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Our team has identified the breast cancer lifetime risk threshold at which preventive mastectomy is cost-effective

X Wei RRM threshold paper

Professor Ranjit Manchanda and his team, with Dr Rosa Legood (London School of Hygiene and Tropical Medicine) and colleagues from Manchester and Peking Universities, have found that it is cost-effective for women aged 30-55 years with a lifetime breast cancer risk of 35% or higher to undergo a preventive mastectomy.

With expanded access to genetic testing and availability of breast cancer risk prediction models identifying more women at increased risk of breast cancer, these results could have significant clinical implications to expand access to preventive mastectomy beyond women with mutations in high-risk genes BRCA1/BRCA2 and PALB2, and this could potentially prevent ~6500 breast cancer cases annually in UK women.

This received widespread attention from the press!

Here are some examples.

 

 

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GCaPPS: Genetic Cancer Prediction through Population Screening
(2008-2019)

Following pre-test counselling and informed consent, 1034 Ashkenazi Jewish men and women were randomised to either population based or clinical criteria (family history) based genetic testing for BRCA founder mutations. Participants were followed up for three years after the test result. The study showed that compared to family-history based testing, population-based BRCA founder mutation testing doesn’t harm psychological health (anxiety, depression, health anxiety, distress, uncertainty)  or quality-of-life and identifies 150% additional BRCA carriers. Overall anxiety decreased with time. Long term follow up data shows a reduction in anxiety with population testing compared to family-history or clinical criteria based testing. We found BRCA testing in the Jewish population is acceptable, feasible, and can be undertaken in a community setting. It had high acceptability and was associated with 88% uptake and high satisfaction rates of ~95%. In a non-inferiority cluster-randomised trial we found that DVD-assisted pre-test counselling for population BRCA-testing is an effective, acceptable, non-inferior, time-saving and cost-efficient alternative to traditional genetic-counselling.

Our cost-effectiveness analysis shows, a population-based BRCA testing approach in the Ashkenazi Jewish population, reduces breast and ovarian cancer incidence, leading to up to an additional 33 days gain in life-expectancy and is extremely cost-effective (cost saving) with a discounted incremental cost-effectiveness ratio (ICER) = -£2960/quality adjusted life year (QALY). Probabilistic sensitivity analysis shows this remains cost-effective for 95% simulations at the £20,000/QALY NICE threshold. Our modelling suggests this could lead to 276 fewer ovarian and 508 fewer breast cancer cases in the UK. Overall, reduction in treatment costs could lead to a discounted cost savings of £3.7 million for the NHS.

Cost-effectiveness Population BRCA testing in Canada(2022-2024)
Evaluation of cost-effectiveness of population based BRCA testing in Canada. This project is being undertaken in collaboration with the team in British Columbia led by Prof Kwon and Prof Dawson.
PROMISE Feasibility Study
(2016-2019)
This pilot study into the impact of population based genetic testing for ovarian/breast cancer gene mutations recruited 103 women from the general population. It found that population-based testing is feasible and acceptable, has high satisfaction, reduces cancer worry/risk perception, and does not negatively impact psychological health/quality of life.
Cost-effectiveness analysis of multigene testing at breast cancer diagnosis

This study investigated whether offering unselected genetic testing of a panel of BRCA1/BRCA2/PALB2 genes to everyone diagnosed with breast cancer was cost-effective compared to the current model of BRCA1/BRCA2 testing based on a patient’s family history/clinical criteria. This study found that unselected panel gene testing for everyone at breast cancer diagnosis was highly cost-effective compared to the current model of testing for UK and US health systems, and could save 2101 cases of ovarian and breast cancer in the UK, and 2406 in the US per year.

Value based genetic technology for breast cancer in China. (2020-2023)

Evaluating cost-effectiveness of population based panel genetic testing for ovarian/breast cancer gene mutations in the general population (2016-2019)
This study evaluated the cost-utility of unselected genetic testing (for BRCA1/BRCA2/PALB2) for all patients diagnosed with breast cancer in the UK and USA, compared to the traditional family history/clinical criteria approach. Unselected testing was cost-effective in both systems, and could prevent 2101 cases of breast/ovarian cancer in the UK, and 9733 cases in the USA.
Cost-effectiveness analysis of multigene testing at breast cancer diagnosis

This study investigated whether offering unselected genetic testing of a panel of BRCA1/BRCA2/PALB2 genes to everyone diagnosed with breast cancer was cost-effective compared to the current model of BRCA1/BRCA2 testing based on a patient’s family history/clinical criteria. This study found that unselected panel gene testing for everyone at breast cancer diagnosis was highly cost-effective compared to the current model of testing for UK and US health systems, and could save 2101 cases of ovarian and breast cancer in the UK, and 2406 in the US per year.

Value based genetic technology for breast cancer in China. (2020-2023)

RRESDO Study

A multicentre UK cohort questionnaire study to 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.

We found that RRESDO has high acceptability among premenopausal women at increased ovarian cancer risk, particularly those concerned about sexual dysfunction.

Economic Evaluation of Population-Based BRCA1/BRCA2 Mutation Testing across Multiple Countries and Health Systems

This study evaluated the cost-effectiveness of population-based BRCA testing in general population women across different countries/health systems. Our findings are split across high-income (HIC), upper-middle income (UMIC) and low-middle income countries (LMIC). Our findings suggest that population-based BRCA testing for countries evaluated is extremely cost-effective across high (US/UK/Netherlands) and upper/middle income countries’ health systems (China/Brazil), is cost-saving for high-income health systems from a societal perspective, and can prevent tens of thousands more breast or ovarian cancer cases.

Defining the ‘risk thresholds’ for risk reducing salpingo-oophorectomy (RRSO) for ovarian cancer prevention

We for the first time defined the precise ovarian cancer risk thresholds at which risk reducing salpingo oophorectomy (preventive surgery) should be undertaken for ovarian cancer prevention in both pre- and post-menopausal women. 

Our findings show this is cost-effective in intermediate risk women too, saving 7-10 years of a woman’s life. This has significant implications for a number of women who currently can’t access risk reducing surgery. It also provides clinical utility for genetic testing of intermediate risk ovarian cancer genes. This has led to change in guidelines/practice for surgical prevention of ovarian cancer.

Previous projects supported by our team

Value based genetic technology for breast cancer in China (2020-2023)

Investigating BRCAness in epithelial ovarian cancer (EOC) in India to develop stratified surgical and chemotherapy options (2017-2020)

Correlation of p53 IHC expression with TP53 mutation status in Endometrial Carcinoma (Co-investigator) (2017-2019)

UK FOCSS – UK Familial Ovarian Cancer Screening Study

UKCTOCS – UK Collaborative Trial of Ovarian Cancer Screening

ALDO – Avoiding late diagnosis of ovarian cancer

Shape Up following cancer treatment

SOCQER2

Use of Plasmajet in ultra-radical surgery for advanced Ovarian Cancer (2015-2019)

SURAKSHA- South Asian Breast Cancer Risk Prediction, Genetic testing & Health Management programme (2020-2021)

SHAPE

STATEC

MAPPING

ROCkeTS

SCCAN

GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V)

For more details on these support projects, click here!

PROTECTOR: Preventing Ovarian Cancer Through early Excision of Tubes & late Ovarian Removal

PROTECTOR is a research study for women who are at an increased risk of developing ovarian cancer, due a strong family history of cancer, or an alteration in genes (such as BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, or PALB2). This study assesses the impact of surgery to remove the fallopian tubes and ovaries to prevent ovarian cancer. 

Participants can choose whether to have no surgery, the usual operation to remove both tubes and ovaries, or a new 2-step approach of removing the fallopian tubes first followed by a second operation to remove the ovaries later. 

The study assesses the impact of these surgeries on sexual function, hormone levels, quality of life and overall satisfaction. 41 sites across the UK are recruiting. PROTECTOR is funded by Barts Charity & Rosetrees Trust.

PROTECTOR Phase 1 has completed recruitment, and we are looking to open for Phase 2 in January 2025. 

For more information please visit: http://www.protector.org.uk/
DETECT-2: Direct to Patient testing at Cancer diagnosis for Precision Prevention-2

DETECT-2 is a study investigating if genetic testing can be offered to people in their own home.

In this study, participants who have been diagnosed with ovarian, womb, or bowel cancer are randomly assigned to be offered either conventional genetic testing by their cancer team or genetic testing at home. This new model is called “direct-to-patient” testing and includes offering genetic testing information on an interactive app or website, and offering genetic testing by a home saliva kit posted to participants.

DETECT-2 will assess if direct-to-patient genetic testing impacts participants’ willingness to accept genetic testing, or has an impact on their quality-of-life, satisfaction, or mental wellbeing. It will also assess if direct-to-patient testing is cost-effective.

DETECT-2 is supported by GSK and the North East London Cancer Alliance

For more information please visit: https://www.detect-2.co.uk/
PRESCORES: Prevention of endometrial cancer: Utility scores of risk-reducing strategies
PRESCORES is a research study looking into the quality of life of women after an operation to prevent womb (endometrial) cancer. This operation is known as risk-reducing hysterectomy. We will use this to understand whether more people at risk of this cancer could benefit from this operation.
For more information please visit: PRESCORES – Wolfson Institute of Population Health (qmul.ac.uk)
PROTECT-C: Population based germline testing for early detection and prevention of cancer

PROTECT-C is offering genetic testing to women (women, trans men and non-binary people with female reproductive organs) to see if they have an increased risk of breast, ovary, bowel and/or womb cancer. This is regardless of whether they or their families have had cancer.

Specially trained counsellors are available through a helpline (telephone, virtual, email). If a participant decides to proceed with genetic testing, they will be sent a saliva kit for genetic testing at home (a “direct-to-patient” approach).

PROTECT-C aims to find out how many women decide to have genetic testing, their experience, and how this affects their quality of life, satisfaction and mental well-being. 

PROTECT-C will assess the number of people identified to be at increased risk, and how many of them take up screening and prevention options. The study will also assess whether it is cost-effective for the NHS to offer genetic testing to all women in the population.

PROTECT-C is funded by a £3.89 million research grant from Yorkshire Cancer Research, and is aiming to launch in 2025.

For more information please visit: https://protect-c.co.uk

JHCR: The Jewish Hereditary Cancer Review

This project aims to review the status of BRCA awareness, community support and BRCA testing provision, experience and satisfaction in the ‘at-increased-risk’ Jewish community in the UK.

The review will focus on hereditary cancers associated with BRCA1 and BRCA2 gene mutations. It will concentrate on the provision of BRCA information and testing in the UK and also look at BRCA-related activities in Jewish communities internationally.

Delivery of the research will be carried out by researchers based at Queen Mary University of London in partnership with the JHCR project director, and under the guidance of expert advisors.

Research outcomes will help identify priority needs and recommendations to improve BRCA awareness in, and access to responsible BRCA testing for, the UK Jewish community.

Findings will be published in a community report and scientific papers – raising awareness and promoting positive action to improve hereditary cancer management and prevention in the UK Jewish community.

For more information please visit: https://wpprevention.org/jhcr-the-jewish-hereditary-cancer-review/ 
OVACATCH: Ovarian Cancer Targeted Early Detection for Faster Diagnosis at a Curable Stage

Ovarian cancer is typically diagnosed at a late stage which is associated with a worse prognosis. There are also no effective screening tests available for ovarian cancer. 

OVACATCH aims to improve earlier diagnosis of ovarian cancer or identify cancers that current investigations may miss, by using longitudinal multiple biomarker algorithms derived from serum blood tests.

These will be validated using prospectively collected longitudinal serum samples held in biobanks from women with cancer diagnoses and healthy controls. A prospective cohort screening trial will then be conducted to evaluate these multi-marker algorithms compared to current methods of ovarian cancer surveillance using ROCA (Risk of Ovarian Cancer Algorithm). 

OVACATCH will evaluate false positive rate, feasibility, compliances, satisfaction and anxiety with screening. This will provide the initial data needed to design a large multicentre screening trial for ovarian cancer, moving the needle forward towards developing an effective screening strategy for ovarian cancer.

SECRETS: Serous endometrial cancer risk and role of risk-reducing hysterectomy in BRCA carriers

The current literature around risk of serous endometrial cancer in BRCA pathogenic variant (PV) carriers is equivocal. There have been few studies that have stratified the risk in serous endometrial cancers and none focusing specifically on this histopathological subtype of endometrial cancer.

 There have been no case-control studies to address this issue and the cohort studies demonstrating increased risk report large confidence intervals, while some others found no increase in risk. The true prevalence of BRCA1/BRCA2 PVs in prospective unselected UK serous EC patients is unknown. There remains continued uncertainty around whether BRCA1 PV carriers should undergo preventive hysterectomy (or not).

This study will address knowledge gaps such as the risk of serous endometrial cancer in patients with BRCA1/BRCA2 PVs, if hysterectomy would be cost-effective in the UK for BRCA1 and BRCA2 PV carriers, and if hysterectomy is acceptable alongside risk-reducing salpingo-oophorectomy for these carriers. 

UKCOGS: UK COVID and Gynaecological Cancer Study 

UKCOGS is a national study into the changes in diagnosis and treatment of gynaecological oncology patients that occurred in response to COVID-19. It aims to understand the decisions made by multi-disciplinary teams working in gynaecological oncology hospitals, the changes that occurred in these hospitals, and the impact of these changes on the health and survival of cancer patients.

The study is endorsed and supported by the British Gynaecological Cancer Society, Royal College of Obstetricians and Gynaecologists, NCRI Gynaecological Cancer Clinical Studies Group, British Association of Gynaecological Pathologists, and charities including Ovacome, The Eve Appeal, Target Ovarian Cancer, Ovarian Cancer Action, Jo’s Cervical Cancer trust and GO Girls.

For more information please visit: https://www.bgcs.org.uk/professionals/covid19-resources/research-studies/

SIGNPOST: Systematic genetic testing for personalised ovarian cancer therapy (SIGNPOsT)

Genetic testing in ovarian cancer patients is now being implemented across the NHS.  It’s hoped that by doing this, patients across the NHS will have even better treatments and that in some families, cancers will be prevented. This trial offers a genetic test to women with certain types of ovarian cancer. This is to detect gene alterations that may be a cause of ovarian cancer.

In this study we aim to find out more about:

  • what effect genetic counselling has on women’s emotional quality of life 
  • the gene changes women with ovarian cancer have
  • whether women with gene changes choose to have screening or treatment to prevent ovarian cancer
  • what are the costs of this new genetic testing strategy 

We also want to investigate the factors that affect the risk of developing ovarian cancer. This includes looking at how gene changes and other factors that might affect:

  • the risk of getting it
  • treatment 
  • how well the treatment works (outcome) 

SIGNPOST entails collecting samples including cancer, blood, and genetic information. 

The study is open to women who:

  • have had genetic testing 
  • have been offered testing but refused
  • haven’t had testing

For more information please visit:  https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-study-looking-at-genetic-testing-for-ovarian-cancer-signpost

Evaluation of the BRCA-Direct SBRI programme

The team has conducted a service evaluation of the BRCA-DIRECT pathway to assess the impact of implementing unselected genetic testing at the point of breast cancer diagnosis in London.

This evaluation encompassed clinical service performance, cost-effectiveness modelling, and patient satisfaction.

We have preliminary data we have presented recently at the BGCS Annual Scientific Meeting, and are working towards disseminating these results soon. 

Evaluation of NHS Jewish BRCA Testing Programme
The Jewish BRCA Testing Programme is being implemented by the NHS National Cancer Programme team, working with ICR, North Thames GLH, Royal Marsden Hospital, Manchester and QMUL teams along with community organisations and stakeholders including Chai Cancer Care and Jnetics.

For more information please visit J-BRCA (nhsjewishbrcaprogramme.org.uk)

Genetic testing for Lynch syndrome at endometrial cancer diagnosis e-learning modules
This teaching programme aims to develop the skills, knowledge, and confidence of gynaecology and gynaecological cancer care professionals in delivering testing for Lynch syndrome for patients diagnosed with endometrial cancer. This is to support implementation of the national standard set by NICE diagnostic guidance 42 as well as other national and international guidelines on Lynch syndrome testing for all women with endometrial cancer. 

For more information please visit https://learninghub.nhs.uk/catalogue/ec-lynch-testing/about

Acceptability of risk-reducing strategies at different lifetime risk thresholds to reduce the risk of breast cancer

Now that we have identified the lifetime risk threshold of breast cancer at which a risk-reducing mastectomy (RRM) would be cost-effective, it is important prior to clinical implementation to evaluate the acceptability of this risk-reducing strategy. 

We will be undertaking a vignette study and randomising general population women into 5 groups with different lifetime risks of breast cancer, and asking a series of questions on acceptability of RRM. 

MISSION-O: Menopausal Impact of Opportunistic Salpingectomy for Ovarian Cancer Prevention

Previous studies have analyzed complications and menopausal symptoms of opportunistic salpingectomy (removing the fallopian tubes during other gynecological surgeries), but so far have not evaluated the age of menopause – an important factor because early menopause can have negative consequences for bone health, the cardiovascular system, sexual health and cognitive function.

We will analyze blood samples from participants in the HOPPSA study, where 2,700 women have undergone hysterectomy with or without opportunistic salpingectomy. They are offered to provide blood samples on two occasions: 1–8 and 2–9 years after the operation. In this way, we can compare the age of menopause between those who have undergone opportunistic salpingectomy and those who have not.

Cost-effectiveness of colorectal cancer screening for people in the UK with Lynch syndrome

This project will evaluate the cost-effectiveness of colorectal cancer surveillance for people in the UK with Lynch syndrome, in collaboration with teams at St Mark’s Hospital and Amsterdam University Medical Center (UMC).

Using retrospective, patient-level colonoscopy records and established colorectal cancer simulation models adapted for Lynch syndrome, we will estimate the costs and health outcomes of alternative surveillance schedules. Results may help quantify the potential benefits of identifying Lynch syndrome via genetic testing and inform future policy and guideline development for colorectal cancer prevention in this population.