Evaluation of the Effect of Antibiotic Prophylaxis During Lumpectomy for Breast Cancer: Prospective Randomised Double-blind Noninferiority Study of Placebo vs Cefazolin

Background and Rationale Breast-conserving surgery is the reference treatment for early-stage breast cancer and is performed in a large proportion of women undergoing surgery for this condition. Although surgical antibiotic prophylaxis (SAP) is widely used to prevent surgical site infections (SSIs), its benefit specifically in breast-conserving surgery remains uncertain. Available evidence is limited by the relatively small number of randomized controlled trials, the inclusion of heterogeneous breast surgical procedures, and differences in antibiotic prophylaxis regimens. Many previous studies included patients undergoing more extensive procedures, such as total mastectomy or axillary lymph node dissection, which may carry different risks of postoperative infection. Consequently, the benefit of routine antibiotic prophylaxis in patients undergoing breast-conserving surgery alone has not been clearly established. Although generally well tolerated, antibiotic prophylaxis may cause adverse drug reactions, including hypersensitivity reactions, and contribute to alterations in the gut microbiota and the selection of antimicrobial resistance. Avoiding unnecessary antibiotic exposure is therefore an important objective of antimicrobial stewardship, particularly for frequently performed surgical procedures. Study Design and Methodology PROPHY-SEIN is a multicenter, randomized, double-blind, placebo-controlled non-inferiority trial designed to provide robust evidence regarding the need for routine SAP in breast-conserving surgery for cancer. Randomization is performed in a 1:1 ratio, with stratification by participating center and whether a sentinel lymph node procedure is performed. Treatment allocation is concealed from participants, surgeons, anesthesiologists, and study investigators. Study treatments are prepared by healthcare personnel not involved in the participants' perioperative management or postoperative assessment, ensuring that the administered solutions are indistinguishable. The non-inferiority margin is set at an absolute difference of 2 percentage points in the incidence of SSIs. This margin represents the maximum additional risk of infection considered clinically acceptable with a strategy without antibiotic prophylaxis. Its selection reflects the relatively low incidence of SSIs after breast-conserving surgery, their predominantly superficial nature, and the potential benefits of reducing unnecessary antibiotic exposure. The primary analysis will assess non-inferiority using the Farrington-Manning method, with a one-sided significance level of 2.5%. Analyses will be conducted in both the intention-to-treat and per-protocol populations, with consistent findings required to establish non-inferiority. If non-inferiority is not demonstrated, a prespecified secondary analysis will assess whether cefazolin is superior to placebo in preventing SSIs. To minimize assessment bias, suspected SSIs will be independently reviewed by a blinded adjudication committee comprising experts in anesthesiology, surgery, and infectious diseases, using predefined diagnostic criteria. Expected Contribution PROPHY-SEIN is intended to address an important evidence gap in perioperative care for breast cancer surgery. By focusing specifically on breast-conserving procedures and using a rigorous randomized, double-blind design, the trial aims to clarify whether routine antibiotic prophylaxis provides a clinically meaningful benefit in this setting. The findings may help inform future clinical practice guidelines and support a more evidence-based approach to antibiotic prophylaxis, balancing the prevention of postoperative infections against the individual and collective consequences of unnecessary antibiotic exposure.