Ranjit Manchanda

Consent model for tumour genetic testing in ovarian cancer

Prospective parallel genetic testing of both germline and tumour DNA in ovarian cancer patients (OC) is the recommended model in several different countries across the globe and the UK. The high (∼67%) chance of identifying germline PVs in patients with tumour PVs has led to a discourse surrounding the need for consent for tumour genetic testing in OC. We discussed with OC patients during focus group workshops, physicians, and charity representatives about consent options for tumour testing in OC patients: verbal consent prior to testing (Option 1) and reflex testing (Option 2). Most patients (97%; 33/34) did not feel that consent was required and were happy with reflex testing (Option 2). Physician consensus was that reflex testing was preferred and most charity representatives (4/5; 80%) agreed. All groups wanted an opt-out option and a patient information sheet about tumour testing. This can inform new recommendations in the UK and foster further discussions regarding consent for OC tumour testing.

Uptake and patient-related outcomes of mainstreaming genetic testing: a systematic review and meta-analysis

Mainstreaming genetic testing refers to genetic testing for cancer susceptibility genes following cancer diagnosis, which is provided by nongenetic health professionals of the cancer-treating team. Mainstreaming can be used to guide cancer treatment and secondary cancer prevention in the patient and to identify carriers in the family members of patients who test positive through cascade testing. We aimed to assess uptake and patient-reported outcomes of mainstreaming genetic testing. We searched PubMed and the Cochrane Library from inception to June 2024. Our population included adult patients offered mainstreaming genetic testing (intervention). Outcomes included testing uptake, satisfaction, decisional conflict/regret, anxiety, depression, and cancer-related distress. We followed a prospective protocol according to Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines (International Prospective Register of Systematic Reviews: CRD42023467312). Qualitative synthesis and random effects meta-analyses were performed. Quality assessment was performed using the Methodological Index for Non-Randomized Studies. Searches yielded 5314 studies; 29 studies (n=13,219) were included, of which 14 were on ovarian cancer (n=6039), 6 on breast cancer (n=4354), 3 on prostate cancer (n=772), 1 on endometrial cancer (n=302), and 5 on multiple cancers (n=1752). There were no studies for colorectal cancer. Pooled genetic testing uptake was 91% (95% confidence interval=86-96, I Mainstreaming genetic testing uptake is associated with high uptake and satisfaction and low decision conflict, regret, and post-test distress. Quality and quantity of evidence across different types of cancers vary significantly.

Current practices for the management of advanced high-grade epithelial ovarian cancer in the UK: OC-NOW survey (2023)

The NHS England Jewish BRCA Testing Programme: overview after first year of implementation (2023–2024)

Background The NHS Jewish BRCA Testing Programme is offering germline BRCA1 and BRCA2 genetic testing to people with ≥1 Jewish grandparent. Who have an increased likelihood of having an Ashkenazi Jewish (AJ) founder germline pathogenic variant (gPV) compared with the general population. Testing is offered via a self-referral, home-based saliva sampling pathway, supported by a genetic counsellor telephone helpline. A first-of-its-kind in the United Kingdom (UK) for population genetic testing, outside of research. Methods We reviewed data from germline testing of 5389 people who registered during the soft-launch phase (January 2023–January 2024) and their families to observe trends in uptake and outcomes of testing. Results Of the 5389 self-referrals, 4339 (80.5%) consented to testing. Of those with results returned, 2.3% (98/4,274) had a gPV (89.8% AJ founder and 10.2% non-AJ founder). Notably, the detection rate was higher in men (42/790, 5.3%) compared with women (56/3484, 1.6%), with the proportion reporting known BRCA variants within the family prior to consent also significantly increased (13.1% compared with 9.2%, respectively). Conclusion Overall detection rates of gPVs are similar to those reported elsewhere from Jewish population testing. The pathway, particularly for males, may attract uptake of testing by those previously aware of familial gPVs.

British Gynaecological Cancer Society/British Association of Gynaecological Pathology consensus for genetic testing in epithelial ovarian cancer in the United Kingdom

Standard of care genetic testing has undergone significant changes in recent years. The British Gynecological Cancer Society and the British Association of Gynecological Pathologists (BGCS/BAGP) has re-assembled a multidisciplinary expert consensus group to update the previous guidance with the latest standard of care for germline and tumor testing in patients with ovarian cancer. For the first time, the BGCS/BAGP guideline group has incorporated a patient advisor at the initial consensus group meeting. We have used patient focused groups to inform discussions related to reflex tumor testing - a key change in this updated guidance. This report summarizes recommendations from our consensus group deliberations and audit standards to support continual quality improvement in routine clinical settings.

Venous thromboembolism during neoadjuvant chemotherapy for ovarian cancer

To determine the incidence of venous thromboembolism in patients with advanced epithelial ovarian cancer undergoing neoadjuvant chemotherapy in UK gynecological cancer centers. Secondary outcomes included incidence and timing of venous thromboembolism since cancer presentation, impact on cancer treatment, and mortality. All UK gynecological cancer centers were invited to participate in this multi-center retrospective audit through the British Gynecological Cancer Society. Data were captured on all patients undergoing neoadjuvant chemotherapy for International Federation of Gynecology and Obstetrics (FIGO) stage III/IV epithelial ovarian cancer within a 12-month period during 2021-2022. Patients on anticoagulation prior to cancer presentation were excluded. Patients who were diagnosed with venous thromboembolism between cancer presentation and commencing neoadjuvant chemotherapy were also excluded from our analysis of venous thromboembolism rates from neoadjuvant chemotherapy. Fourteen UK gynecological cancer centers returned data on 660 eligible patients. The median age was 67 years (range 34-96). In total, 131/660 (19.8%) patients were diagnosed with venous thromboembolism from cancer presentation until discharge following cytoreductive surgery. Between commencing neoadjuvant chemotherapy and post-operative discharge, 65/594 (10.9%) patients developed venous thromboembolism (median 11.3%, IQR 5.9-11.3); 55/594 (9.3%) during neoadjuvant chemotherapy, 10/594 (1.7%) during post-operative admission. There was no significant difference across centers (p=0.47). Of these 65 patients, 44 (68%) were diagnosed with pulmonary embolism and 30 (46%) with deep-vein thrombosis (nine had both), including in major abdominal/pelvic vessels, with 36 (55%) presenting symptomatically and 29 (45%) diagnosed incidentally on imaging. Venous thromboembolism resulted in mortality (n=3/65, 5%), and delays/changes/cancelation of treatment (n=18/65, 28%). Across a large, representative sample of UK gynecological cancer centers, one in five patients undergoing neoadjuvant chemotherapy were diagnosed with a potentially preventable venous thromboembolism, including one in nine diagnosed after commencing chemotherapy. This led to adverse clinical consequences for one third, including delay to oncological treatment and mortality. This high venous thromboembolism rate justifies the consideration of thromboprophylaxis in this patient group.

Association of hysterectomy and invasive epithelial ovarian and tubal cancer: a cohort study within UKCTOCS

ObjectiveTo investigate the association between hysterectomy with conservation of one or both adnexa and ovarian and tubal cancer.DesignProspective cohort study.SettingThirteen NHS Trusts in England, Wales and Northern Ireland.PopulationA total of 202 506 postmenopausal women recruited between 2001 and 2005 to the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and followed up until 31 December 2014.MethodsMultiple sources (questionnaires, hospital notes, Hospital Episodes Statistics, national cancer/death registries, ultrasound reports) were used to obtain accurate data on hysterectomy (with conservation of one or both adnexa) and outcomes censored at bilateral oophorectomy, death, ovarian/tubal cancer diagnosis, loss to follow up or 31 December 2014. Cox proportional hazards regression models were used to assess the association.Main outcome measuresInvasive epithelial ovarian and tubal cancer (WHO 2014) on independent outcome review.ResultsHysterectomy with conservation of one or both adnexa was reported in 41 912 (20.7%; 41 912/202 506) women. Median follow up was 11.1 years (interquartile range 9.96–12.04), totalling >2.17 million woman‐years. Among women who had undergone hysterectomy, 0.55% (231/41 912) were diagnosed with ovarian/tubal cancer, compared with 0.59% (945/160 594) of those with intact uterus. Multivariable analysis showed no evidence of an association between hysterectomy and invasive epithelial ovarian/tubal cancer (hazard ratio 0.98, 95% CI 0.85–1.13, P = 0.765).ConclusionsThis large cohort study provides further independent validation that hysterectomy is not associated with alteration of invasive epithelial ovarian and tubal cancer risk. These data are important both for clinical counselling and for refining risk prediction models.Tweetable abstractHysterectomy does not alter risk of invasive epithelial ovarian and tubal cancer.

Screening and prevention of ovarian cancer

Summary Ovarian cancer remains the most lethal gynaecological malignancy with 314 000 cases and 207 000 deaths annually worldwide. Ovarian cancer cases and deaths are predicted to increase in Australia by 42% and 55% respectively by 2040. Earlier detection and significant downstaging of ovarian cancer have been demonstrated with multimodal screening in the largest randomised controlled trial of ovarian cancer screening in women at average population risk. However, none of the randomised trials have demonstrated a mortality benefit. Therefore, ovarian cancer screening is not currently recommended in women at average population risk. More frequent surveillance for ovarian cancer every three to four months in women at high risk has shown good performance characteristics and significant downstaging, but there is no available information on a survival benefit. Population testing offers an emerging novel strategy to identify women at high risk who can benefit from ovarian cancer prevention. Novel multicancer early detection biomarker, longitudinal multiple marker strategies, and new biomarkers are being investigated and evaluated for ovarian cancer screening. Risk‐reducing salpingo‐oophorectomy (RRSO) decreases ovarian cancer incidence and mortality and is recommended for women at over a 4–5% lifetime risk of ovarian cancer. Pre‐menopausal women without contraindications to hormone replacement therapy (HRT) undergoing RRSO should be offered HRT until 51 years of age to minimise the detrimental consequences of premature menopause. Currently risk‐reducing early salpingectomy and delayed oophorectomy (RRESDO) should only be offered to women at increased risk of ovarian cancer within the context of a research trial. Pre‐menopausal early salpingectomy is associated with fewer menopausal symptoms and better sexual function than bilateral salpingo‐oophorectomy. A Sectioning and Extensively Examining the Fimbria (SEE‐FIM) protocol should be used for histopathological assessment in women at high risk of ovarian cancer who are undergoing surgical prevention. Opportunistic salpingectomy may be offered at routine gynaecological surgery to all women who have completed their family. Long term prospective opportunistic salpingectomy studies are needed to determine the effect size of ovarian cancer risk reduction and the impact on menopause.

Patient decision aids in mainstreaming genetic testing for women with ovarian cancer: A prospective cohort study

AbstractObjectiveTo evaluate patient preference for short (gist) or detailed/extensive decision aids (DA) for genetic testing at ovarian cancer (OC) diagnosis.DesignCohort study set within recruitment to the Systematic Genetic Testing for Personalised Ovarian Cancer Therapy (SIGNPOST) study (ISRCTN: 16988857).SettingNorth‐East London Cancer Network (NELCN) population.Population/SampleWomen with high‐grade non‐mucinous epithelial OC.MethodsA more detailed DA was developed using patient and stakeholder input following the principles/methodology of IPDAS (International Patients Decision Aids Standards). Unselected patients attending oncology clinics evaluated both a pre‐existing short and a new long DA version and then underwent mainstreaming genetic testing by a cancer clinician. Appropriate inferential descriptive and regression analyses were undertaken.Main outcome measuresSatisfaction, readability, understanding, emotional well‐being and preference for long/short DA.ResultsThe mean age of patients was 66 years (interquartile range 11), and 85% were White British ethnicity. Of the participants, 74% found DAs helpful/useful in decision‐making. Women reported higher levels of satisfaction (86% versus 58%, p < 0.001), right amount of information provided (76.79% versus49.12%, p < 0.001) and improved understanding (p < 0.001) with the long DA compared with the short DA. There was no statistically significant difference in emotional outcomes (feeling worried/concerned/reassured/upset) between ‘short’ and ‘long’ DA; 74% of patients preferred the long DA and 24% the short DA. Patients undergoing treatment (correlation coefficient (coef) = 0.603; 95% CI 0.165–1.041, p = 0.007), those with recurrence (coef = 0.493; 95% CI 0.065–0.92, p = 0.024) and older women (coef = 0.042; 95% CI 0.017–0.066, p = 0.001) preferred the short DA. Ethnicity did not affect outcomes or overall preference for long/short DA.ConclusionsA longer DA in OC patients has higher satisfaction without increasing emotional distress. Older women and those undergoing treatment/recurrence prefer less extensive information, whereas those in remission preferred a longer DA.

Patient-reported quality of life following prophylactic surgery for breast and ovarian cancer prevention: response

Outcomes of minimal access retroperitoneal para-aortic lymphadenectomy in patients with locally advanced cervical cancer

To evaluate outcomes of laparoscopic retroperitoneal para-aortic lymphadenectomy for stage 1b3-3b cervical cancer. Pathology databases searched for all para-aortic lymphadenectomy cases 2005-2016. Descriptive statistics were used to analyse baseline characteristics, cox models for treatment affect after accounting for variables, and Kaplan Meier curves for survival (STATA v15). 191 patients had 1b3-3b cervical cancer of which 110 patients had Para-aortic lymphadenectomy. 8 (7.3%) patients stage 1b3, 82 (74.6%) stage 2b, and 20 (18.1%) stage 3b cervical cancer. Mean lymph node count 11.7 (SD7.6). The intra-operative and post-operative 30 day complication rates were 8.8% (CI: 4.3%, 15.7%) and 5.3% (CI: 1.9%, 11.2%) respectively.Para-aortic nodes were apparently positive on CT/MRI in 5/110 (5%) cases. Cancer was found in 10 (8.9%, CI: 4.3%, 15.7%) cases on histology, all received extended field radiotherapy. Only 2 were identified on pre-operative CT/MRI imaging. 3 of 10 suspected node-positive cases on CT/MRI had negative histology. Para-aortic lymphadenectomy led to alteration in staging and radiotherapy management in 8 (8%, CI: 3.7%, 14.6%) patients. Mean overall survival 42.81 months (SD = 31.79 months). Survival was significantly higher for women undergoing PAN (50.57 (SD 30.7) months) compared to those who didn't (31.27 (SD 32.5) months). Laparoscopic retroperitoneal para-aortic lymphadenectomy is an acceptable procedure which can guide treatment in women with locally advanced cervical cancer.

Quality of life after risk-reducing surgery for breast and ovarian cancer prevention: a systematic review and meta-analysis

This study aimed to assess the impact of risk-reducing surgery for breast cancer and ovarian cancer prevention on quality of life. We considered risk-reducing mastectomy, risk-reducing salpingo-oophorectomy, and risk-reducing early salpingectomy and delayed oophorectomy. We followed a prospective protocol (International Prospective Register of Systematic Reviews: CRD42022319782) and searched MEDLINE, Embase, PubMed, and Cochrane Library from inception to February 2023. We followed a PICOS (population, intervention, comparison, outcome, and study design) framework. The population included women at increased risk of breast cancer or ovarian cancer. We focused on studies reporting quality of life outcomes (health-related quality of life, sexual function, menopause symptoms, body image, cancer-related distress or worry, anxiety, or depression) after risk-reducing surgery, including risk-reducing mastectomy for breast cancer and risk-reducing salpingo-oophorectomy or risk-reducing early salpingectomy and delayed oophorectomy for ovarian cancer. We used the Methodological Index for Non-Randomized Studies (MINORS) for study appraisal. Qualitative synthesis and fixed-effects meta-analysis were performed. A total of 34 studies were included (risk-reducing mastectomy: 16 studies; risk-reducing salpingo-oophorectomy: 19 studies; risk-reducing early salpingectomy and delayed oophorectomy: 2 studies). Health-related quality of life was unchanged or improved in 13 of 15 studies after risk-reducing mastectomy (N=986) and 10 of 16 studies after risk-reducing salpingo-oophorectomy (N=1617), despite short-term deficits (N=96 after risk-reducing mastectomy and N=459 after risk-reducing salpingo-oophorectomy). Sexual function (using the Sexual Activity Questionnaire) was affected in 13 of 16 studies (N=1400) after risk-reducing salpingo-oophorectomy in terms of decreased sexual pleasure (-1.21 [-1.53 to -0.89]; N=3070) and increased sexual discomfort (1.12 [0.93-1.31]; N=1400). Hormone replacement therapy after premenopausal risk-reducing salpingo-oophorectomy was associated with an increase (1.16 [0.17-2.15]; N=291) in sexual pleasure and a decrease (-1.20 [-1.75 to -0.65]; N=157) in sexual discomfort. Sexual function was affected in 4 of 13 studies (N=147) after risk-reducing mastectomy, but stable in 9 of 13 studies (N=799). Body image was unaffected in 7 of 13 studies (N=605) after risk-reducing mastectomy, whereas 6 of 13 studies (N=391) reported worsening. Increased menopause symptoms were reported in 12 of 13 studies (N=1759) after risk-reducing salpingo-oophorectomy with a reduction (-1.96 [-2.81 to -1.10]; N=1745) in the Functional Assessment of Cancer Therapy - Endocrine Symptoms. Cancer-related distress was unchanged or decreased in 5 of 5 studies after risk-reducing mastectomy (N=365) and 8 of 10 studies after risk-reducing salpingo-oophorectomy (N=1223). Risk-reducing early salpingectomy and delayed oophorectomy (2 studies, N=413) led to better sexual function and menopause-specific quality of life. Risk-reducing surgery may be associated with quality of life outcomes. Risk-reducing mastectomy and risk-reducing salpingo-oophorectomy reduce cancer-related distress, and do not affect health-related quality of life. Women and clinicians should be aware of body image problems after risk-reducing mastectomy, and of sexual dysfunction and menopause symptoms after risk-reducing salpingo-oophorectomy. Risk-reducing early salpingectomy and delayed oophorectomy may be a promising alternative to mitigate quality of life-related risks of risk-reducing salpingo-oophorectomy.

Preventing Ovarian Cancer through early Excision of Tubes and late Ovarian Removal (PROTECTOR): protocol for a prospective non-randomised multi-center trial

Risk-reducing salpingo-oophorectomy is the 'gold standard' for preventing tubo-ovarian cancer in women at increased risk. However, when performed in pre-menopausal women, it results in premature menopause and associated detrimental health consequences. This, together with acceptance of the central role of the fallopian tube in etiopathogenesis of high-grade serous carcinoma, by far the most common type of tubo-ovarian cancer, has led to risk-reducing early salpingectomy with delayed oophorectomy being proposed as a two-step surgical alternative for pre-menopausal women declining/delaying oophorectomy. To evaluate the impact on sexual function of risk-reducing early salpingectomy, within a two-step, risk-reducing, early salpingectomy with delayed oophorectomy tubo-ovarian cancer prevention strategy in pre-menopausal women at increased risk of tubo-ovarian cancer. Risk-reducing early salpingectomy is non-inferior for sexual and endocrine function compared with controls; risk-reducing early salpingectomy is superior for sexual/endocrine function, non-inferior for quality-of-life, and equivalent in satisfaction to the standard risk-reducing salpingo-oophorectomy. Multi-center, observational cohort trial with three arms: risk-reducing early salpingectomy with delayed oophorectomy; risk-reducing salpingo-oophorectomy; controls (no surgery). Consenting individuals undergo an ultrasound, serum CA125, and follicle-stimulating hormone measurements and provide information on medical history, family history, quality-of-life, sexual function, cancer worry, psychological well-being, and satisfaction/regret. Follow-up by questionnaire takes place annually for 3 years. Women receiving risk-reducing early salpingectomy can undergo delayed oophorectomy at a later date of their choosing, or definitely by the menopause. Inclusion criteria: pre-menopausal; aged >30 years; at increased risk of tubo-ovarian cancer (mutation carriers or on the basis of a strong family history); completed their family (for surgical arms). post-menopausal; previous bilateral salpingectomy or bilateral oophorectomy; pregnancy; previous tubal/ovarian/peritoneal malignancy; <12 months after cancer treatment; clinical suspicion of tubal/ovarian cancer at baseline. Sexual function measured by validated questionnaires. 1000 (333 per arm). It is estimated recruitment will be completed by 2023 and results published by 2027. ISRCTN registry: 25 173 360 (https://doi.org/10.1186/ISRCTN25173360).

Attitudes towards risk‐reducing early salpingectomy with delayed oophorectomy for ovarian cancer prevention: a cohort study

ObjectiveTo determine risk‐reducing early salpingectomy and delayed oophorectomy (RRESDO) acceptability and effect of surgical prevention on menopausal sequelae/satisfaction/regret in women at increased ovarian cancer (OC) risk.DesignMulticentre, cohort, questionnaire study (IRSCTN:12310993).SettingUnited Kingdom (UK).PopulationUK women without OC ≥18 years, at increased OC risk, with/without previous RRSO, ascertained through specialist familial cancer/genetic clinics and BRCA support groups.MethodsParticipants completed a 39‐item questionnaire. Baseline characteristics were described using descriptive statistics. Logistic/linear regression models analysed the impact of variables on RRESDO acceptability and health outcomes.Main outcomesRRESDO acceptability, menopausal sequelae, satisfaction/regret.ResultsIn all, 346 of 683 participants underwent risk‐reducing salpingo‐oophorectomy (RRSO). Of premenopausal women who had not undergone RRSO, 69.1% (181/262) found it acceptable to participate in a research study offering RRESDO. Premenopausal women concerned about sexual dysfunction were more likely to find RRESDO acceptable (odds ratio [OR] = 2.9, 95% CI 1.2–7.7, P = 0.025). Women experiencing sexual dysfunction after premenopausal RRSO were more likely to find RRESDO acceptable in retrospect (OR = 5.3, 95% CI 1.2–27.5, P &lt; 0.031). In all, 88.8% (143/161) premenopausal and 95.2% (80/84) postmenopausal women who underwent RRSO, respectively, were satisfied with their decision, whereas 9.4% (15/160) premenopausal and 1.2% (1/81) postmenopausal women who underwent RRSO regretted their decision. HRT uptake in premenopausal individuals without breast cancer (BC) was 74.1% (80/108). HRT use did not significantly affect satisfaction/regret levels but did reduce symptoms of vaginal dryness (OR = 0.4, 95% CI 0.2–0.9, P = 0.025).ConclusionData show high RRESDO acceptability, particularly in women concerned about sexual dysfunction. Although RRSO satisfaction remains high, regret rates are much higher for premenopausal women than for postmenopausal women. HRT use following premenopausal RRSO does not increase satisfaction but does reduce vaginal dryness.Tweetable abstractRRESDO has high acceptability among premenopausal women at increased ovarian cancer risk, particularly those concerned about sexual dysfunction.

Population-based Genetic Testing for Precision Prevention

Abstract Global interest in genetic testing for cancer susceptibility genes (CSG) has surged with falling costs, increasing awareness, and celebrity endorsement. Current access to genetic testing is based on clinical criteria/risk model assessment which uses family history as a surrogate. However, this approach is fraught with inequality, massive underutilization, and misses 50% CSG carriers. This reflects huge missed opportunities for precision prevention. Early CSG identification enables uptake of risk-reducing strategies in unaffected individuals to reduce cancer risk. Population-based genetic testing (PGT) can overcome limitations of clinical criteria/family history–based testing. Jewish population studies show population-based BRCA testing is feasible, acceptable, has high satisfaction, does not harm psychologic well-being/quality of life, and is extremely cost-effective, arguing for changing paradigm to PGT in the Jewish population. Innovative approaches for delivering pretest information/education are needed to facilitate informed decision-making for PGT. Different health systems will need context-specific implementation strategies and management pathways, while maintaining principles of population screening. Data on general population PGT are beginning to emerge, prompting evaluation of wider implementation. Sophisticated risk prediction models incorporating genetic and nongenetic data are being used to stratify populations for ovarian cancer and breast cancer risk and risk-adapted screening/prevention. PGT is potentially cost-effective for panel testing of breast and ovarian CSGs and for risk-adapted breast cancer screening. Further research/implementation studies evaluating the impact, clinical efficacy, psychologic and socio–ethical consequences, and cost-effectiveness of PGT are needed.

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

ObjectiveUnselected 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.DesignRandomised controlled trial (RCT) (ISRCTN73338115) GCaPPS, with two‐arms: (i) population‐screening (PS); (ii) FH/clinical‐criteria‐based testing.SettingNorth London Ashkenazi‐Jewish (AJ) population.Population/SampleAJ women/men.MethodsPopulation‐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 &gt;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 measuresValidated questionnaires (HADS/MICRA/HAI/SF12) used to analyse psychological wellbeing/quality‐of‐life outcomes at baseline/1‐year/2‐year/3‐year follow up.ResultsIn 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‐&amp;‐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 &lt; 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%).ConclusionPopulation‐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 abstractPopulation BRCA testing in Ashkenazi Jews reduces anxiety and does not adversely affect psychological health or quality of life.

Comprehensive epithelial tubo-ovarian cancer risk prediction model incorporating genetic and epidemiological risk factors

Background Epithelial tubo-ovarian cancer (EOC) has high mortality partly due to late diagnosis. Prevention is available but may be associated with adverse effects. A multifactorial risk model based on known genetic and epidemiological risk factors (RFs) for EOC can help identify women at higher risk who could benefit from targeted screening and prevention. Methods We developed a multifactorial EOC risk model for women of European ancestry incorporating the effects of pathogenic variants (PVs) in BRCA1 , BRCA2 , RAD51C , RAD51D and BRIP1 , a Polygenic Risk Score (PRS) of arbitrary size, the effects of RFs and explicit family history (FH) using a synthetic model approach. The PRS, PV and RFs were assumed to act multiplicatively. Results Based on a currently available PRS for EOC that explains 5% of the EOC polygenic variance, the estimated lifetime risks under the multifactorial model in the general population vary from 0.5% to 4.6% for the first to 99th percentiles of the EOC risk distribution. The corresponding range for women with an affected first-degree relative is 1.9%–10.3%. Based on the combined risk distribution, 33% of RAD51D PV carriers are expected to have a lifetime EOC risk of less than 10%. RFs provided the widest distribution, followed by the PRS. In an independent partial model validation, absolute and relative 5-year risks were well calibrated in quintiles of predicted risk. Conclusion This multifactorial risk model can facilitate stratification, in particular among women with FH of cancer and/or moderate-risk and high-risk PVs. The model is available via the CanRisk Tool ( www.canrisk.org ).

UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes: RAD51C, RAD51D, BRIP1 and PALB2

Germline pathogenic variants (GPVs) in the cancer predisposition genes BRCA1, BRCA2, MLH1, MSH2, MSH6, BRIP1, PALB2, RAD51D and RAD51C are identified in approximately 15% of patients with ovarian cancer (OC). While there are clear guidelines around clinical management of cancer risk in patients with GPV in BRCA1, BRCA2, MLH1, MSH2 and MSH6, there are few guidelines on how to manage the more moderate OC risk in patients with GPV in BRIP1, PALB2, RAD51D and RAD51C, with clinical questions about appropriateness and timing of risk-reducing gynaecological surgery. Furthermore, while recognition of RAD51C and RAD51D as OC predisposition genes has been established for several years, an association with breast cancer (BC) has only more recently been described and clinical management of this risk has been unclear. With expansion of genetic testing of these genes to all patients with non-mucinous OC, new data on BC risk and improved estimates of OC risk, the UK Cancer Genetics Group and CanGene-CanVar project convened a 2-day meeting to reach a national consensus on clinical management of BRIP1, PALB2, RAD51D and RAD51C carriers in clinical practice. In this paper, we present a summary of the processes used to reach and agree on a consensus, as well as the key recommendations from the meeting.

Surgical decision making in premenopausal BRCA carriers considering risk-reducing early salpingectomy or salpingo-oophorectomy: a qualitative study

BackgroundAcceptance of the role of the fallopian tube in ‘ovarian’ carcinogenesis and the detrimental sequelae of surgical menopause in premenopausal women following risk-reducing salpingo-oophorectomy (RRSO) has resulted in risk-reducing early-salpingectomy with delayed oophorectomy (RRESDO) being proposed as an attractive alternative risk-reducing strategy in women who decline/delay oophorectomy. We present the results of a qualitative study evaluating the decision-making process among BRCA carriers considering prophylactic surgeries (RRSO/RRESDO) as part of the multicentre PROTECTOR trial (ISRCTN:25173360).MethodsIn-depth semistructured 1:1 interviews conducted using a predeveloped topic-guide (development informed by literature review and expert consultation) until informational saturation reached. Wording and sequencing of questions were left open with probes used to elicit additional information. All interviews were audio-recorded, transcribed verbatim, transcripts analysed using an inductive theoretical framework and data managed using NVIVO-v12.ResultsInformational saturation was reached following 24 interviews. Seven interconnected themes integral to surgical decision making were identified: fertility/menopause/cancer risk reduction/surgical choices/surgical complications/sequence of ovarian-and-breast prophylactic surgeries/support/satisfaction. Women for whom maximising ovarian cancer risk reduction was relatively more important than early menopause/quality-of-life preferred RRSO, whereas those more concerned about detrimental impact of menopause chose RRESDO. Women managed in specialist familial cancer clinic settings compared with non-specialist settings felt they received better quality care, improved hormone replacement therapy access and were more satisfied.ConclusionMultiple contextual factors (medical, physical, psychological, social) influence timing of risk-reducing surgeries. RRESDO offers women delaying/declining premenopausal oophorectomy, particularly those concerned about menopausal effects, a degree of ovarian cancer risk reduction while avoiding early menopause. Care of high-risk women should be centralised to centres with specialist familial gynaecological cancer risk management services to provide a better-quality, streamlined, holistic multidisciplinary approach.

The avoiding late diagnosis of ovarian cancer (ALDO) project; a pilot national surveillance programme for women with pathogenic germline variants inBRCA1andBRCA2

BackgroundOur study aimed to establish ‘real-world’ performance and cost-effectiveness of ovarian cancer (OC) surveillance in women with pathogenic germlineBRCA1/2variants who defer risk-reducing bilateral salpingo-oophorectomy (RRSO).MethodsOur study recruited 875 femaleBRCA1/2-heterozygotes at 13 UK centres and via an online media campaign, with 767 undergoing at least one 4-monthly surveillance test with the Risk of Ovarian Cancer Algorithm (ROCA) test. Surveillance performance was calculated with modelling of occult cancers detected at RRSO. The incremental cost-effectiveness ratio (ICER) was calculated using Markov population cohort simulation.ResultsOur study identified 8 OCs during 1277 women screen years: 2 occult OCs at RRSO (both stage 1a), and 6 screen-detected; 3 of 6 (50%) were ≤stage 3a and 5 of 6 (83%) were completely surgically cytoreduced. Modelled sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) for OC were 87.5% (95% CI, 47.3 to 99.7), 99.9% (99.9–100), 75% (34.9–96.8) and 99.9% (99.9–100), respectively. The predicted number of quality-adjusted life years (QALY) gained by surveillance was 0.179 with an ICER cost-saving of -£102,496/QALY.ConclusionOC surveillance for women deferring RRSO in a ‘real-world’ setting is feasible and demonstrates similar performance to research trials; it down-stages OC, leading to a high complete cytoreduction rate and is cost-saving in the UK National Health Service (NHS) setting. While RRSO remains recommended management, ROCA-based surveillance may be considered for femaleBRCA-heterozygotes who are deferring such surgery.

British Gynaecological Cancer Society/British Association of Gynaecological Pathology consensus for germline and tumor testing for BRCA1/2 variants in ovarian cancer in the United Kingdom

The British Gynecological Cancer Society and the British Association of Gynecological Pathologists established a multidisciplinary consensus group comprising experts in surgical gynecological oncology, medical oncology, genetics, and laboratory science, and clinical nurse specialists to identify the optimal pathways to

Randomised trial of population‐based BRCA testing in Ashkenazi Jews: long‐term secondary lifestyle behavioural outcomes

AbstractObjectiveAshkenazi‐Jewish (AJ) population‐based BRCA testing is acceptable, cost‐effective and amplifies primary prevention for breast &amp; ovarian cancer. However, data describing lifestyle impact are lacking. We report long‐term results of population‐based BRCA testing on lifestyle behaviour and cancer risk perception.DesignTwo‐arm randomised controlled trials (ISRCTN73338115, GCaPPS): (a) population‐screening (PS); (b) family history (FH)/clinical criteria testing.SettingNorth London AJ‐population.Population/SampleAJ women/men &gt;18 years. Exclusions: prior BRCA testing or first‐degree relatives of BRCA‐carriers.MethodsParticipants were recruited through self‐referral. All participants received informed pre‐test genetic counselling. The intervention included genetic testing for three AJ BRCA‐mutations: 185delAG(c.68_69delAG), 5382insC(c.5266dupC) and 6174delT(c.5946delT). This was undertaken for all participants in the PS arm and participants fulfilling FH/clinical criteria in the FH arm. Patients filled out customised/validated questionnaires at baseline/1‐year/2‐year/3‐year follow‐ups. Generalised linear‐mixed models adjusted for covariates and appropriate contrast tests were used for between‐group/within‐group analysis of lifestyle and behavioural outcomes along with evaluating factors associated with these outcomes. Outcomes are adjusted for multiple testing (Bonferroni method), with P &lt; 0.0039 considered significant.Outcome measuresLifestyle/behavioural outcomes at baseline/1‐year/2‐year/3‐year follow‐ups.Results1034 participants were randomised to PS (n = 530) or FH (n = 504) arms. No significant difference was identified between PS‐ and FH‐based BRCA testing approaches in terms of dietary fruit/vegetable/meat consumption, vitamin intake, alcohol quantity/ frequency, smoking behaviour (frequency/cessation), physical activity/exercise or routine breast mammogram screening behaviour, with outcomes not affected by BRCA test result. Cancer risk perception decreased with time following BRCA testing, with no difference between FH/PS approaches, and the perception of risk was lowest in BRCA‐negative participants. Men consumed fewer fruits/vegetables/vitamins and more meat/alcohol than women (P &lt; 0.001).ConclusionPopulation‐based and FH‐based AJ BRCA testing have similar long‐term lifestyle impacts on smoking, alcohol, dietary fruit/vegetable/meat/vitamin, exercise, breast screening participation and reduced cancer risk perception.

Quality of life from cytoreductive surgery in advanced ovarian cancer: Investigating the association between disease burden and surgical complexity in the international, prospective, SOCQER‐2 cohort study

AbstractObjectiveTo investigate quality of life (QoL) and association with surgical complexity and disease burden after surgical resection for advanced ovarian cancer in centres with variation in surgical approach.DesignProspective multicentre observational study.SettingGynaecological cancer surgery centres in the UK, Kolkata, India, and Melbourne, Australia.SamplePatients undergoing surgical resection (with low, intermediate or high surgical complexity score, SCS) for late‐stage ovarian cancer.Main Outcome MeasuresPrimary: change in global score on the European Organisation for Research and Treatment of Cancer (EORTC) core quality‐of‐life questionnaire (QLQ‐C30). Secondary: EORTC ovarian cancer module (OV28), progression‐free survival.ResultsPatients’ preoperative disease burden and SCS varied between centres, confirming differences in surgical ethos. QoL response rates were 90% up to 18 months. Mean change from the pre‐surgical baseline in the EORTC QLQ‐C30 was 3.4 (SD 1.8, n = 88) in the low, 4.0 (SD 2.1, n = 55) in the intermediate and 4.3 (SD 2.1, n = 52) in the high‐SCS group after 6 weeks (p = 0.048), and 4.3 (SD 2.1, n = 51), 5.1 (SD 2.2, n = 41) and 5.1 (SD 2.2, n = 35), respectively, after 12 months (p = 0.133). In a repeated‐measures model, there were no clinically or statistically meaningful differences in EORTC QLQ‐C30 global scores between the three SCS groups (p = 0.840), but there was a small statistically significant improvement in all groups over time (p &lt; 0.001). The high‐SCS group experienced small to moderate decreases in physical (p = 0.004), role (p = 0.016) and emotional (p = 0.001) function at 6 weeks post‐surgery, which resolved by 6–12 months.ConclusionsThe global QoL of patients undergoing low‐, intermediate‐ and high‐SCS surgery improved at 12 months after surgery and was no worse in patients undergoing extensive surgery.Tweetable AbstractCompared with surgery of lower complexity, extensive surgery does not result in poorer quality of life in patients with advanced ovarian cancer.

Diagnostic Accuracy of FEC-PET/CT, FDG-PET/CT, and Diffusion-Weighted MRI in Detection of Nodal Metastases in Surgically Treated Endometrial and Cervical Carcinoma

Abstract Purpose: Preoperative nodal staging is important for planning treatment in cervical cancer and endometrial cancer, but remains challenging. We compare nodal staging accuracy of 18F-ethyl-choline-(FEC)-PET/CT, 18F-fluoro-deoxy-glucose-(FDG)-PET/CT, and diffusion-weighted-MRI (DW-MRI) with conventional morphologic MRI. Experimental Design: A prospective, multicenter observational study of diagnostic accuracy for nodal metastases was undertaken in 5 gyne-oncology centers. FEC-PET/CT, FDG-PET/CT, and DW-MRI were compared with nodal size and morphology on MRI. Reference standard was strictly correlated nodal histology. Eligibility included operable cervical cancer stage ≥ 1B1 or endometrial cancer (grade 3 any stage with myometrial invasion or grade 1–2 stage ≥ II). Results: Among 162 consenting participants, 136 underwent study DW-MRI and FDG-PET/CT and 60 underwent FEC-PET/CT. In 118 patients, 267 nodal regions were strictly correlated at histology (nodal positivity rate, 25%). Sensitivity per patient (n = 118) for nodal size, morphology, DW-MRI, FDG- and FEC-PET/CT was 40%*, 53%, 53%, 63%*, and 67% for all cases (*, P = 0.016); 10%, 10%, 20%, 30%, and 25% in cervical cancer (n = 40); 65%, 75%, 70%, 80% and 88% in endometrial cancer (n = 78). FDG-PET/CT outperformed nodal size (P = 0.006) and size ratio (P = 0.04) for per-region sensitivity. False positive rates were all &amp;lt;10%. Conclusions: All imaging techniques had low sensitivity for detection of nodal metastases and cannot replace surgical nodal staging. The performance of FEC-PET/CT was not statistically different from other techniques that are more widely available. FDG-PET/CT had higher sensitivity than size in detecting nodal metastases. False positive rates were low across all methods. The low false positive rate demonstrated by FDG-PET/CT may be helpful in arbitration of challenging surgical planning decisions.

Diagnostic performance of quantitative measures from [18F]FDG PET/CT, [18F]FEC PET/CT, and DW-MRI in the detection of lymph node metastases in endometrial and cervical cancer: data from the MAPPING study

Abstract Purpose To evaluate the diagnostic performance of quantitative measures derived from [ 18 F]FDG PET/CT, [ 18 F]FEC PET/CT, and DW-MRI in the detection of lymph node metastases in endometrial and cervical cancer with comparison to standard visual PET analysis with histology as the reference standard. Methods Subanalysis of quantitative data from the prospective multicentre MAPPING study. Nodal and tumour SUV max from [ 18 F]FDG PET/CT and [ 18 F]FEC PET/CT and ADC mean from DW-MRI were documented. Nodal-to-tumour ratios (NTR) and SUV max -to-ADC mean ratio (STAR) were calculated. Optimal cut-offs of quantitative measures were compared to visual assessment on a regional basis using histopathology as the reference standard. Results Scans from 112 patients (36 cervical and 76 endometrial cancers; 340 nodal regions) were eligible for quantitative image analysis. Lower ADC mean on DW-MRI was observed in metastatic nodes for cervical cancer but not for endometrial cancer. Quantitative measures were significantly higher in malignant than benign nodal regions on [ 18 F]FDG PET/CT and [ 18 F]FEC PET/CT in endometrial cancer. SUV max cut-offs showed similar performance to visual assessment in the diagnosis of metastatic lymph nodes in endometrial cancer whilst ADC mean cut-offs showed significantly lower specificity than visual assessment. Interobserver agreement was excellent for SUV max measurements on both [ 18 F]FDG PET/CT and [ 18 F]FEC PET/CT, but poor for ADC mean on DW-MRI. Conclusion Quantitative measures from [ 18 F]FDG PET/CT, [ 18 F]FEC PET/CT, or DW-MRI did not outperform visual assessment in the detection of nodal metastases in endometrial cancer. Therefore, the implementation of these quantitative measures as standalone diagnostic tools in routine clinical practice is not recommended.

Immunotherapy that improves response to chemotherapy in high-grade serous ovarian cancer

AbstractSingle-cell RNA sequencing (scRNAseq) of tumour-infiltrating immune cells in high-grade serous ovarian cancer (HGSOC) omental biopsies reveals potential targets that could enhance response to neo-adjuvant chemotherapy (NACT). Analysis of 64,097 cells identifies NACT-induced overexpression of stabilin-1 (clever-1) on macrophages and FOXP3 in Tregs that is confirmed at the protein level. STAB1 inhibition in vitro induces anti-tumour macrophages. FOXP3 anti-sense oligonucleotide (FOXP3-ASO), repolarises Tregs to an effector T cell phenotype. ScRNAseq on 69,781 cells from an HGSOC syngeneic mouse model recapitulates the patients’ data. Combining chemotherapy with anti-stabilin1 antibody and/or Foxp3-ASO significantly increases survival of mice with established peritoneal disease in two HGSOC syngeneic models and progression-free survival in a third model. Long-term survivors (300 days + ) are resistant to tumour rechallenge. Anti-stabilin1 antibody enriches the tumours with CXCL9+ macrophages and Foxp3-ASO increases TBET cell infiltration. Our results suggest that targeting these molecules in immune cells may improve chemotherapy response in patients.

Human 3D Ovarian Cancer Models Reveal Malignant Cell–Intrinsic and –Extrinsic Factors That Influence CAR T-cell Activity

Abstract In vitro preclinical testing of chimeric antigen receptor (CAR) T cells is mostly carried out in monolayer cell cultures. However, alternative strategies are needed to take into account the complexity and the effects of the tumor microenvironment. Here, we describe the modulation of CAR T-cell activity by malignant cells and fibroblasts in human three-dimensional (3D) in vitro cell models of increasing complexity. In models combining mucin-1 (MUC1) and TnMUC1 CAR T cells with human high-grade serous ovarian cancer cell spheroids, malignant cell–intrinsic resistance to CAR T-cell killing was due to defective death receptor signaling involving TNFα. Adding primary human fibroblasts to spheroids unexpectedly increased the ability of CAR T cells to kill resistant malignant cells as CCL2 produced by fibroblasts activated CCR2/4+ CAR T cells. However, culturing malignant cells and fibroblasts in collagen gels engendered production of a dense extracellular matrix that impeded CAR T-cell activity in a TGFβ-dependent manner. A vascularized microfluidic device was developed that allowed CAR T cells to flow through the vessels and penetrate the gels in a more physiological way, killing malignant cells in a TNFα-dependent manner. Complex 3D human cell models may provide an efficient way of screening multiple cytotoxic human immune cell constructs while also enabling evaluation of mechanisms of resistance involving cell–cell and cell–matrix interactions, thus accelerating preclinical research on cytotoxic immune cell therapies in solid tumors. Significance: Three-dimensional in vitro models of increasing complexity uncover mechanisms of resistance to CAR T cells in solid tumors, which could help accelerate development of improved CAR T-cell constructs.

A 3D Bioprinted Hormone-producing Model for BRCA Mutated Patients After Risk Reducing Surgery: the DISC-OVARY Trial

Selecting theca and granulosa cells from removed ovaries of BRCA1/2mut patients undergoing Risk-reducing salpingo-oophorectomy (RRSO) and developing a 3D bioprinted hormone-producing bioprosthetic model. If efficacy and tolerability are confirmed in vivo, this bioprosthetic model might be used to replace hormones' production in BRCA mutated patients undergoing prophylactic surgery.