71 Timing of Neoadjuvant Immunotherapy and Pathological Response in Early-Stage Triple-Negative Breast Cancer: A Literature Review and Case Series

Background

Emerging evidence suggests that the efficacy of immunotherapy (IO) may be influenced by the timing of drug administration, driven by circadian-regulated immune activity. Retrospective studies in metastatic melanoma, renal cell carcinoma, and non–small cell lung cancer (NSCLC) show that patients receiving IO infusions later in the day experienced worse progression-free survival and overall survival compared with those treated earlier in the day. A recent abstract presented at the 2025 American Society of Clinical Oncology described a randomized, phase 3 trial in NSCLC in which earlier day infusion improved outcomes, though full peer-reviewed publication is pending. Despite this growing evidence, the impact of IO timing on treatment outcomes in early-stage triple-negative breast cancer (TNBC) has not been explored.

Objective

To evaluate whether the timing of IO infusion timing is associated with pathological complete response (pCR), recurrence, survival in patients with early-stage TNBC treated with neoadjuvant pembrolizumab and chemotherapy.

Design

We conducted a retrospective chart review of patients diagnosed with early-stage TNBC who received neoadjuvant pembrolizumab infusion per the KEYNOTE 522 trial between July 2021 and July 2025 at our institution. The cutoff for early vs late infusion was defined as 12:27 pm as the median time of the first 3 IO infusions, based on prior IO timing literature in metastatic melanoma. Patients receiving all first 3 infusions after 12:27 pm were categorized as “late.” pCR was defined as ypT0/TisypN0.

Case Series Summary

Ten randomly selected patients were reviewed (Table). Among the 5 “late” patients, 4 failed to achieve pCR and 1 developed distant recurrence to the lung. In contrast, 4 of 5 “early” patients achieved pCR and all 5 remained recurrence-free to date. No treatment-related deaths or severe IO toxicities were reported.

Conclusions

This preliminary case series suggested a potential association between late IO infusion timing and reduced pCR rates in early-stage TNBC. While limited by sample size, these findings mirror trends reported in other solid tumors and raised important question about the role of IO timing in breast cancer. Further analysis of a larger dataset is underway to validate these observations and explore their implications for clinical scheduling.