Breast Cancer Risk, Cancer Gene Mutation, Ovarian Cancer Risk
Conditions
Keywords
Population based genetic testing, BRCA, Lynch Syndrome, breast cancer risk, ovarian cancer risk
Brief summary
PROTECT-C is a research study offering genetic testing to people to see whether they have a genetic change that increases their risk of breast, ovary, bowel, and/or womb cancer. This is regardless of whether they or their families have had cancer. Breast, ovary, bowel, and womb cancers make up half of all cancers in women. Around 15-20% (15 to 20 in 100 cases) of ovary and 3-4% (3 to 4 in 100 cases) of breast, womb, and bowel cancers are linked to cancer genes and may be prevented. People with a genetic change that puts them at increased risk of any of these cancers have ways to help them manage their risk through the NHS. This may include screening to find cancers earlier when they are easier to treat, and surgery or medication to prevent cancers from developing. This can save lives. Currently, genetic testing is only available on the NHS to people who meet certain criteria. For example, those who have had certain cancers, have a strong family history of cancer, or those with Jewish ancestry. But many people may not have a strong family history or meet NHS testing criteria. This means that this system of testing misses 50% to 80% of people (50 to 80 in 100 people) who have a genetic change. It is thought that only around 3 in 100 people overall who have a genetic change that increases their risk of cancer know about it. Given the effective screening and preventive options that are available, this represents a huge, missed opportunity to prevent cancers or find them earlier. The PROTECT-C study aims to evaluate the option of offering genetic testing to everyone who may want it. This is regardless of whether they or their families have had cancer. We will offer genetic testing to 5000 people. People may take part if they: * Are over the age of 18 years and * Are a woman, trans man, or non-binary person with female reproductive organs (ovaries, fallopian tubes, and/or a uterus) and * Have never had genetic testing for the cancer genes tested for in the study and * Do not have first-degree family members (e.g.: parent, sibling, child) or second-degree family members (e.g.: aunt, uncle, niece, nephew, grandchild, grandparent, half-sibling) with genetic changes in the cancer genes tested for in the study PROTECT-C is a completely digital study. The study team will give participants access to an app developed specifically for this study. They can download this app using a smartphone or tablet or access it on any internet browser using a computer or laptop. Before they can access the app, participants will need to complete a consent form. They will also be asked to fill in a short questionnaire about themselves and their health. The PROTECT-C app contains information to help participants decide if they would like to have genetic testing. If they decide to have genetic testing, they will complete a consent form for genetic testing on the app. The study team will send them a saliva based test kit in the post. The study will look at how many people decide to have genetic testing and how many of them are found to have a genetic change. It will evaluate their experience with using the app and how this approach to genetic testing affects their quality-of-life, satisfaction, and mental well-being. This will give us a better understanding of how well the app works as a way of offering genetic testing to people. The study is interested to see how people found to be at increased risk decide to manage their risk. We will assess the uptake of screening and prevention options. Few participants will be invited to have 1:1 interviews by the study team. This will evaluate their experience of making a decision about genetic testing and taking part in the study. Taking part in these interviews is optional. The study will also assess if this way of offering genetic testing to people is affordable for the NHS.
Interventions
GENETICGenetic testing for Cancer Susceptibility Genes (CSGs) (BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2, MLH1, MSH2, MSH6) and personalised breast and ovarian cancer risk
Genetic testing for Cancer Susceptibility Genes (CSGs) (BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2, MLH1, MSH2, MSH6) and personalised breast and ovarian cancer risk for all women (including trans-men, and non-binary individuals with female reproductive organs) over the age of 18 years independent of any family or personal history of cancer.
Sponsors
Queen Mary University of London
University of Cambridge
University of Manchester
London School of Hygiene and Tropical Medicine
Institute of Cancer Research, United Kingdom
University of Leeds
Imperial College London
University College, London
VU University Medical Center (VUmc)
St George's, University of London
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
Interventional cohort study offering genetic testing for moderate to high penetrance Cancer Susceptibility Genes (CSGs) (BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2, MLH1, MSH2, MSH6) and a personalised breast and ovarian cancer risk prediction using a digital app and saliva based DNA testing.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Women, trans men, and non-binary people with female reproductive organs * ≥18 years at consent
Exclusion criteria
* Individuals who have previously undergone genetic testing for one or more of the following CSGs: BRCA1, BRCA2, PALB2, RAD51C, RAD51D, BRIP1, MLH1, MSH2, MSH6 * One or more first- or second-degree relative with a PV in any of above CSGs * Inability to provide informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathogenic variant (PV) prevalence for multiple moderate to high penetrance CSGs (BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2, MLH1, MSH2, MSH6) in women from unselected population-based genetic testing compared with FH-based genetic testing | 1 year after completing recruitment | The primary outcome measure is the proportion of women with one or more CSGs who have undergone genetic testing and received a valid result. PV prevalence will be estimated by the number of observed PVs divided by the total number of individuals tested. An overall rate and CSG specific rates will be calculated. Standard NHS criteria at time of the study (i.e. Amsterdam-2 Criteria for Lynch Syndrome and 10% BRCA probability threshold for HBOC) will be used to evaluate family history criteria for genetic testing. The proportion of PVs fulfilling NHS testing criteria (FH positive) will be estimated. 95% Confidence Intervals for these outcomes will be calculated as per methods specified in the SAP (statistical analysis plan). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Satisfaction and regret (Satisfaction) | measured at acceptance, 21 days, 6 months and 12 months | Satisfaction is measured as the proportion of positive responses to the statement "I am satisfied with the decision I have made" |
| Satisfaction and regret (Regret) | measured at acceptance, 21 days, 6 months and 12 months | Regret is measured as the proportion who score 10 or less using the Decision Regret Scale questionnaire (scale 5-25 where 5 indicates completely dissatisfied and 25 indicates completely satisfied). |
| Quality of life using EQ5D- 5L | Pre-genetic testing and at 21 days, 6 months and 12 months | Quality of Life is measured using the EORTC Questionnaire EQ5D- 5L. Mean score (range 0-1) with higher scores indicating higher quality of life. |
| Psychosocial wellbeing - Cancer worry | Pre-genetic testing and at 21 days, 6 months and 12 months | a. Cancer worry score is measured using the Cancer Worry Scale questionnaire (4-item Cancer Worry Scale questionnaire on a 4-point Likert scale). Mean Cancer Worry Scale score (range 4-16) and self-reported VAS score (range 0-100); with higher score indicates greater concern |
| Psychosocial wellbeing - Risk perception | Pre-genetic testing and at 21 days, 6 months and 12 months | Risk perception is measured as the proportion responding as at "high or much higher" chance of cancer to the statement "compared with other people of your age, do you think your chances of getting cancer at some point in your life are…" |
| Psychosocial wellbeing - Anxiety and depression | Pre-genetic testing and at 21 days, 6 months and 12 months | Anxiety is measured using the Hospital Anxiety and Depression Scale (HADS) anxiety questionnaire- Anxiety score (7-item questionnaire on a 4-point Likert scale). Depression is measured using the HADS depression questionnaire -(7-item questionnaire on a 4-point Likert scale). Scores range from 0-21 with higher scores indicating higher levels of anxiety/depression. |
| Psychosocial wellbeing - Distress | Pre-genetic testing and at 21 days, 6 months and 12 months | Distress is measured using the Impact of Events (IES) questionnaire (22-item IES questionnaire on a 5-point Likert scale). Mean score IES Intrusive scale (range 0-35) and IES Avoidance scale (range 0-38); where higher scores indicate greater distress. |
| Psychosocial wellbeing - Impact | Pre-genetic testing and at 21 days, 6 months and 12 months | Impact is measured using the Multidimensional Impact of Cancer (MICRA) questionnaire. Mean score overall (range 0 -105) with separate scores for distress, positive experiences and uncertainty. MICRA distress scale (range 0-30), MICRA positive experiences scale (range 0-20) and MICRA uncertainty scale (range 0-45); where higher scores indicates higher impact. |
| Uptake of risk management options | collected annually over 8 years | Uptake of risk management options (for breast, ovarian, endometrial and bowel cancers) are measured using self-reported, clinical and/or registry data 1. Breast: Proportion of CSG carriers who undergo of self-examination, mammography, MRI, risk reducing mastectomy, medical prevention 2. Ovary: Proportion of CSG carriers who undergo surveillance, or surgical prevention (risk reducing salpingo-oophorectomy or risk reducing early salpingectomy) 3. Endometrial: Proportion of CSG carriers who undergo risk reducing hysterectomy (with bilateral salpingo-oophorectomy in women with Lynch Syndrome); endometrial cancer surveillance 4. Bowel: Proportion of CSG carriers who undergo FIT test, colonoscopy, take aspirin 5. Proportion of CSG carriers who undergo pre-implantation genetic testing in individuals planning a family |
| Uptake of cascade testing | 2 years post return of last result in those recruited | Uptake of cascade testing is measured as the total number of people who undergo cascade testing per family in an individual with a PV in a CSG at 2 years after the return of the last test result |
| VUS carrier frequency | 6 months after return of the last test result | measured as the proportion of VUS carriers in women who have undergone testing at 6 months after return of the last test result |
| Cost-effectiveness of genetic testing | 12 months after return of last test result - initial analysis | Is measured by incremental cost-effectiveness ratio (ICER) comparing population testing strategy with a family history based testing strategy. ICER per QALY is compared to the NICE willingness to pay threshold in the UK (£30,000/QALY). Incremental costs, incremental QALYs and number of cancers/deaths prevented will be calculated and one-way and probabilistic sensitivity analysis undertaken. |
Countries
United Kingdom
Contacts
CONTACTRanjit Manchanda, PhD
CONTACTCaitlin Fierheller, PhD
PRINCIPAL_INVESTIGATORRanjit Manchanda, PhD
Wolfson Institute of Population Health, Queen Mary University of London
Outcome results
None listed