Systems Medicine of Cancer: Bringing Together Clinical Data and Nonlinear Dynamics of Genetic Networks

Editoria

Risk threshold for surgical prevention of ovarian cancer

BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) is the most effective intervention to prevent ovarian cancer (OC). It is only available to high-risk women with >10% lifetime OC risk. This threshold has not been formally tested for cost-effectiveness. OBJECTIVE: To specify the OC risk thresholds for RRSO being cost-effective for preventing OC in premenopausal women. METHODS: The costs as well as effects of surgical prevention ('RRSO') were compared over a lifetime with 'no RRSO' using a decision analysis model. RRSO was undertaken in premenopausal women >40 years. The model was evaluated at lifetime OC risk levels: 2%, 4%, 5%, 6%, 8% and 10%. Costs and outcomes are discounted at 3.5%. Uncertainty in the model was assessed using both deterministic sensitivity analysis and probabilistic sensitivity analysis (PSA). Outcomes included in the analyses were OC, breast cancer (BC) and additional deaths from coronary heart disease. Total costs and effects were estimated in terms of quality-adjusted life-years (QALYs); incidence of OC and BC; as well as incremental cost-effectiveness ratio (ICER). DATA SOURCES: Published literature, Nurses Health Study, British National Formulary, Cancer Research UK, National Institute for Health and Care Excellence guidelines and National Health Service reference costs. The time horizon is lifetime and perspective: payer. RESULTS: Premenopausal RRSO is cost-effective at 4% OC risk (life expectancy gained=42.7 days, ICER=£19 536/QALY) with benefits largely driven by reduction in BC risk. RRSO remains cost-effective at >8.2% OC risk without hormone replacement therapy (ICER=£29 071/QALY, life expectancy gained=21.8 days) or 6%if BC risk reduction=0 (ICER=£27 212/QALY, life expectancy gained=35.3 days). Sensitivity analysis indicated results are not impacted much by costs of surgical prevention or treatment of OC/ BC or cardiovascular disease. However, results were sensitive to RRSO utility scores. Additionally, 37%, 61%, 74%, 84%, 96% and 99.5% simulations on PSA are cost-effective for RRSO at the 2%, 4%, 5%, 6%, 8% and 10% levels of OC risk, respectively. CONCLUSIONS: Premenopausal RRSO appears to be extremely cost-effective at ≥4% lifetime OC risk, with ≥42.7 days gain in life expectancy if compliance with hormone replacement therapy is high. Current guidelines should be re-evaluated to reduce the RRSO OC risk threshold to benefit a number of at-risk women who presently cannot access risk-reducing surgery.The study is supported by researchers at the National Institute for Health Research University College London Hospitals Biomedical Research CentreThis is the author accepted manuscript. It is currently under an indefinite embargo pending publication by BMJ Group

Genetic screening for gynecological cancer: where are we heading?

The landscape of cancer genetics in gynecological oncology is rapidly changing. The traditional family history-based approach has limitations and misses >50% mutation carriers. This is now being replaced by population-based approaches. The need for changing the clinical paradigm from family history-based to population-based BRCA1/BRCA2 testing in Ashkenazi Jews is supported by data that demonstrate population-based BRCA1/BRCA2 testing does not cause psychological harm and is cost effective. This article covers various genetic testing strategies for gynecological cancers, including population-based approaches, panel and direct-to-consumer testing as well as the need for innovative approaches to genetic counseling. Advances in genetic testing technology and computational analytics have facilitated an integrated systems medicine approach, providing increasing potential for population-based genetic testing, risk stratification, and cancer prevention. Genomic information along-with biological/computational tools will be used to deliver predictive, preventive, personalized and participatory (P4) and precision medicine in the future

Quality of Life after Risk-Reducing Hysterectomy for Endometrial Cancer Prevention: A Systematic Review

BACKGROUND: Risk-reducing hysterectomy (RRH) is the gold-standard prevention for endometrial cancer (EC). Knowledge of the impact on quality-of-life (QoL) is crucial for decision-making. This systematic review aims to summarise the evidence. Methods: We searched major databases until July 2022 (CRD42022347631). Given the paucity of data on RRH, we also included hysterectomy as treatment for benign disease. We used validated quality-assessment tools, and performed qualitative synthesis of QoL outcomes. RESULTS: Four studies (64 patients) reported on RRH, 25 studies (1268 patients) on hysterectomy as treatment for uterine bleeding. There was moderate risk-of-bias in many studies. Following RRH, three qualitative studies found substantially lowered cancer-worry, with no decision-regret. Oophorectomy (for ovarian cancer prevention) severely impaired menopause-specific QoL and sexual-function, particularly without hormone-replacement. Quantitative studies supported these results, finding low distress and generally high satisfaction. Hysterectomy as treatment of bleeding improved QoL, resulted in high satisfaction, and no change or improvements in sexual and urinary function, although small numbers reported worsening. CONCLUSIONS: There is very limited evidence on QoL after RRH. Whilst there are benefits, most adverse consequences arise from oophorectomy. Benign hysterectomy allows for some limited comparison; however, more research is needed for outcomes in the population of women at increased EC-risk

Semi-supervised analysis of myeloid and T cell behavior in ex vivo ovarian tumor slices reveals changes in cell motility after treatments

Studies of the high-grade serous ovarian cancer (HGSOC) tumor microenvironment, the most lethal gynecological cancer, aim to enhance the efficiency of established therapies. Cell motility is an important process of anti-tumor response. Using ex vivo human and mouse HGSOC tumor slices combined with time-lapse imaging, we assessed the motility of CD8+ T and myeloid cells. We developed a semi-supervised analysis of cell movements, identifying four cell behaviors: migrating, long migrating, static, and wobbling. Tumor slices were maintained 24h ex vivo, retaining viability and cell movements. Ex vivo treatments with lipopolysaccharide altered CD8+ T and myeloid cell behavior. In vivo chemotherapy reduced ex vivo cell movements in human and mouse tumors and differentially affected CD8+ T and myeloid cells in chemo-sensitive and chemo-resistant mouse models. Ex vivo tumor slices can extend in vivo mouse studies to human, providing a stepping stone to translate mouse cancer studies to clinical trials

Breast Cancer Risk and Breast-Cancer-Specific Mortality following Risk-Reducing Salpingo-Oophorectomy in BRCA Carriers : A Systematic Review and Meta-Analysis

Funding This research was funded by Rosetrees Trust, grant number CF1\100001, and Barts Charity, grant number ECMG1C3R. The funders had no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.Peer reviewedPublisher PD

Cost effectiveness of population based BRCA1 founder mutation testing in Sephardi Jewish women.

BACKGROUND: Population-based BRCA1/BRCA2 founder-mutation testing has been demonstrated as cost effective compared with family history based testing in Ashkenazi Jewish women. However, only 1 of the 3 Ashkenazi Jewish BRCA1/BRCA2 founder mutations (185delAG[c.68_69delAG]), 5382insC[c.5266dupC]), and 6174delT[c.5946delT]) is found in the Sephardi Jewish population (185delAG[c.68_69delAG]), and the overall prevalence of BRCA mutations in the Sephardi Jewish population is accordingly lower (0.7% compared with 2.5% in the Ashkenazi Jewish population). Cost-effectiveness analyses of BRCA testing have not previously been performed at these lower BRCA prevalence levels seen in the Sephardi Jewish population. Here we present a cost-effectiveness analysis for UK and US populations comparing population testing with clinical criteria/family history-based testing in Sephardi Jewish women. STUDY DESIGN: A Markov model was built comparing the lifetime costs and effects of population-based BRCA1 testing, with testing using family history-based clinical criteria in Sephardi Jewish women aged ≥30 years. BRCA1 carriers identified were offered magnetic resonance imaging/mammograms and risk-reducing surgery. Costs are reported at 2015 prices. Outcomes include breast cancer, ovarian cancer, and excess deaths from heart disease. All costs and outcomes are discounted at 3.5%. The time horizon is lifetime, and perspective is payer. The incremental cost-effectiveness ratio per quality-adjusted life-year was calculated. Parameter uncertainty was evaluated through 1-way and probabilistic sensitivity analysis. RESULTS: Population testing resulted in gain in life expectancy of 12 months (quality-adjusted life-year = 1.00). The baseline discounted incremental cost-effectiveness ratio for UK population-based testing was £67.04/quality-adjusted life-year and for US population was $308.42/quality-adjusted life-year. Results were robust in the 1-way sensitivity analysis. The probabilistic sensitivity analysis showed 100$100,000/quality-adjusted life-year US willingness-to-pay thresholds. Scenario analysis showed that population testing remains cost effective in UK and US populations, even if premenopausal oophorectomy does not reduce breast cancer risk or if hormone replacement therapy compliance is nil. CONCLUSION: Population-based BRCA1 testing is highly cost effective compared with clinical criteria-driven approach in Sephardi Jewish women. This supports changing the paradigm to population-based BRCA testing in the Jewish population, regardless of Ashkenazi/Sephardi ancestry

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

OBJECTIVE: To assess the impact of risk-reducing surgery (RRS) for breast cancer (BC) and ovarian cancer (OC) prevention on quality-of-life (QoL). We consider risk-reducing mastectomy (RRM), risk-reducing salpingo-oophorectomy (RRSO), and risk-reducing early-salpingectomy and delayed-oophorectomy (RRESDO). DATA SOURCES: We followed a prospective protocol (PROSPERO: CRD42022319782) and searched MEDLINE, EMBASE, PubMed, and Cochrane Library from inception to February 2023. STUDY ELIGIBILITY CRITERIA: We followed a PICOS framework. The population included women at increased risk of BC or OC. We focused on studies reporting QoL outcomes (health-related QoL (HRQoL), sexual function, menopause symptoms, body image, cancer-related distress or worry, anxiety or depression) after RRS, including RRM for BC and RRSO or RRESDO for OC. STUDY APPRAISAL AND SYNTHESIS METHODS: We used the Methodological Index for Non-Randomized Studies (MINORS) for study appraisal. Qualitative synthesis and fixed-effects meta-analysis was performed. RESULTS: Thirty-four studies were included (RRM:16 studies, RRSO: 19 studies, RRESDO: 2 studies). HRQoL was unchanged or improved in 13/15 studies post-RRM (N=986) and 10/16 studies post-RRSO (N=1617), despite short-term deficits (N=96 post-RRM and N=459 post-RRSO). Sexual function (using Sexual Activity Questionnaire) was affected in 13/16 studies (N=1400) post-RRSO, in terms of decreased sexual pleasure (-1.21[-1.53,-0.89]; N=3070) and increased sexual discomfort (1.12[0.93,1.31]; N=1400). Hormone replacement therapy after pre-menopausal RRSO was associated with an increase (1.16[0.17,2.15]; N=291) in sexual pleasure and a decrease (-1.20[-1.75,-0.65]; N=157) in sexual discomfort. Sexual function was affected in 4/13 studies (N=147) post-RRM, but stable in 9/13 studies (N=799). Body image was unaffected in 7/13 studies (N=605) post-RRM, whereas 6/13 studies (N=391) reported worsening. Increased menopause symptoms were reported in 12/13 studies (N=1759) post-RRSO with a reduction (-1.96[-2.81,-1.10]; N=1745) in Functional Assessment of Cancer Therapy-Endocrine Subscale. Cancer-related distress was unchanged or decreased in 5/5 studies post-RRM (N=365) and 8/10 studies post-RRSO (N=1223). RRESDO (2 studies, N=413) had better sexual function and menopause-specific QoL. CONCLUSION: RRS may be associated with QoL outcomes. RRM and RRSO reduce cancer-related distress, and do not affect HRQoL. Women and clinicians should be aware of body image problems post-RRM, together-with sexual dysfunction and menopause symptoms post-RRSO. RRESDO may be a promising alternative to mitigate QoL-related risks of RRSO

Genetic testing for gynaecological cancer

© 2016 Elsevier Ltd 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