Breast CancerSafe-DeNCT05058183
Safe De-escalation of Chemotherapy for Stage 1 Breast Cancer
A study testing ctDNA in people with Breast Cancer, run by Royal Marsden NHS Foundation Trust at 13 sites in United Kingdom.
Trial summary
The SAFE-DE study investigates whether circulating tumour DNA (ctDNA) testing can guide adjuvant treatment decisions in patients with stage I breast cancer, identifying those who may be able to avoid chemotherapy after surgery. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Breast Cancer
- What is being tested?
- ctDNA
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 800 participants
- Where
- 13 sitesUnited Kingdom
- Study dates
- 5 Jun 2023to 1 Jan 2038
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 18 years or older
- Eastern Cooperative Oncology Group (ECOG) performance status of 0,1 or 2
- Have an estimated life expectancy of at least 5 years
- Histologically confirmed breast cancer that is either:
- HER2-positive as defined by 2023 ASCO-CAP guidelines determined by local testing* or (B) Triple negative defined as ER negative (ER staining in <1% tumour cells or ER Allred score <3/8) and PR negative (PR staining in <10% tumour cells or PR Allred score <6/8) and HER2-negative by 2023 ASCO-CAP guidelines determined by local testing. Patients without PR testing results may enrol on the basis of ER and HER2 results.
- Note: Patients negative for ER and PR may enrol whilst awaiting HER2 testing results
Show all 17Show fewer
- Pathological stage 1 cancer as below: **
- EITHER
- HER2-positive invasive tumour size 5-20mm OR
- TNBC invasive tumour size 5-20mm, with high TILs (stromal tumour infiltration lymphocytes >30%) determined by central testing
- AND (c) Node negative (isolated tumour cells are allowed)
- Patients may be enrolled pre-operatively with clinical stage 1 cancer with primary tumour size on imaging 5-20mm and a normal axilla ultrasound or a biopsy negative axilla. Patients enrolled before surgery will only continue in study after surgery when confirmed pathological stage 1
- Planned for and fit enough to receive standard post-operative chemotherapy, with HER2 targeting as appropriate, in the opinion of the investigator
- Able and willing to provide written informed consent or remote consent
- Negative serum pregnancy test at screening (females of childbearing potential). Patients able to have children are advised to use a method of contraception, or abstinence, throughout the ctDNA surveillance period
- Willing and able to comply with scheduled visits, laboratory tests and other procedures
- Available tissue from breast surgery or diagnostic core (preference to diagnostic core for rapidity of tissue sequencing).
Who cannot join
- Prior treatment for the current breast cancer, other than surgery if recruited post-operatively
- Multifocal invasive cancer
- Micrometastasis or macrometastasis in axillary lymph nodes
- pT1a invasive tumour size <5mm
- Distant metastatic disease on imaging performed as part of standard of care
- Planned participation in an alternative treatment trial
Show all 9Show fewer
- Diagnosis of alternative cancer within the last 5 years except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or cervix
- Known HIV or AIDS-related illness
- Known positive HBV or HCV test indicating acute or chronic infection
Trial locations and contacts
13 sites in 1 country. Contact the study team or a site near you to ask about taking part.
13 sites in 1 country
United Kingdom13 sites, 13 recruiting
- Recruiting
Royal Bournemouth Hospital
Bournemouth, BH7 7DW
Dr Renu Ragupathi, 0300 019 4789, Renu.Ragupathi4@nhs.net
- Recruiting
The Clatterbridge Cancer Centre
Liverpool
Professor Carlo Palmieri, 0151 556 5277, cpalmi@liverpool.ac.uk
- Recruiting
Whittington Hospital
London, N19 5NF
Dr Karen DeSouza, karen.desouza2@nhs.net
- Recruiting
University College London Hospital
London, NW1 2BU
Dr Rebecca Roylance, r.roylance@ucl.ac.uk
- Recruiting
The Royal Free Hospital
London, NW3 2QG
Dr Neha Chopra, 02073528171, neha.chopra@nhs.net
- Recruiting
The Royal Marsden NHS Foundation Trust, Chelsea
London, SW3 6JJ
Trial Manager, 020 7808 2887, SAFE-DE@rmh.nhs.uk
- Recruiting
Barts Health NHS Trust
London
Dr Angelis Vasileios, v.angelis@nhs.net
- Recruiting
The Christie NHS Foundation Trust
Manchester, M20 4BX
Dr Ciara O'Brien, Ciara.obrien3@nhs.net
- Recruiting
Nottingham University Hospitals NHS Trust, City Hospital Campus
Nottingham, NG5 1PB
Dr Tahir Shafiq, 0115 696 1169 ext. 76236, tahir.shafiq2@nhs.net
- Recruiting
University Hospitals Dorset: Poole Hospital
Poole, BH15 2JB
Dr Renu Ragupathi, 0300 019 4789, Renu.Ragupathi4@nhs.net
- Recruiting
The Royal Marsden NHS Foundation Trust, Sutton
Sutton, SM5 5PT
Trial Manager, 02078082887, safe-de@rmh.nhs.uk
- Recruiting
Royal Cornwall Hospitals NHS Trust
Truro, Cornwall, TR1 3lJ
Dr Ebunoluwa Abowari-Sapeh, 01872 25 8343, e.abowari-sapeh@nhs.net
- Recruiting
The Royal Albert Edward Infirmary
Wigan, WN1 2NN
Dr Elena Takeuchi, Elena.Takeuchi@wwl.nhs.uk
About this study
The SAFE-DE study investigates whether circulating tumour DNA (ctDNA) testing can guide adjuvant treatment decisions in patients with stage I breast cancer, identifying those who may be able to avoid chemotherapy after surgery. The study includes patients with stage I HER2-positive breast cancer and patients with stage I triple-negative breast cancer (TNBC) with high levels of tumour-infiltrating lymphocytes (TILs). The Signatera personalised ctDNA assay is used to detect molecular residual disease (MRD), which may indicate that cancer remains in the body after surgery.
SAFE-DE comprises two parts. Part A, which is closed to recruitment, investigated the incidence of post-operative ctDNA detection and its association with subsequent outcomes, including the potential prognostic significance of pre-operative ctDNA. Part B builds on this work by prospectively evaluating whether ctDNA-guided treatment and surveillance can reduce the use of adjuvant chemotherapy while maintaining favourable cancer outcomes.
Read more
Patients may be enrolled before surgery to facilitate pre-operative sampling and timely post-operative testing. Blood samples will be collected after surgery, including at 2 and 4 weeks. The results of the 2- and 4-week post-operative ctDNA tests will be shared with patients and their treating clinicians to inform treatment decisions in accordance with the study protocol and individual clinical circumstances. Pre-operative ctDNA results will be investigated as an exploratory measure and will not be disclosed for treatment decisions.
Patients with detectable ctDNA after surgery will be recommended standard adjuvant systemic treatment. Patients with no detectable ctDNA at both 2 and 4 weeks after surgery will be recommended not to receive adjuvant chemotherapy and will instead enter a ctDNA surveillance programme. If ctDNA becomes detectable during surveillance, patients will then be offered standard adjuvant treatment.
The primary purpose of Part B is to assess whether patients with undetectable ctDNA following surgery can remain free from distant recurrence without adjuvant chemotherapy. Additional outcomes include recurrence and survival, adjuvant treatment use, ctDNA detection during surveillance, quality of life and the cost-effectiveness of ctDNA-guided treatment.
Read the detailed description
Patients with stage I breast cancer generally have a favourable prognosis following surgery. However, patients with stage I HER2-positive breast cancer and triple-negative breast cancer (TNBC) remain at risk of recurrence and are commonly offered adjuvant systemic treatment following surgery. Although shorter chemotherapy regimens are used to reduce treatment-related morbidity, some patients may remain disease-free without chemotherapy, while others have residual cancer after surgery and remain at risk of recurrence despite treatment. Identifying patients who can safely avoid adjuvant chemotherapy, while ensuring that those at increased risk receive appropriate treatment, remains an important clinical challenge.
Circulating tumour DNA (ctDNA) provides a potential means of detecting molecular residual disease (MRD), which refers to cancer that remains in the body following treatment but may not be detectable using conventional clinical assessments. As tumour cells proliferate and die, tumour-derived DNA can be released into the circulation. Sequencing a patient's tumour to identify tumour-specific alterations enables highly sensitive analysis of plasma DNA for these alterations. Detection of ctDNA following potentially curative treatment is associated with an increased risk of subsequent disease recurrence.
The SAFE-DE study uses the Signatera personalised ctDNA assay to investigate the role of ctDNA testing in patients with stage I HER2-positive breast cancer and stage I TNBC with high levels of tumour-infiltrating lymphocytes (TILs). The study comprises two parts.
Part A, which is closed to recruitment, investigated the incidence of ctDNA detection in patients with stage I HER2-positive and triple-negative breast cancer following surgery. Its purpose was to identify patients with evidence of molecular residual disease and investigate the association between ctDNA detection and subsequent outcomes. The study also explored pre-operative ctDNA detection as a potential prognostic measure. Pre-operative results were not disclosed to patients or treating clinicians for treatment decisions because their clinical significance was less established than that of post-operative ctDNA detection.
Part A provided the foundation for the next stage of the study by investigating the use of ctDNA testing to identify patients who may be at increased risk of recurrence following surgery.
Part B builds on Part A by prospectively evaluating whether post-operative ctDNA results can be used to guide adjuvant treatment decisions, with the aim of reducing unnecessary chemotherapy while maintaining favourable cancer outcomes.
Patients may be enrolled before surgery to facilitate collection of pre-operative samples and timely post-operative testing. Pre-operative ctDNA will be investigated as an exploratory measure, and results will not be made available to patients or their treating clinicians for treatment decisions.
Following surgery, blood samples will be collected for ctDNA testing, including at 2 and 4 weeks after surgery. The results of these post-operative tests will be shared with patients and their treating clinicians and used to guide treatment in accordance with the study protocol.
Patients with detectable ctDNA after surgery will receive standard adjuvant systemic treatment, reflecting the increased risk of recurrence associated with molecular residual disease.
Patients with no detectable ctDNA at both 2 and 4 weeks after surgery will be recommended not to receive adjuvant chemotherapy and will instead enter a ctDNA surveillance programme. Serial blood testing during follow-up will allow the study to assess whether ctDNA remains undetectable or becomes detectable over time. If ctDNA becomes detectable during surveillance, patients will be offered standard adjuvant treatment.
The primary purpose of Part B is to determine whether patients with undetectable ctDNA following surgery can remain free from distant recurrence without receiving adjuvant chemotherapy. The study will also assess other measures of recurrence and survival, patterns of anticancer treatment use, ctDNA detection during surveillance, quality of life and the cost-effectiveness of using ctDNA to guide treatment decisions.
By evaluating a ctDNA-guided treatment and surveillance strategy, SAFE-DE aims to provide further evidence on whether molecular residual disease testing can support more personalised management of early breast cancer, reducing exposure to chemotherapy in selected patients while identifying those who may require additional treatment.
- Conditions
- Breast Cancer
- Being tested
- ctDNA
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ctDNADiagnostic test
Patients with stage 1 HER2-positive breast cancer or stage 1 triple-negative breast cancer (TNBC) with high tumour infiltrating lymphocytes (TILs) will have access to the Signatera genome ctDNA assay alongside standard clinical care. Patients will preferably be enrolled prior to surgery and will have ctDNA testing before and after surgery. The pre-surgery ctDNA result will not be made available to patients or their treating clinicians. Post-surgery ctDNA results will be made available to treating clinicians and will be used to inform clinical decision-making regarding adjuvant systemic treatment.
Patients with undetectable ctDNA after surgery may be managed without adjuvant chemotherapy and will undergo further ctDNA surveillance instead. Patients with detectable ctDNA after surgery, who are considered to have a higher risk of relapse, will not enter the surveillance population in which adjuvant systemic treatment is omitted.
| Study group | Role | What they receive |
|---|---|---|
| All participants | Experimental | All participants Receives: Diagnostic Test: ctDNA |
What is being measured
The primary outcome is the main question the study is designed to answer.
Distant recurrence-free interval in patients with undetectable post-surgery ctDNA
The time from the date of surgery to the first recorded event of distant recurrence or death from breast cancer. This will be evaluated in patients who proceed to surgery and have at least one undetectable ctDNA result at either 2 and/or 4 weeks post-surgery, with no detected ctDNA result at either post-surgery timepoint. Patients without a recorded event will be censored at the first occurrence of death from another cause, complete withdrawal from trial follow-up, or diagnosis of a new primary cancer. This will be assessed separately in patients with stage 1 HER2-positive breast cancer and patients with stage 1 TNBC with high tumour infiltrating lymphocytes (TILs).
Measured: From the date of surgery until first documented event, assessed up to 10 years.
Secondary outcomes (6)
Distant recurrence-free interval in all patients
The time from the date of surgery to the first recorded event of distant recurrence or death from breast cancer, evaluated in all patients who proceed to surgery regardless of their ctDNA status at 2 and 4 weeks post-surgery. Results will be reported in the HER2-positive cohort, TNBC cohort, and both cohorts combined.
Measured: From the date of surgery until first documented event, assessed up to 10 years.
Invasive disease-free survival (IDFS)
The time from the date of surgery to the first occurrence of an invasive ipsilateral breast tumour recurrence, local/regional invasive recurrence, distant recurrence, death from breast cancer, death from another cause, death from an unknown cause, invasive contralateral breast cancer, or a second primary invasive cancer (non-breast). This will be evaluated in patients with undetectable ctDNA MRD following surgery.
Measured: From the date of surgery until first documented event, assessed up to 10 years.
Recurrence-free interval (RFI)
The time from the date of surgery to the first occurrence of an invasive ipsilateral breast tumour recurrence, local/regional invasive recurrence, distant recurrence, or death from breast cancer. This will be evaluated in patients with undetectable ctDNA MRD following surgery.
Measured: From the date of surgery until first documented event, assessed up to 10 years.
Distant recurrence-free survival (DRFS)
The time from the date of surgery to the first occurrence of distant recurrence or death from breast cancer. This will be evaluated in patients with undetectable ctDNA MRD following surgery.
Measured: From the date of surgery until first documented event, assessed up to 10 years.
Breast cancer-specific survival (BCSS)
The time from the date of surgery to death from breast cancer. This will be evaluated in patients with undetectable ctDNA MRD following surgery.
Measured: From the date of surgery until documented date of death from breast cancer, assessed up to 10 years.
Overall survival (OS)
The time from the date of surgery to death from any cause. This will be evaluated in patients with undetectable ctDNA MRD following surgery.
Measured: From the date of surgery until date of death, assessed up to 10 years.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Sep 2021
- Study start5 Jun 2023
- Primary completion1 Jan 2038 (estimated)
- Study completion1 Jan 2038 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (13)Papers the sponsor has linked to this study.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- More trials run by Royal Marsden NHS Foundation TrustThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- The study is looking into the ctDNA diagnostic test, this is given after breast cancer surgery to see whether patient is clear from cancer
- Masking
- None (open label)
- Enrolment
- 800 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Royal Marsden NHS Foundation Trust
- Sponsor type
- University, hospital or other
- Collaborators
- Natera, Inc., Institute of Cancer Research, United Kingdom
- Responsible party
- Sponsor
- Investigators
- Nicholas Turner, Principal investigator, Royal Marsden NHS Foundation Trust
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05058183
- Sponsor's protocol ID
- CCR5348
- Acronym
- Safe-De
- Status last verified
- Oct 2026
- First submitted
- 19 Aug 2021
- Last updated
- 29 Oct 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Abbosh C, Birkbak NJ, Wilson GA, Jamal-Hanjani M, Constantin T, Salari R, Le Quesne J, Moore DA, Veeriah S, Rosenthal R, Marafioti T, Kirkizlar E, Watkins TBK, McGranahan N, Ward S, Martinson L, Riley J, Fraioli F, Al Bakir M, Gronroos E, Zambrana F, Endozo R, Bi WL, Fennessy FM, Sponer N, Johnson D, Laycock J, Shafi S, Czyzewska-Khan J, Rowan A, Chambers T, Matthews N, Turajlic S, Hiley C, Lee SM, Forster MD, Ahmad T, Falzon M, Borg E, Lawrence D, Hayward M, Kolvekar S, Panagiotopoulos N, Janes SM, Thakrar R, Ahmed A, Blackhall F, Summers Y, Hafez D, Naik A, Ganguly A, Kareht S, Shah R, Joseph L, Marie Quinn A, Crosbie PA, Naidu B, Middleton G, Langman G, Trotter S, Nicolson M, Remmen H, Kerr K, Chetty M, Gomersall L, Fennell DA, Nakas A, Rathinam S, Anand G, Khan S, Russell P, Ezhil V, Ismail B, Irvin-Sellers M, Prakash V, Lester JF, Kornaszewska M, Attanoos R, Adams H, Davies H, Oukrif D, Akarca AU, Hartley JA, Lowe HL, Lock S, Iles N, Bell H, Ngai Y, Elgar G, Szallasi Z, Schwarz RF, Herrero J, Stewart A, Quezada SA, Peggs KS, Van Loo P, Dive C, Lin CJ, Rabinowitz M, Aerts HJWL, Hackshaw A, Shaw JA, Zimmermann BG; TRACERx consortium; PEACE consortium; Swanton C. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature. 2017 Apr 26;545(7655):446-451. doi: 10.1038/nature22364.
PubMed 28445469Coombes RC, Page K, Salari R, Hastings RK, Armstrong A, Ahmed S, Ali S, Cleator S, Kenny L, Stebbing J, Rutherford M, Sethi H, Boydell A, Swenerton R, Fernandez-Garcia D, Gleason KLT, Goddard K, Guttery DS, Assaf ZJ, Wu HT, Natarajan P, Moore DA, Primrose L, Dashner S, Tin AS, Balcioglu M, Srinivasan R, Shchegrova SV, Olson A, Hafez D, Billings P, Aleshin A, Rehman F, Toghill BJ, Hills A, Louie MC, Lin CJ, Zimmermann BG, Shaw JA. Personalized Detection of Circulating Tumor DNA Antedates Breast Cancer Metastatic Recurrence. Clin Cancer Res. 2019 Jul 15;25(14):4255-4263. doi: 10.1158/1078-0432.CCR-18-3663. Epub 2019 Apr 16.
PubMed 30992300Early Breast Cancer Trialists' Collaborative Group (EBCTCG); Peto R, Davies C, Godwin J, Gray R, Pan HC, Clarke M, Cutter D, Darby S, McGale P, Taylor C, Wang YC, Bergh J, Di Leo A, Albain K, Swain S, Piccart M, Pritchard K. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012 Feb 4;379(9814):432-44. doi: 10.1016/S0140-6736(11)61625-5. Epub 2011 Dec 5.
PubMed 22152853Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005 May 14-20;365(9472):1687-717. doi: 10.1016/S0140-6736(05)66544-0.
PubMed 15894097Garcia-Murillas I, Chopra N, Comino-Mendez I, Beaney M, Tovey H, Cutts RJ, Swift C, Kriplani D, Afentakis M, Hrebien S, Walsh-Crestani G, Barry P, Johnston SRD, Ring A, Bliss J, Russell S, Evans A, Skene A, Wheatley D, Dowsett M, Smith IE, Turner NC. Assessment of Molecular Relapse Detection in Early-Stage Breast Cancer. JAMA Oncol. 2019 Oct 1;5(10):1473-1478. doi: 10.1001/jamaoncol.2019.1838.
PubMed 31369045Garcia-Murillas I, Schiavon G, Weigelt B, Ng C, Hrebien S, Cutts RJ, Cheang M, Osin P, Nerurkar A, Kozarewa I, Garrido JA, Dowsett M, Reis-Filho JS, Smith IE, Turner NC. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med. 2015 Aug 26;7(302):302ra133. doi: 10.1126/scitranslmed.aab0021.
PubMed 26311728Jones S, Holmes FA, O'Shaughnessy J, Blum JL, Vukelja SJ, McIntyre KJ, Pippen JE, Bordelon JH, Kirby RL, Sandbach J, Hyman WJ, Richards DA, Mennel RG, Boehm KA, Meyer WG, Asmar L, Mackey D, Riedel S, Muss H, Savin MA. Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735. J Clin Oncol. 2009 Mar 10;27(8):1177-83. doi: 10.1200/JCO.2008.18.4028. Epub 2009 Feb 9.
PubMed 19204201Loibl S, O'Shaughnessy J, Untch M, Sikov WM, Rugo HS, McKee MD, Huober J, Golshan M, von Minckwitz G, Maag D, Sullivan D, Wolmark N, McIntyre K, Ponce Lorenzo JJ, Metzger Filho O, Rastogi P, Symmans WF, Liu X, Geyer CE Jr. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol. 2018 Apr;19(4):497-509. doi: 10.1016/S1470-2045(18)30111-6. Epub 2018 Feb 28.
PubMed 29501363Reinert T, Henriksen TV, Christensen E, Sharma S, Salari R, Sethi H, Knudsen M, Nordentoft I, Wu HT, Tin AS, Heilskov Rasmussen M, Vang S, Shchegrova S, Frydendahl Boll Johansen A, Srinivasan R, Assaf Z, Balcioglu M, Olson A, Dashner S, Hafez D, Navarro S, Goel S, Rabinowitz M, Billings P, Sigurjonsson S, Dyrskjot L, Swenerton R, Aleshin A, Laurberg S, Husted Madsen A, Kannerup AS, Stribolt K, Palmelund Krag S, Iversen LH, Gotschalck Sunesen K, Lin CJ, Zimmermann BG, Lindbjerg Andersen C. Analysis of Plasma Cell-Free DNA by Ultradeep Sequencing in Patients With Stages I to III Colorectal Cancer. JAMA Oncol. 2019 Aug 1;5(8):1124-1131. doi: 10.1001/jamaoncol.2019.0528.
PubMed 31070691Tie J, Wang Y, Tomasetti C, Li L, Springer S, Kinde I, Silliman N, Tacey M, Wong HL, Christie M, Kosmider S, Skinner I, Wong R, Steel M, Tran B, Desai J, Jones I, Haydon A, Hayes T, Price TJ, Strausberg RL, Diaz LA Jr, Papadopoulos N, Kinzler KW, Vogelstein B, Gibbs P. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med. 2016 Jul 6;8(346):346ra92. doi: 10.1126/scitranslmed.aaf6219.
PubMed 27384348Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK, Albain KS, Rugo HS, Ellis M, Shapira I, Wolff AC, Carey LA, Overmoyer BA, Partridge AH, Guo H, Hudis CA, Krop IE, Burstein HJ, Winer EP. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med. 2015 Jan 8;372(2):134-41. doi: 10.1056/NEJMoa1406281.
PubMed 25564897Tolaney SM, Guo H, Pernas S, Barry WT, Dillon DA, Ritterhouse L, Schneider BP, Shen F, Fuhrman K, Baltay M, Dang CT, Yardley DA, Moy B, Marcom PK, Albain KS, Rugo HS, Ellis MJ, Shapira I, Wolff AC, Carey LA, Overmoyer B, Partridge AH, Hudis CA, Krop IE, Burstein HJ, Winer EP. Seven-Year Follow-Up Analysis of Adjuvant Paclitaxel and Trastuzumab Trial for Node-Negative, Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer. J Clin Oncol. 2019 Aug 1;37(22):1868-1875. doi: 10.1200/JCO.19.00066. Epub 2019 Apr 2.
PubMed 30939096von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer. N Engl J Med. 2017 Jul 13;377(2):122-131. doi: 10.1056/NEJMoa1703643. Epub 2017 Jun 5.
PubMed 28581356
Study at a glance
From the registry record, last updated by the sponsor on 29 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Safe De-escalation of Chemotherapy for Stage 1 Breast Cancer
- ClinicalTrials.gov ID
- NCT05058183
- Acronym / sponsor ID
- Safe-De / CCR5348
- Conditions
- Breast Cancer
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 800 participants (estimated)
- Lead sponsor
- Royal Marsden NHS Foundation TrustUniversity, hospital or other
- Collaborators
- Natera, Inc., Institute of Cancer Research, United Kingdom
- Study start
- 5 Jun 2023 (actual)
- Primary completion
- 1 Jan 2038 (estimated)
- Study completion
- 1 Jan 2038 (estimated)
- First posted
- 27 Sep 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The SAFE-DE study investigates whether circulating tumour DNA (ctDNA) testing can guide adjuvant treatment decisions in patients with stage I breast cancer, identifying those who may be able to avoid chemotherapy after surgery. The study includes patients with stage I HER2-positive breast cancer and patients with stage I triple-negative breast cancer (TNBC) with high levels of tumour-infiltrating lymphocytes (TILs). The Signatera personalised ctDNA assay is used to detect molecular residual disease (MRD), which may indicate that cancer remains in the body after surgery.
SAFE-DE comprises two parts. Part A, which is closed to recruitment, investigated the incidence of post-operative ctDNA detection and its association with subsequent outcomes, including the potential prognostic significance of pre-operative ctDNA. Part B builds on this work by prospectively evaluating whether ctDNA-guided treatment and surveillance can reduce the use of adjuvant chemotherapy while maintaining favourable cancer outcomes.
Patients may be enrolled before surgery to facilitate pre-operative sampling and timely post-operative testing. Blood samples will be collected after surgery, including at 2 and 4 weeks. The results of the 2- and 4-week post-operative ctDNA tests will be shared with patients and their treating clinicians to inform treatment decisions in accordance with the study protocol and individual clinical circumstances. Pre-operative ctDNA results will be investigated as an exploratory measure and will not be disclosed for treatment decisions.
Patients with detectable ctDNA after surgery will be recommended standard adjuvant systemic treatment. Patients with no detectable ctDNA at both 2 and 4 weeks after surgery will be recommended not to receive adjuvant chemotherapy and will instead enter a ctDNA surveillance programme. If ctDNA becomes detectable during surveillance, patients will then be offered standard adjuvant treatment.
The primary purpose of Part B is to assess whether patients with undetectable ctDNA following surgery can remain free from distant recurrence without adjuvant chemotherapy. Additional outcomes include recurrence and survival, adjuvant treatment use, ctDNA detection during surveillance, quality of life and the cost-effectiveness of ctDNA-guided treatment.
Detailed description
Patients with stage I breast cancer generally have a favourable prognosis following surgery. However, patients with stage I HER2-positive breast cancer and triple-negative breast cancer (TNBC) remain at risk of recurrence and are commonly offered adjuvant systemic treatment following surgery. Although shorter chemotherapy regimens are used to reduce treatment-related morbidity, some patients may remain disease-free without chemotherapy, while others have residual cancer after surgery and remain at risk of recurrence despite treatment. Identifying patients who can safely avoid adjuvant chemotherapy, while ensuring that those at increased risk receive appropriate treatment, remains an important clinical challenge.
Circulating tumour DNA (ctDNA) provides a potential means of detecting molecular residual disease (MRD), which refers to cancer that remains in the body following treatment but may not be detectable using conventional clinical assessments. As tumour cells proliferate and die, tumour-derived DNA can be released into the circulation. Sequencing a patient's tumour to identify tumour-specific alterations enables highly sensitive analysis of plasma DNA for these alterations. Detection of ctDNA following potentially curative treatment is associated with an increased risk of subsequent disease recurrence.
The SAFE-DE study uses the Signatera personalised ctDNA assay to investigate the role of ctDNA testing in patients with stage I HER2-positive breast cancer and stage I TNBC with high levels of tumour-infiltrating lymphocytes (TILs). The study comprises two parts.
Part A, which is closed to recruitment, investigated the incidence of ctDNA detection in patients with stage I HER2-positive and triple-negative breast cancer following surgery. Its purpose was to identify patients with evidence of molecular residual disease and investigate the association between ctDNA detection and subsequent outcomes. The study also explored pre-operative ctDNA detection as a potential prognostic measure. Pre-operative results were not disclosed to patients or treating clinicians for treatment decisions because their clinical significance was less established than that of post-operative ctDNA detection.
Part A provided the foundation for the next stage of the study by investigating the use of ctDNA testing to identify patients who may be at increased risk of recurrence following surgery.
Part B builds on Part A by prospectively evaluating whether post-operative ctDNA results can be used to guide adjuvant treatment decisions, with the aim of reducing unnecessary chemotherapy while maintaining favourable cancer outcomes.
Patients may be enrolled before surgery to facilitate collection of pre-operative samples and timely post-operative testing. Pre-operative ctDNA will be investigated as an exploratory measure, and results will not be made available to patients or their treating clinicians for treatment decisions.
Following surgery, blood samples will be collected for ctDNA testing, including at 2 and 4 weeks after surgery. The results of these post-operative tests will be shared with patients and their treating clinicians and used to guide treatment in accordance with the study protocol.
Patients with detectable ctDNA after surgery will receive standard adjuvant systemic treatment, reflecting the increased risk of recurrence associated with molecular residual disease.
Patients with no detectable ctDNA at both 2 and 4 weeks after surgery will be recommended not to receive adjuvant chemotherapy and will instead enter a ctDNA surveillance programme. Serial blood testing during follow-up will allow the study to assess whether ctDNA remains undetectable or becomes detectable over time. If ctDNA becomes detectable during surveillance, patients will be offered standard adjuvant treatment.
The primary purpose of Part B is to determine whether patients with undetectable ctDNA following surgery can remain free from distant recurrence without receiving adjuvant chemotherapy. The study will also assess other measures of recurrence and survival, patterns of anticancer treatment use, ctDNA detection during surveillance, quality of life and the cost-effectiveness of using ctDNA to guide treatment decisions.
By evaluating a ctDNA-guided treatment and surveillance strategy, SAFE-DE aims to provide further evidence on whether molecular residual disease testing can support more personalised management of early breast cancer, reducing exposure to chemotherapy in selected patients while identifying those who may require additional treatment.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- The study is looking into the ctDNA diagnostic test, this is given after breast cancer surgery to see whether patient is clear from cancer
| Arm | Type | Receives |
|---|---|---|
| All participants | Experimental | Diagnostic Test: ctDNAAll participants |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- Age 18 years or older
- Eastern Cooperative Oncology Group (ECOG) performance status of 0,1 or 2
- Have an estimated life expectancy of at least 5 years
- Histologically confirmed breast cancer that is either:
- Pathological stage 1 cancer as below: **
Key exclusion criteria (9 listed)
- Prior treatment for the current breast cancer, other than surgery if recruited post-operatively
- Multifocal invasive cancer
- Micrometastasis or macrometastasis in axillary lymph nodes
- pT1a invasive tumour size <5mm
- Distant metastatic disease on imaging performed as part of standard of care
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ctDNAPatients with stage 1 HER2-positive breast cancer or stage 1 triple-negative breast cancer (TNBC) with high tumour infiltrating lymphocytes (TILs) will have access to the Signatera genome ctDNA assay alongside standard clinical care. Patients will preferably be enrolled prior to surgery and will have ctDNA testing before and after surgery. The pre-surgery ctDNA result will not be made available to patients or their treating clinicians. Post-surgery ctDNA results will be made available to treating clinicians and will be used to inform clinical decision-making regarding adjuvant systemic treatment. Patients with undetectable ctDNA after surgery may be managed without adjuvant chemotherapy and will undergo further ctDNA surveillance instead. Patients with detectable ctDNA after surgery, who are considered to have a higher risk of relapse, will not enter the surveillance population in which adjuvant systemic treatment is omitted. | Diagnostic test | All participants |
Primary outcome
Distant recurrence-free interval in patients with undetectable post-surgery ctDNA
Time frame: From the date of surgery until first documented event, assessed up to 10 years.
The time from the date of surgery to the first recorded event of distant recurrence or death from breast cancer. This will be evaluated in patients who proceed to surgery and have at least one undetectable ctDNA result at either 2 and/or 4 weeks post-surgery, with no detected ctDNA result at either post-surgery timepoint. Patients without a recorded event will be censored at the first occurrence of death from another cause, complete withdrawal from trial follow-up, or diagnosis of a new primary cancer. This will be assessed separately in patients with stage 1 HER2-positive breast cancer and patients with stage 1 TNBC with high tumour infiltrating lymphocytes (TILs).
6 secondary outcomes
Distant recurrence-free interval in all patients
Time frame: From the date of surgery until first documented event, assessed up to 10 years.
Invasive disease-free survival (IDFS)
Time frame: From the date of surgery until first documented event, assessed up to 10 years.
Recurrence-free interval (RFI)
Time frame: From the date of surgery until first documented event, assessed up to 10 years.
Distant recurrence-free survival (DRFS)
Time frame: From the date of surgery until first documented event, assessed up to 10 years.
Breast cancer-specific survival (BCSS)
Time frame: From the date of surgery until documented date of death from breast cancer, assessed up to 10 years.
Overall survival (OS)
Time frame: From the date of surgery until date of death, assessed up to 10 years.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Oct 2026.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Nicholas Turner principal investigator
Royal Marsden NHS Foundation Trust
13 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing ctDNA in people with Breast Cancer, run by Royal Marsden NHS Foundation Trust at 13 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 29 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 13 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Project Manager (020 7808 2887, SAFE-DE@rmh.nhs.uk), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Distant recurrence-free interval in patients with undetectable post-surgery ctDNA (time frame: From the date of surgery until first documented event, assessed up to 10 years.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05058183, which also lists 13 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Oct 2026.