The current clinical model for genetic testing is based on clinical-criteria/family-history (FH) and a pre-defined mutation probability threshold. It requires people to develop cancer before ...identifying unaffected individuals in the family to target prevention. This process is inefficient, resource intensive and misses >50% of individuals or mutation carriers at risk. Population genetic-testing can overcome these limitations. It is technically feasible to test populations on a large scale; genetic-testing costs are falling and acceptability and awareness are rising. MEDLINE, EMBASE, Pubmed, CINAHL and PsychINFO databases were searched using free-text and MeSH terms; retrieved reference lists of publications were screened; additionally, web-based platforms, Google, and clinical-trial registries were searched. Quality of studies was evaluated using appropriate check-lists. A number of studies have evaluated population-based
-testing in the Jewish population. This has been found to be acceptable, feasible, clinically-effective, safe, associated with high satisfaction rates and extremely cost-effective. Data support change in guidelines for population-based
-testing in the Jewish population. Population panel testing for
gene mutations is the most cost-effective genetic-testing strategy in general-population women and can prevent thousands more breast and ovarian cancers than current clinical-criteria based approaches. A few ongoing studies are evaluating population-based genetic-testing for multiple cancer susceptibility genes in the general population but more implementation studies are needed. A future population-testing programme could also target other chronic diseases.
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The medical complexity of surgical patients is increasing, and surgical risk calculators are crucial in providing high-value, patient-centered surgical care. However, pre-existing models are not ...validated to accurately predict risk for major gynecological oncology surgeries, and many are not generalizable to low- and middle-income country settings (LMICs). The international GO SOAR database dataset was used to develop a novel predictive surgical risk calculator for post-operative morbidity and mortality following gynecological surgery. Fifteen candidate features readily available pre-operatively across both high-income countries (HICs) and LMICs were selected. Predictive modeling analyses using machine learning methods and linear regression were performed. The area-under-the-receiver-operating characteristic curve (AUROC) was calculated to assess overall discriminatory performance. Neural networks (AUROC 0.94) significantly outperformed other models (p < 0.001) for evaluating the accuracy of prediction across three groups, i.e., minor morbidity (Clavien–Dindo I-II), major morbidity (Clavien–Dindo III-V), and no morbidity. Logistic-regression modeling outperformed the clinically established SORT model in predicting mortality (AUROC 0.66 versus 0.61, p < 0.001). The GO SOAR surgical risk prediction model is the first that is validated for use in patients undergoing gynecological surgery. Accurate surgical risk predictions are vital within the context of major cytoreduction surgery, where surgery and its associated complications can diminish quality-of-life and affect long-term cancer survival. A model that requires readily available pre-operative data, irrespective of resource setting, is crucial to reducing global surgical disparities.
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Risk-reducing salpingo-oophorectomy (RRSO) is the gold standard method of ovarian cancer risk reduction, but the data are conflicting regarding the impact on breast cancer (BC) outcomes. This study ...aimed to quantify BC risk/mortality in
/
carriers after RRSO.
We conducted a systematic review (CRD42018077613) of
/
carriers undergoing RRSO, with the outcomes including primary BC (PBC), contralateral BC (CBC) and BC-specific mortality (BCSM) using a fixed-effects meta-analysis, with subgroup analyses stratified by mutation and menopause status.
RRSO was not associated with a significant reduction in the PBC risk (RR = 0.84, 95%CI: 0.59-1.21) or CBC risk (RR = 0.95, 95%CI: 0.65-1.39) in
and
carriers combined but was associated with reduced BC-specific mortality in BC-affected
and
carriers combined (RR = 0.26, 95%CI: 0.18-0.39). Subgroup analyses showed that RRSO was not associated with a reduction in the PBC risk (RR = 0.89, 95%CI: 0.68-1.17) or CBC risk (RR = 0.85, 95%CI: 0.59-1.24) in
carriers nor a reduction in the CBC risk in
carriers (RR = 0.35, 95%CI: 0.07-1.74) but was associated with a reduction in the PBC risk in
carriers (RR = 0.63, 95%CI: 0.41-0.97) and BCSM in BC-affected
carriers (RR = 0.46, 95%CI: 0.30-0.70). The mean NNT = 20.6 RRSOs to prevent one PBC death in
carriers, while 5.6 and 14.2 RRSOs may prevent one BC death in BC-affected
and
carriers combined and
carriers, respectively.
RRSO was not associated with PBC or CBC risk reduction in
and
carriers combined but was associated with improved BC survival in BC-affected
and
carriers combined and
carriers and a reduced PBC risk in
carriers.
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Gynaecological malignancies affect women in low and middle income countries (LMICs) at disproportionately higher rates compared with high income countries (HICs) with little known about variations in ...access, quality, and outcomes in global cancer care. Our study aims to evaluate international variation in post-operative morbidity and mortality following gynaecological oncology surgery between HIC and LMIC settings. Study design consisted of a multicentre, international prospective cohort study of women undergoing surgery for gynaecological malignancies (NCT04579861). Multilevel logistic regression determined relationships within three-level nested-models of patients within hospitals/countries. We enrolled 1820 patients from 73 hospitals in 27 countries. Minor morbidity (Clavien-Dindo I-II) was 26.5% (178/672) and 26.5% (267/1009), whilst major morbidity (Clavien-Dindo III-V) was 8.2% (55/672) and 7% (71/1009) for LMICs/HICs, respectively. Higher minor morbidity was associated with pre-operative mechanical bowel preparation (OR = 1.474, 95%CI = 1.054-2.061,
= 0.023), longer surgeries (OR = 1.253, 95%CI = 1.066-1.472,
= 0.006), greater blood loss (OR = 1.274, 95%CI = 1.081-1.502,
= 0.004). Higher major morbidity was associated with longer surgeries (OR = 1.37, 95%CI = 1.128-1.664,
= 0.002), greater blood loss (OR = 1.398, 95%CI = 1.175-1.664,
≤ 0.001), and seniority of lead surgeon, with junior surgeons three times more likely to have a major complication (OR = 2.982, 95%CI = 1.509-5.894,
= 0.002). Of all surgeries, 50% versus 25% were performed by junior surgeons in LMICs/HICs, respectively. We conclude that LMICs and HICs were associated with similar post-operative major morbidity. Capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention.
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Clinical criteria/Family history-based BRCA testing misses a large proportion of BRCA carriers who can benefit from screening/prevention. We estimate the cost-effectiveness of population-based BRCA ...testing in general population women across different countries/health systems. A Markov model comparing the lifetime costs and effects of BRCA1/BRCA2 testing all general population women ≥30 years compared with clinical criteria/FH-based testing. Separate analyses are undertaken for the UK/USA/Netherlands (high-income countries/HIC), China/Brazil (upper–middle income countries/UMIC) and India (low–middle income countries/LMIC) using both health system/payer and societal perspectives. BRCA carriers undergo appropriate screening/prevention interventions to reduce breast cancer (BC) and ovarian cancer (OC) risk. Outcomes include OC, BC, and additional heart disease deaths and incremental cost-effectiveness ratio (ICER)/quality-adjusted life year (QALY). Probabilistic/one-way sensitivity analyses evaluate model uncertainty. For the base case, from a societal perspective, we found that population-based BRCA testing is cost-saving in HIC (UK-ICER = $−5639/QALY; USA-ICER = $−4018/QALY; Netherlands-ICER = $−11,433/QALY), and it appears cost-effective in UMIC (China-ICER = $18,066/QALY; Brazil-ICER = $13,579/QALY), but it is not cost-effective in LMIC (India-ICER = $23,031/QALY). From a payer perspective, population-based BRCA testing is highly cost-effective in HIC (UK-ICER = $21,191/QALY, USA-ICER = $16,552/QALY, Netherlands-ICER = $25,215/QALY), and it is cost-effective in UMIC (China-ICER = $23,485/QALY, Brazil−ICER = $20,995/QALY), but it is not cost-effective in LMIC (India-ICER = $32,217/QALY). BRCA testing costs below $172/test (ICER = $19,685/QALY), which makes it cost-effective (from a societal perspective) for LMIC/India. Population-based BRCA testing can prevent an additional 2319 to 2666 BC and 327 to 449 OC cases per million women than the current clinical strategy. Findings suggest that population-based BRCA testing for countries evaluated is extremely cost-effective across HIC/UMIC health systems, is cost-saving for HIC health systems from a societal perspective, and can prevent tens of thousands more BC/OC cases.
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We present findings of a cancer multidisciplinary-team (MDT) coordinated mainstreaming pathway of unselected 5-panel germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 and parallel somatic BRCA1/BRCA2 testing ...in all women with epithelial-OC and highlight the discordance between germline and somatic testing strategies across two cancer centres. Patients were counselled and consented by a cancer MDT member. The uptake of parallel multi-gene germline and somatic testing was 97.7%. Counselling by clinical-nurse-specialist more frequently needed >1 consultation (53.6% (30/56)) compared to a medical (15.0% (21/137)) or surgical oncologist (15.3% (17/110)) (p < 0.001). The median age was 54 (IQR = 51–62) years in germline pathogenic-variant (PV) versus 61 (IQR = 51–71) in BRCA wild-type (p = 0.001). There was no significant difference in distribution of PVs by ethnicity, stage, surgery timing or resection status. A total of 15.5% germline and 7.8% somatic BRCA1/BRCA2 PVs were identified. A total of 2.3% patients had RAD51C/RAD51D/BRIP1 PVs. A total of 11% germline PVs were large-genomic-rearrangements and missed by somatic testing. A total of 20% germline PVs are missed by somatic first BRCA-testing approach and 55.6% germline PVs missed by family history ascertainment. The somatic testing failure rate is higher (23%) for patients undergoing diagnostic biopsies. Our findings favour a prospective parallel somatic and germline panel testing approach as a clinically efficient strategy to maximise variant identification. UK Genomics test-directory criteria should be expanded to include a panel of OC genes.
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Primary surgical prevention in the form of risk-reducing salpingo-oophorectomy (RRSO) is the most effective option and the gold standard for ovarian cancer (OC) risk-reduction, particularly given the ...absence of an effective national OC screening programme. However, premenopausal RRSO leads to premature surgical menopause with detrimental long-term health sequelae particularly in women who do not/are unable to take hormone replacement therapy (HRT). HRT uptake in women undergoing pre-menopausal oophorectomy appears low and is dependent on informed counselling, the safety of HRT and efficacy in mitigating the health sequelae of premature menopause. Acceptance of a central role for the fallopian tube in OC etiopathogenesis, coupled with the detrimental consequences of premature menopause, has led to the attractive proposal of early-salpingectomy with delayed oophorectomy as an alternative OC surgical prevention strategy in premenopausal women who have completed childbearing but decline or wish to delay RRSO. The successful implementation of risk reducing surgery for OC prevention depends on the acceptability of surgery to both, recipients (e.g. BRCA1/BRCA2 carriers) and intervention deliverers (healthcare professionals/researchers). Acceptability is also informed by an understanding of health outcomes following risk reducing surgery and the safety of HRT. It is therefore vital to understand the effects of surgery on important health outcomes such as cardiovascular health, neurological function and bone health. We present a comprehensive review of acceptability, the selected health outcomes mentioned above and HRT safety following risk reducing surgery.
•Acceptability of surgical prevention of ovarian-cancer in BRCA-carriers is a dynamic concept.•Acceptability is influenced by counselling on health outcomes after surgery and HRT safety.•Premenopausal oophorectomy increases the risk of osteoporosis, heart-disease and neurocognitive-decline.•HRT use until natural-menopause mitigates risks and data supports safety of short term use in BRCA-carriers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Genetic testing for gynaecological cancer Gaba, Faiza M; Manchanda, Ranjit
Obstetrics, gynaecology and reproductive medicine,
01/2017, Volume:
27, Issue:
1
Journal Article
Peer reviewed
Open access
Abstract The traditional family-history approach to genetic testing involves taking a detailed three generation family-history from both sides of the family, ethnicity, type of cancer, age of onset ...and death. Testing for BRCA1/BRCA2 mutations is offered at a ≥10% combined BRCA1/BRCA2 probability. Risk models such as the Manchester scoring system, BOADICEA and BRCAPRO can be used to calculate BRCA1/BRCA2 probability. High-risk women identified should be referred to a regional genetics service for genetic counselling and testing. The Amsterdam-Criteria-2 have been traditionally used to identify Lynch syndrome (caused by a mismatch repair gene ( MLH1/MSH2/MSH6/PMS2 ) mutation). Molecular (immunohistochemistry and Microsatellite instability) analysis of tumour tissue is now established as an initial step, with genetic testing undertaken for protein deficient or MSI unstable tumours. This is offered for those fulfilling Bethesda criteria and recently for all colorectal cancer cases <60 years. BRCA1/BRCA2 testing is recommended for all non-mucinous invasive epithelial ovarian cancers irrespective of family-history (10–20% have a BRCA1/BRCA2 mutation). This is being undertaken by non-genetics clinicians. A population-based approach to genetic testing identifies 50% more carriers at risk. It has been extensively investigated in the Ashkenazi-Jewish population and found to be extremely cost-effective in this community. This is expected to lead to change in guidelines in the future.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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