BRCA-DIRECT: Randomised Evaluation in Women Diagnosed With Breast Cancer of Digitally-delivered Pre-test Information for BRCA-testing
Phase: NA
Conditions: Breast Neoplasm Female
Sponsor: Institute of Cancer Research, United Kingdom

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BRCA-DIRECT_IRAS278052CCR5234_Protocol_v0.61_17_03_202317_03_2023 
Full Study Title 
BRCA-DIRECT: randomised evaluation in women diagnosed with breast cancer of 
digitally-delivered pre-test information for BRCA-testing 
Short Title: BRCA-DIRECT 
Version: 0.61 
Date: 17th March 2023 
Effective date: 29th March 2023 
Sponsor: The Institute of Cancer Research 
123 Old Brompton Road, London SW7 3RP 
Funder: Cancer Research UK (C61296/A29423) 
Protocol Reference: CCR5234 

 
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BRCA-DIRECT_IRAS278052CCR5234_Protocol_v0.61_17_03_202317_03_2023 
 
 
 
Summary of Investigators  
Chief Investigator 
Professor Clare Turnbull 
Co-Investigators 
Professor Gareth Evans  
Dr Angela George 
Mr Ashu Gandhi 
Dr Zoe Kemp 
Professor Dame Lesley Fallowfield 
Professor Valerie Jenkins 
Professor Stephen Bremner 
Dr Mike Hubank 
Ms Nicola Perry (Clinical Trials Manager) 
Rochelle Gold (Patient representative) 
Study Statistician 
Dr Christopher Jones 
Study approvals 
IRAS Project ID IRAS278052 
NRES REC number: 20/LO/1200 
NRES REC approval date: 04/01/2021 
Sponsor - Committee for Clinical 
Research (CCR) number: 
CCR5234 
Sponsor - CCR approval date: 15/09/2020 
Study Management 
Chief Investigator: 
email: clare.turnbull@icr.ac.uk 
Study management: 
 
email: BRCADirect@icr.ac.uk 
Study Management Office address: 
 
Division of Genetics and Epidemiology,  
Institute of Cancer Research, 
Sutton, 
Surrey, 
London 
SM2 5NG 
Tel: 020 8722 4626 
 
 
 
 

 
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Protocol Synopsis 
Title 
BRCA-DIRECT: randomised evaluation in women diagnosed with breast cancer of 
digitally-delivered pre-test information for BRCA-testing 
 
 
Short Title 
BRCA-DIRECT  
Anticipated 
Study 
Start/End 
Dates 
01/01/2021 – 31/12/2022 
 
Number of 
participants 
1000 
Study 
objectives 
Primary Objective 
To evaluate whether digital delivery of pre-test information for BRCA-testing in 
breast cancer patients is non-inferior to current standard practice of 1:1 delivery 
from a healthcare professional regarding uptake of genetic test.   
Secondary Objectives 
• 
To assess knowledge about genetic testing for BRCA genes, following 
delivery of pre-test information, in the two allocated groups 
• 
To assess anxiety following delivery of pre-test information, and test 
results, in the two allocated groups 
 
Additional secondary objectives: 
• 
To assess uptake of digital genetic testing 
• 
To compare ‘Test-offer-to-results’ time between BRCA-DIRECT digital 
model and contemporaneous clinical service 
• 
To evaluate uptake of telephone helpline 
• 
To evaluate Healthcare professional satisfaction with BRCA-DIRECT 
digital model 
• 
To evaluate Patient satisfaction with BRCA-DIRECT digital model 
Centres 
Royal Marsden NHS Foundation Trust (RMH)  
Manchester University Hospitals NHS Foundation Trust (MFT) 
Study 
Endpoints 
Primary Outcome 
Uptake of genetic testing for BRCA genes in women with a diagnosis of breast 
cancer 
Secondary Outcomes 
• 
Knowledge about genetic testing for BRCA genes (12-point knowledge test 
administered Day 1 following pre-test information) 
• 
Anxiety (Intolerance of Uncertainty and STAI Y-1/Y-2 state/trait anxiety) 
  
Additional secondary outcomes: 
• 
Potential participant decline on account of lack of digital access  
• 
‘Test-offer-to-results’ time 

 
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BRCA-DIRECT_IRAS278052CCR5234_Protocol_v0.61_17_03_202317_03_2023 
 
o Study compared to audit of contemporaneous timings from referral  
to results at participating centres 
• 
Helpline usage 
o Evaluate proportion of patients receiving digital pre-test information 
who require 1:1 discussion via helpline 
• 
Healthcare professional satisfaction  
• 
Patient satisfaction  
Inclusion 
criteria 
• 
Diagnosis of invasive breast cancer or high-grade ductal carcinoma in situ 
(DCIS) 
• 
Female 
• 
Aged 18 years or over   
• 
Access to smartphone or email + internet 
• 
Good comprehension of the English Language 
 
Exclusion 
criteria 
Previous testing for BRCA1/2 
 
Table of Contents   
Summary of Investigators ............................................................................................................................. 2 
Study approvals ............................................................................................................................................ 2 
Study Management ...................................................................................................................................... 2 
Protocol Synopsis ......................................................................................................................................... 3 
SUMMARY ................................................................................................................................................... 7 
1 
BACKGROUND AND RATIONALE ........................................................................................................ 8 
1.1 
Targeting screening and prevention for those at a priori elevated risk of cancer ............................. 8 
1.2 
gBRCA1/BRCA2 as a biomarker of cancer risk .............................................................................. 8 
1.3 
gBRCA1/BRCA2 as a biomarker for predicting treatment response ............................................... 9 
1.4 
Transformation in genetic technologies and its impact on the current landscape of 
gBRCA1/BRCA2 biomarker testing ........................................................................................................... 9 
1.5 
Expansion of gBRCA1/BRCA2 biomarker testing ......................................................................... 10 
1.6 
Clinically-Integrated, Clinician-Independent, Rapid, Digital, Genetic Susceptibility Biomarker 
Testing (CICIRDGSBT) – why we need a trial now .................................................................................. 11 
1.7 
Prior relevant research ................................................................................................................. 12 
1.7.1 
Moving genetic testing of cancer patients out of Clinical Genetics .................... 12 
1.7.2 
Alternative methods to traditional ‘genetic counselling’ for genetic information-giving
 
12 
1.7.3 
Health economic analyses ...................................................................................... 12 
1.7.4 
Study recruitment through non-traditional mechanisms ..................................... 12 
1.8 
Rationale for the study design ...................................................................................................... 13 
2 
HYPOTHESIS AND STUDY OBJECTIVES.......................................................................................... 13 

 
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2.2 
Primary Objective ......................................................................................................................... 13 
2.3 
Secondary Objectives ................................................................................................................... 13 
3 
STUDY DESIGN .................................................................................................................................. 14 
3.1 
Internal pilot .................................................................................................................................. 14 
4 
PARTICIPANTS ................................................................................................................................... 14 
4.1 
Inclusion criteria: .......................................................................................................................... 14 
4.2 
Exclusion criteria: ......................................................................................................................... 14 
5 
STUDY INTERVENTIONS ................................................................................................................... 15 
5.1 
Pre-test information delivery about genetic testing for BRCA genes BRCA1/BRCA2/PALB2 ........ 15 
5.2 
Delivery of genetic test results ...................................................................................................... 15 
6 
OUTCOMES ........................................................................................................................................ 16 
6.1 
Primary Outcome ......................................................................................................................... 16 
6.2 
Secondary Outcomes ................................................................................................................... 16 
7 
MEASUREMENT OF STUDY ENDPOINTS ......................................................................................... 16 
8 
PARTICIPANT PATHWAY including COVID-19 pathway variation ...................................................... 18 
8.1 
Enrolment ..................................................................................................................................... 18 
8.1.1 
Study resources/paperwork ................................................................................... 18 
8.1.2 
Baseline checks and 24 hour pause ...................................................................... 19 
8.2 
Commencing participation in BRCA-DIRECT ............................................................................... 20 
8.3 
Delivery of information about genetic testing for BRCA genes BRCA1, BRCA2, PALB2 .............. 20 
8.4 
Consent to proceed to genetic testing .......................................................................................... 21 
8.5 
Assessment of knowledge and anxiety following consent for genetic testing to proceed .............. 21 
8.6 
Delivery of BRCA test result ......................................................................................................... 21 
8.6.1 
Digital receipt of result (participants with no pathogenic_variant detected) ...... 22 
8.6.2 
Receipt of result via telephone consultation with a genetic counsellor (all participants 
with pathogenic_variant plus 2.5% with a normal result) ................................................... 22 
8.7 
Post-test result anxiety assessment ............................................................................................. 22 
8.8 
Participant user feedback ............................................................................................................. 22 
8.9 
Final anxiety assessment ............................................................................................................. 23 
8.9.1 
Schedule of patient reported outcome assessments ........................................... 23 
8.10 
Additional notification of test results to the participant’s health care team ..................................... 24 
8.11 
Clinical Genetics referral .............................................................................................................. 24 
8.12 
Participant withdrawal ................................................................................................................... 24 
9 
PARTICIPANT PATHWAY FLOWCHART (STANDARD CONDITIONS) .............................................. 25 
9.1 
PARTICIPANT PATHWAY FLOWCHART (COVID-19 CONTINGENCY) ..................................... 26 
10 
DEFINITION OF END OF STUDY ................................................................................................... 27 
11 
STUDY DISCONTINUATION ........................................................................................................... 27 

 
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12 
STATISTICS .................................................................................................................................... 28 
12.1 
Sample size and power calculation for measurement of study endpoints ..................................... 28 
12.2 
Randomisation ............................................................................................................................. 29 
12.2.1 
Randomisation to pre-test information delivery ................................................... 29 
12.2.2 
Randomisation to receipt of genetic test results via telephone appointment with a 
genetic counsellor (participants with normal genes) .......................................................... 29 
12.3 
Internal pilot .................................................................................................................................. 29 
12.4 
Statistical analysis ........................................................................................................................ 30 
13 
DEVELOPMENT OF THE BRCA-DIRECT DIGITAL SYSTEM ......................................................... 31 
14 
STANDARD NHS GENETIC TEST FOR BRCA1/BRCA2/PALB2 .................................................... 34 
15 
DATA HANDLING AND RECORD KEEPING .................................................................................. 35 
15.1 
Data acquisition ............................................................................................................................ 35 
15.2 
Data quality .................................................................................................................................. 35 
15.3 
Data access ................................................................................................................................. 35 
15.4 
Source data .................................................................................................................................. 35 
15.5 
Data security ................................................................................................................................ 36 
16 
REGULATORY ................................................................................................................................ 36 
16.1 
Research Ethics approval ............................................................................................................. 36 
16.2 
Ethical considerations and informed consent ................................................................................ 36 
16.3 
Confidentiality ............................................................................................................................... 37 
17 
TRIAL MANAGEMENT .................................................................................................................... 38 
17.1 
Public and Patient Involvement .................................................................................................... 38 
17.2 
Trial management and oversight .................................................................................................. 38 
17.3 
Trial monitoring ............................................................................................................................. 38 
17.4 
End of study transfer of data ......................................................................................................... 38 
17.5 
Archiving ...................................................................................................................................... 39 
17.6 
Publication policy .......................................................................................................................... 39 
17.7 
Data sharing ................................................................................................................................. 39 
17.8 
Indemnity ...................................................................................................................................... 40 
17.9 
Funder .......................................................................................................................................... 40 
18 
Protocol Signature Page .................................................................................................................. 41 
19 
References ...................................................................................................................................... 42 
 
 
 
 

 
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SUMMARY 
BRCA-DIRECT is a pragmatic randomised non-inferiority evaluation. 
 
Primary Objective 
To evaluate whether digital delivery of pre-test information for BRCA-testing in breast cancer 
patients is non-inferior compared to current standard practice of 1:1 delivery from a healthcare 
professional regarding uptake of genetic test.   
Participants 
Women with a diagnosis of breast cancer or high-grade ductal carcinoma in situ, currently attending 
breast clinics at the Royal Marsden NHS Foundation Trust and Manchester University Hospitals 
NHS Foundation Trust, for management/follow up of their breast cancer.  
Interventions 
Current standard of care (500): 
1:1 delivery via genetic counsellor of pre-test information and results for BRCA gene-testing 
(Standard of care is 1:1 delivery face-to-face, by telephone or by video-conference.  In this study we 
shall use telephone only). 
Intervention under test (500): 
Digital delivery of pre-test information and results for BRCA gene-testing. 
Primary Outcome 
• 
Uptake of genetic testing (proportion of patients proceeding with BRCA-test following receipt of pre-
test information) 
 
Secondary Outcomes 
• 
Knowledge about genetic testing for BRCA genes, following delivery of pre-test information 
• 
Anxiety following delivery of pre-test information and test results 
 
Additional secondary outcomes 
• 
Study decline rates on account of lack of access to digital interface  
• 
‘Test-offer-to-results’ time (study compared to audit of timings under current pathways at participating 
centres) 
• 
Helpline usage 
• 
Healthcare professional satisfaction  
• 
Patient satisfaction  
 
Sample size 
1000 participants 
 
Internal Pilot 
For the first 60 participants in each arm, pilot capture of outcome measures, including patient-
reported, clinician and logistical outcome measures.  
 

 
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Study Duration 
Two years total including development, set-up and shut-down 
 
1 BACKGROUND AND RATIONALE 
 
1.1 Targeting screening and prevention for those at a priori elevated risk of cancer  
In the UK, there are >360,000 new presentations of cancer and >160,000 cancer deaths per year. More 
than half of cases present with advanced stage disease, for which outcomes typically remain poor.   
Near inevitable evolution of polyclonal drug resistance is casting increasingly long shadows over the 
anticipation that precision oncology might be the panacea by which we might reduce the bulk of cancer-
related mortality from advanced presentation of solid tumours 1. Accordingly, there has been renewed 
interest in programmes of cancer screening, early detection and/or prevention (SPED).  Any SPED 
strategy is likely a priori to have significantly more impact if targeted at those individuals at highest risk 
of developing cancer, for example those who carry a mutation (pathogenic_variant) in a high risk cancer 
susceptibility gene 2. For this high-risk population, we can offer interventions not clinically acceptable 
or economically feasible at population-level-risk, for example risk-reducing mastectomy for breast 
cancer patients or chemoprophylaxis.  
 
1.2 gBRCA1/BRCA2 as a biomarker of cancer risk  
Compared to the general female population, women who carry a pathogenic_variant in 
BRCA1/BRCA2/PALB2 have a dramatically elevated lifetime risk of breast cancer (11% compared to 
72%, 69%, 44% respectively) and ovarian cancer (1.5% compared to 44%, 17%, ~5%)(Figure 1) 3-5. 
Pathogenic_variants in BRCA2 also confer increased risk of prostate and pancreatic cancers 6-9. 
BRCA1 and BRCA2 constitute far and away the most dramatic contribution to breast and ovarian 
cancer genetic susceptibility; pathogenic_variants in PALB2 confer a risk of non-syndromic breast 
cancer that is well quantified and warrants equivalent clinical actions for BRCA1/BRCA2, but the 
frequency in the population of pathogenic_variants is much lower. 
 
 

 
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Opportunities provided by identification of a pathogenic_variant in BRCA1/BRCA2/PALB2 in a woman 
with breast cancer are as follows:  
 
 
Secondary prevention in the woman herself 
Serous ovarian cancers  
On account of the poor prognosis and lack of effective screening, women typically opt for bilateral risk 
reducing salpingo-oophorectomy, which reduces their ovarian cancer risk by 80-95%10.  
 
Second breast cancer 
 The average lifetime risk of a second breast cancer is 53% for BRCA1, 65% for BRCA2 
pathogenic_variant carriers 3.  Hence, if a BRCA1/BRCA2/PALB2 pathogenic_variant is identified 
during breast cancer diagnostic work-up, instead of breast conserving surgery, women may elect 
upfront for bilateral mastectomy for treatment of the current cancer and prevention of future (ipsi- and 
contralateral) breast cancers. This treatment approach also potentially avoids need for breast 
radiotherapy.   
 
Primary prevention in family members  
Once a pathogenic_variant is identified in a family, cascade testing through the family is initiated, by 
which on average 3-5 unaffected carriers of the pathogenic_variant are identified 11.   
Unaffected pathogenic_variant carriers may be offered risk-reducing breast and ovarian surgery, 
intensive breast cancer surveillance (annual MRI scans from age 30 years), chemoprophylaxis with 
drugs that reduce oestrogen signalling, prostate cancer surveillance and/or reproductive counselling 
(including preimplantation genetic diagnosis) 12.   
Individuals not carrying the familial pathogenic_variant can be taken out of high-risk screening 
instigated on the basis of family history, and alleviated of the anxiety related to their cancer family 
history.  
 
 
1.3 gBRCA1/BRCA2 as a biomarker for predicting treatment response  
More recently gBRCA1/BRCA2 status has emerged as an important biomarker predicting treatment 
response in breast, ovarian and prostate cancers13 14.  BRCA1/BRCA2 deficient tumours exhibit 
homologous recombination deficiency, resulting in dramatically enhanced response to platinum-based 
chemotherapy and PARP-inhibitors 13.  Rapid genetic testing at diagnosis of all individuals with these 
cancer types can ensure that people have access to the best treatment for their cancer. 
 
1.4 Transformation in genetic technologies and its impact on the current landscape of 
gBRCA1/BRCA2 biomarker testing 
Genetic testing was previously restricted on account of the direct costs of genetic analysis however 
over the last ten years the technological step-change of so-called Next Generation Sequencing (NGS) 
has revolutionised this field, enabling massively parallelised sequencing of multiple genes/samples 15.  
The throughput, turnaround time, accuracy and cost of genomic sequencing have been transformed by 
orders of magnitude but within the NHS, clinician time and administration are now cost- and capacity-
limiting.   

 
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The current international standard for delivery of gBRCA1/BRCA2 biomarker testing (Table 1) typically 
involves extensive “counselling”, as per models first put in place for Huntington’s disease. Because the 
volume of breast cancer cases is so huge, BRCA-testing has had to be restricted.  The complex and 
restricted eligibility criteria regarding personal and family history and the much higher patient: clinician 
ratios in breast clinics, have meant that BRCA-testing for breast cancer patients is highly limited and 
inconsistently delivered.  Less than 20% of breast cancer patients and very few prostate cancer patients 
are ‘eligible’ for testing 16.  In order to be equitable in allocation of BRCA-tests, the restricted resource 
of expert genetics manpower is further diverted towards complex evaluations of eligibility for each 
patient/family referred.  
 
 
 
Patients are increasingly seeking to circumvent the limited availability of testing and lengthy delays for 
results by accessing direct to consumer (DTC) testing, which brings with it highly variable and poorly 
regulated levels of interpretation and accuracy 17-19. Furthermore these results are wholly divorced from 
the NHS clinical infrastructure, NHS laboratory governance and NHS genetic data management. 
 
 
1.5 Expansion of gBRCA1/BRCA2 biomarker testing 
Recent trials have shown significant clinical effects of PARP Inhibitors for pancreatic cancer and 
advanced castrate resistant prostate cancer.  For both of these tumour types, it is challenging to procure 
tumour tissue.  Hence, in both cases we are likely to see over the forthcoming 2-3 years, a dramatic 
surge in demand for germline genetic testing of genes associated with homologous recombination 
deficiency (i.e. BRCA1/BRCA2/PALB2 +/- other genes).   
Through national funding, simple eligibility, high detection rate and more modest patient volume 
significant progress has been made in delivery of BRCA-testing in serous ovarian cancer.   
Breast cancers are less “enriched” than ovarian cancer for BRCA1/BRCA2/PALB2 pathogenic_variants 
with pick-up rates reported at 2.1% 20 to 3% (unpublished data, Fergus Couch, BRIDGES Study), 
(unpublished data, Doug Easton SEARCH study).  On BRCA-testing of unselected breast cancer 
cases, in approximately 3% of women we would also detect a rare variant for which, due to lack of 
available evidence, the pathogenicity status is unclear: this is termed variant of uncertain significance 
(VUS). 
There are 55,000 new cases of breast cancer per year and an estimated >800,000 prevalent cases 
alive in the UK.  It is widely agreed across the UK clinical genetics community that transformation of 

 
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BRCA1/BRCA2 testing in breast cancer patients is the most urgent priority on account of (i) clear 
opportunities for secondary prevention, in particular to mitigate unnecessary death from ovarian cancer 
in a woman who has survived her breast cancer, (ii) opportunities for precision oncology management 
of their current cancer, and (iii) primary prevention opportunities for the family 21-23. 
 
The pick-up rate for BRCA1/BRCA2/PALB2 pathogenic_variants in the general population is ~ 1 in 200 
24 25 and in due course it is highly likely genetic susceptibility testing may be rolled out to the broader 
(unaffected) population.  
 
1.6 Clinically-Integrated, Clinician-Independent, Rapid, Digital, Genetic Susceptibility 
Biomarker Testing (CICIRDGSBT) – why we need a trial now 
Improvement in identification of carriers of BRCA pathogenic_variants has been cited as being a key 
priority in many public health systems. To date we have ascertained <5% of BRCA1/BRCA2 carriers 
in the UK 26, and the targets for BRCA-testing in the 2015 UK Independent Cancer Task Force Report 
have not been met 27. To redress this and avert further expansion of DTC testing, new approaches are 
urgently required to maintain robustness but enable dramatic expansion of volume.  
 
Key features of any system of expanded testing must include: 
Clinical integration within 
• 
NHS genetic laboratory services, so that both positive and negative analyses are to the robust 
standard of a UKAS-approved NeQAS-accredited diagnostic laboratory  
• 
NHS data systems, so that results are held within the NHS NGIS database, to ensure that patients 
benefit from reclassification of VUSs 
• 
NHS cancer services, so that clinicians and the MDT receive the test results in real time to enable 
best management 
Rapid turnaround 
• 
To inform clinical decision-making at time of cancer diagnosis 
 
Patient-centred and patient-managed 
• 
To afford the patient choice regarding how, when and how much information they want about their 
genetic test and where, when and how soon they receive their results 
 
‘Clinician-lite’ pathway 
• 
To expand capacity for testing, improve turnaround time and reduce costs.  In our pathway we 
propose that a hot-line is the most clinician-efficient patient-centred mechanism by which to enable 
access to experienced professionals for patients with specific queries/issues, and those who require 
more support 
 
Flexibility 
• 
Regarding bio-sampling (i.e. use of saliva rather than blood) 
 
Digital platform to facilitate 
• 
Delivery of high quality, standardised information  
• 
Robust and rapid process management, sample-tracking, administration and communication 
 

 
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This paradigm shift in testing is essential to afford benefit to cancer patients. Clinically-Integrated, Clinician-
Independent, Rapid, Digital, Genetic Susceptibility Biomarker Testing (CICIRDGSBT) aims to integrate all of 
these key features within a single web-based system.  The BRCA-DIRECT study aims to test the feasibility 
and acceptability of this approach.  It is hoped that the study will be a stepping stone in the transition to a 
new paradigm. 
1.7 Prior relevant research  
1.7.1 Moving genetic testing of cancer patients out of Clinical Genetics  
The Wellcome-funded Mainstreaming Cancer Genetics Program (Deputy Directors: Turnbull, 
George), developed pathways, protocols and training materials to empower oncology professionals 
to undertake genetic testing and deliver pre-test counselling within the oncology clinic.    
Subsequent surveys revealed that adoption of ‘mainstreaming’ was relatively popular amongst 
gynaecological surgeons/oncologists for ovarian cancer patients, but low in breast cancer services, 
especially outside of specialist centres 28-31.  Survey responses regarding the underlying reasons 
included (i) overwhelming patient volume (ii) lack of available time in breast cancer clinic 
appointments (iii) complexity in evaluating eligibility for BRCA-testing (iv) lack of expertise in genetic 
counselling 30 32.  
 
1.7.2 Alternative methods to traditional ‘genetic counselling’ for genetic information-giving 
A number of international studies have demonstrated non-inferiority in information uptake/recall and 
patient satisfaction of tele-counselling compared to in-person face-to-face counselling 33-35. Tele-
counselling is now standard of care in UK clinical genetics centres. 
Studies of web-based information and aids as a supplement to 1:1 genetic counselling have been 
largely positive 36-39.  
The Genetic Cancer Prediction through Population Screening (GCaPPS) trial compared web-based 
information vs 1:1 counselling in unaffected Ashkenazi Jewish individuals, demonstrating non-
inferiority of cluster-randomised DVD-based pre-test counselling to traditional genetic-counselling 40 
41.  
  
1.7.3 Health economic analyses 
Recent UK health economic analyses have demonstrated that testing for breast-ovarian cancer 
susceptibility genes as cost-effective at £20,000-30,000 per quality-adjusted life-year UK 
willingness-to-pay thresholds in (i) unselected breast cancer patients 42 (ii) unselected ovarian 
cancer patients 43 and (ii) in women in the general population 44.  
  
1.7.4 Study recruitment through non-traditional mechanisms 
Whilst standard practice in recruiting patients to CTIMPs studies is face-to-face explanation by a 
trained clinical professional in the clinical environment, recruitment to non-CTIMPS studies has 
been democratised and extended via a number of innovative non-face-to-face models of recruitment 
45-53. 
 
 

 
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1.8  Rationale for the study design  
This study aims to investigate the feasibility, acceptability and safety of CICIRDGSBT.  In order to 
test whether patient-centred genetic testing for BRCA genes would be feasible within NHS breast 
cancer clinics, this study employs a number of patient-led procedures.  
 
The patient pathway under test is: 
• 
Digital delivery of information about genetic testing, followed by 
• 
Patient-initiated consent for genetic testing to proceed, followed by 
• 
Digital delivery of test results where no pathogenic_variant has been identified 
 
The laboratory testing is a standard NHS genetic test. This is delivered for both the intervention arm 
and the stand-of-care arm. 
 
Key features of the study design are: 
• 
Patient-led saliva sample preparation 
• 
Patient-led consent to join the study 
• 
Remote access to the BRCA-DIRECT platform 
• 
Digital delivery of pre-test information about genetic counselling 
• 
Digital consent for genetic testing to proceed 
• 
Digital delivery of genetic test results for patients with no pathogenic_variants identified 
2 HYPOTHESIS AND STUDY OBJECTIVES 
 
2.1.  Hypothesis 
Digital delivery of pre-test information for BRCA-testing in breast cancer patients is non-inferior to 
current standard practice of 1:1 delivery from a healthcare professional 
 
2.2 Primary Objective 
To evaluate whether digital delivery of pre-test information for BRCA-testing in breast cancer patients 
is non-inferior to current standard practice of 1:1 delivery from a healthcare professional as measured 
by rate of uptake of the genetic testing. 
 
2.3 Secondary Objectives 
• 
To assess knowledge about genetic testing for BRCA genes, following delivery of pre-test 
information, in the two allocated groups 
 
• 
To assess anxiety following delivery of pre-test information, and test results, in the two allocated 
groups 
 
This study will be conducted in compliance with the protocol, standard operating procedures, policies, 
local R&D management guidance, Good Clinical Practice including the Research Governance 
Framework 2005 (2nd edition) and other applicable regulatory requirements as amended from time to 
time. 
 

 
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3 STUDY DESIGN 
 
BRCA-DIRECT is a pragmatic, randomised, non-inferiority evaluation.  Estimated sample size is 1000 
women. 
3.1 Internal pilot 
The first 60 women recruited to each arm will form an internal pilot sample from which recruitment 
rate, retention and data completeness will be assessed with a good level of precision and, if deemed 
necessary, changes will be made to the protocol to maximise chances of delivery of the study.  
 
Detailed user feedback, via an optional telephone interview, will be available during this pilot phase – 
capped at 50 interviews.   
 
 
 
4 PARTICIPANTS 
 
Women with a diagnosis of breast cancer or high-grade ductal carcinoma in situ, currently attending 
breast clinics at the Royal Marsden NHS Foundation Trust and Manchester University Hospitals NHS 
Foundation Trust, for management/follow up of their breast cancer.  
4.1 Inclusion criteria:  
Women will be eligible if all of the criteria below are satisfied: 
• 
Diagnosis of invasive breast cancer or high-grade ductal carcinoma in situ (DCIS) 
• 
Aged 18 years or over   
• 
Access to smartphone or email + internet 
• 
Good comprehension of the English Language 
 
4.2 Exclusion criteria:  
• 
Previous testing for BRCA1, BRCA2, PALB2 genes 
 
 
 
 
 
 
 

 
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5 STUDY INTERVENTIONS 
 
5.1 Pre-test information delivery about genetic testing for BRCA genes 
BRCA1/BRCA2/PALB2 
Participants will be randomised 1:1 to receive either:  
 
Telephone consultation with a genetic counsellor (standard of care) 
The telephone consultations will be as per standard practice of the qualified genetic counsellor 
delivering the pre-test information. 
 
Digital delivery of pre-test information via BRCA-DIRECT platform (intervention) 
Participants will receive a link to the digital pre-test information.  This will consist of text covering: 
• 
Genetics and cancer risk 
• 
Genetics testing 
• 
What will happen if your test is positive 
• 
What will happen if your test is negative 
• 
Implications for insurance 
 
Where relevant, parts of the text will be linked through to additional information, such as insurance 
advice from the ABI.  
Participants in the intervention arm will be able to call a genetic counsellor on the hotline during 
weekday office hours, should they have any questions or require further information. 
 
5.2 Delivery of genetic test results 
It is predicted that 5-6% (3% VUSs and 2-3% pathogenic_variant) of individuals will have a positive 
result (pathogenic_variant or VUS detected). All participants whose test results indicate the presence 
of a pathogenic_variant or VUS will be informed of their result by telephone from a genetic counsellor. 
A priori, 2.5% participants will be selected at random to also receive their result (if negative) by 
telephone from a genetic counsellor. 
97.5% of participants will be randomised to receive their result (if negative) digitally, however any 
individuals with a positive result will receive their result by telephone. 
 
Telephone consultation with a genetic counsellor (current standard of care) 
The telephone consultations will follow current practice.   
 
Digital delivery of results (intervention) 
Participants will receive a digital message that their results are available.  When they click this, they 
will receive digital notification of their negative (normal) result in short form.  Full details will be 
provided in an individualised letter. 
 
 

 
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BRCA-DIRECT_IRAS278052CCR5234_Protocol_v0.61_17_03_202317_03_2023 
 
6 OUTCOMES 
 
6.1 Primary Outcome 
• 
Uptake of genetic testing  
 
6.2 Secondary Outcomes 
• 
Knowledge about genetic testing for BRCA genes, following delivery of pre-test information 
• 
Anxiety following delivery of pre-test information and test results 
 
Additional secondary outcomes are the following: 
• 
Potential participant decline on account of lack of digital access  
• 
‘Test-offer-to-results’ time 
o study compared to audit of contemporaneous timings from referral to results at participating 
centres 
• 
Helpline usage 
o Evaluate proportion of patients receiving digital pre-test information who require 1:1 discussion 
via helpline 
• 
Healthcare professional satisfaction  
• 
Patient satisfaction  
 
7 MEASUREMENT OF STUDY ENDPOINTS 
 
Uptake of genetic testing will be measured as the proportion of participants proceeding to genetic 
testing following delivery of pre-test information either digitally, or via a telephone consultation with a 
genetic counsellor. 
Knowledge will be assessed using a study-specific questionnaire, designed to test knowledge in key 
areas of genetic susceptibility awareness for breast/ovarian cancer.  The questionnaire has been (i) 
developed using two previously published questionnaires developed to evaluate knowledge following 
delivery of genetic counselling information about increased risk for breast cancer, (ii) tested on 3 
clinical genetics professionals, 3 oncologists, and (iii) reviewed by our PPI panel comprising patients 
with breast cancer and patients who have undergone BRCA-testing40, 54.  
Anxiety will be measured using the Spielberger state-trait anxiety inventory 55 and the short form 
Intolerance of Uncertainty scale 56.   
 
The Spielberger state-trait anxiety inventory consists of two self-administered, 20-item questionnaires, 
with each item rated on a four-point Likert scale.  It assesses anxiety proneness (trait) and the current 
state of anxiety change (state). The Trait anxiety is measured only once and the State at each time 
point.  High STAI scores signify greater anxiety. 
 
Research suggests that intolerance of uncertainty may be very important in understanding worry and 
may play a key role in the etiology and maintenance of worry.  Evidence for the connection between 
intolerance of uncertainty and worry comes from studies that established that worriers possess a 
number of characteristics that set them apart from non-worriers.  For example, worriers have been 

 
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BRCA-DIRECT_IRAS278052CCR5234_Protocol_v0.61_17_03_202317_03_2023 
 
shown to require more information before arriving at a decision 57. The need for additional information 
may be a means for lowering the level of uncertainty. 
Decline on account of lack of access to digital interface will be assessed from completed anonymous 
study summary forms posted into the secure study hub drop boxes. 
‘Test-offer-to-results’ time (study compared to audit of timings under current pathways at participating 
centres) 
Helpline usage will be assessed from a central log of the number, content and duration of calls made 
to the genetic counsellor telephone hot line.  
Healthcare professional satisfaction will be assessed using a study specific survey  
Patient satisfaction will be measured using a digital study specific survey.   
 
 

 
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8 PARTICIPANT PATHWAY including COVID-19 pathway variation 
 
 
8.1 Enrolment 
• 
There will be a study hub in the breast clinic making available study summary sheets, study 
information packs and a locked drop-box (for submission of study paperwork and saliva samples).  
BRCA-DIRECT posters will be on display at breast clinics. 
• 
The patient will be made aware of the BRCA-DIRECT study via: 
o Recommendation and sign-posting towards the study from their doctor/specialist breast care 
nurse 
o The study-hub/poster  
• 
A BRCA-DIRECT research genetic counsellor or research nurse will be available in clinic to answer 
questions.  
 
• 
COVID-19 addendum: All COVID-19 related government guidelines applicable during the 
recruitment period of the study will be followed, (e.g regarding the wearing of personal protective 
equipment and social distancing).   
 
8.1.1 Study resources/paperwork 
Study Summary sheet 
Patients will be invited to read a study summary sheet which outlines the study and asks those 
interested in participating to collect a study information pack and saliva sample kit.  A section at the 
bottom of the sheet invites patients not interested in participating in BRCA-DIRECT to complete it 
anonymously, providing their reason why from the categories listed, and post it in the secure study 
drop box. 
Study Information pack 
Patients interested in participating will be given a study information pack containing: 
• 
A front sheet 
• 
Patient information leaflet 
• 
Saliva kit and Expression of Interest form  
• 
Study consent form and pre-paid envelope 
 
Saliva sample collection and Expression of Interest 
• 
Patients interested in participating in BRCA-DIRECT will be encouraged to provide a saliva sample 
in clinic, before leaving hospital (this avoids delays in testing, the need for an additional visit to 
hospital and the possibility of saliva samples being spoiled in transit).  
• 
The patient will be asked to produce their own labelled saliva sample (following the instructions 
provided in the saliva sample kit).   
• 
Healthcare professionals will be available to assist, if required.   
• 
Patients will be asked to complete an Expression of Interest form, located inside the saliva sample 
kit, to provide their name and preferred contact details (mobile phone, email) and permission for 
their saliva sample to be stored while they decide whether to participate in BRCA-DIRECT.   
• 
This form will be placed together with the saliva sample inside the sample bag and placed in the 
secure study drop box. 
• 
Expression of Interest details and receipt of sample will be entered onto the BRCA-DIRECT study 
databases. 

 
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BRCA-DIRECT_IRAS278052CCR5234_Protocol_v0.61_17_03_202317_03_2023 
 
• 
If there are any problems with the saliva sample e.g. tube not sealed properly, damage etc., the 
local site genetic counsellor will contact the potential participant and arrange for another sample to 
be collected. 
 
• 
COVID-19 addendum: In the event of COVID-19 regulations disallowing generation of saliva 
samples in clinic, we will enable participation in the study via (a) a saliva sample generated at home 
and posted back to ICR (b) supply of a blood sample in clinic (if the patient is having routine bloods 
taken in clinic). Thus, we shall make available in clinic two types of study packs (a) “home-saliva 
study-pack”, including tube for home saliva collection and secure sample postal kit and (b) “blood 
study-pack”, including bottle and forms to be handed to phlebotomy.  The “home-saliva study-pack” 
can also be posted out to potential participants undergoing telephone consultation.  These pathways 
offer flexibility regarding (i) prohibition of saliva generation in hospital clinic setting (ii) 
discontinuation of laboratory analysis of saliva samples (iii) additional reduction in face-to-face 
appointments (see participant pathway flowchart COVID-19 contingency). 
 
Patient information leaflet and consent to join BRCA-DIRECT 
Potential participants can take home their patient information leaflet and study consent form.  The 
telephone number of the local site research genetic counsellor is listed in the patient information 
leaflet. A study telephone hotline, manned by the local site research genetic counsellor, will be 
available to all participants ahead of recruitment to address any questions they have about the 
study. Those wishing to join the study are instructed to sign and return the study consent form in the 
pre-paid envelope provided.  This form also contains a section for patients to complete and return if 
they don’t want to participate in the study.  
Some patients may choose to read the patient information leaflet and sign their study consent form 
whilst in clinic.  This will be permitted because participants will not be contacted by the BRCA-
DIRECT study databases for at least 24 hours.  The study interface contains a link to take a 
participant to a study withdrawal screen, which will be available at all stages of participation. 
All participants will receive a copy of their signed study consent form via a secure method 
(encrypted email or post). 
If a signed study consent form is not received from a potential participant who provided a 
saliva/blood sample, the BRCA-DIRECT study system will send four consecutive reminders 1, 7, 12 
and 17 days after the sample was deposited, using the patient’s preferred contact (mobile 
phone/email).  If signed consent is not received after six weeks, the temporarily stored sample and 
Expression of Interest form will be destroyed.  
8.1.2 Baseline checks and 24 hour pause 
On receipt of a signed study consent form, the local site will confirm the patient’s eligibility and enter 
details required for study conduct onto the BRCA-DIRECT databases.  If, in exceptional 
circumstances, a patient is found to be ineligible for the study, they will be telephoned by their 
consultant or the study genetic counsellor. 
After 24 hours, the participant will be sent a link to the BRCA-DIRECT study platform interface.  This 
link enables the participant to:  
• 
Withdraw from the study if they have changed their mind 
• 
Progress through the BRCA-DIRECT study 
 
 

 
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8.2 Commencing participation in BRCA-DIRECT 
Participants will complete digitally: 
• 
A cancer family history questionnaire 
• 
Intolerance of Uncertainty questionnaire 
• 
STAI Y-1/Y-2 state/trait anxiety questionnaires 
• 
Knowledge questionnaire 
 
If baseline questionnaires are not completed, an SMS/email reminder to complete them will be sent 
to the participant 1, 2 and 3 days after receiving the initial link to BRCA-DIRECT study interface. 
 
 
 
 
8.3 Delivery of information about genetic testing for BRCA genes BRCA1, BRCA2, PALB2 
Participants will be randomised 1:1 to: 
(i) 
Receiving digital information about genetic testing for BRCA genes via the BRCA-
DIRECT study interface 
• 
Participants will be able to scroll forwards and backwards through the information visiting 
links etc.  
• 
The BRCA-DIRECT study system will record participant activity to confirm that they have 
visited the information before proceeding to the next stage of the study. 
• 
Participants will be able to call the telephone hotline with queries or if they would like further 
information.  
• 
The final screen will provide a link to access the digital ‘BRCA-test consent’ form.  
Participants will be able to call the telephone hotline if they would like to be taken through the 
clauses on the form. 
 
Or 
(ii) 
Receiving a current standard of care telephone consultation with a genetic counsellor  
• 
Participants will be instructed to book an appointment with a genetic counsellor via a digital 
calendar located on the BRCA-DIRECT interface. They will be asked to book an 
appointment within the next three working days, if possible.  
• 
At the end of the consultation, the genetic counsellor will inform the participant that a digital 
‘BRCA-test consent’ form is available to be completed and signed via the BRCA-DIRECT 
interface.  An explanation of the individual clauses within the form will be given. 
• 
The genetic counsellor will log the consultation as completed and enable the digital consent 
form. 
• 
A standard summary of the consultation will be sent via post to the participant. 
 
If a participant does not book a genetic counselling appointment or commence viewing the digital 
pre-test information, an SMS/email reminder will be sent 1, 2 and 3 days after notification of the 
randomised allocation was received.  
If a participant is unavailable during the booked appointment time they will be invited to book 
another appointment three additional times by the BRCA-DIRECT study system.  

 
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BRCA-DIRECT_IRAS278052CCR5234_Protocol_v0.61_17_03_202317_03_2023 
 
 
 
8.4 Consent to proceed to genetic testing 
• 
For both arms, if a participant decides to proceed with the genetic test they will sign a digital 
‘BRCA-test consent’ form, which will be formatted to BSGM (British Society of Genomic 
Medicine) standards.   All participants will receive a copy of their signed BRCA-test consent 
form via secure email/post. 
• 
The participant will have two days following test-consent to reverse the decision to proceed 
with the BRCA-test.  Beyond those two days, the test will proceed. 
• 
If a signed ‘BRCA-test consent’ form is not received from a participant, the BRCA-DIRECT 
study system will send three reminders 1, 2 and 3 days after the participant viewed the 
digital pre-test information or had a telephone consultation with a genetic counsellor.  
• 
If signed consent is not received after 8 weeks, the temporarily stored sample and 
Expression of Interest form will be destroyed and the participant will be withdrawn from the 
study. 
• 
If a participant subsequently decides to proceed to genetic testing during the active period of 
the study, and is willing to provide another saliva/blood sample, this will be discussed with 
the patient and a test conducted if feasible. 
 
8.5 Assessment of knowledge and anxiety following consent for genetic testing to 
proceed 
24 hours after signing consent for the genetic test to proceed, participants will complete digitally: 
• 
Knowledge questionnaire 
• 
STAI Y-1 anxiety questionnaire 
 
If these questionnaires are not completed, an SMS/email reminder to complete them will be sent to 
the participant 4, 5 and 6 days after signing consent for the genetic test to proceed. 
 
8.6 Delivery of BRCA test result 
The BRCA-DIRECT system will alert participants when their test result is ready. They will either 
receive their result digitally or via a telephone consultation with a genetic counsellor.   
It is anticipated that 94-95% of the study cohort will have a negative (normal) result and 5-6% will 
have a positive result indicating the presence of a pathogenic_variant or a VUS. 
• 
All participants with a positive result will receive their results via telephone consultation with 
a genetic counsellor (estimate 5-6%of total cohort) 
• 
The majority of participants with a negative result indicating normal genes will receive their 
result digitally (97.5%of total cohort) 
• 
An additional randomly selected 2.5% of participants with a  negative result will receive their 
results via telephone consultation with a genetic counsellor (2.5% of total cohort)  
 

 
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8.6.1 Digital receipt of result (participants with no pathogenic_variant detected) 
The participant will receive a message informing that their test results are available. The message 
will contain a link to digital notification of their negative (normal) result. A results letter and copy of 
the molecular genetics laboratory report will be sent to the participant via secure email/post.  
 
8.6.2 Receipt of result via telephone consultation with a genetic counsellor (all participants with 
pathogenic_variant plus 2.5% with a normal result) 
The participant will receive a message informing that their test results are available. The message 
will contain a link to the study digital calendar to book an appointment with a genetic counsellor.  
Following the appointment, a results letter and copy of the pathology report will be sent to the 
participant via secure email/post. 
If a participant does not book a genetic counselling appointment, an SMS/email reminder will be 
sent 3,4 and 5 days after notification that test results are available.  
 
8.7 Post-test result anxiety assessment 
Seven days after notification that their test results are available, participants will be asked to 
complete digitally: 
• 
STAI Y-1 anxiety questionnaire 
If this questionnaire is not completed, an SMS/email reminder to complete it will be sent to the 
participant 10, 11 and 12 days after notification that test results are available. 
 
8.8 Participant user feedback 
Seven days after receiving their test results, participants will be invited to complete a digital user 
feedback survey exploring user experience of the BRCA-DIRECT platform and acceptability of the 
method for providing information about genetic testing and results. 
During the internal pilot phase participants will also have the opportunity to register for an optional 
telephone interview with a BRCA-DIRECT researcher to explore their experience of participating in 
the study in more detail, to highlight any unanticipated logistical problems that require resolution.  
This will be capped at 50 participants. 
Following the pilot phase participants will have the opportunity to register interest for an optional 
video (or telephone if required) interview with a BRCA-DIRECT researcher. The interviews will 
expand on data from the pilot phase interviews and will explore the participant’s motivations for, and 
experiences of, BRCA-testing via the BRCA-DIRECT digital platform at an early stage in their breast 
cancer diagnosis and treatment. Information will inform future adaptations or considerations for 
implementation of the pathway more broadly.  
We will be conducting interviews in participants who are newly diagnosed, pre-surgical at time of 
enrolment to the study AND randomised to the digital pre-test information arm. We aim to complete 
interviews with all eligible participants who register their interest OR a minimum of 50 eligible 
participants, whichever is lower. No retrospective invitations to participate will be sent to participants 
who have already completed their involvement in BRCA-DIRECT.   

 
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BRCA-DIRECT_IRAS278052CCR5234_Protocol_v0.61_17_03_202317_03_2023 
 
 
8.9 Final anxiety assessment 
Twenty eight days after receiving their test results, participants will be asked to complete digitally: 
• 
STAI Y-1 anxiety questionnaire 
• 
Knowledge questionnaire 
If this questionnaire is not completed, an SMS/email reminder to complete it will be sent to the 
participant 31, 32 and 33 days after notification that test results are available. 
Participants will also be offered a second opportunity to provide user feedback if this was not done 
previously. 
 
 
 
 
 
 
 
 
8.9.1 Schedule of patient reported outcome assessments 
 
Time point 
STAI 
Trait 
(Y-2) 
STAI 
State 
(Y-1) 
Intolerance 
of 
Uncertainty 
Knowledge 
Score 
Participant 
Satisfaction 
Survey (+ optional 
telephone 
interview) 
T0 - Baseline 
✓ 
✓ 
✓ 
✓ 
 
T1 – 24 hours after giving 
consent for genetic test to 
proceed 
 
✓ 
 
✓ 
 
T2 – 7 days after 
notification that test results 
are available 
 
✓ 
 
 
✓ 
T3 – 28 days after 
notification that test results 
are available 
 
✓ 
 
✓ 
✓ (reminder if not 
done at T2) 

 
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BRCA-DIRECT_IRAS278052CCR5234_Protocol_v0.61_17_03_202317_03_2023 
 
 
All calls to the telephone hotline will be logged on BRCA-DIRECT system by the genetic counsellor 
who took the call (content and duration of call). 
 
8.10 Additional notification of test results to the participant’s health care team 
For each participant, a copy of the genetic test results will also be sent securely to:  
• 
The participant’s oncology consultant and breast care nurse 
• 
The local site molecular diagnostic laboratory 
• 
The local clinical genetics service 
• 
The participant’s GP   
Regular summaries of results and those in whom testing is underway will be sent securely to the 
breast MDT coordinators at a frequency according to local site preference. 
 
8.11 Clinical Genetics referral 
For all individuals in whom a BRCA1/BRCA2/ PALB2 pathogenic_variant is detected, clinical 
genetics referral will be advised on the report and patient letter.  The results will also be sent to 
clinical genetics so they can ensure all positive participants are referred. 
For all individuals with a significant family history of breast/ovarian cancer in whom no BRCA 
pathogenic_variant was detected, additional detailed evaluation of family history will be advised on 
the report and in an individualised standard patient letter.  
 
 
8.12 Participant withdrawal 
Participants may withdraw from the study at any time, if they so wish, without giving a reason.  
Information about withdrawal is included in the patient information leaflet, as well as on the BRCA-
DIRECT platform. Participants can withdraw by contacting their clinical team, the study hotline or 
emailing BRCADirect@icr.ac.uk. 
No further data will be collected about that individual. Study data collected up to that point will be 
retained for audit purposes.  Samples derivatives (DNA) and data generated within the NHS 
diagnostic environment will be retained.   
 
 

 
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9 PARTICIPANT PATHWAY FLOWCHART (STANDARD CONDITIONS) 
 

 
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9.1 PARTICIPANT PATHWAY FLOWCHART (COVID-19 CONTINGENCY) 
 

 
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10 DEFINITION OF END OF STUDY 
The end of the study is defined as the final data collection for the last participant.  This will be the 
final STAI Y-1 questionnaire completed 28 days after receipt of genetic test results and collection of 
user feedback. 
11 STUDY DISCONTINUATION 
The study may be stopped if the Sponsor or REC terminate it before the planned end date.  The 
Sponsor and the Funder have the right to discontinue the study at any time for failure to meet 
recruitment goals, safety or other administrative reasons. 
 
 
 

 
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BRCA-DIRECT_IRAS278052CCR5234_Protocol_v0.61_17_03_202317_03_2023 
 
 
12 STATISTICS 
We are seeking to evaluate whether digital delivery of pre-test information for BRCA-testing in 
breast cancer patients is non-inferior to current standard practice of 1:1 delivery from a healthcare 
professional regarding uptake of genetic test. Although the study is not primarily powered for these 
outcomes, data on measures relating to safety, effectiveness and clinician/patient acceptability will 
be collected. 
12.1 Sample size and power calculation for measurement of study endpoints 
Sample size 
To ensure >95% likelihood of identifying ≥5 individuals with a pathogenic_variant  at each of the two 
recruitment sites (prevalence in unselected breast cancer of BRCA pathogenic_variants is ~2-3%) 
and to test thoroughly the respective pathway logistics as shown below: 
• 
Digital pre-test information – genetic test – digital notification of results 
• 
Digital pre-test information  - genetic test – notification of results from genetic counsellor 
• 
Pre-test information from genetic counsellor – genetic test – digital notification of results 
• 
Pre-test information from genetic counsellor – genetic test – notification of results from 
genetic counsellor 
 
Recruiting 500 cases per site would give 97% probability to detect ≥5 individuals with a 
pathogenic_variant per site (assuming, conservatively, the frequency of BRCA pathogenicity is 2%).    
 
Power calculation for measurement of study endpoints   
The table below illustrates the non-inferiority margin in the patient reported outcome measures we 
would predict on one-sided analysis for non-inferiority of BRCA-DIRECT against standard pathway. 
  
Attrition Predicted 
available 
participants 
(following 
attrition) 
Assumptions 
(reference *) 
Power 
Sample size 
required for 80% 
power (digital: 
clinician = 1:1)  
Significance 
level (one-
sided) 
Non-
inferiority 
margin 
Notes 
Test uptake 
0% 
1000 
90% test 
uptake in 
both groups 
80-85% with 
1000 
participants 
934 
0.025 
5.5% 
Calculated using 
http://www.hwasoon.kim/NISSC/#!/binary  
STAI state T1 
0% 
1000 
Mean 43.2, 
SD 13.5 
 
(*58) 
90-95% with 
1000 
participants 
636 
0.025 
3 
Calculated using 
http://www.hwasoon.kim/NISSC/#!/continuous  
  
STAI state T2 
10% 
900 
Mean 43.2, 
SD 13.5 
 
(*58) 
90-95% with 
900 
participants 
636 
0.025 
3 
STAI state T3 
20% 
800 
Mean 43.2, 
SD 13.5 
 
(*58) 
85-90% with 
800 
participants 
636 
0.025 
3 
Patient 
satisfaction 
20% 
800 
Mean 3.75, 
SD 1 
 
(*59) 
90-95% with 
800 
participants 
  
56 
0.025 
0.75 
Knowledge 
score T1 
20% 
800 
Mean 5.71, 
SD 1.55 
 
(*36) 
>95% with 
800 
participants 
38 
0.025 
1.40 
 

 
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BRCA-DIRECT_IRAS278052CCR5234_Protocol_v0.61_17_03_202317_03_2023 
 
 
12.2 Randomisation 
 
12.2.1 Randomisation to pre-test information delivery 
• 
Participants will be randomised equally between standard care and digital delivery of pre-test 
information. 
• 
Randomisation will be stratified by site and will use random block sizes up to 12.     
 
12.2.2 Randomisation to receipt of genetic test results via telephone appointment with a genetic 
counsellor (participants with normal genes) 
• 
We estimate that 94-95% (940-950) participants will have a negative (normal) test result  
• 
Randomisation lists, stratified by site, will be produced to randomly pre-select 2.5% of this 
cohort to receive their test results via a telephone appointment with a genetic counsellor. 
 
Randomisation lists will be generated by the study statisticians using Sealed Envelope’s 
randomisation list generator: https://www.sealedenvelope.com/simple-randomiser/v1/lists.  
 
 
 
12.3 Internal pilot 
When 120 participants have been enrolled (60 participants in each arm), recruitment will pause and 
study data will be reviewed as follows: 
Recruitment:  
Actual recruitment will be compared with predicted recruitment.  Any potential barriers to recruitment 
will be identified through liaison with local sites and information collected on Study Summary Sheets 
completed by patients who were not interested in taking part in BRCA-DIRECT. 
Retention:  
Retention will be evaluated by reviewing:  
• 
Participant initiated withdrawal 
• 
Drop out as a result of non-completion of study tasks  
Where participants have provided a reason why they wished to withdraw, these will be examined for 
any consistent themes.  Drop out time point will be examined to search for any problems within the 
BRCA-DIRECT study pathway. 
Compliance: 
Timeliness of completion of study tasks throughout the participant pathway will be compared to 
expected timelines, to identify any non-random delays at study timepoints.  Data from the Participant 
Satisfaction Survey and telephone interviews (user feedback) will be examined to assist with 
identifying the cause of any such delays. 
Completion of the full pathway will be compared to expected compliance.  If compliance is less than 
expected, reasons why will be identified and resolved, where possible. 

 
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BRCA-DIRECT_IRAS278052CCR5234_Protocol_v0.61_17_03_202317_03_2023 
 
 
Preliminary review of participant knowledge following receipt of pre-test information and 
consent for genetic test: 
We aim to provide participants with a clinician independent means of receiving information about 
genetic testing for BRCA genes that is not inferior to current practice.  Review of Knowledge 
questionnaire data, user feedback and consent for genetic testing in 120 participants will highlight any 
major differences between the study arms that may require further investigation and resolution before 
recruitment recommences.   
Data completeness: 
Individual questionnaires will contain checks to prevent incomplete data.  Non- completion of 
questionnaires will be examined at each study timepoint to search for any problematic timepoints.  
Reasons for non-completion of questionnaires will be identified and resolved, where possible. 
Knowledge questionnaire and Participant Satisfaction Survey: 
Pooled data will be examined to search for any consistent themes that may require resolution before 
recruitment recommences. 
These study specific questionnaires are unvalidated.  We will examine the pooled data for quality, 
and any deviations or exceptions to confirm that they are collecting secondary endpoint data robustly. 
Referral to Independent Expert Group: 
Any problems identified will be discussed by the BRCA-DIRECT Management Committee (MC) and 
local sites, as required, to resolve any issues.  The progress of the study, including the internal pilot 
data, will be referred to the Independent Steering Advisory Group, along with any major problems 
identified that could affect the scientific integrity or quality of the study, including major barriers to 
recruitment. 
The Independent Steering Advisory Group may seek further expert advice regarding continuation of 
the study, if required. 
 
 
12.4 Statistical analysis 
During this study and its internal pilot on the first 60 women randomised to each arm, we shall 
monitor closely and evaluate time taken for data collection, processing and analysis.  
The progress of participants through the trial will be shown in a CONSORT60 flowchart. Summary 
statistics will be calculated by trial group at baseline and at each follow-up time point. Normally 
distributed variables will be described by their means and standard deviations, skewed continuous 
variables by their medians and interquartile ranges and categorical variables by frequencies and 
percentages. The primary analysis will be on the per protocol population but we will also perform an 
analysis of complete cases following intention to treat principles. Further, we may use multiple 
imputation methods for quantitative outcome measures such as STAI, Patient satisfaction and 
Knowledge scores. 

 
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Continuous outcomes will be analysed using linear mixed effects models with fixed effects for 
baseline measure of outcome, randomisation arm, centre and time point, with a random effect for 
participant. Binary outcomes will be analysed using mixed effects logistic regression models with 
the same set of fixed/random effects. Other baseline covariates considered a priori to be prognostic 
of outcome may be included in these models. We will report two-sided 95% confidence intervals for 
each outcome comparison between the arms, with the main focus on comparison of the lower 95% 
confidence limit and the margin for non-inferiority.  A full statistical analysis plan will be written and 
signed off prior to data analysis. Analyses will be conducted in Stata version 17.061 or higher.  
 
 
13 DEVELOPMENT OF THE BRCA-DIRECT DIGITAL SYSTEM 
The BRCA-DIRECT study databases and user-interface will be developed prior to recruitment with 
inbuilt user testing during development. 
User interfaces required are: 
• 
Participants 
• 
Genetic counsellors 
• 
Pathology lab 
• 
Study coordination team 
Functionality requirements are: 
• 
Login/access at any time 
• 
Withdrawal option available at any time 
• 
Data entry 
• 
Provision of digital pre-test information 
• 
Digital consent form completion and signature 
• 
Calendar management  
• 
Saliva/blood sample management 
• 
Automated reminders for uncompleted actions 
• 
Automated messages linked to actions 
• 
Production of test results letters   
• 
Production of reports 
• 
Participant pathway management to prevent deviations from protocol 
• 
Notification/alerts of participant enrolment, non-compliance and withdrawals 
• 
Communication between research team 
• 
View and download key data including digital consent forms 
 
Additional requirements:  
• 
1:1 randomisation to pre-test information delivery method 
• 
Selective randomisation of BRCA negative participants to receive results from a genetic 
counsellor 
 
During development, the system will be user tested to ensure correct functionality. Previous breast 
cancer patients will provide PPI review of the ‘look and feel’ of the system, and its ease of use. 

 
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Further evaluation will take place during the ‘pause’ after 120 participants have been enrolled in 
case any major unanticipated user problems are identified.  These will be resolved before 
recruitment re-commences. 

 
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PID-free data transfer
Interactions with the patients mobile device are linked to a unique PIN. 
No transfer of PID.  
There is transfer via web interface of sensitive data (STAI, family and personal medical history), but no PID is included.
PID-containing data transfer
PID is stored in a separate PID-containing database that does not communicate with the patient mobile device PID. 
BRCA-Direct Data Flow Diagram 
PID-containing
Secure
study database
(Location ICR)
PID-free
Secure operational
study database
(Location ICR)
Unique pin
Contains:
•
email address
•
mobile phone 
number
Contains:
•
Name
•
DOB
•
Address
•
Health Information 
from EPR
Manual data entry by GC
Secure password protected database front end.  
Only accessible to clinical staff and ICR study personnel
Manual scan-in entry by GC
Manual data entry by GC
Sent to patient by secure email/letter
NHS Diagnostic 
Lab database 
system  
(NIHR RMH 
CMP) 
BRCA test initiation
Name, DOB
BRCA genetic result
Name, DOB, genetic result
HOSPITAL EPR
PATIENT
EPR  data
Local access by clinical 
professional
Name, diagnosis, 
treatment date, Postal 
address
Paper study consent  
form
In person in clinic/by 
post
Name
Results letter
Name, DOB
Secure email/letter
Secure email/letter
PATIENT 
DEVICE
Reminders
Calendar bookings
Logistical responses
Information on 
Satisfaction
Consent for test
Information on  
Knowledge status
Family history 
information 
Information on anxiety 
state/Intolerance of 
uncertainty
Sent to patient by secure email/letter
Paper EOI form 
Completed in person in 
clinic
Name, DOB, postcode, 
phone, email
Test consent
Name, DOB
BRCA-DIRECT PLATFORM
Key
PID data flow
Sensitive data flow
Non-sensitive data flow 
Source
Data collection method
Data
 

 
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14 STANDARD NHS GENETIC TEST FOR BRCA1/BRCA2/PALB2 
Genetic Testing will be delivered by the NHS North Thames Genomic Laboratory Hub NIHR 
Biomedical Research Centre for Molecular Pathology (ICR/RMH CMP), located at the Royal 
Marsden Hospital, Surrey. The ICR/RMH CMP is a NeQAS-approved, ISO 15189 accredited 
medical diagnostic molecular genetics laboratory.  Sample handling, sequencing and reporting will 
be performed to NHS diagnostic standard.  
 
Saliva/blood samples will be supplied by participants at the Royal Marsden Hospitals (RMH) and 
Manchester Foundation Trust (MFT) NHS Hospitals, and will be identified via four patient identifiers 
marked on the tube (first name, surname, DOB, postcode).  Samples collected at MFT will be 
transferred to the ICR/RMH CMP and will be stored and managed in accordance with established 
standards for NHS diagnostic patient samples.  Transfer of saliva/blood samples will comply with 
biological sample transfer guidelines of the European Agreement concerning the International 
Carriage of Dangerous Goods by Road (ADR).  
 
The request for a BRCA test will be initiated by the BRCA-DIRECT study databases 48 hours after a 
participant has given digital consent for genetic testing to proceed.  The request will contain a 
unique study patient identifier (PIN), first name, surname, DOB, postcode and hospital number and 
will be transferred securely to the LIMS (Laboratory Information Management System) at ICR/RMH 
CMP.  The genomic result and interpretation will then be returned from the CMP LIMS to the secure 
BRCA-DIRECT study databases via a secure upload. 
 
DNA will be extracted from the saliva/blood samples and quantified via Qubit.  Targeted libraries will 
be created via Qiaseq library preparation with DDR capture Panel hybridisation and enrichment 
comprising all coding exons and intron-exon boundaries of BRCA1/BRCA2/PALB2, and sequencing 
will be performed to NHS diagnostic test standards (minimum median coverage 50x, minimum per-
base coverage 25x, with bidirectional reads).  Data processing and calling of sequence variants and 
exon-level aberrations of dosage will be undertaken using established analytical pipelines and 
variant interpretation/classification using ACMG standards. The test results will be as valid as any 
other generated in the NHS and will therefore be valid for NHS clinical use. 
 
Following the test, unused saliva/blood sample will be destroyed.  Extracted DNA will be stored 
securely at the ICR/RMH CMP for an indefinite period of time. 
 
If digital consent is not received from a participant, or a request to destroy a sample is made by the 
local site or participant, the sample will be destroyed in a manner appropriate for biological waste 
according to ICR guidelines and a record kept of this destruction. 
 
 
 
 

 
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15 DATA HANDLING AND RECORD KEEPING 
 
15.1 Data acquisition 
Data will be entered via the BRCA-DIRECT interface onto the BRCA-DIRECT data storage system. 
Each participant will be assigned a unique participant identifier (PIN) and all of their data will be stored 
under this PIN. 
Data will be entered by the following persons: 
• 
Participant – family history, questionnaires, consent for genetic testing to proceed, user 
feedback survey 
• 
Local site genetic counsellor – baseline data (including patient identifiable data), sample receipt, 
sample transfer, telephone hotline useage, record of consultations conducted 
• 
ICR/RMH CMP - sample receipt, test results, record of destruction (unprocessed samples) 
 
This data storage system will be comprised of two databases. The first database will handle PID. This 
will be partitioned and linked via PIN to the second, which will be PID-free, serving an operational 
purpose for the interface. These databases will meet all data security standards and be held within 
the ICR. 
  
15.2 Data quality 
Electronic participant questionnaires will be designed to constrain answers that can be supplied 
(range checks) and to prevent submission of incomplete forms.  Computerised and manual 
consistency checks will be performed on a regular basis via downloads/reports from the study 
databases.  
Newly entered family history questionnaires will be checked by the local site genetic counsellor and 
queries issued in case of inconsistencies.  
The ICR/RMH CMP utilises a secure Line Information Management System (LIMS) by which the 
PID and genetic data generated are stored and QC (quality control) checks are implemented as 
routine.  Sample handling, sequencing and reporting will be performed to NHS diagnostic standard. 
 
15.3 Data access 
Access to the central study databases will be limited according to user type.  The restrictions will be 
built into the system as it is developed.   
Access to the BRCA-DIRECT interface by the participant will require a login process. This will allow 
the participants journey through the study material to be mapped, and help authorise that all digital 
consenting and questionnaires are completed by the intended person. 
 
15.4 Source data 
Hardcopy source data will be filed at the local site.  These will include current medical records, 
consent forms signed at enrolment, hardcopies of consent forms that were signed digitally and 
records of genetic counselling appointments and test results.  The primary source of questionnaire 
and family history data will be electronic. 

 
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Source data regarding sample handling will be kept at the local site and the ICR/RMH CMP 
according to standard NHS procedures. 
 
15.5 Data security 
All data will be handled according to best practice principles and in compliance with the NHS Digital 
Data Security and Protection Toolkit. 
Sensitive personal or medical data will be held in a partitioned, secure, firewalled database. 
Recordings of telephone/video interviews will be stored at ICR on secure servers. 
Participants will receive study notifications and reminders for uncompleted actions either by SMS or 
by email, using their study ID (PIN) only. 
Data transferred or downloaded for quality checking, reports and analyses will be identified by PIN 
only. 
NHS North Thames Genomic Laboratory Hub NIHR Biomedical Research Centre for Molecular 
Pathology is an established NHS molecular diagnostic laboratory undertaking routine analyses of 
cancer susceptibility genes. Divisional-level infrastructure and expertise are in place, with policies 
documenting systems for access, security and daily backup of the Divisional databases.   
 
16 REGULATORY 
 
16.1 Research Ethics approval 
The Chief Investigator or their delegate will obtain approval from the Research Ethics 
Committee/Health Research Authority.  The study will be submitted for local approval at each 
participating site and confirmation of Capacity and Capability will be obtained before participation 
commences. 
The study will be conducted in accordance with the conditions of ethical approval. 
The Chief Investigator will provide reports to the research Ethics Committee. 
The protocol has been approved by the Committee for Clinical Research at the Royal Marsden NHS 
Foundation Trust and Institute for Cancer Research.  
 
16.2 Ethical considerations and informed consent 
This study will be carried out in accordance with the declaration of Helsinki (1996). 
In order to avoid the need for patients to make extra visits to clinic, potential participants who are 
interested in participating in BRCA-DIRECT may be required to provide an ‘upfront’ saliva/blood 
sample before they have taken at least 24 hours to read the patient information leaflet and sign a 
consent form.  To enable temporary storage of their saliva/blood sample, potential participants will 
be asked to complete and sign an Expression of Interest form, listing their email/mobile phone 

 
37 
 
BRCA-DIRECT_IRAS278052CCR5234_Protocol_v0.61_17_03_202317_03_2023 
 
contact details and giving the local site permission to store their sample while they decide whether 
to participate in the study.   
Potential participants will be provided with a patient information leaflet and a study consent form that 
can be completed at home and returned in a pre-paid envelope.  A telephone hot line to the local 
site genetic counsellor will be available during weekday office hours for patients to call if they 
require more information or have any queries. 
In order to issue automated reminders to potential participants, their email/mobile phone details 
supplied on the EOI will be temporarily held on the BRCA-DIRECT study databases.  
Upon receipt of a signed study consent form, the local site will enter a participant’s baseline data 
onto the study databases to activate their account but the BRCA-DIRECT platform will not contact 
the participant for a further 24 hours.  A link to a withdrawal screen will be available to participants 
immediately upon participation, so that they can withdraw at baseline. 
If a potential participant decides not to participate in the study, or a signed study consent form is not 
received, their saliva/blood sample and Expression of Interest form will be destroyed and their 
contact details removed from the study databases.  
Participants will not be able to sign digital BRCA-test consent for their saliva/blood sample to be 
tested until the BRCA-DIRECT system has recorded receipt of pre-test information, via data entry 
that a genetic counselling appointment has taken place, or electronic confirmation that the digital 
pre-test information has been visited.   
There will be a 48 hour pause following receipt of digital consent for genetic testing to proceed 
before the instruction to process a sample is generated. 
 
16.3 Confidentiality 
Each participant will be assigned a unique participant identifier (PIN) and data will be stored under 
this number.    
The study databases will hold all data securely. Patient identifiable data will be held in a partitioned 
firewalled database.   
Information about participants will be kept confidential at the local sites.  Access to data held at site 
will be restricted to members of the local study team as indicated on the delegation log.  Hard copy 
data, for example paper copies of patient study-consent forms with identifiers, will be stored in 
locked, fireproof cabinets within the Division of Genetics and Epidemiology ICR, with access limited 
to staff working on the study who are trained in Data Protection policies and legislation. 
Data downloaded for the creation of reports or analyses will be identified by PIN only.  Any report 
data held at Sussex CTU/Sussex Health Outcomes Research & Education in Cancer (SHORE-C) 
will be held in password protected documents, with limited access.   
 
 
 
 
 
 

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BRCA-DIRECT_IRAS278052CCR5234_Protocol_v0.61_17_03_202317_03_2023 
17 TRIAL MANAGEMENT 
17.1 Public and Patient Involvement 
Initial expert patient input on the study design was provided by the founder of the ‘BRCA journeys’ 
patient support group, who reviewed the application submitted to the funder.   All patient facing 
documents have been reviewed by members of our PPI group, comprising members of BRCA 
journeys and/ expert breast cancer patients.  
The screen text to be used in the BRCA-DIRECT platform has been reviewed by these volunteers 
prior to its development.  Further user testing by expert patients will be carried out during the 
development phase. 
17.2 Trial management and oversight 
The BRCA-DIRECT Management Committee (MC) (comprising PIs and study coordinator), will be 
responsible for the day-to-day management of the study and will meet regularly throughout 
recruitment.  The Group will review recruitment, compliance and data quality.  
An independent Steering Advisory Group, which will include expert patient representation, will be 
convened to provide independent trial oversight.  It is not anticipated that there will be a need for a 
Data Monitoring Committee, however should any major problems be identified, the Independent 
Steering Advisory group  may seek further expert advice regarding continuation of the study. 
17.3 Trial monitoring 
Site initiation visits will be conducted by the chief investigator and trial coordinator before 
recruitment commences. If recruitment does not proceed as anticipated, the chief investigator and 
trial coordinator will liaise with the site to identify and resolve any issues. 
Monitoring of recruitment and data quality will be conducted by the BRCA-DIRECT Management 
Committee (MC) through regular reviews of data downloads and reports.  The study has an inbuilt 
pause after 120 participants have been enrolled to enable any emerging problems to be identified. 
During software development and the pilot phase, safety of the automated system will be closely 
monitored regarding system generated messages and reminders and provision of documents to 
participants.   Following the pilot phase, safety will continue to be monitored as part of the regular 
data review. 
17.4 End of study transfer of data 
At the end of the study, the BRCA-DIRECT platform and study databases will be dismantled.  All 
electronic data will be securely transferred to the Institute of Cancer Research for secure storage 
and archiving. A copy of the following raw data will also be transferred securely to Sussex Clinical 
Trial Unit (CTU)/ Sussex Health Outcomes Research & Education in Cancer (SHORE-C) for 
analysis.   
•
Intolerance of Uncertainty questionnaire data
•
STAI Y-1/Y-2 state/trait anxiety questionnaires
•
User feedback and telephone interview data

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BRCA-DIRECT_IRAS278052CCR5234_Protocol_v0.61_17_03_202317_03_2023 
17.5 Archiving 
All study data and documentation will be archived at the Institute of Cancer research for 5 years 
beyond the end of the study.  Study data will be stored by PIN only.  Following this period, data will 
be destroyed according to Institute of Cancer Research policy. 
Following analysis and publication of main trial results, data analysis files created at Sussex Clinical 
Trial Unit (CTU)/ Sussex Health Outcomes Research & Education in Cancer (SHORE-C) will be 
transferred to ICR for archiving and all copies of raw data and analysis files at Sussex 
CTU/SHORE-C will be destroyed. 
The genomic data (and related patient identifiers) will be retained within the NHS North Thames 
Genomic Laboratory Hub NIHR Biomedical Research Centre for Molecular Pathology at the Royal 
Marsden/ICR indefinitely, will form part of the NHS clinical record and will be held under the 
standards, terms and security processes employed for outputs of standard NHS diagnostic testing 
(under review by RMH Caldicott Guardian).The testing is being performed to NHS diagnostic 
standards and results will be utilised within the clinical care of the patient.  Hence, the genetic result 
may be accessed and used for clinical care and also, potentially, may be referenced downstream 
(with procedural patient consents) when additional family members are requesting genetic testing, 
as is standard practice in clinical genetics.  
17.6 Publication policy 
The study results will be published in peer reviewed journals and presented at scientific 
conferences. It will not be possible to identify any individuals.  Links to publications will also be 
available via the ICR and SHORE-C websites.   
There is no plan to disseminate a summary of the results to participants because the study 
interventions (digital delivery of information about genetic testing for BRCA genes and digital 
delivery of test result for patients with negative (normal) results will have no impact on their 
subsequent clinical care.  The results will be publicised through the BRCA Journeys support group. 
17.7 Data sharing 
Any requests from external parties for data collected for BRCA-DIRECT will be considered by the 
BRCA-DIRECT Management Committee (MC).  The final decision will rest with the Custodian of the 
data.   
Genetic data resulting from the standard NHS genetic tests will form part of the NHS clinical record.  
Summary data will be combined with other similar NHS genetic test data that is released back to the 
UK diagnostic laboratory community and made public by the CanVar UK website 
(http://www.canvar.org/).  Individual level genetic data will be linked to NCRAS datasets in the 
section-251 compliant area of Public Health England/NHS Digital. 

40 
BRCA-DIRECT_IRAS278052CCR5234_Protocol_v0.61_17_03_202317_03_2023 
17.8 Indemnity 
The study sponsor, the Institute of Cancer Research, has no special compensation arrangements 
for this study. The NHS Litigation Authority covers standard clinical negligence of NHS employees, 
staff and health professionals under its Clinical Negligence Scheme for Trusts.   
Each participating site is responsible for ensuring insurance and indemnity arrangements are in 
place to cover the liability of the principal Investigator. 
17.9 Funder 
This study has received funding from Cancer Research UK via a Population Research Committee 
Award C61296/A29423.  

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BRCA-DIRECT_IRAS278052CCR5234_Protocol_v0.61_17_03_202317_03_2023 
18 Protocol Signature Page 
BRCA-DIRECT: development and piloting of a digital platform to deliver Clinically-
Integrated, Clinician-Independent, Rapid, Digital, Genetic Susceptibility Biomarker 
Testing 
BRCA-DIRECT-pilot 
I have read this protocol and agree to conduct the study as outlined herein, in accordance with Good 
Clinical Practices (GCPs) and the Declaration of Helsinki, and complying with the obligations and 
requirements of the clinical investigators.  
Site: Institute of Cancer Research and The Royal Marsden 
Chief Investigator’s Signature : 
 Date:  17/03/2023 
Chief Investigator’s Name and Affiliation : 
Prof Clare Turnbull MD PhD 
Research Team Leader in Genetics and Epidemiology 
Honorary Consultant in Clinical Genetics 
Institute of Cancer Research/Royal Marsden Hospital 
15 Cotswold Road,  
Sutton,  
Surrey,  
SM2 5NG. 
Tel: 020 8722 4485  
Fax: 020 8722 4359  
Email: clare.turnbull@icr.ac.uk 

 
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