Population Based Germline Testing for Early Detection and Prevention of Cancer (PROTECT-C)

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.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer Risk; Cancer Gene Mutation; Ovarian Cancer Risk
• Intervention / Treatment: Genetic: Genetic testing for Cancer Susceptibility Genes (CSGs) (BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2, MLH1, MSH2, MSH6) and personalised breast and ovarian cancer risk

• Study Type: Interventional
• Enrollment (Estimated): 6000
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ranjit Manchanda, PhD; Phone Number: +44 8008620236; Email: r.manchanda@qmul.ac.uk
• Study Contact Backup: Name: Caitlin Fierheller, PhD; Phone Number: +44 8008620236; Email: protectc.study@qmul.ac.uk

Study Locations

• United Kingdom
  • London, United Kingdom, EC1M 6BQ
    • Recruiting
    • Wolfson Institute of Population Health, Queen Mary University of London
    • Contact: Ranjit Manchanda, PhD; Phone Number: +44 8008620236; Email: r.manchanda@qmul.ac.uk
    • Contact: Caitlin Fierheller, PhD; Phone Number: +44 8008620236; Email: protectc.study@qmul.ac.uk
    • Principal Investigator: Ranjit Manchanda, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Genetic testing; Genetic testing for Cancer Susceptibility Genes (CSGs) (BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2, MLH1, MSH2, MSH6) and personalised breast and ovarian cancer risk prediction

Genetic: Genetic 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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).	1 year after completing recruitment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Satisfaction and regret (Satisfaction)	Satisfaction is measured as the proportion of positive responses to the statement "I am satisfied with the decision I have made"	measured at acceptance, 21 days, 6 months and 12 months
Satisfaction and regret (Regret)	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).	measured at acceptance, 21 days, 6 months and 12 months
Quality of life using EQ5D- 5L	Quality of Life is measured using the EORTC Questionnaire EQ5D- 5L. Mean score (range 0-1) with higher scores indicating higher quality of life.	Pre-genetic testing and at 21 days, 6 months and 12 months
Psychosocial wellbeing - Cancer worry	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	Pre-genetic testing and at 21 days, 6 months and 12 months
Psychosocial wellbeing - Risk perception	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…"	Pre-genetic testing and at 21 days, 6 months and 12 months
Psychosocial wellbeing - Anxiety and depression	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.	Pre-genetic testing and at 21 days, 6 months and 12 months
Psychosocial wellbeing - Distress	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.	Pre-genetic testing and at 21 days, 6 months and 12 months
Psychosocial wellbeing - Impact	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.	Pre-genetic testing and at 21 days, 6 months and 12 months
Uptake of risk management options	Uptake of risk management options (for breast, ovarian, endometrial and bowel cancers) are measured using self-reported, clinical and/or registry data; Breast: Proportion of CSG carriers who undergo of self-examination, mammography, MRI, risk reducing mastectomy, medical prevention; Ovary: Proportion of CSG carriers who undergo surveillance, or surgical prevention (risk reducing salpingo-oophorectomy or risk reducing early salpingectomy); Endometrial: Proportion of CSG carriers who undergo risk reducing hysterectomy (with bilateral salpingo-oophorectomy in women with Lynch Syndrome); endometrial cancer surveillance; Bowel: Proportion of CSG carriers who undergo FIT test, colonoscopy, take aspirin; Proportion of CSG carriers who undergo pre-implantation genetic testing in individuals planning a family	collected annually over 8 years
Uptake of cascade testing	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	2 years post return of last result in those recruited
VUS carrier frequency	measured as the proportion of VUS carriers in women who have undergone testing at 6 months after return of the last test result	6 months after return of the last test result
Cost-effectiveness of genetic testing	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.	12 months after return of last test result - initial analysis

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine the uptake of population-based genetic testing	Proportion of women with who consent to undergo genetic testing (amongst those consenting to the study) 6 months after return of the last test result.	6 months after return of the last test result
Proportion of women categorised as moderate and high risk of breast cancer (BC) and moderate and moderate and high risk of ovarian cancer (OC)	Number of women categorised as moderate or high risk for BC or moderate or high risk for OC using the CAN-RISK model Number of women categorised as moderate or high risk for BC using the Tyrer-Cuzick model Number of women categorised as moderate or high risk of BC using the Tyrer-Cuzick model, and difference compared with use of the CAN-RISK model	6 months after return of the last test resut.
PV prevalence for individual CSG : BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2, MLH1, MSH2, MSH6	PV prevalence for "individual" CSG : BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2, MLH1, MSH2, MSH6 calculated by Proportion of women who have undergone genetic testing and found to have a "specific" CSG Proportion of women identified as FH positive in women who test positive with PVs in "individual" CSGs	6 months after return of the last test result.
Satisfaction and regret with population-based testing Longer term	Satisfaction: 1-item ("I am satisfied with the decision I have made") on a 5-point Likert scale Regret: Score as calculated from the 5-item Decision Regret Scale on a 5-point Likert scale. 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).	Years 2, 3 post-test result
The experience of using and usability of the PROTECT-C app	9-questions from App Evaluation Questionnaire. Evaluated separately for women who accept and decline genetic testing using. Accept/decline and 6-month post-test questionnaire.; Proportion of women who used the app; Proportion of women who accessed written infor-mation; Proportion of women who accessed each section; Proportion of women who "strongly and very strongly agree" with the statement: 1-item usefulness of written information statement ("Looking at this in-formation after receiving my results was helpful") on 5-point Likert scale); Proportion of women who accessed videos; Proportion of women who accessed videos, by topic; 1-item usefulness of video information statement ("Watching these videos after receiving my results was helpful") on 5-point Likert scale. Proportion of women who "strongly and very strongly agree" with the statement; Suggestions for improvement (free text); Unhelpful features of app (y/n and free text)	6-month post-test result (or decision not to test in decliners)
Use of a helpline in population testing - Proportion	Helpline evaluation questionnaire and telephone or booking system record database. b. Reasons for helpline use- Proportion of consented women who called by reason c. Mode of helpline use - Proportion of calls by mode of use d. Ease of access - Proportion who found the helpline "very easy or easy" to use in those who used the helpline e. Satisfaction- Proportion who were "very satisfied or satisfied" with the helpline in those who used the helpline	Accept/decline, 21-days and 6-month post-test questionnaire
Use of a helpline in population testing - Frequency	Helpline evaluation questionnaire and telephone or booking system record database. a. Frequency of use of helpline- Total number of calls and proportion of consented women who contacted the helpline f. Frequency of use of booking system- Total number of people who used the online booking system	Accept/decline, 21-days and 6-month post-test questionnaire
Impact of genetic testing on health behaviours - Vitamin, alcohol, physical activity	specific measures on Lifestyle and Behaviours using a customised questionnaire. Measuring average change in proportions between the baseline questionnaire and 6-month post-test questionnaire, as well as 1-3 year questionnaire in women who consent to genetic testing.; Vitamin supplement use (y/n); Alcohol consumption (y/n); Physical activity (y/n)	baseline questionnaire and 6-month post-test questionnaire, as well as 1-3 year questionnaire
Impact of genetic testing on health behaviours - Diet	specific measures on Lifestyle and Behaviours using a customised questionnaire. Measuring average change in proportions between the baseline questionnaire and 6-month post-test questionnaire, as well as 1-3 year questionnaire in women who consent to genetic testing. - Diet: Meat/Vegetable/Fruit consumption measured on a 7-point Likert scale for each	baseline questionnaire and 6-month post-test questionnaire, as well as 1-3 year questionnaire
Impact of genetic testing on health behaviours - Smoking	specific measures on Lifestyle and Behaviours using a customised questionnaire. Measuring average change in proportions between the baseline questionnaire and 6-month post-test questionnaire, as well as 1-3 year questionnaire in women who consent to genetic testing. - Smoking frequency (current/former/never) and quantity	baseline questionnaire and 6-month post-test questionnaire, as well as 1-3 year questionnaire
Women's motivations and experiences of panel genetic testing and personalised BC and OC risk estimation for cancer screening and prevention	Qualitative interview transcripts. Nvivo will be used to identify themes, index, chart, map, synthesize and interpret data, including comparison between relevant groups.	For decliners - Baseline (post decision) For those with a PV or moderate or high risk result - Baseline (post decision), 9-12 months post decision For VUS: Baseline (post decision), 12-18 months post decision
Impact of return of VUS results - Reclassification	VUS reclassification recorded on the study database (updated every 6-months) and returned to participant.; VUS reclassification rate: proportion of VUS re-classified in women with at least one VUS and timepoint at which most VUS's get reclassified	End of study (end of year 8)
Impact of return of VUS results - Quality of life	VUS reclassification recorded on the study database (updated every 6-months) and returned to participant. - Quality of life and psychosocial outcomes in individuals with VUS, over time (baseline, 6 months, 1-3 years)	End of study (end of year 8)
Feasibility of running a study within a trial (SWAT): performance uptake	Performance uptake report. Proportion of individuals who registered on the website and indicated they received a letter, who could be linked to which type (one of two) of letter. To be reported at 6 months.	6 months post last recruit.
Effectiveness of different letters on registration interest in the trial	Self-reported letter type within the registration questionnaire. Difference in proportions of those who received each letter and registered from those invited, by letter type. To be reported at 6 months	Reported at 6 months after recruitment completed.
Evaluate association of sociodemographic factors	Measures on the first questionnaire including: Marital status (5 categories); Education status (9 categories); Income (6 categories); Race/ethnicity (5 broad categories); Religion (8 categories) Differences in sociodemographic factors between accepters and decliners to be evaluated at 6 months	6 months post last test result.
Quality of life EQ5D-5L longer term - EQ5D score	Quality of life measured using EORTC EQ5D-5L score (5 domains each with 5 levels). Mean EQ5D score (range 0-1) with higher score indicating higher quality of life. Evaluation of change in proportions/average scores between pre-genetic testing questionnaires, 6-months and 1-3 years post-test questionnaires in women who consent to genetic testing	baseline, 6 months, 1 year, 2 year, 3 years
Quality of life EQ5D-5L longer term - Visual Analogue Scale	Quality of life measured using self-reported Visual Analogue Scale (VAS) score (range 0-100) with higher score indicating higher quality of life. Evaluation of change in proportions/average scores between pre-genetic testing questionnaires, 6-months and 1-3 years post-test questionnaires in women who consent to genetic testing	baseline, 6 months, 1 year, 2 year, 3 years
Psychosocial wellbeing longer term - Cancer worry	Evaluation of change in proportions/average scores between pre-genetic testing questionnaires, 6-months and 1-3 years post-test questionnaires in women who consent to genetic testing. Mean cancer Worry Scale score (4-item Cancer Worry Scale questionnaire on a 4-point Likert scale) (range 4-16) with higher score indicates greater concern.	Pre-genetic testing, 6months, 1 year, 2 years, 3 years
Psychosocial wellbeing longer term - Risk pereception	Evaluation of change in proportions/average scores between pre-genetic testing questionnaires, 6-months and 1-3 years post-test questionnaires in women who consent to genetic testing. 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…"	Pre-genetic testing, 6months, 1 year, 2 years, 3 years
Psychosocial wellbeing longer term - Anxiety and Depression	Evaluation of change in proportions/average scores between pre-genetic testing questionnaires, 6-months and 1-3 years post-test questionnaires in women who consent to genetic testing. 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.	Pre-genetic testing, 6months, 1 year, 2 years, 3 years
Psychosocial wellbeing longer term - Distress	Evaluation of change in proportions/average scores between pre-genetic testing questionnaires, 6-months and 1-3 years post-test questionnaires in women who consent to genetic testing. 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.	Pre-genetic testing, 6months, 1 year, 2 years, 3 years
Psychosocial wellbeing longer term - Impact	Evaluation of change in proportions/average scores between pre-genetic testing questionnaires, 6-months and 1-3 years post-test questionnaires in women who consent to genetic testing. 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.	Pre-genetic testing, 6months, 1 year, 2 years, 3 years

Collaborators and Investigators

• Sponsor: Queen Mary University of London
• Collaborators: London School of Hygiene and Tropical Medicine; Imperial College London; University College, London; University of Leeds; University of Cambridge; Institute of Cancer Research, United Kingdom; University of Manchester; St George's, University of London; VU University Medical Center (VUmc)
• Investigators: Principal Investigator: Ranjit Manchanda, PhD, Wolfson Institute of Population Health, Queen Mary University of London

Publications and helpful links

Helpful Links

• PROTECT-C Web site

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2025
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2040

Study Registration Dates

• First Submitted: December 29, 2025
• First Submitted That Met QC Criteria: March 23, 2026
• First Posted (Actual): March 27, 2026

Study Record Updates

• Last Update Posted (Actual): March 27, 2026
• Last Update Submitted That Met QC Criteria: March 23, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: BRCA; Lynch Syndrome; breast cancer risk; Population based genetic testing; ovarian cancer risk
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Genetic Diseases, Inborn; Metabolic Diseases; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Colonic Diseases; Neoplastic Syndromes, Hereditary; DNA Repair-Deficiency Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Colorectal Neoplasms, Hereditary Nonpolyposis; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Health Services; Health Care Facilities Workforce and Services; Preventive Health Services; Genetic Techniques; Genetic Services; Diagnostic Services; Genetic Testing; RAD51C protein, human; G-T mismatch-binding protein
• Other Study ID Numbers: IRAS 328404; REC Reference 24/NW/0294 (Other Identifier: North West Preston Research Ethics Committee)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Patient data may be shared after completion of study and publication of all results, on reasonable request and communication from the Chief Investigator - via email - r.manchanda@qmul.ac.uk

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No