Prospective Study to Correlate the Treatment Sensitivity of Patient-derived Organoids With Clinical Outcomes in Breast Cancer Patients With Brain and/or Extra-cranial Metastases
Conditions: Breast Neoplasms
Sponsor: King's College London

 
 
 
Official Title 
SOTO-BC: Prospective study to correlate the treatment Sensitivity of 
patient-derived Organoids with Treatment Outcomes in breast cancer 
patients with brain and/or extra-cranial metastases 
NCT Number 
NCT06468124 
Document Date  
23rd May 2025 

                                                                       
 
 
 
 
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1. Protocol details 
1.1 Protocol title 
SOTO-BC: Prospective study to correlate the treatment Sensitivity of 
patient-derived Organoids with Treatment Outcomes in breast 
cancer patients with brain and/or extra-cranial metastases 
 
1.2 Names (titles), roles and contact details of: 
Sponsor 
Name of Sponsoring Organisation: King’s College London 
Name of Sponsor Representative: Prof. Bashir Al-Hashimi, Vice President 
Address: Room 5.31, Room 8.11, 8th Floor Melbourne House 
44-46 Aldwych, London, WC2B 4LL 
Tel: 02078487306 
Email: vpri@kcl.ac.uk  
 
Name of Co-Sponsoring Organisation: Guy's & St Thomas' NHS Foundation Trust  
Name of Co-Sponsor Representative: Rachel Fay  
Address: Guy's & St Thomas' NHS Foundation Trust  
R&D Department  
16th Floor, Tower Wing  
Great Maze Pond,  
London SE1 9RT  
Tel: 02071889811  
Fax: 02071881295  
Email: gstt.randd@nhs.net 
 
Chief Investigator 
Name: Dr. Anthony Kong 
Address: Comprehensive Cancer Centre 
King’s College London, Guy’s Campus 
Room 2.36b New Hunt’s House, London SE1 1UL 
Telephone: 0207 848 8302 
Email: Anthony.kong@kcl.ac.uk;  anthony.kong2@nhs.net  
 
 
 
 
 
 
 
 
 
 

                                                                       
 
 
 
 
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Co-Investigator  
Prof. Keyoumars Ashkan 
Professor of Neurosurgery, KCL and 
Consultant Neurosurgeon 
Department of Neurosurgery, 
King’s College Hospital  
Denmark Hill, 
London SE5 9RS 
Tel: 0203 2993285 
Fax: 0203 2993280 
k.ashkan@nhs.net  
 
Translational research lead  
Dr. Rachel Evans 
KCL-AZ fellow 
Comprehensive cancer centre 
Guy’s Campus, KCL 
E-mail: rachel.1.evans@kcl.ac.uk 
 
Neuropathology lead 
Prof. Safa Al-Sarraj 
Consultant neuropathologist 
Neuropathology department 
King’s College Hospital 
E-mail: safa.al-sarraj@nhs.net  
 
Name and address of other co-investigators and collaborators 
Name: Ms. Caroline Murphy 
Address: King’s Clinical Trial Unit 
Research Management and Innovation Directorate, KCTU 
KCL 
Telephone: 020 7848 0532 
Email: caroline.murphy@kcl.ac.uk 
Name: Prof. Elinor Sawyer 
Address:  
Professor of Clinical Oncology, KCL and  
Consultant Clinical Oncologist 
Clinical oncology and radiotherapy 
Guy’s Cancer Centre 
Guy’s Hospital 
Great Maze Pond, 
London, SE1 9RT 
Email:  esawyer@nhs.net; Elinor.Sawyer@kcl.ac.uk; 
 
 
 

                                                                       
 
 
 
 
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Name: Dr Lucy Brazil 
Address: Clinical oncology and radiotherapy 
Guy’s Cancer Centre, Guy’s Hospital 
Great Maze Pond, 
London, SE1 9RT 
Email: Lucy.Brazil@gstt.nhs.uk  
 
Name: Dr. Omar Al-Salihi 
Address: Clinical oncology and radiotherapy 
Guy’s Cancer Centre, Guy’s Hospital 
Great Maze Pond, 
London, SE1 9RT 
Email: Omar.Al-Salihi@gstt.nhs.uk  
 
Name: Dr. Kazumi Chia 
Address: Clinical oncology and radiotherapy 
Guy’s Cancer Centre 
Guy’s Hospital 
Great Maze Pond, 
London, SE1 9RT 
Email: Kazumi.Chia@gstt.nhs.uk  
 
Name: Dr. Angela Swampillai 
Address: Clinical oncology and radiotherapy 
Guy’s Cancer Centre 
Guy’s Hospital 
Great Maze Pond, 
London, SE1 9RT 
Email: Angela.Swampillai@gstt.nhs.uk 
 
Name: Dr Fiona Castell 
Address: Clinical oncology and radiotherapy 
Guy’s Cancer Centre, Guy’s Hospital 
Great Maze Pond, 
London, SE1 9RT 
Email: Fiona.Castell@gstt.nhs.uk  
 
Name: Dr. Chin Chin Lim 
Address: Clinical oncology and radiotherapy 
Guy’s Cancer Centre, Guy’s Hospital 
Great Maze Pond, 
London, SE1 9RT 
Email: Chin.Lim@gstt.nhs.uk  
 
 
 
 
 

                                                                       
 
 
 
 
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Name: Dr. Amanda Fitzpatrick 
Address: Medical Oncology 
Guy’s Cancer Centre, Guy’s Hospital 
Great Maze Pond, 
London, SE1 9RT 
Email: Amanda.Fitzpatrick@gstt.nhs.uk 
 
Name: Dr. Vindhya Prasad 
Address: Neurosciences Research Office, RDU1 
Coldharbour Works, 245a Coldharbour Lane 
London, SW9 8RR 
Email: vindhya.prasad@nhs.net 
 
Name: Ms Natalie Long  
Address: Neurosciences Research Office, RDU1 
Coldharbour Works, 245a Coldharbour Lane 
London, SW9 8RR 
Email: natalielong@nhs.net 
 
Senior Trial manager 
Dr. Gabriella Wojewodka 
Address: OCRU 
King’s College London, Guy’s Hospital 
26th Floor, Tower Wing, 
London SE1 9RT 
E-mail:  Gabriella.wojewodka@kcl.ac.uk 
 
Laboratories 
Name: Dr. Abul Azad  
Postdoctoral research associate 
Address: Dr. Anthony Kong’s Lab 
Comprehensive Cancer Centre 
King’s College London, Guy’s Campus 
Room 2.36b New Hunt’s House, London SE1 1UL 
Telephone: 0207-848-8302 
Email: abul.azad.@kcl.ac.uk 
 
Trial Coordinator 
Name: Ms Taylor McKenzie 
Address: Comprehensive Cancer Centre 
King’s College London, Guy’s Campus 
Room 2.36b New Hunt’s House, London SE1 1UL 
Email: Taylor.mckenzie@gstt.nhs.uk 
 
 
 
 
 

                                                                       
 
 
 
 
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Trial Coordinator 
Name: Christiana Cattaneo 
Address: Comprehensive Cancer Centre 
King’s College London, Guy’s Campus 
Room 2.36b New Hunt’s House, London SE1 1UL 
christiana.cattaneo@gstt.nhs.uk 
 
1.3 Protocol details 
Version number 1.1 
Final 
Date: 23 May 2025 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

                                                                       
 
 
 
 
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2 Signature Page 
The Chief Investigator and the R&D (sponsor office) have discussed this protocol. The investigators 
agree to perform the investigations and to abide by this protocol  
The investigator agrees to conduct the trial in compliance with the approved protocol, EU GCP, the UK 
Data Protection Act (2018), the Trust Information Governance Policy (or other local equivalent), the 
Research Governance Framework (2005’ 2nd Edition; as amended), the Sponsor’s SOPs, and other 
regulatory requirements as amended. 
Chief investigator 
Dr. Anthony Kong 
 
 
 
Signature 
Date 
 
 
 
 
 
 
 
 
 
 

                                                                       
 
 
 
 
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3 Contents Page 
1. 
Protocol details ............................................................................................................................... 0 
1.1 
Protocol title ........................................................................................................................... 1 
1.2 
Names (titles), roles and contact details of: ........................................................................... 1 
1.3 
Protocol details ....................................................................................................................... 5 
2 
Signature Page ................................................................................................................................ 6 
3 
Contents Page ................................................................................................................................. 7 
4 
List of Abbreviations and Definitions .............................................................................................. 9 
5 
Summary/Synopsis ........................................................................................................................ 10 
6 
Introduction .................................................................................................................................. 11 
6.1 
Background ........................................................................................................................... 11 
6.2 
Rationale of the study ........................................................................................................... 13 
7 
Trial objectives and purpose ......................................................................................................... 13 
8 
Study design & Flowchart ............................................................................................................. 14 
8.1 
Study Design.......................................................................................................................... 14 
8.2 
Treatment visits .................................................................................................................... 15 
9 
Subject selection ........................................................................................................................... 15 
9.1 
Subject inclusion criteria ....................................................................................................... 16 
9.2 
Subject exclusion criteria ...................................................................................................... 16 
10 Study procedures .......................................................................................................................... 16 
10.1 
Subject recruitment .............................................................................................................. 16 
10.2 
Screening Procedures ........................................................................................................... 18 
10.3 
Schedule of assessments for each visit ................................................................................. 18 
10.4 
Follow up Procedures ........................................................................................................... 18 
10.5 
Radiology Assessments ......................................................................................................... 18 
10.6 
End of Study Definition ......................................................................................................... 19 

                                                                       
 
 
 
 
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11 Laboratories and sample storage.................................................................................................. 19 
11.1 
Data Recording/Reporting .................................................................................................... 19 
11.2 
Sample Receipt/Chain of Custody/Accountability ................................................................ 20 
11.3 
Sample Transfer to sites outside the Organisation ............................................................... 20 
12 Assessment of Safety .................................................................................................................... 20 
12.1 
Ethics Reporting .................................................................................................................... 20 
12.2 
Trial Steering Committee ...................................................................................................... 20 
12.3 
Ethics & Regulatory Approvals .............................................................................................. 21 
13 Compliance and withdrawal ......................................................................................................... 21 
13.1 
Subject compliance ............................................................................................................... 21 
13.2 
Withdrawal / dropout of subjects ......................................................................................... 21 
13.3 
Protocol Compliance ............................................................................................................. 21 
14 Data ............................................................................................................................................... 22 
14.1 
Data management ................................................................................................................ 22 
15 Statistical considerations .............................................................................................................. 22 
16 Ethical considerations ................................................................................................................... 23 
16.1 
Research Ethics Committee (REC) review & reports ............................................................ 23 
16.2 
Peer review ........................................................................................................................... 23 
16.3 
Regulatory Compliance ......................................................................................................... 23 
17 Financing and Insurance ............................................................................................................... 23 
18 Reporting and dissemination ........................................................................................................ 24 
19 References .................................................................................................................................... 25 
 

                                                                       
 
 
 
 
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4 List of Abbreviations and Definitions 
APR 
Annual Progress Report 
BM 
Brain metastasis 
cfDNA 
Circulating free DNA (deoxynucleic acid) 
CI 
Chief Investigator 
CSF 
Cerebrospinal fluid 
CRF 
Case Report Form 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
GSTT 
Guy’s and St-Thomas’ Trust 
HTA 
Human Tissue Act 
IC50 
Half maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
KCL 
 
King’s College London 
NHS R&D 
National Health Service Research & Development   
Participant 
An individual who takes part in a clinical trial 
PBMC 
Peripheral blood mononuclear cell 
PDO(s) 
Patient derived organoid(s) 
PI 
Principal Investigator 
PPI 
Patient and public involvement 
REC 
Research Ethics Committee 
SOP 
Standard Operating Procedure 
SRS 
Stereotactic radiosurgery 
TNBC 
Triple negative breast cancer  
WBRT  
Whole brain radiotherapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

                                                                       
 
 
 
 
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5 Summary/Synopsis 
 
Trial Title 
Prospective study to correlate the treatment sensitivity of 
patient-derived organoids with clinical outcomes in breast 
cancer patients with brain and/or extra-cranial metastases 
Internal ref. no. (or short title) 
SOTO-BC: Sensitivity of Organoids to predict Treatment 
Outcome in Breast Cancer 
Protocol Version number and Date 
version 1.1, 23 May 2025 
Study Phase if not mentioned in title 
N/A. It is an observation study 
IRAS Number 
315973 
REC Reference 
24/NE/0022 
Study Duration 
2.5 years (1.5 year of recruitment and 12 months’ follow-up) 
Sponsor name 
King’s College London and Guy's & St Thomas' NHS 
Foundation Trust  
Chief Investigator 
Dr. Anthony Kong, King’s College London 
Co- investigator 
Prof. Keyoumars Ashkan, King’s College Hospital 
Funder 
Guy’s Cancer Charity  
Medical condition or disease under 
investigation 
Breast cancer with brain and/or extra-cranial metastases 
 
Objectives 
Endpoints 
Primary 
 
The percentage of successful 
generated organoids from 
tissues in breast cancer 
patients with brain or extra-
cranial metastases 
Rates of successful 
organoid cultures 
Secondary 
 
1) To assess the sensitivity of 
radiotherapy in PDOs  
2) To assess the sensitivity of 
the same systemic treatments 
that the patients previously 
had and will have in PDOs 
 
 
1) To determine the IC50 
doses and dose response 
curves of radiotherapy 
2) To determine the IC50 
doses and dose response 
curves of the previous 
systemic treatments that 
patients had and will have 
in PDOs  
 

                                                                       
 
 
 
 
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3) To correlate the treatment 
sensitivities of PDOs above 
with the treatment outcome of 
patients  
 
4) To correlate the treatment 
sensitivities of PDOs with the 
objective response rates of 
patients 
undergoing 
same 
systemic treatment 
3) To correlate the IC50 
doses and dose response 
curves above with the 
recurrence 
rates 
and 
progression-free survival of 
patients  
4) 
To 
correlate 
IC50 
doses/dose 
response 
curves above with the 
objective response rates of 
patients undergoing same 
systemic treatment 
Number of Subjects/Patients 
20 patients 
Study Type 
Observational 
Main Inclusion Criteria 
- Breast cancer patients with brain metastases who are 
suitable for surgical resection 
- Breast cancer patients with extra-cranial metastases 
undergoing surgical resection or biopsy 
- Age > 18 years old 
Statistical Methodology and Analysis 
This is a pilot observation study, and the results will be used 
to estimate the sample size for future prospective 
observation study 
Human Tissue Samples (if 
applicable) 
Tumour and normal tissues, blood, saliva, oral swabs, urine 
and stool 
Data collected/storage (if 
applicable) 
Data on demographics, medical history, diagnosis, treatment 
plans and clinical outcomes 
6 Introduction 
6.1 Background 
Breast cancer is the most common cancer in the UK and nearly all breast-cancer deaths are related to 
metastasis rather than primary cancer. HER2 positive breast cancer and triple negative breast cancer 
(TNBC) can present with early recurrence and distant metastasis, whereas the luminal type of breast 
cancer can have a long dormancy before presenting with metastasis many years later. In addition, 
they can present with distinct metastasis behaviour (1). HER2-positive breast cancer can metastasize 

                                                                       
 
 
 
 
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to many organs including brain, lung, liver, bones and lymph nodes. In TNBC, brain metastasis could 
be the first site of distant spread in 26% patients or after dissemination to the lungs. And in luminal 
subtype, brain metastasis is not common and distant spread to the bones and lungs is more frequent 
(2-3). In a study of 222 breast cancer patients with brain metastases, the proportions of patients with 
HER2-positive, triple negative and luminal breast cancer were 53%, 28% and 19%, respectively (2), 
indicating that triple-negative and HER2-positive breast cancer have a special predisposition to brain 
metastases. The median survival for the entire group was 7.5 months and in HER2-positive, triple-
negative and luminal subtypes, they were 9, 3.7 and 15 months, respectively. The prognosis of patients 
with untreated brain metastasis is extremely poor and whole-brain radiotherapy (WBRT) may increase 
median survival of these patients from 3-4 months to 6 months.  
 
In patients with oligometastases in the brain and good performance status, surgical excision or 
stereotactic radiosurgery (SRS) with or without whole brain radiotherapy (WBRT) is the standard of 
care and the median survival may be up to 1–2 years for some of these patients (2-3). SRS delivers 
high dose radiation within a tumour while avoiding radiation to the surrounding healthy tissue, which 
includes a variety of different methods and systems such as Gamma knife, stereotactic Linear 
Accelerator (Linac) and the Cyberknife. The 1-year tumour control rates could range between 69% and 
81% although lower local control rate of 60% is achieved in tumors larger than 2 cm (4). The objective 
response rate after SRS has been shown to be 38% in one study (5). However, the assessment of 
objective response after SRS is difficult and can be variable depending on the given SRS doses, tumour 
sizes, time points of radiological assessment and tumour types etc. Therefore, local tumour control 
rates (defined as absence of regrowth of a treated lesion) instead of objective responses are 
considered to be better measurement of the treatment outcome for SRS.  
 
Surgical excision may be preferred for histological confirmation, single or large metastases, 
symptomatic mass, whereas SRS may be done for patients with smaller lesions without mass effect 
and if the tumours are located in surgically inaccessible regions such as brainstem (6). In an EORTC 
phase III trial, patients with one to three brain metastases of solid tumours were treated with either 
surgery or SRS and were randomly assigned to adjuvant WBRT (30 Gy in 10 fractions) or observation 
(OBS) (7). Although the addition of whole brain radiotherapy after surgical excision or SRS reduced 
intracranial relapses, it did not improve overall survival and may negatively impact on neurocognitive 
outcomes and quality of life (6-7). Thus, WBRT has been largely omitted after SRS or surgical resection 
at many centres. However, there is significantly higher local and distant brain relapse rate for patients 
who do not have WBRT (7). Without WBRT, the relapse rates for patients who had surgery & SRS 
without WBRT were 59% & 31% at initial sites, and 42% & 48% at new sites respectively, causing death 
due to intracranial progression in 44% of patients (7).  
 
In a randomised phase 3 trial, patients who had a complete resection of one to three brain metastases 
were randomly assigned with to either SRS of the resection cavity (within 30 days of surgery) or 
observation. The 12-month freedom from local recurrence was 72% in the SRS group compared with 
43% in the observation group and no adverse events or treatment-related deaths in either group (8). 
In another randomised phase 3 trial, patients with one resected brain metastasis were randomly 

                                                                       
 
 
 
 
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assigned to either postoperative SRS or WBRT with the co-primary endpoints to be cognitive-
deterioration-free survival and overall survival (9). It was shown that cognitive deterioration-free 
survival was slightly longer in patients assigned to SRS compared to those assigned to WBRT, 3.7 
months versus 3 months respectively and the cognitive deterioration at 6 months was more frequent 
in patients who received WBRT compared to those received SRS (85% versus 52% respectively). There 
was no difference in the median overall survival, 12.2 months for SRS versus 11.6 months for WBRT 
and the surgical bed median relapse-free survival (RFS) was similar for both groups, 7.5 months in SRS 
group versus 7.7 months for WBRT but SRS had inferior 6-month local control (p=0·00068) and shorter 
time to intracranial tumour progression (HR 2·45, 95% CI 1·62–3·72; p<0·0001) compared with WBRT 
(9). Although SRS to surgical cavity has been proposed by these two trials as alternative to WBRT to 
surgical cavity, there is still a concern of the worse intracranial control rate of SRS compared to WBRT 
(10). 
6.2 Rationale of the study 
Previously large-scale drug screens of transformed cell line panels have failed to translate most 
preclinical compounds in clinical trials in view of the limitations of these preclinical models. Patient-
derived organoids (PDOs) have been shown to recapitulate patients’ tumour characteristics more 
closely and could help to identify effective therapeutic regimens (11-15). We have been generating 
PDOs from primary breast cancer tissues based on the published protocol (16). We would now like to 
generate organoids from brain and/or extra-cranial metastasis samples from breast cancer patients 
who may subsequently undergo SRS to surgical cavity for brain metastases and/or systemic 
treatments. We will do a pilot observation study to assess the potential of these PDOs in predicting 
treatment outcome in patients. 
 
7 Trial objectives and purpose 
Overall aim and hypothesis  
This study aims to address the hypothesis that it would be possible to generate patient-derived 
organoids (PDOs) from resected brain or resected/biopsied extra-cranial metastases and to collect 
preliminary data on the ability of PDOs to predict patients’ treatment response and their 
radiosensitivity and chemosensitivity can be correlated with their survival outcome. 
Patient cohorts 
1) Breast cancer patients with brain metastases undergoing surgical resection with or without further 
radiotherapy (SRS or whole brain radiotherapy)  
2) Breast cancer patients with extra-cranial metastases undergoing surgical resection or biopsy 
Primary objective 
To assess the percentage of successful generated organoids from resected brain or resected/biopsied 
extra-cranial metastases of breast cancer patients 
Secondary objectives 
1) To assess the sensitivity of radiotherapy in PDOs  

                                                                       
 
 
 
 
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2) To assess the sensitivity of the same systemic treatments that the patients previously had and will 
have in PDOs 
3) To correlate the treatment sensitivities of PDOs above with the treatment outcome of patients  
4) To correlate IC50 doses/dose response curves above with the objective response rates of patients 
undergoing same systemic treatment 
Exploratory objectives  
1) To assess and correlate the histopathological (including immune markers), genomic and 
transcriptomic features of patients’ samples with PDOs 
2) To assess peripheral immune responses in patients before and after radiation +/- systemic 
treatments and to correlate the results with those in PDOs 
3) To assess the sensitivities of PDOs to various targeted therapies based on their genomic profiles 
and mutations 
4) To assess the novel treatment combination of radiotherapy with immunotherapy and other agents 
in patient-derived organoids co-cultured with immune cells 
5) Collection of archival tissues, blood samples, saliva, oral swab, cerebrospinal fluid (CSF), urine or 
stool samples for other translational research  
8 Study design & Flowchart 
8.1 Study Design 
This is a prospective observation study to establish the pathways required to successfully generate 
PDOs from resected brain or resected/biopsied extra-cranial metastases and to test their treatment 
sensitivity in correlation with patients’ treatment outcomes. In addition, the time required to generate 
organoids and to assess treatment response in order to correlate with patients’ outcome will be 
evaluated. 
Endpoints 
This main endpoint is the success rate in generating PDOs from brain or extra-cranial metastases of 
breast cancer patients. 
Primary endpoint 
The percentage of individuals whose successful organoid samples from metastases are obtained 
 
Secondary endpoints 
1) To determine the IC50 doses and dose response curves of radiotherapy  
2) To determine the IC50 doses and dose response curves of the previous and same systemic 
treatments that patients had or will have in PDOs  

                                                                       
 
 
 
 
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3) To correlate the IC50 doses and dose response curves above with the recurrence rates and 
progression-free survival of patients  
4) To correlate IC50 doses/dose response curves above with the objective response rates of patients 
undergoing same systemic treatment 
Exploratory endpoints 
1) Tumour immune markers (including CD4 and CD8 T cells, FoxP3, PDL1), exome sequencing and RNA 
sequencing of PDOs and patients’ samples 
2) Peripheral immune responses (including CD8-T cell with exhaustion and cytolytic activity marker, 
CD4/FoxP3 Tregs) in patients before and after radiation +/- systemic treatments and correlation of the 
results with those in PDOs 
3) The IC50 doses of various targeted therapies based on actionable genetic mutations + cell viability 
data of PDOs  
4) The promising treatment combination of radiotherapy with immunotherapy and other agents in 
PDOs co-cultured with immune cells 
5) To conduct further translational research using the patients’ samples including assessing plasma 
and CSF ctDNA before and after treatments in patients  
8.2 Treatment visits 
This is an observation study and the patients will continue their clinical visits and follow-up as per 
normal standard of care.  
 
9 Subject selection 
This study will be open at King’s Health Partners, including King’s College London, Guy’s and St. 
Thomas’ NHS Foundation trust and King’s College Hospital NHS Foundation trust. Potential eligible 
patients will be identified and enrolled at King’s College Hospital or at Guy’s Hospital. After their 
surgery at King’s College Hospital or Guy’s and St. Thomas’ NHS Foundation trust, participants will 
receive their radiotherapy or radiosurgery at Guy’s Hospital or systemic treatments at their hospitals, 
as per standard protocol. 
The study may be opened to other centres in the future if there is an extension of the study and/or if 
another centre would be able to follow the protocol to generate organoids as specified. If this is the 
case, an appropriate study protocol amendment will be submitted and ethical approval will be 
obtained before another site is opened. 
We will include breast cancer patients with resectable brain or extra-cranial metastases and 
undergoing postoperative radiotherapy (SRS and/or WBRT) or palliative radiotherapy to extracranial 
metastases if necessary +/- other systemic treatments after resection. Patients who will undergo a 

                                                                       
 
 
 
 
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biopsy of the extra-cranial metastases may be recruited and asked to consent for an additional 
research biopsy at the same time as standard of care biopsy. 
9.1 Subject inclusion criteria 
-  Breast cancer patients with brain metastases who are suitable for surgical resection or Breast 
cancer patients with extra-cranial metastases undergoing surgical resection or biopsy 
- Age  > 18 years old  
9.2 Subject exclusion criteria  
- Patients unable to give informed consent e.g., mental disability or vulnerable adults 
10 Study procedures 
10.1 Subject recruitment 
Method of recruitment 
Potential eligible patients will be identified from multi-disciplinary meetings and breast clinics at King’s 
College Hospital and Guy’s Hospital.  These patients will be checked to see whether they will meet 
inclusion criteria.  
Breast cancer patients with resectable brain or extra-cranial metastases or who will undergo a biopsy 
of the extra-cranial metastases will be asked to consent for this study and for their resected/biopsied 
samples to be used to generate PDOs. We aim to recruit 20 patients in the pilot phase of the study. 
When the PDOs contain sufficient cells, these cells will be treated with increasing doses of 
radiotherapy and/or relevant systemic treatments in order to determine the IC50 and to obtain dose-
response curves of these PDOs to the treatments. In particular, we will treat the PDOs with the same 
treatments that the patients had or will receive in order to correlate the responses to radiotherapy 
and/or systemic treatments including immunotherapy (co-cultured with immune cells). 
The response of these PDOs will be compared to the treatment outcome and survivals in these 
patients. 
Payment  
The participants will not be paid for this study since patients will not be required to have additional 
visits other than their standard of care visits. 
 
 
Consent  
This pilot study will initially be opened at King’s College Hospital NHS Foundation Trust and Guy’s and 
St Thomas’ NHS foundation trust although we will open the study to other centres for participation if 
they would be able to follow the protocol to generate organoids from metastases as specified. The 
Principal Investigator (PI) retains overall responsibility for the conduct of research at participating 
site(s) with delegation of duties to appropriate clinical sub-investigators (e.g., clinical fellows or other 

                                                                       
 
 
 
 
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consultants or specialist registrars), which includes the taking of informed consent of participants at 
their site with the processes below:  
• 
Checking the inclusion and the exclusion criteria  
• 
A discussion with the potential participants about the research including the nature and 
objectives of this study and possible risks associated with their participation 
• 
Patient information leaflet and consent form will be given to patients, usually at least 24 
hours before consent although it can be on the same day for this observation study if 
required 
• 
Potential participants will be given the opportunity to ask questions 
• 
Assessment of the mental capacity for the participants to consent will be performed by 
either the PI or the appropriate clinical sub-investigators  
The PI will ensure that any person delegated the responsibility to participate in the informed consent 
process is duly authorised, trained and competent to participate according to the ethically approved 
protocol, principles of Good Clinical Practice (GCP) and Declaration of Helsinki. 
Translational research: Participants will be asked to give generic consent for their samples, derived 
organoids and data for use in future research.  This includes the transfer and use of samples/data to 
KCL and its partners including the commercial sector and overseas organisations (including genetic 
research and whole genome sequencing).  
Based on this consent, archival tissues may be requested, and translational research blood, saliva, oral 
swab, CSF, urine and stool samples will be stored at Guy’s and St Thomas’ biobank beyond the ethics 
approval date of the project and stored under the HTA licence (HTA licence is 12121; the Designated 
Individual is Cheryl Gillett). All material will be handled in accordance with the Human Tissue Act 2004 
and other relevant legislation relating to the use of cell lines. Specific agreements will be put in place 
as required by the Sponsor including material transfer agreements where necessary.  
Blood and other biological sample collection time points: We may ask patients to provide blood 
samples before surgery and/or radiotherapy (baseline), during treatment (week 1), at 4 to 6 weeks, at 
3 months and at 12 months after the completion of their treatments as well as at disease 
recurrence/progression if possible. We may also ask them to donate other samples such as saliva, oral 
swab, CSF, urine or faeces for future research at the same time points as above. If possible, the 
collection samples will normally be done during patients’ routine clinical appointments. Translational 
research may be conducted for up to 5 years after the recruitment period. 
Participants may be asked to provide other tumour samples and surrounding tissue if having further 
surgery and/or biopsies for tumours (primary or metastasis) located in other areas besides the brain 
and if having further resection of new/other brain metastasis. These samples will be used to correlate 
findings from the PDOs generated from resected metastasis of the brain or resected/biopsied extra-
cranial metastasis with the original sample(s) taken when first consented. If the participants have 
other available archival tissue samples in the pathological laboratories or in the biobank, we may 

                                                                       
 
 
 
 
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request for these samples to be released (sections or blocks) for the SOTO-BC study via the Guy’s and 
St Thomas’ biobank. Some participants may have primary breast tumour tissues and/or metastasis 
samples stored, and this will further link outcomes between brain metastases and the primary breast 
tumour as well as any other available extracranial metastasis.  
10.2 Screening Procedures  
Potential eligible patients will be identified from multi-disciplinary meetings. These patients will be 
checked to see whether they will meet inclusion criteria. No extra screening investigations are needed 
for this study. Patients will undergo routine standard of care investigations and treatments apart from 
consenting to this study and for their samples to be used for translational research during their routine 
standard of care procedures. 
10.3 Schedule of assessments for each visit  
Patients will undergo assessments as per normal standard of care and the schedule will not be 
changed due to this study. Tumour (and occasionally normal tissue if available) will be obtained at 
the time of surgical resection of brain metastases or during biopsy/resection of extra-cranial 
metastases. We may ask patients to provide blood samples before surgery or biopsy. 
10.4 Follow up Procedures 
The follow-up procedures will be as per normal standard of care and the schedule will not be 
changed due to this study. Participants will undergo radiotherapy at the cancer centre at Guy’s 
Hospital (Guy’s and St-Thomas’ Trust) and thus follow-up sample collection will occur at this site.  
Blood and other biological sample collection time points: We may ask patients to provide blood 
samples before radiotherapy (week 0), during treatment (week 1), at 4 to 6 weeks after starting 
treatment, at 3 months which is usually the end of treatment, and at 12 months after the completion 
of their treatment, as well as at disease recurrence/progression, if possible. We may also ask patients 
to donate other samples such as saliva, oral swab, CSF, urine or faeces for future research at the same 
time points above. If possible, the collection samples will normally be done during patients’ routine 
clinical appointments and only when patients have consented to donating these additional samples. 
CSF will only be obtained during standard of care procedures if the patient has consented to this and 
only if it is possible to obtain (5 mins if obtained during surgery and 30 mins if obtained through lumbar 
puncture). 
Sample collection will be conducted throughout the recruitment period and the follow-up period. 
After this stage, we will continue to monitor treatment outcomes through the patients’ medical 
records or through their GP for up to 5 years from their start in the study.  
10.5 Radiology Assessments  
The radiology assessments will be as per normal standard of care and the schedule will not be 
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10.6 End of Study Definition  
The patient recruitment for the pilot study will last 18 months and the follow-up period for additional 
sample collection will last another 12 months. We will assess whether the endpoints and outcomes 
are met but the patients will be followed up for their long-term treatment outcome and survival for 
up to 5 years. The end of the study definition for the pilot study is the end of the 30 months’ period 
after the commencement of the study regardless of the number of patients recruited. We will submit 
the protocol for a substantial amendment approximately 1 year after the recruitment of the first 
participant so that the SOTO-BC study will continue as a prospective observation study for up to 
additional 3 years including further recruitment or as a new main study if funding is obtained. If no 
funding is obtained by the end of 18 months, we will end the patient recruitment and continue to 
collect samples from recruited patients for 12 months.  
In addition to obtaining funding, the criteria for progression beyond pilot study are set as below: 
1) More than 50% of the approached participants will consent to taking part in SOTO-BC study  
2) At least 30% of the tissue samples will be successfully used to generate organoids 
3) Further funding is obtained to continue beyond the 18-month recruitment period 
 
11 Laboratories and sample storage 
The fresh tissue samples will be processed for organoids within 24 to 48 hours of surgery/biopsy. Once 
the experiments on the organoids have been completed, they will be frozen for future analysis and stored 
in Dr. Kong’s laboratory at KCL. Blood samples will be processed according to standard laboratory SOP in 
Dr. Kong’s Laboratory (KCL, London, UK) for PMBCs and plasma collection. Plasma and/or CSF samples 
will also be processed to assess ctDNA in the future. The additional biological samples including saliva, 
oral swab, urine or stool samples if obtained will be stored at Guy’s Hospital biobank. Once collected, 
these samples will be stored directly with the biobank. All unused samples will be stored for 5 years from 
the end of the SOTO study under the biobank’s HTA license (reference 12121, Designated Individual 
Cheryl Gillett). At the end of this storage period, the unused biological samples stored at Guy’s biobank 
will be handled and/or destroyed according to the biobank’s Standard Operating Procedure (SOP) if the 
agreement to store the samples has expired and/or not extended.  
Further details on the sample collection, processing, storage and analysis will be found in the laboratory 
manual. 
 
11.1 Data Recording/Reporting  
Data generated from laboratory testing of organoids will be recorded and stored on computers at 
King’s College London. Laboratory data will be linked to the participant through a participant trial 
number. No identifying information will be used on the samples or when used in the laboratory. The 
data obtained from the laboratory tests will not be used for clinical purposes and will not be reported 
to the clinical team. Separate diagnostic testing will be done by the clinical teams as per normal 
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11.2 Sample Receipt/Chain of Custody/Accountability  
A member of the research team will collect the samples and process them in Dr. Kong’s Laboratory at 
KCL. Tumour tissues will be processed for organoid cultures and blood samples processed for PBMC 
and plasma storage. CSF will also be processed for storage at Dr. Kong’s laboratory. Processed blood 
samples (PBMC isolates and plasma), and processed CSF, along with all other samples (saliva, oral 
swab, urine and stool) will be given to the biobank at Guy’s Hospital for storage. The receipt, 
processing and transfer of samples will be documented through Sample Processing Forms. Upon 
receipt of the tumour samples, the laboratory will ensure that the physical integrity of these samples 
have not been compromised in transit. If it has, it is important that the study teams, as well as the 
sponsor, are informed of this. Tumour samples will be processed for organoid cultures and will be kept 
in Dr. Kong’s laboratory for the duration of the study and frozen for long-term storage. Upon receipt 
of samples laboratory staff will ensure that all samples are accounted for as per the labeling. All 
samples received will be logged in a study sample log. 
Samples will be transferred on foot at the Guy’s campus between Guy’s Hospital and New Hunt’s 
House. Samples will be transferred using the KHP staff bus when collecting samples from KCH.  
11.3 Sample Transfer to sites outside the Organisation 
Individual informed consent will be obtained from the patients to specify whether they would agree 
for their samples to be transferred to collaborating third parties including overseas and commercial 
laboratories on behalf of KCL.  This may include but not be limited to validation of research results. 
The patient samples and derived organoids (with linked data) may be shared with collaborating 
laboratories, nationally or internationally, for the purposes of facilitating the research aims.  Specific 
agreements will be put in place as required by the Sponsor including material transfer agreements 
where necessary. Any commercialisation of the results of this study will be specified in contractual 
arrangements between parties where necessary and participants will be informed that they would not 
benefit financially. 
12  Assessment of Safety 
This is an observation study and the patients participated in this study will undergo routine treatments 
and the safety of the treatments will be assessed as per standard of care. No serious adverse events 
are expected to occur following the tissue sampling involved in this study, as they will be done during 
standard care procedures. Participants will be followed-up by their treating clinicians as per normal 
practice.   
12.1  Ethics Reporting 
Annual progress reports will be submitted to the Research Ethics Committee as per normal 
regulatory processes.  
12.2 Trial Steering Committee 
No formal trial steering committee will be set up for this feasibility study.  

                                                                       
 
 
 
 
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12.3 Ethics & Regulatory Approvals 
Study protocol and other documentation will be submitted to the North East - Tyne & Wear South 
Research Ethics Committee (REF 24/NE/0022) for ethical approval.   
13 Compliance and withdrawal 
13.1 Subject compliance 
We will monitor the percentage of approached participants who consent to taking part in the study 
during the first year of recruitment. 
13.2 Withdrawal / dropout of subjects 
The right of a participant to refuse participation without giving reasons will be respected. The 
participant will remain free to withdraw at any time from the trial without giving reasons and without 
prejudicing his/her further treatment and will be provided with a contact point where he/she may 
obtain further information about the trial. Patients will be made aware of the terms and conditions 
around withdrawal. If a patient withdraws from the study, the research team can retain any tissue 
samples, DNA/RNA samples and organoids/cell lines that have been created up until the time of the 
patient’s withdrawal if the patient agrees. Any unused samples taken for research purpose can be 
destroyed if patient requests to do so. Any demographic and medical information already provided or 
results from tests already performed on their samples will continue to be used in the study, however 
no further data or sample collection will be performed. If a participant consents to the study but 
subsequently loses the capacity to consent during the study, we will withdraw the participant from 
sample collection. However, we will retain and make further use of any identifiable data and collected 
tissues until the point of withdrawal. We will stop taking any further blood or other samples from the 
participant although we will continue collecting information about the participant’s health from the 
hospital record and/or GP for up to 5 years. 
We will monitor the percentage of participants who withdraw consent from the study after taking 
part. If no longer wishing to take part, participants will consent to have their collected samples and 
data included in the research after they have withdrawn and to consent to follow their clinical 
outcomes through their medical notes. The patient recruitment for the pilot study will last 18 months 
with additional follow-up for another 12 months. If there is withdrawal of consent from any patients 
before the organoids are successfully generated from the samples, we will recruit more participants 
to back fill those who may have withdrawn or dropped out, provided that this is within the recruitment 
period stated above. 
13.3 Protocol Compliance  
The patients will undergo routine treatments as per standard of care. We will monitor whether we 
will miss the blood samples from patients during specific time points. 

                                                                       
 
 
 
 
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14 Data 
14.1 Data management 
As this is an observation study, we will only be collecting data from patients that are already available 
in the hospital record on patients’ demographics, menopausal state, tumour characteristics (including 
ER/PR and HER2 status), previous treatments and proposed treatment plans. The patients’ treatment 
details, treatment responses, recurrences and survivals will also be obtained from clinical record. The 
data will be recorded on paper Case Report Forms (CRFs). Participant files and paper CRFs will be 
identified using a Participant Identification Number. Personal information will not be stored on CRFs. 
Data will be entered into an electronic CRF database (Excel) designed by the research team and stored 
on secured servers at King’s College London. Access to the database will be granted by the Chief 
Investigator.  
Screening and enrolment logs will be maintained by the research team. For enrolled participants, 
identifiable patient data will be stored in an Excel file for the purposes of gathering follow-up data. 
This file will password protected and stored on the GSTT secured network, whereby access is only 
granted by the site PI to named individuals.  
Consent forms and an Investigator Site File will be kept at the recruiting sites. Paper CRFs, copies of 
consent forms and the Trial Master File will be stored in locked filing cabinets within the Dr. Kong’s 
Laboratory (KCL, Guy’s Campus) and the Oral Clinical Research Unit (KCL, Guy’s Hospital, London, UK).  
Data generated from laboratory processes related to the generation of PDOs and subsequent testing 
will be kept in the research laboratory. These data will be identified with the PIN and no personal data 
will be used in the lab records.  
Data linkage 
If the participating patients have come from or will move to different health care providers, we will 
attempt to get either available archival tissues and/or data from the relevant health care providers 
after sending them the relevant patients’ consent forms. We may also go to the central national 
databases with a patient’s NHS number to get clinical data if necessary. 
Full dataset and linked code with patient identifiers will be kept for 5 years at local recruiting sites for 
governance purposes on Trust networks. This dataset will be accessed by the research team for long 
term follow-up of participants for up to 5 years of their recruitment to the study. Subsequently 
identifiable data will be deleted (name, NHS/hospital number and date of birth). A pseudonymised 
dataset will be kept for 5 years after study completion at King’s College London which will link 
participant trial numbers to their age at consent, ethnicity, gender, clinical information and treatment 
outcome.  
15 Statistical considerations 
The first year of recruitment will serve as a pilot study for this observation study and no formal power 
calculation is performed for year 1. We expect more than 50% of the approached participants will 
consent to taking part in SOTO-BC study and at least 30% of the tissue samples will be successfully 

                                                                       
 
 
 
 
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used to generate organoids. A successful pilot study will be defined as one that meets the pre-defined 
expectation. The data from study will be used to calculate the sample size required to extend the 
observation study, which will be submitted as a major amendment. 
16 Ethical considerations 
16.1  Research Ethics Committee (REC) review & reports 
Before the start of the trial, approval will be sought from an NHS REC for the trial protocol, informed 
consent forms, patient information sheet, and GP information letters.   
Any amendments to the protocol or study documents will be reviewed by the Sponsor, sent to the 
REC for review and approvals. No changes will be implemented until approval has been received from 
the REC and approved by the Trust R&D department, if required.   
All correspondence with the REC will be retained in the Trial Master File.  
An annual progress report (APR) will be submitted to the REC within 30 days of the anniversary date 
on which the favourable opinion was given, and annually until the trial is declared ended. The Chief 
Investigator’s will approve the annual report, which will be submitted by the CI or delegate. 
The Chief Investigator will notify the REC of the end of the trial within 90 days of the end of the study. 
If the trial is ended prematurely, the Chief Investigator will notify the REC, including the reasons for 
the premature termination. 
Within one year after the end of the trial, the Chief Investigator will submit a final report with the 
results, including any publications/abstracts, to the REC. 
16.2  Peer review 
This study was previously presented to the Guy’s and St. Thomas breast cancer research working party 
and have also sent for external peer review from experts as well as PPI members. 
16.3 Regulatory Compliance  
The trial will not commence until a Favourable REC opinion is obtained and R&D has provided 
greenlight for recruitment. 
All amendments to the protocol and study documents will be reviewed by the Sponsor and submitted 
for REC approval. Subsequently, documents and approvals will be sent to the Trust R&D for 
confirmation of implementation.  
17 Financing and Insurance 
The study is linked to the SOTO study (IRAS 305689) which is a prospective pilot study looking at 
growing organoids from head and neck tumours. The research team working on SOTO-BC is funded 
through a Guy’s Cancer Charity grant.  

                                                                       
 
 
 
 
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The study is co-sponsored by King’s College London (KCL) and Guys and St Thomas’ NHS Foundation 
Trust (GSTT). The sponsors will, at all times, maintain adequate insurance in relation to the study. 
KCL through its’ own professional indemnity (Clinical Trials) and no-fault compensation and the GSTT 
having a duty of care to patients via NHS indemnity cover, in respect of any claims arising as a result 
of negligence by its employees, brought by or on behalf of a study participant. 
King’s College London employees are indemnified by the University insurers for negligent harm caused 
by the design or co-ordination of the clinical trials they undertake whilst in the University’s 
employment. 
King’s College London cannot offer indemnity for non-negligent harm.  
 
18 Reporting and dissemination 
The results of this trial will be submitted for publication in peer-reviewed journals. The manuscripts 
will be prepared by the chief investigator and co-investigators. The authorship will be determined by 
mutual agreement. A copy of the publication will be provided to the participants if interested and 
requested.  

                                                                       
 
 
 
 
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