Population‐based genetic testing for cancer susceptibility genes: quo vadis?

Manchanda, Ranjit; Sideris, Michail

doi:10.1111/1471-0528.17283

Cited by 10 publications

(11 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Population genetic testing is cost-effective in the Jewish population and the general population for the hereditary breast and ovarian cancer CSGs studied in this article . Jewish population testing programs were recently implemented in the UK and Israel, and general population studies are ongoing in the UK and Australia . These strategies will detect more PV carriers, and our analysis can facilitate choosing appropriate cancer risk-management strategies tailored to each CSG.…”

Section: Discussionmentioning

confidence: 99%

“… 3 , 4 , 5 , 6 , 7 BRCA1 , BRCA2 , PALB2 , RAD51C , and RAD51D PVs also confer elevated lifetime breast cancer (BC) risks of 65% to 72%, 61% to 69%, 53%, 21%, and 20%, respectively. 3 , 4 , 5 , 6 Increasing awareness and acceptability of genetic testing and falling costs, coupled with changing clinical practices, including increasing genetic testing at cancer diagnosis 1 , 8 , 9 and recent calls for population testing, 10 , 11 , 12 , 13 are leading to ever-increasing identification of women with PVs in moderate- or high-penetrance OC or BC CSGs.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cost-Effectiveness of Gene-Specific Prevention Strategies for Ovarian and Breast Cancer

Wei,

Sun,

Slade

et al. 2024

JAMA Netw Open

Self Cite

View full text Add to dashboard Cite

ImportancePathogenic variants (PVs) in BRCA1, BRCA2, PALB2, RAD51C, RAD51D, and BRIP1 cancer susceptibility genes (CSGs) confer an increased ovarian cancer (OC) risk, with BRCA1, BRCA2, PALB2, RAD51C, and RAD51D PVs also conferring an elevated breast cancer (BC) risk. Risk-reducing surgery, medical prevention, and BC surveillance offer the opportunity to prevent cancers and deaths, but their cost-effectiveness for individual CSGs remains poorly addressed.ObjectiveTo estimate the cost-effectiveness of prevention strategies for OC and BC among individuals carrying PVs in the previously listed CSGs.Design, Setting, and ParticipantsIn this economic evaluation, a decision-analytic Markov model evaluated the cost-effectiveness of risk-reducing salpingo-oophorectomy (RRSO) and, where relevant, risk-reducing mastectomy (RRM) compared with nonsurgical interventions (including BC surveillance and medical prevention for increased BC risk) from December 1, 2022, to August 31, 2023. The analysis took a UK payer perspective with a lifetime horizon. The simulated cohort consisted of women aged 30 years who carried BRCA1, BRCA2, PALB2, RAD51C, RAD51D, or BRIP1 PVs. Appropriate sensitivity and scenario analyses were performed.ExposuresCSG-specific interventions, including RRSO at age 35 to 50 years with or without BC surveillance and medical prevention (ie, tamoxifen or anastrozole) from age 30 or 40 years, RRM at age 30 to 40 years, both RRSO and RRM, BC surveillance and medical prevention, or no intervention.Main Outcomes and MeasuresThe incremental cost-effectiveness ratio (ICER) was calculated as incremental cost per quality-adjusted life-year (QALY) gained. OC and BC cases and deaths were estimated.ResultsIn the simulated cohort of women aged 30 years with no cancer, undergoing both RRSO and RRM was most cost-effective for individuals carrying BRCA1 (RRM at age 30 years; RRSO at age 35 years), BRCA2 (RRM at age 35 years; RRSO at age 40 years), and PALB2 (RRM at age 40 years; RRSO at age 45 years) PVs. The corresponding ICERs were −£1942/QALY (−$2680/QALY), −£89/QALY (−$123/QALY), and £2381/QALY ($3286/QALY), respectively. RRSO at age 45 years was cost-effective for RAD51C, RAD51D, and BRIP1 PV carriers compared with nonsurgical strategies. The corresponding ICERs were £962/QALY ($1328/QALY), £771/QALY ($1064/QALY), and £2355/QALY ($3250/QALY), respectively. The most cost-effective preventive strategy per 1000 PV carriers could prevent 923 OC and BC cases and 302 deaths among those carrying BRCA1; 686 OC and BC cases and 170 deaths for BRCA2; 464 OC and BC cases and 130 deaths for PALB2; 102 OC cases and 64 deaths for RAD51C; 118 OC cases and 76 deaths for RAD51D; and 55 OC cases and 37 deaths for BRIP1. Probabilistic sensitivity analysis indicated both RRSO and RRM were most cost-effective in 96.5%, 89.2%, and 84.8% of simulations for BRCA1, BRCA2, and PALB2 PVs, respectively, while RRSO was cost-effective in approximately 100% of simulations for RAD51C, RAD51D, and BRIP1 PVs.Conclusions and RelevanceIn this cost-effectiveness study, RRSO with or without RRM at varying optimal ages was cost-effective compared with nonsurgical strategies for individuals who carried BRCA1, BRCA2, PALB2, RAD51C, RAD51D, or BRIP1 PVs. These findings support personalizing risk-reducing surgery and guideline recommendations for individual CSG-specific OC and BC risk management.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cost-Effectiveness of Gene-Specific Prevention Strategies for Ovarian and Breast Cancer

Wei,

Sun,

Slade

et al. 2024

JAMA Netw Open

Self Cite

View full text Add to dashboard Cite

show abstract

“…• Women with high grade epithelial ovarian cancer should be offered panel genetic testing for ovarian cancer susceptibility genes • BRCA testing should be offered to all Jewish individuals (unselected population testing), irrespective of family history, following informed consent • Unselected general population-based genetic testing studies are being undertaken in Australia (DNA Screen) 78,80,81 and the UK (PROTECT-C) 79 • Individuals with a strong family history of cancer should be referred for counselling and testing for an ovarian cancer susceptibility gene if the overall pre-test probability is ≥ 10% • Opportunistic bilateral salpingectomy (OBS) may be offered at routine gynaecological surgery to all women who have completed their family following informed counselling of advantages and disadvantages…”

Section: Genetic Testingmentioning

confidence: 99%

“…Prospective general population‐based genetic testing trials are being pioneered in the UK and Australia to identify individuals at increased cancer risk for targeted screening and prevention 78 . The PROTECT‐C study 79,80 is evaluating the impact of panel genetic testing for nine medically actionable ( BRCA1, BRCA2 , PALB2 , RAD51C , RAD51D , BRIP1 , MLH1 , MSH2 , MSH6 ) hereditary breast and ovarian cancer and Lynch syndrome genes, along with concurrent personalised breast cancer and ovarian cancer risk prediction using PRS and epidemiological and reproductive factors in unselected UK women aged over 18 years. The Australian DNA Screen study 81 is offering routine genetic testing for medically actionable hereditary breast and ovarian cancer, Lynch syndrome and familial hypercholesterolaemia genes ( BRCA1 , BRCA2 , MLH1 , MSH2 , MSH6 , PMS2 , LDLR , APOB , PCSK9 ) to 18–40‐year‐old individuals 81 .…”

Section: Improving Identification Of Women At Increased Risk Of Ovari...mentioning

confidence: 99%

Screening and prevention of ovarian cancer

Sideris,

Menon,

Manchanda

2024

Medical Journal of Australia

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…5,6 This compares to the population lifetime risk of 12.9-15% for BC and 1.3-2% for OC. 7,8 Increasing awareness and acceptability of genetic testing, falling costs, coupled with changes in clinical practice including increasing genetic testing at cancer diagnosis 3,9 and recent calls for population testing [10][11][12][13] are leading to ever increasing identification of unaffected women at increased BC/OC risk. Additionally, complex risk algorithms incorporating genetic (CSGs and polygenic risk score (PRS)) along-with non-genetic (family history (FH)/epidemiologic/reproductive/hormonal profile/mammographic density) variables are now available and provide personalised risk prediction for BC and OC.…”

Section: Introductionmentioning

confidence: 99%