Early salpingectomy (TUbectomy) with delayed oophorectomy to improve quality of life as alternative for risk-reducing salpingo-oophorectomy in BRCA1/2 mutation carriers (TUBA study): a prospective non-randomised multicentre study.

BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) around the age of 40 is currently recommended to BRCA1/2 mutation carriers. This procedure decreases the elevated ovarian cancer risk by 80-96% but it initiates premature menopause as well. The latter is associated with short-term and long-term morbidity, potentially affecting quality of life (QoL). Based on recent insights into the Fallopian tube as possible site of origin of serous ovarian carcinomas, an alternative preventive strategy has been put forward: early risk-reducing salpingectomy (RRS) and delayed oophorectomy (RRO). However, efficacy and safety of this alternative strategy have to be investigated. METHODS: A multicentre non-randomised trial in 11 Dutch centres for hereditary cancer will be conducted. Eligible patients are premenopausal BRCA1/2 mutation carriers after completing childbearing without (a history of) ovarian carcinoma. Participants choose between standard RRSO at age 35-40 (BRCA1) or 40-45 (BRCA2) and the alternative strategy (RRS upon completion of childbearing and RRO at age 40-45 (BRCA1) or 45-50 (BRCA2)). Women who opt for RRS but do not want to postpone RRO beyond the currently recommended age are included as well. Primary outcome measure is menopause-related QoL. Secondary outcome measures are ovarian/breast cancer incidence, surgery-related morbidity, histopathology, cardiovascular risk factors and diseases, and cost-effectiveness. Mixed model data analysis will be performed. DISCUSSION: The exact role of the Fallopian tube in ovarian carcinogenesis is still unclear. It is not expected that further fundamental research will elucidate this role in the near future. Therefore, this clinical trial is essential to investigate RRS with delayed RRO as alternative risk-reducing strategy in order to improve QoL. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT02321228 ).

Risk-reducing salpingectomy with delayed oophorectomy in BRCA1/2 mutation carriers: patients' and professionals' perspectives.

OBJECTIVE: To identify influencing factors of BRCA1/2 mutation carriers and their professionals for risk-reducing salpingectomy (RRS) with delayed oophorectomy (RRO) as a substitute for risk-reducing salpingo-oophorectomy (RRSO) and for study participation on this concept. METHODS: A qualitative study was performed by four focus group interviews with 39 BRCA1/2 mutation carriers and semi-structured in-depth interviews with 23 professionals in the field of hereditary cancer. We used a theoretical framework of determinants of innovation within healthcare organizations to classify influencing factors (barriers and facilitators). RESULTS: Among BRCA1/2 mutation carriers, main barriers for RRS with delayed RRO were seriousness of ovarian cancer, family history, and previous breast cancer. Among professionals, delay of risk-reducing effect of oophorectomy on breast cancer risk and a second operation were recognized as main barriers. Both BRCA1/2 mutation carriers and professionals found uncertainty about the effect of RRS with delayed RRO and ease of the decision to undergo RRSO important barriers. The main facilitator mentioned by both was longer maintenance of ovarian function thereby delaying negative effects of early surgical menopause. For study participation, BRCA1/2 mutation carriers mentioned a randomized study design as the main barrier, whereas professionals identified two facilitators, namely willingness of BRCA1/2 mutation carriers for study participation and uniform counseling. Furthermore, most BRCA1/2 mutation carriers and professionals were willing to consider participation in a future non-randomized study. CONCLUSIONS: We identified several barriers and facilitators for RRS with delayed RRO, and for study participation which can be addressed to optimize the design and implementation of a non-randomized study.

Added value of family history in counseling about risk of BRCA1/2 mutation in early-onset epithelial ovarian cancer.

OBJECTIVES: Epithelial ovarian cancer in women 40 years or younger is rare; diagnosis at this age justifies referral for genetic testing. We evaluated clinical data, family history, and risk of identifying BRCA1/2 mutations in women with early-onset epithelial ovarian cancer. MATERIALS/METHODS: Women 40 years or younger with epithelial ovarian cancer tested for BRCA1/2 mutation at our department of human genetics between 1996 and 2012 were included. The rate of BRCA1/2 mutation was obtained; carriers were compared to noncarriers regarding clinical data. RESULTS: Ten (19%) of 52 women had a BRCA1/2 mutation. This mutation was detected in 67% of women with and in 9% of the women without first-degree relatives with breast and/or ovarian cancer (P < 0.001; Fisher exact test). The median age at diagnosis was lower in the noncarriers compared to the carriers (30 vs 38 years; P = 0.014). Among the BRCA1/2 mutation carriers, 60% had serous tumors, 80% had moderately to poorly differentiated tumors, and 70% had International Federation of Gynecology and Obstetrics stage III/IV compared to 55%, 43%, and 45%, respectively, in the noncarriers. CONCLUSIONS: The risk of finding a BRCA1/2 mutation in women 40 years or younger is comparable to women of all ages with epithelial ovarian cancer. Prior probability of finding a BRCA1/2 mutation in these young women is largely determined by their family history, which can help caregivers in informing ahead of genetic counseling and testing.

Experiences of Clinical Clerkship Students With Mindfulness-Based Stress Reduction: A Qualitative Study on Long-Term Effects.

Purpose: To explore the mindfulness practice, its long-term effects, facilitators and barriers, in clinical clerkship students 2 years after participation in an 8-week mindfulness-based stress reduction (MBSR) training. Method: A qualitative study was performed by semi-structured in-depth interviews with 16 clinical clerkship students selected by purposive sampling. Students had participated in a MBSR training 2 years before and were asked about their current mindfulness practice, and the long-term effects of the MBSR training. Thematic analysis was conducted using the constant comparison method. Data saturation was reached after 16 interviews. Results: Most interviewees were still engaged in regular, predominantly informal, mindfulness practice, although some discontinued mindfulness practice and reported an "unchanged lifestyle." Three main themes came forward; (1) "focused attention and open awareness" during daily activities as core elements of long-term mindfulness practice; (2) "changes in behavior and coping" that resulted from taking a pause, reflecting, recognizing automatic behavioral patterns and making space for a conscious response; (3) "integration in personal and professional life" by enhanced enjoyment of daily activities, improved work-life-balance and making different career choices. Barriers and facilitators in starting and maintaining mindfulness practice were (1) understanding and intention as "pre-conditions"; (2) practical, personal, and professional factors of students in maintaining practice. Conclusion: Two years after participation in a MBSR training, many interviewees were still engaged in (mostly informal) mindfulness practice contributing to both personal and professional changes. In light of the high clerkship demands, MBSR training could be a valuable addition to medical curricula, supporting medical students in developing necessary competencies to become well-balanced professionals.

High demoralization in a minority of oophorectomized BRCA1/2 mutation carriers influences quality of life.

INTRODUCTION: Demoralization is a relatively neglected issue in which low morale and poor coping result from a stressor such as familial cancer risk. Female BRCA1/2 mutation carriers are highly susceptible for developing breast and ovarian cancer. The aim of this study was to evaluate demoralization in oophorectomized BRCA1/2 mutation carriers and its relation to quality of life. METHODS: This cross-sectional study examined 288 oophorectomized BRCA1/2 mutation carriers using the following standardized self-report measures: Demoralization Scale, EORTC Quality of Life Questionnaire-C30, State-Trait Anxiety Inventory and the Cancer Worry Scale. RESULTS: The mean score on the Demoralization Scale was 17.8 (SD 14.0). A clinically significant level of demoralization, defined as a score ≥30, was found in 45 BRCA1/2 mutation carriers (16%). Being highly demoralized was associated with a significantly lower quality of life, and higher levels of physical problems, anxiety and cancer worries. No demographic or clinical factors could predict higher levels of demoralization. CONCLUSIONS: Our findings established that a clear proportion of oophorectomized BRCA1/2 mutation carriers experience demoralization impacting on their well-being. Further research is needed to explore the natural trajectory of demoralization and the resultant need for support in these women.

Self-compassion, physical fitness and climacteric symptoms in oophorectomized BRCA1/2 mutation carriers.

OBJECTIVES: To reduce the risk of ovarian cancer, BRCA1/2 mutation carriers are advised to undergo salpingo-oophorectomy (RRSO) around the age of 40 years. This may induce severe climacteric symptoms, potentially lowering their quality of life. Personal positive resources such as physical fitness and self-compassion may help women to deal with these symptoms. We investigated the association of climacteric symptoms with self-compassion and physical fitness in oophorectomized BRCA1/2 mutation carriers. STUDY DESIGN: A cross-sectional study was conducted in 165 BRCA1/2 mutation carriers, aged 40-63 years, who underwent an RRSO at age 45 years or younger and at least 5 years previously. MAIN OUTCOME MEASURES: Climacteric symptoms were measured by the Greene Climacteric Scale. Self-compassion was rated using the Self-Compassion Scale-Short Form, and physical fitness using the Duke Activity Status Index. RESULTS: BRCA1/2 mutation carriers reported low levels of climacteric symptoms (mean 10.28 [SD 6.45], and being highly self-compassionate and physically fit. After adjustment for possible covariates, higher self-compassion (ß=-1.65, 95% CI -2.46, -0.84) and physical fitness (ß=-0.25, 95% CI -0.34, -0.16) were associated with fewer climacteric symptoms. Current smoking was independently associated with more climacteric symptoms (ß=2.66, 95% CI 0.26, 5.07). CONCLUSIONS: Being self-compassionate and physically fit were associated with fewer climacteric symptoms. Future research is needed to investigate the effect of training in self-compassion and physical fitness on climacteric symptoms in BRCA1/2 mutation carriers.

Salpingectomy With Delayed Oophorectomy in BRCA1/2 Mutation Carriers: Estimating Ovarian Cancer Risk.

OBJECTIVE: To estimate BRCA1/2 mutation carriers' cumulative ovarian cancer risks after risk-reducing salpingectomy at various ages with delayed oophorectomy several years later compared with risk-reducing salpingo-oophorectomy. METHODS: A literature search was performed on cumulative ovarian cancer risks and effects of risk-reducing salpingo-oophorectomy and salpingectomy. Results were used in a modeling study to estimate cumulative ovarian cancer risks for various scenarios of salpingectomy with delayed oophorectomy and risk-reducing salpingo-oophorectomy using Cox proportional hazard models. RESULTS: Estimated cumulative ovarian cancer risks at age 70 years for risk-reducing salpingectomy with delayed oophorectomy are highest for BRCA1 mutation carriers undergoing surgeries at higher age. Maximum increase in point estimates (from 1.8% to 4.1%) occurs in 40-year-old BRCA1 mutation carriers undergoing oophorectomy at age 45 years after nonprotective salpingectomy instead of salpingo-oophorectomy at age 40 years. In the best-case scenario, assuming 65% risk reduction by salpingectomy and 96% by salpingo-oophorectomy, point estimates increase (from 1.8% to 2.6%) or decrease (from 3.4% to 3.3%) depending on age. In the worst-case scenario for BRCA2, point estimates maximally increase from 0.6% to 1.8% in 45-year-old carriers when oophorectomy is performed at age 50 years instead of risk-reducing salpingo-oophorectomy at age 45 years. In the best-case scenario, point estimates increase (from 1.3% to 1.5%) or decrease (from 1.5 to 1.3%). CONCLUSION: Differences in estimated ovarian cancer risks between risk-reducing salpingo-oophorectomy and salpingectomy with delayed oophorectomy are small, even if salpingectomy is ineffective. Presented estimated ovarian cancer risks can be used in counseling BRCA1/2 mutation carriers, thereby facilitating a personalized and well-informed choice for either strategy.

Germline BRCA1/2 mutation testing is indicated in every patient with epithelial ovarian cancer: A systematic review.

The presence of a germline BRCA1/2 mutation improves options for tailored risk-reducing strategies and treatment in both breast and ovarian cancer patients and their relatives. Currently, referral for germline BRCA1/2 mutation testing of women with epithelial ovarian cancer (EOC) varies widely, based on different criteria, such as age of onset, family history of breast and/or ovarian cancer and histological type of EOC. The overall probability of a germline BRCA1/2 mutation in women with EOC is above 10%, and a substantial part of the germline BRCA1/2 mutation carriers is missed when applying these criteria for referral. Therefore, we strongly recommend referral of all women with EOC for genetic counselling and DNA analysis.