Safe De-escalation of Chemotherapy for Stage 1 Breast Cancer

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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.