Safe De-escalation of Chemotherapy for Stage 1 Breast Cancer

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.

Inclusion Criteria: 1. Age 18 years or older 2. Eastern Cooperative Oncology Group (ECOG) performance status of 0,1 or 2 3. Have an estimated life expectancy of at least 5 years 4. Histologically confirmed breast cancer that is either: (A) HER2-positive as defined by 2023 ASCO-CAP guidelines determined by local testing\* or (B) Triple negative defined as ER negative (ER staining in \