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
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
Objective. Risk-reducing surgery is advised to BRCA1/2 pathogenic variant (PV) carriers around the age of 40 years to reduce ovarian cancer risk. In the TUBA-study, a multicenter preference study ... Show moreObjective. Risk-reducing surgery is advised to BRCA1/2 pathogenic variant (PV) carriers around the age of 40 years to reduce ovarian cancer risk. In the TUBA-study, a multicenter preference study (NCT02321228), BRCA1/2-PV carriers are offered a choice: the standard strategy of risk-reducing salpingo-oophorectomy or the novel strategy of risk-reducing salpingectomy with delayed oophorectomy. We evaluated feasibility and effectiveness of a patient decision aid for this choice. Methods. Premenopausal BRCA1/2-PV carriers were counselled for risk-reducing surgical options in the TUBA study; the first cohort was counselled without and the second cohort with decision aid. Evaluation was performed using digital questionnaires for participating women and their healthcare professionals. Outcome measures included actual choice, feasibility (usage and experiences) and effectiveness (knowledge, cancer worry, decisional conflict, decisional regret and self-estimated influence on decision). Results. 283 women were counselled without and 282 women with decision aid. The novel strategy was chosen less frequently in women without compared with women with decision aid (67% vs 78%, p = 0.004). The decision aid was graded with an 8 out of 10 by both women and professionals, and 78% of the women would rec-ommend this decision aid to others. Users of the decision aid reported increased knowledge about the options and increased insight in personal values. Knowledge on cancer risk, decisional conflict, decisional regret and can-cer worry were similar in both cohorts. Conclusions. The use of the patient decision aid for risk-reducing surgery is feasible, effective and highly ap-preciated among BRCA1/2-PV carriers facing the decision between salpingo-oophorectomy or salpingectomy with delayed oophorectomy. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). Show less
BACKGROUND: Approximately 20% of women with endometrial cancer have advanced-stage disease or suffer from a recurrence. For these women, prognosis is poor, and palliative treatment options include... Show moreBACKGROUND: Approximately 20% of women with endometrial cancer have advanced-stage disease or suffer from a recurrence. For these women, prognosis is poor, and palliative treatment options include hormonal therapy and chemotherapy. Lack of predictive biomarkers and suboptimal use of existing markers for response to hormonal therapy have resulted in overall limited efficacy.OBJECTIVE: This study aimed to improve the efficacy of hormonal therapy by relating immunohistochemical expression of estrogen and progesterone receptors and estrogen receptor pathway activity scores to response to hormonal therapy.STUDY DESIGN: Patients with advanced or recurrent endometrial cancer and available biopsies taken before the start of hormonal therapy were identified in 16 centers within the European Network for Individualized Treatment in Endometrial Cancer and the Dutch Gynecologic Oncology Group. Tumor tissue was analyzed for estrogen and progesterone receptor expressions and estrogen receptor pathway activity using a quantitative polymerase chain reaction-based messenger RNA model to measure the activity of estrogen receptor-related target genes in tumor RNA. The primary endpoint was response rate defined as complete and partial response using the Response Evaluation Criteria in Solid Tumors. The secondary endpoints were clinical benefit rate and progression-free survival.RESULTS: Pretreatment biopsies with sufficient endometrial cancer tissue and complete response evaluation were available in 81 of 105 eligible cases. Here, 22 of 81 patients (27.2%) with a response had estrogen and progesterone receptor expressions of >50%, resulting in a response rate of 32.3% (95% confidence interval, 20.9-43.7) for an estrogen receptor expression of >50% and 50.0% (95% confidence interval, 35.2-64.8) for a progesterone receptor expression of >50%. Clinical benefit rate was 56.9% for an estrogen receptor expression of >50% (95% confidence interval, 44.9-68.9) and 75.0% (95% confidence interval, 62.2-87.8) for a progesterone receptor expression of >50%. The application of the estrogen receptor pathway test to cases with a progesterone receptor expression of >50% resulted in a response rate of 57.6% (95% confidence interval, 42.1-73.1). After 2 years of follow-up, 34.3% of cases (95% confidence interval, 20-48) with a progesterone receptor expression of >50% and 35.8% of cases (95% confidence interval, 20-52) with an estrogen receptor pathway activity score of >15 had not progressed.CONCLUSION: The prediction of response to hormonal treatment in endometrial cancer improves substantially with a 50% cutoff level for progesterone receptor immunohistochemical expression and by applying a sequential test algorithm using progesterone receptor immunohistochemical expression and estrogen receptor pathway activity scores. However, results need to be validated in the prospective Prediction of Response to Hormonal Therapy in Advanced and Recurrent Endometrial Cancer (PROMOTE) study. 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
Wenzel, H.H.B.; Kruitwagen, R.F.P.M.; Nijman, H.W.; Bekkers, R.L.M.; Gorp, T. van; Kroon, C.D. de; ... ; Aa, M.A. van der 2020
Introduction Centralization has, among other aspects, been argued to have an impact on quality of care in terms of surgical morbidity. Next, monitoring quality of care is essential in identifying... Show moreIntroduction Centralization has, among other aspects, been argued to have an impact on quality of care in terms of surgical morbidity. Next, monitoring quality of care is essential in identifying areas of improvement. This nationwide cohort study was conducted to determine the rate of short-term surgical complications and to evaluate its possible predictors in women with early-stage cervical cancer.Material and methods Women diagnosed with early-stage cervical cancer, 2009 FIGO stages IB1 and IIA1, between 2015 and 2017 who underwent radical hysterectomy with pelvic lymphadenectomy in 1 of the 9 specialized medical centers in the Netherlands, were identified from the Netherlands Cancer Registry. Women were excluded if primary treatment consisted of hysterectomy without parametrial dissection or radical trachelectomy. Women in whom radical hysterectomy was aborted during the procedure, were also excluded. Occurrence of intraoperative and postoperative complications and type of complications, developing within 30 days after surgery, were prospectively registered. Multivariable logistic regression analysis was used to identify predictors of surgical complications.Results A total of 472 women were selected, of whom 166 (35%) developed surgical complications within 30 days after radical hysterectomy. The most frequent complications were urinary retention with catheterization in 73 women (15%) and excessive perioperative blood loss >1000 mL in 50 women (11%). Open surgery (odds ratio [OR] 3.42; 95% CI 1.73-6.76), chronic pulmonary disease (OR 3.14; 95% CI 1.45-6.79), vascular disease (OR 1.90; 95% CI 1.07-3.38), and medical center (OR 2.83; 95% CI 1.18-6.77) emerged as independent predictors of the occurrence of complications. Body mass index (OR 0.94; 95% CI 0.89-1.00) was found as a negative predictor of urinary retention. Open surgery (OR 36.65; 95% CI 7.10-189.12) and body mass index (OR 1.15; 95% CI 1.08-1.22) were found to be independent predictors of excessive perioperative blood loss.Conclusions Short-term surgical complications developed in 35% of the women after radical hysterectomy for early-stage cervical cancer in the Netherlands, a nation with centralized surgical care. Comorbidities predict surgical complications, and open surgery is associated with excessive perioperative blood loss. Show less
Purpose: To determine the accuracy of MRI in detecting craniocaudal tumour extension, compared to histopathology, of the hysterectomy specimen in patients with early-stage uterine cervical cancer.... Show morePurpose: To determine the accuracy of MRI in detecting craniocaudal tumour extension, compared to histopathology, of the hysterectomy specimen in patients with early-stage uterine cervical cancer. Three complementary methods were investigated.Materials and methods: Thirty-four patients with early-stage cervical cancer had pre-operative MRI, followed by radical hysterectomy or trachelectomy. 1) craniocaudal tumour extension was measured on MRI by two radiologists and compared to microscopy by a pathologist, 2) to compensate for changes in uterine shape between pre-operative MRI and the surgical specimen, craniocaudal tumour extensions were directly compared and appreciated as being a part of a 3-dimensional tumour by a radiation oncologist and resident, and 3) tumour size on MRI was compared macroscopically after digital non-rigid registration of the uterus, uterine cavity and tumour of both modalities.Results: The craniocaudal tumour extension measured on histopathology minus MRI gives: 1) on average +3 mm difference when measured by a radiologist compared to the microscopic extension (range -13 to +15 mm), 2) -0.2 mm (range -11 to +6.0 mm) when evaluated on MRI by a radiation oncologist compared to the macroscopic tumour; 3) after non-rigid organ registration, a margin of 10 mm around the tumour on MRI would be needed to cover 95% of the tumour in 90% of the patients.Conclusions: Results indicate that microscopic tumour extension towards the uterine fundus is within a margin of 10 mm around the visible tumour on MRI. The major source of measurement uncertainty is post-surgical change of organ shape and form. (C) 2019 The Author(s). Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology. Show less
Derks, M.; Velden, J. van der; Kroon, C.D. de; Nijman, H.W.; Lonkhuijzen, L.R.C.W. van; Zee, A.G.J. van der; ... ; Kenter, G.G. 2018
