Risk-Reducing Salpingo-Oophorectomy and the Use of Hormone Replacement Therapy Below the Age of Natural Menopause: Scientific Impact Paper No. 66 October 2021: Scientific Impact Paper No. 66.

This paper deals with the use of hormone replacement therapy (HRT) after the removal of fallopian tubes and ovaries to prevent ovarian cancer in premenopausal high risk women. Some women have an alteration in their genetic code, which makes them more likely to develop ovarian cancer. Two well-known genes which can carry an alteration are the BRCA1 and BRCA2 genes. Examples of other genes associated with an increased risk of ovarian cancer include RAD51C, RAD51D, BRIP1, PALB2 and Lynch syndrome genes. Women with a strong family history of ovarian cancer and/or breast cancer, may also be at increased risk of developing ovarian cancer. Women at increased risk can choose to have an operation to remove the fallopian tubes and ovaries, which is the most effective way to prevent ovarian cancer. This is done after a woman has completed her family. However, removal of ovaries causes early menopause and leads to hot flushes, sweats, mood changes and bone thinning. It can also cause memory problems and increases the risk of heart disease. It may reduce libido or impair sexual function. Guidance on how to care for women following preventative surgery who are experiencing early menopause is needed. HRT is usually advisable for women up to 51 years of age (average age of menopause for women in the UK) who are undergoing early menopause and have not had breast cancer, to minimise the health risks linked to early menopause. For women with a womb, HRT should include estrogen coupled with progestogen to protect against thickening of the lining of the womb (called endometrial hyperplasia). For women without a womb, only estrogen is given. Research suggests that, unlike in older women, HRT for women in early menopause does not increase breast cancer risk, including in those who are BRCA1 and BRCA2 carriers and have preventative surgery. For women with a history of receptor-negative breast cancer, the gynaecologist will liaise with an oncology doctor on a case-by-case basis to help to decide if HRT is safe to use. Women with a history of estrogen receptor-positive breast cancer are not normally offered HRT. A range of other therapies can be used if a woman is unable to take HRT. These include behavioural therapy and non-hormonal medicines. However, these are less effective than HRT. Regular exercise, healthy lifestyle and avoiding symptom triggers are also advised. Whether to undergo surgery to reduce risk or not and its timing can be a complex decision-making process. Women need to be carefully counselled on the pros and cons of both preventative surgery and HRT use so they can make informed decisions and choices.

Jewish cultural and religious factors and uptake of population-based BRCA testing across denominations: a cohort study.

OBJECTIVE: To evaluate the association of Jewish cultural and religious identity and denominational affiliation with interest in, intention to undertake and uptake of population-based BRCA (Breast Cancer Gene)-testing. DESIGN: Cohort-study set within recruitment to GCaPPS-trial (ISRCTN73338115). SETTING: London Ashkenazi-Jewish (AJ) population. POPULATION OR SAMPLE: AJ men and women, >18 years. METHODS: Participants were self-referred, and attended recruitment clinics (clusters) for pre-test counselling. Subsequently consenting individuals underwent BRCA testing. Participants self-identified to one Jewish denomination: Conservative/Liberal/Reform/Traditional/Orthodox/Unaffiliated. Validated scales measured Jewish Cultural-Identity (JI) and Jewish Religious-identity (JR). Four-item Likert-scales analysed initial 'interest' and 'intention to test' pre-counselling. Item-Response-Theory and graded-response models, modelled responses to JI and JR scales. Ordered/multinomial logistic regression modelling evaluated association of JI-scale, JR-scale and Jewish Denominational affiliation on interest, intention and uptake of BRCA testing. MAIN OUTCOME MEASURES: Interest, intention, uptake of BRCA testing. RESULTS: In all, 935 AJ women/men of mean age = 53.8 (S.D = 15.02) years, received pre-test education and counselling through 256 recruitment clinic clusters (median cluster size = 3). Denominational affiliations included Conservative/Masorti = 91 (10.2%); Liberal = 82 (9.2%), Reform = 135 (15.1%), Traditional = 212 (23.7%), Orthodox = 239 (26.7%); and Unaffiliated/Non-practising = 135 (15.1%). Overall BRCA testing uptake was 88%. Pre-counselling, 96% expressed interest and 60% intention to test. JI and JR scores were highest for Orthodox, followed by Conservative/Masorti, Traditional, Reform, Liberal and Unaffiliated Jewish denominations. Regression modelling showed no significant association between overall Jewish Cultural or Religious Identity with either interest, intention or uptake of BRCA testing. Interest, intention and uptake of BRCA testing was not significantly associated with denominational affiliation. CONCLUSIONS: Jewish religious/cultural identity and denominational affiliation do not appear to influence interest, intention or uptake of population-based BRCA testing. BRCA testing was robust across all Jewish denominations. TWEETABLE ABSTRACT: Jewish cultural/religious factors do not affect BRCA testing, with robust uptake seen across all denominational affiliations.

Randomised trial of population-based BRCA testing in Ashkenazi Jews: long-term outcomes.

OBJECTIVE: Unselected population-based BRCA testing provides the opportunity to apply genomics on a population-scale to maximise primary prevention for breast-and-ovarian cancer. We compare long-term outcomes of population-based and family-history (FH)/clinical-criteria-based BRCA testing on psychological health and quality of life. DESIGN: Randomised controlled trial (RCT) (ISRCTN73338115) GCaPPS, with two-arms: (i) population-screening (PS); (ii) FH/clinical-criteria-based testing. SETTING: North London Ashkenazi-Jewish (AJ) population. POPULATION/SAMPLE: AJ women/men. METHODS: Population-based RCT (1:1). Participants were recruited through self-referral, following pre-test genetic counselling from the North London AJ population. INCLUSION CRITERIA: AJ women/men >18 years old; exclusion-criteria: prior BRCA testing or first-degree relatives of BRCA-carriers. INTERVENTIONS: Genetic testing for three Jewish BRCA founder-mutations: 185delAG (c.68_69delAG), 5382insC (c.5266dupC) and 6174delT (c.5946delT), for (i) all participants in PS arm; (ii) those fulfilling FH/clinical criteria in FH arm. Linear mixed models and appropriate contrast tests were used to analyse the impact of BRCA testing on psychological and quality-of-life outcomes over 3 years. MAIN OUTCOME MEASURES: Validated questionnaires (HADS/MICRA/HAI/SF12) used to analyse psychological wellbeing/quality-of-life outcomes at baseline/1-year/2-year/3-year follow up. RESULTS: In all, 1034 individuals (691 women, 343 men) were randomised to PS (n = 530) or FH (n = 504) arms. There was a statistically significant decrease in anxiety (P = 0.046) and total anxiety-&-depression scores (P = 0.0.012) in the PS arm compared with the FH arm over 3 years. No significant difference was observed between the FH and PS arms for depression, health-anxiety, distress, uncertainty, quality-of-life or experience scores associated with BRCA testing. Contrast tests showed a decrease in anxiety (P = 0.018), health-anxiety (P < 0.0005) and quality-of-life (P = 0.004) scores in both PS and FH groups over time. Eighteen of 30 (60%) BRCA carriers identified did not fulfil clinical criteria for BRCA testing. Total BRCA prevalence was 2.9% (95% CI 1.97-4.12%), BRCA1 prevalence was 1.55% (95% CI 0.89-2.5%) and BRCA2 prevalence was 1.35% (95% CI 0.74-2.26%). CONCLUSION: Population-based AJ BRCA testing does not adversely affect long-term psychological wellbeing or quality-of-life, decreases anxiety and could identify up to 150% additional BRCA carriers. TWEETABLE ABSTRACT: Population BRCA testing in Ashkenazi Jews reduces anxiety and does not adversely affect psychological health or quality of life.

Attitude towards and factors affecting uptake of population-based BRCA testing in the Ashkenazi Jewish population: a cohort study.

OBJECTIVE: To evaluate factors affecting unselected population-based BRCA testing in Ashkenazi Jews (AJ). DESIGN: Cohort-study set within recruitment to the GCaPPS trial (ISRCTN73338115). SETTING: North London AJ population. POPULATION OR SAMPLE: Ashkenazi Jews women/men >18 years, recruited through self-referral. METHODS: Ashkenazi Jews women/men underwent pre-test counselling for BRCA testing through recruitment clinics (clusters). Consenting individuals provided blood samples for BRCA testing. Data were collected on socio-demographic/family history/knowledge/psychological well-being along with benefits/risks/cultural influences (18-item questionnaire measuring 'attitude'). Four-item Likert-scales analysed initial 'interest' and 'intention-to-test' pre-counselling. Uni- and multivariable logistic regression models evaluated factors affecting uptake/interest/intention to undergo BRCA testing. Statistical inference was based on cluster robust standard errors and joint Wald tests for significance. Item-Response Theory and graded-response models modelled responses to 18-item questionnaire. MAIN OUTCOME MEASURES: Interest, intention, uptake, attitude towards BRCA testing. RESULTS: A total of 935 individuals (women = 67%/men = 33%; mean age = 53.8 (SD = 15.02) years) underwent pre-test genetic-counselling. During the pre-counselling, 96% expressed interest in and 60% indicated a clear intention to undergo BRCA testing. Subsequently, 88% opted for BRCA testing. BRCA-related knowledge (P = 0.013) and degree-level education (P = 0.01) were positively and negatively (respectively) associated with intention-to-test. Being married/cohabiting had four-fold higher odds for BRCA testing uptake (P = 0.009). Perceived benefits were associated with higher pre-counselling odds for interest in and intention to undergo BRCA testing. Reduced uncertainty/reassurance were the most important factors contributing to decision-making. Increased importance/concern towards risks/limitations (confidentiality/insurance/emotional impact/inability to prevent cancer/marriage ability/ethnic focus/stigmatisation) were significantly associated with lower odds of uptake of BRCA testing, and discriminated between acceptors and decliners. Male gender/degree-level education (P = 0.001) had weaker correlations, whereas having children showed stronger (P = 0.005) associations with attitudes towards BRCA testing. CONCLUSIONS: BRCA testing in the AJ population has high acceptability. Pre-test counselling increases awareness of disadvantages/limitations of BRCA testing, influencing final cost-benefit perception and decision-making on undergoing testing. TWEETABLE ABSTRACT: BRCA testing in Ashkenazi Jews has high acceptability and uptake. Pre-test counselling facilitates informed decision-making.

Pivotal role of families in doctor-patient communication in oncology: a qualitative study of patients, their relatives and cancer clinicians.

Families are a unique source of support for many cancer patients. Most advanced communication skills training for oncologists are patient centred and do not cover interactions with family members. The current study used in-depth qualitative interviews of patients, relatives and cancer clinicians with thematic analysis to explore the role of family members in the communication process. Forty-one participants included 10 cancer patients, 10 relatives ensuring proportionate representation of both gender and primary cancer site and 21 doctors representing both medical and surgical oncology. Nineteen of 20 patients and relatives wanted an "open and honest" discussion with their doctors. All patients, relatives and doctors preferred involvement of the family at most stages of cancer treatment. Five themes were identified in relation to communication with family members. The participants highlighted the "importance of family for physical and psychological care," they emphasised the need to "balance patient autonomy and relatives desire to be protective" using varied "negotiating strategies" that are influenced by "socioeconomic circumstances of both patient and family." The doctor-patient-relative communication process was not static with preferences changing over time. The data suggests that communication skills training of cancer clinicians should incorporate modules on better communication with relatives.

Factors influencing uptake and timing of risk reducing salpingo-oophorectomy in women at risk of familial ovarian cancer: a competing risk time to event analysis.

OBJECTIVE: To evaluate factors affecting uptake of risk-reducing salpingo-oophorectomy (RRSO) over time in women at high-risk of familial ovarian cancer. DESIGN: Prospective observational cohort. SETTING: Tertiary high-risk familial gynaecological cancer clinic. POPULATION/SAMPLE: New clinic attendees between March 2004 and November 2009, fulfilling the high-risk criteria for the UK Familial Ovarian Cancer Screening Study. METHODS: Risk management options discussed included RRSO and ovarian surveillance. Outcome data were analysed from a bespoke database. The competing risk method was used to model the cumulative incidence function (CIF) of RRSO over time, and the sub-hazard ratio (SHR) was used to assess the strength of the association of variables of interest with RRSO. Gray's test was used to evaluate the difference in CIF between two groups and multivariable competing risk regression analysis was used to model the cumulative probabilities of covariates on the CIF. RESULTS: Of 1133 eligible women, 265 (21.4%) opted for RRSO and 868 (69.9%) chose screening. Women undergoing RRSO were older (49 years, interquartile range 12.2 years) than those preferring screening (43.4 years, interquartile range 11.9 years) (P < 0.0005). The CIF for RRSO at 5 years was 0.55 (95% CI 0.45-0.64) for BRCA1/2 carriers and 0.22 (95% CI 0.19-0.26) for women of unknown mutation status (P < 0.0001); 0.42 (95% CI 0.36-0.47) for postmenopausal women (P < 0.0001); 0.29 (95% CI 0.25-0.33) for parity ≥1 (P = 0.009) and 0.47 (95% CI 0.39-0.55) for a personal history of breast cancer (P < 0.0001). Variables of significance from the regression analysis were: a BRCA1/2 mutation (SHR 2.31, 95% CI 1.7-3.14), postmenopausal status (SHR 2.16, 95% CI 1.62-2.87)) and a personal history of breast cancer (SHR 1.5, 95% CI 1.09-2.06). CONCLUSIONS: Decision-making is a complex process and women opt for surgery many years after initial risk assessment. BRCA carriers, postmenopausal women and women who had breast cancer are significantly more likely to opt for preventative surgery.

Outcome of risk-reducing salpingo-oophorectomy in BRCA carriers and women of unknown mutation status.

OBJECTIVE: To compare surgical outcomes and occult cancer rates at risk-reducing salpingo-oophorectomy in BRCA carriers and high-risk women who had not undergone genetic testing. DESIGN: Prospective cohort study. SETTING: Tertiary high-risk familial gynaecological cancer clinic. POPULATION: Women undergoing risk-reducing salpingo-oophorectomy between January 2005 and November 2009. METHODS: Women at high-risk of ovarian/tubal cancer were identified on the basis of the inclusion criteria for the UK Familial Ovarian Cancer Screening Study. Risk management options discussed with 1456 high-risk women included risk-reducing salpingo-oophorectomy. A strict histopathological protocol with serial slicing was used to assess tubes and ovaries. RESULTS: In total, 308 high-risk women (191 with unknown mutation status; 117 known BRCA1/BRCA2 carriers) chose risk-reducing surgery; 94.5% of procedures were performed laparoscopically. The surgical complication rate was 3.9% (95% CI 2.0-6.7). Four ovarian and ten tubal occult invasive/in situ cancers were found. The overall occult invasive cancer rate was 5.1% (95% CI 1.9-10.83) in BRCA1/BRCA2 carriers and 1.05% (95% CI 0.13-3.73) in untested women. When tubal in situ cancers were included, the overall rate was 4.55% (95% CI 2.5-7.5). Two untested women with tubal carcinoma in situ were subsequently found to be BRCA carriers. The median ages of BRCA carriers (58 years; IQR 13.4 years) and untested women (49.5 years; IQR 20.6 years) with occult invasive/in situ cancer were not significantly different (P = 0.454). CONCLUSIONS: Both high-risk women of unknown mutation status and BRCA carriers have a significant (although higher in the latter group) rate of occult invasive/in situ tubal/ovarian cancer, with a similar age distribution at detection. The data has important implications for counselling high-risk women on the likelihood of occult malignancy and perioperative complications at risk-reducing salpingo-oophorectomy. Women with occult disease should be offered genetic testing.

Screening for distress in cancer patients: is the distress thermometer a valid measure in the UK and does it measure change over time? A prospective validation study.

A prospective validation study was conducted in 171 consenting patients from oncology and palliative care outpatient clinics to validate the Distress Thermometer (DT) against the Hospital Anxiety and Depression Scale (HADS), General Health Questionnaire-12 (GHQ-12) and Brief Symptom Inventory-18 (BSI-18) at baseline, four weeks and eight weeks. Receiver Operating Characteristic analysis was used to examine the sensitivity and specificity of the DT scores against the clinically significant cut-off scores of the criterion measures reporting 95% confidence intervals. Standardised response means were used to compare DT scores with criterion measures over time. For a cut-off of 4 vs 5, sensitivity against HADS was 79%, specificity 81%; against GHQ-12, sensitivity was 63%, specificity 83%; and against BSI-18, sensitivity was 88%, specificity 74%. At both four and eight weeks, DT scores tended to change significantly in the same direction as the criterion measures. Ninety-five percent of patients found completing the DT acceptable. The DT is valid and acceptable for use as a rapid screening instrument for patients in the UK with cancer. Our results indicate that it can be used to monitor change in psychological distress over time, but further work is needed to confirm this.

Schizophrenic inability to judge facial emotion: a controlled study.

The ability of schizophrenics to judge facial emotion was examined using a new test derived to remedy methodological inadequacies in previous studies. The derivation procedure of the test is described. Five groups of 20 subjects each took part: acute schizophrenics, chronic schizophrenics, schizophrenics in remission, in-patients with depressive illness and normal subjects. They were asked to make a dichotomous emotion judgement ('happy' or 'sad') about a set of photographed faces: and then to make a dichotomous non-emotion judgement ('old' or 'young') on a set of photographs chosen from the same original pool to form a task of equal difficulty and discriminating ability. It was predicted, from previous studies, that acute schizophrenics would be specifically impaired on judging emotional expression in faces. Instead, they were found to be impaired on both an emotion and a non-emotion task on photographs of faces when these tasks were matched for difficulty and discriminating ability. They were significantly worse than remitted schizophrenics and normal subjects for both tasks, and for emotion, significantly worse then depressed subjects as well. The findings are considered in the light of current theories of visual processing in schizophrenia and of the neuropsychology of face processing.

Dealing with the unsafe student in clinical practice.

How do social justice issues affect the clinical evaluation of students? An emotionally charged issue, clinical evaluation can become a mine field when it becomes entangled with issues of social justice. The authors discuss the issues of justice and fairness in relation to situations that arise when a student repeatedly fails to meet minimum expectations for clinical performance. They discuss policies developed to deal with such situations and describe the application of these policies in a case study.

What influences midwives in estimating labour pain?

BACKGROUND: Clinicians' estimates of patients' pain are frequently used as a basis for delivering care, and the characteristics of the clinician and of the patient influence this estimate. METHODS: We studied pain estimation by midwives attending women in uncomplicated labour. Sixty-six practising midwives of varied age, ethnicity and professional experience were asked to complete a trait empathy measure and then to estimate the maximum pain and anxiety experienced by six women whose filmed labour contractions they viewed. Additionally, they rated similarity to the labouring women in ethnicity, and described their beliefs about pain expression according to ethnicity. RESULTS: Midwife estimates of pain and anxiety were highly correlated. Longer professional experience was associated with lower pain estimates, while more births to the midwife herself was associated with higher pain estimates. A multiple regression model identified number of births to the midwife herself, and two components of empathy (perspective taking and identification), to be important in predicting midwife pain estimates for women in labour. Midwives expressed clear beliefs about women's expression of pain during labour according to ethnicity, but these beliefs were not consistent across midwives, even between midwives of similar ethnicity. CONCLUSION: Midwives' personal characteristics can bias the estimation of pain in woman in labour and therefore influence treatment.

Population-based, risk-stratified genetic testing for ovarian cancer risk: a focus group study.

STUDY PURPOSE: A population-based risk stratification programme for ovarian cancer (OC) may improve OC survival by identifying women at increased risk and implementing an appropriate risk management strategy. The present study explored attitudes towards an OC risk stratification programme incorporating predictive genetic testing and risk-stratified screening as part of a larger study investigating OC screening. METHODS: Focus groups consisting of 56 members of the general public (mean age 45 years; 34% non-white) were conducted using a hypothetical scenario. The group sessions were recorded, transcribed verbatim and analysed using Framework Analysis. RESULTS: There was strong support for the proposed programme. Genetic testing and risk-stratified screening was thought to raise awareness, offer reassurance and offer opportunities for early intervention. Anxiety was only mentioned in relation to receiving a diagnosis of OC and not with screening per se. Perhaps because lay models of cancer already embrace both environmental and genetic factors, a low-risk result was not anticipated to result in a false sense of immunity. Unexpectedly, participants also wanted to receive cancer prevention advice in conjunction with genetic testing; screening alone was not regarded as sufficient. CONCLUSION: The encouraging results from this small study warrant further large-scale research into risk-stratified OC screening.