Impact of Time to Surgery Post Neoadjuvant Chemotherapy on Breast Cancer Outcomes: A Retrospective Study of Patients Enrolled in the I-SPY 2 Clinical Trial

Background: Neoadjuvant chemotherapy (NAC) is widely used to treat high-risk breast cancer. However, the optimal time to surgery (TTS) following NAC remains undefined. This study investigates the impact of TTS on oncologic outcomes using the I-SPY 2 Trial cohort. Methods: A retrospective analysis of 1877 patients with breast cancer enrolled in the I-SPY 2 Trial was performed. Patients were grouped by TTS post-NAC: 1–4 weeks, 5 weeks, 6–8 weeks, and 9 + weeks. Baseline demographic, clinical, imaging, and treatment response data were collected. Event-free survival (EFS) and local recurrence-free interval (LRFI) were evaluated using Kaplan–Meier analyses and Cox models. Subgroup analyses were performed by tumor receptor subtypes (hormone receptor [HR]+ human epidermal growth factor receptor 2 [HER2]−, HER2 +, and triple-negative breast cancer [TNBC]) and residual cancer burden (RCB) class. Results: Among 1877 patients, 526 (28.0%) underwent surgery between 1–4 weeks, 425 (22.6%) at 5 weeks, 490 (26.1%) between 6–8 weeks, and 436 (23.2%) at 9+ weeks post-NAC. Prolonged TTS was associated with worse 5-year EFS and LRFI on Kaplan–Meier analysis (p < 0.001 for both). Delays particularly affected outcomes in patients with HR+/HER2− and TNBC tumors. In patients with RCB class II/III, a TTS of 9+ weeks was independently associated with worse EFS (hazard ratio [HR] 2.04, p = 0.001) and LRFI (HR 2.77, p = 0.005). Conversely, in patients with a pathologic complete response/RCB class I, delayed surgery did not significantly impact outcomes. Conclusions: TTS of 9+ weeks following NAC is independently associated with worse oncologic outcomes, especially in patients with TNBC and HR+/HER2− tumors and high residual disease.