACT. Loss of skeletal muscle mass or density was defined as >2% decrease per 100 days in SMI or MA during NACT. Results: In total, 111 patients were included. Loss of skeletal muscle density during NACT was associated with developing any postoperative complication <30 days after interval CRS both in univariable (Odds Ratio (OR) 3.69; 95% Confidence Interval (CI) 1.57-8.68) and in multivariable analysis adjusted for functional impairment and WHO performance status (OR 3.62; 95%CI 1.27-10.25). Loss of skeletal muscle density was also associated with infectious complications (OR 3.67; 95%CI 1.42-9.52) and unintended discontinuation of adjuvant chemotherapy (OR 5.07; 95%CI 1.41-18.19). Unlike loss of skeletal muscle density, loss of skeletal muscle mass showed no association with postoperative outcomes. Conclusion: In older patients with ovarian cancer, loss of skeletal muscle density during NACT is asso-ciated with worse postoperative outcomes. These results could add to perioperative risk assessment, guiding the decision to undergo surgery or the need for perioperative interventions. Show less
Bommel, M.H.D. van; Steenbeek, M.P.; IntHout, J.; Hermens, R.P.M.G.; Hoogerbrugge, N.; Harmsen, M.G.; ... ; Hullu, J.A. de 2022
Objective High cancer risks, as applicable to BRCA1 and BRCA2 pathogenic variant (PV) carriers, can induce significant cancer concerns. We examined the degree of cancer worry and the course of this... Show moreObjective High cancer risks, as applicable to BRCA1 and BRCA2 pathogenic variant (PV) carriers, can induce significant cancer concerns. We examined the degree of cancer worry and the course of this worry among BRCA1/2-PV carriers undergoing surgery to prevent ovarian cancer, and identified factors associated with high cancer worry. Methods Cancer worry was evaluated as part of the multicentre, prospective TUBA-study (NCT02321228) in which BRCA1/2-PV carriers choose either novel risk-reducing salpingectomy with delayed oophorectomy or standard risk-reducing salpingo-oophorectomy. The Cancer Worry Scale was obtained before and 3 and 12 months after surgery. Cancer worry patterns were analysed using latent class growth analysis and associated factors were identified with regression analysis. Results Of all 577 BRCA1/2-PV carriers, 320 (57%) had high (>= 14) cancer worry pre-surgery, and 54% had lower worry 12 months post-surgery than pre-surgery. Based on patterns over time, BRCA1/2-PV carriers could be classified into three groups: persistently low cancer worry (56%), persistently high cancer worry (6%), and fluctuating, mostly declining, cancer worry (37%). Factors associated with persistently high cancer concerns were age below 35 (BRCA1) or 40 (BRCA2), unemployment, previous breast cancer, lower education and a more recent BRCA1/2-PV diagnosis. Conclusions Some degree of cancer worry is considered normal, and most BRCA1/2-PV carriers have declining cancer worry after gynaecological risk-reducing surgery. However, a subset of these BRCA1/2-PV carriers has persisting major cancer concerns up to 1 year after surgery. They should be identified and potentially offered additional support. Show less
Background Laparoscopic hysterectomy is accepted worldwide as the standard treatment option for early-stage endometrial cancer. However, there are limited data on long-term survival, particularly... Show moreBackground Laparoscopic hysterectomy is accepted worldwide as the standard treatment option for early-stage endometrial cancer. However, there are limited data on long-term survival, particularly when no lymphadenectomy is performed. We compared the survival outcomes of total laparoscopic hysterectomy (TLH) and total abdominal hysterectomy (TAH), both without lymphadenectomy, for early-stage endometrial cancer up to 5 years postoperatively.MethodsFollow-up of a multi-centre, randomised controlled trial comparing TLH and TAH, without routine lymphadenectomy, for women with stage I endometrial cancer. Enrolment was between 2007 and 2009 by 2:1 randomisation to TLH or TAH. Outcomes were disease-free survival (DFS), overall survival (OS), disease-specific survival (DSS), and primary site of recurrence. Multivariable Cox regression analyses were adjusted for age, stage, grade, and radiotherapy with adjusted hazard ratios (aHR) and 95% confidence intervals (95%CI) reported. To test for significance, non-inferiority margins were defined.ResultsIn total, 279 women underwent a surgical procedure, of whom 263 (94%) had follow-up data. For the TLH (n = 175) and TAH (n = 88) groups, DFS (90.3% vs 84.1%; aHR[recurrence], 0.69; 95%CI, 0.31–1.52), OS (89.2% vs 82.8%; aHR[death], 0.60; 95%CI, 0.30–1.19), and DSS (95.0% vs 89.8%; aHR[death], 0.62; 95%CI, 0.23–1.70) were reported at 5 years. At a 10% significance level, and with a non-inferiority margin of 0.20, the null hypothesis of inferiority was rejected for all three outcomes. There were no port-site or wound metastases, and local recurrence rates were comparable.ConclusionDisease recurrence and 5-year survival rates were comparable between the TLH and TAH groups and comparable to studies with lymphadenectomy, supporting the widespread use of TLH without lymphadenectomy as the primary treatment for early-stage, low-grade endometrial cancer. Show less
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... Show moreBackground: 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. Show less
Zanden, V. van der; Soolingen, N.J. van; Viddeleer, A.R.; Trum, J.W.; Amant, F.; Mourits, M.J.E.; ... ; Souwer, E.T.D. 2021
Objective. To determine the predictive value of lumbar skeletal muscle mass and density for postoperative outcomes in older women with advanced stage ovarian cancer.Methods. A multicenter,... Show moreObjective. To determine the predictive value of lumbar skeletal muscle mass and density for postoperative outcomes in older women with advanced stage ovarian cancer.Methods. A multicenter, retrospective cohort study was performed in women >= 70 years old receiving surgery for primary, advanced stage ovarian cancer. Skeletal muscle mass and density were assessed in axial CT slices on level L3. Low skeletal muscle mass was defined as skeletal muscle index < 38.50 cm(2)/m(2). Low skeletal muscle density was defined as one standard deviation below the mean (muscle attenuation < 22.55 Hounsfield Units). The primary outcome was any postoperative complication <-30 days after surgery. Secondary outcomes included severe complications, infections, delirium, prolonged hospital stay, discharge destination, discontinua-tion of adjuvant chemotherapy and mortality.Results. In analysis of 213 patients, preoperative low skeletal muscle density was associated with postopera-tive complications <-30 days after surgery (Odds Ratio (OR) 2.83; 95% Confidence Interval (CI) 1.41-5.67), severe complications (OR 3.01; 95%CI 1.09-8.33), infectious complications (OR 2.79; 95%CI 1.30-5.99) and discharge to a care facility (OR 3.04; 95%CI 1.16-7.93). Preoperative low skeletal muscle mass was only associated with infec-tious complications (OR 2.32; 95%CI 1.09-4.92). In a multivariable model, low skeletal muscle density was of added predictive value for postoperative complications (OR 2.57; 95%CI 1.21-5.45) to the strongest existing pre-dictor functional impairment (KATZ-ADL >= 2).Conclusion. Low skeletal muscle density, as a proxy of muscle quality, is associated with poor postoperative outcomes in older patients with advanced stage ovarian cancer. These findings can contribute to postoperative risk assessment and clinical decision making. (C) 2021 The Author(s). Published by Elsevier Inc. Show less
Obstetrical complications, often referred to as the "great obstetrical syndromes," are among the most common global causes of mortality and morbidity in young women and their infants. However,... Show moreObstetrical complications, often referred to as the "great obstetrical syndromes," are among the most common global causes of mortality and morbidity in young women and their infants. However, treatments for these syndromes are underdeveloped compared with other fields of medicine and are urgently needed. This current paucity of treatments for obstetrical complications is a reflection of the challenges of drug development in pregnancy. The appetite of pharmaceutical companies to invest in research for obstetrical syndromes is generally reduced by concerns for maternal, fetal, and infant safety, poor definition, and high-risk regulatory paths toward product approval. Notably, drug candidates require large investments for development with an unguaranteed return on investment. Furthermore, the discovery of promising drug candidates is hampered by a poor understanding of the pathophysiology of obstetrical syndromes and their uniqueness to human pregnancies. This limits translational extrapolation and de-risking strategies in preclinical studies, as available for other medical areas, compounded with limited fetal safety monitoring to capture early prenatal adverse reactions. In addition, the ethical review committees are reluctant to approve the inclusion of pregnant women in trials, and in the absence of regulatory guidance in obstetrics, clinical development programs are subject to unpredictable regulatory paths. To develop effective and safe drugs for pregnancy complications, substantial commitment, and investment in research for innovative therapies are needed in parallel with the creation of an enabling ethical, legislative, and guidance framework. Solutions are proposed to enable stakeholders to work with a common set of expectations to facilitate progress in this medical discipline. Addressing this significant unmet need to advance maternal and possibly perinatal health requires the involvement of all stakeholders and specifically patients, couples, and cli-nicians facing pregnancy complications in the dearth of appropriate therapies. This paper focused on the key pharmaceutical research and development challenges to achieve effective and safe treatments for obstetrical syndromes. Show less
Steenbeek, M.P.; Harmsen, M.G.; Hoogerbrugge, N.; Jong, M.A. de; Maas, A.H.E.M.; Prins, J.B.; ... ; Hullu, J.A. de 2021
IMPORTANCE Most women with a BRCA1/2 pathogenic variant undergo premature menopause with potential short- and long-term morbidity due to the current method of ovarian carcinoma prevention: risk... Show moreIMPORTANCE Most women with a BRCA1/2 pathogenic variant undergo premature menopause with potential short- and long-term morbidity due to the current method of ovarian carcinoma prevention: risk-reducing salpingo-oophorectomy (RRSO). Because the fallopian tubes play a key role in ovarian cancer pathogenesis, salpingectomy with delayed oophorectomy may be a novel risk-reducing strategy with benefits of delaying menopause.OBJECTIVE To compare menopause-related quality of life after risk-reducing salpingectomy (RRS) with delayed oophorectomy with RRSO in carriers of the BRCA1/2 pathogenic variant.DESIGN, SETTING, AND PARTICIPANTS A multicenter nonrandomized controlled preference trial (TUBA study), with patient recruitment between January 16, 2015, and November 7, 2019, and follow-up at 3 and 12 months after surgery was conducted in all Dutch university hospitals and a few large general hospitals. In the Netherlands, RRSO is predominantly performed in these hospitals. Patients at the clinical genetics or gynecology department between the ages of 25 and 40 years (BRCA1) or 25 to 45 years (BRCA2) who were premenopausal, had completed childbearing, and were undergoing no current treatment for cancer were eligible.INTERVENTIONS Risk-reducing salpingo-oophorectomy at currently recommended age or RRS after completed childbearing with delayed oophorectomy. After RRSO was performed, hormone replacement therapy was recommended for women without contraindications.MAIN OUTCOMES AND MEASURES Menopause-related quality of life as assessed by the Greene Climacteric Scale, with a higher scale sum (range, 0-63) representing more climacteric symptoms. Secondary outcomes were health-related quality of life, sexual functioning and distress, cancer worry, decisional regret, and surgical outcomes.RESULTS A total of 577 women (mean [SD] age, 37.2 [3.5] years) were enrolled: 297 (51.5%) were pathogenic BRCA1 variant carriers and 280 (48.5%) were BRCA2 pathogenic variant carriers. At the time of analysis, 394 patients had undergone RRS and 154 had undergone RRSO. Without hormone replacement therapy, the adjusted mean increase from the baseline score on the Greene Climacteric Scale was 6.7 (95% CI, 5.0-8.4; P < .001) points higher during 1 year after RRSO than after RRS. After RRSO with hormone replacement therapy, the difference was 3.6 points (95% CI, 2.3-4.8; P < .001) compared with RRS.CONCLUSIONS AND RELEVANCE Results of this nonrandomized controlled trial suggest that patients have better menopause-related quality of life after RRS than after RRSO, regardless of hormone replacement therapy. An international follow-up study is currently evaluating the oncologic safety of this therapy. Show less
Seppala, T.T.; Dominguez-Valentin, M.; Crosbie, E.J.; Engel, C.; Aretz, S.; Macrae, F.; ... ; Moller, P. 2021
Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic... Show morePurpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants.Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years.Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery.Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene-and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syn-drome to improve outcomes. (C) 2021 The Author(s). Published by Elsevier Ltd. Show less
Background: BRCA1/2 mutation carriers are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) at 35 to 45 years of age. RRSO substantially decreases ovarian cancer risk, but at the... Show moreBackground: BRCA1/2 mutation carriers are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) at 35 to 45 years of age. RRSO substantially decreases ovarian cancer risk, but at the cost of immediate menopause. Knowledge about the potential adverse effects of premenopausal RRSO, such as increased risk of cardiovascular disease, osteoporosis, cognitive dysfunction, and reduced health-related quality of life (HRQoL), is limited.Objective: The aim of this study is to assess the long-term health effects of premenopausal RRSO on cardiovascular disease, bone health, cognitive functioning, urological complaints, sexual functioning, and HRQoL in women with high familial risk of breast or ovarian cancer.Methods: We will conduct a multicenter cross-sectional study with prospective follow-up, nested in a nationwide cohort of women at high familial risk of breast or ovarian cancer. A total of 500 women who have undergone RRSO before 45 years of age, with a follow-up period of at least 10 years, will be compared with 250 women (frequency matched on current age) who have not undergone RRSO or who have undergone RRSO at over 55 years of age. Participants will complete an online questionnaire on lifestyle, medical history, cardiovascular risk factors, osteoporosis, cognitive function, urological complaints, and HRQoL. A full cardiovascular assessment and assessment of bone mineral density will be performed. Blood samples will be obtained for marker analysis. Cognitive functioning will be assessed objectively with an online neuropsychological test battery.Results: This study was approved by the institutional review board in July 2018. In February 2019, we included our first participant. As of November 2020, we had enrolled 364 participants in our study.Conclusions: Knowledge from this study will contribute to counseling women with a high familial risk of breast/ovarian cancer about the long-term health effects of premenopausal RRSO. The results can also be used to offer health recommendations after RRSO. Show less
Zanden, V. van der; Soolingen, N.J. van; Viddeleer, A.R.; Trum, J.W.; Amant, F.; Mourits, M.J.E.; ... ; Munster, B.C. van 2021
Background The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective... Show moreBackground The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause. Methods A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women. Results There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar. Conclusion We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO. Show less
