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This retrospective analysis investigated the impact of immune checkpoint inhibitor (ICI) administration timing and tumor-infiltrating lymphocyte (TIL) status on treatment efficacy in breast cancer patients. The study included a perioperative cohort (n=22) receiving neoadjuvant ICI and a metastatic cohort (n=18) treated with ICI. In the perioperative cohort, patients with high TILs treated with morning ICI administration had a 100% pathological complete response (pCR) rate, while those treated in the afternoon had a 55.6% non-pCR rate.
In early-stage breast cancer patients with high TILs receiving neoadjuvant ICI, morning administration was associated with improved pathological complete response compared to afternoon administration.
Circadian rhythms regulate immune responses, but their clinical relevance in cancer immunotherapy remains underexplored. We investigated whether the timing of immune checkpoint inhibitor (ICI) administration, in conjunction with tumor-infiltrating lymphocyte (TIL) status, influences treatment efficacy in breast cancer. We conducted a retrospective analysis of two cohorts: a perioperative cohort receiving neoadjuvant ICI (n = 22, early-stage) and a metastatic cohort treated with ICI in the advanced setting (n = 18). For each patient, the median time of ICI administration was determined and dichotomized as morning (<12:00) or afternoon (≥12:00). In the perioperative cohort, pathological complete response (pCR) was assessed; in the metastatic cohort, progression-free survival (PFS) was analyzed. Pre-treatment stromal TIL levels were evaluated and stratified by median value (TIL-high vs. TIL-low). Associations between administration time, TIL status, and treatment outcomes were explored. In the perioperative cohort, neither administration timing nor TIL level alone showed a significant association with pCR. However, when stratifying by both variables, an interaction emerged: among 9 patients with high TILs, those treated in the morning (n = 4) achieved a 100% pCR rate, while those treated in the afternoon (n = 5) had a 55.6% non-pCR rate. In contrast, patients with low TILs had high pCR rates regardless of administration time (morning: 83.3%, afternoon: 80.0%). In the metastatic cohort, PFS did not significantly differ between morning and afternoon administration, nor by PD-L1 or TIL status, although trends suggested numerically shorter PFS in afternoon-treated patients with high PD-L1 expression. Across both cohorts, no meaningful association was observed between time of administration and immune-related adverse events. While overall efficacy was not significantly influenced by ICI administration time, subgroup analysis revealed a paradoxical pattern among TIL-high patients in the perioperative setting: afternoon administration was associated with reduced pCR rates. This finding suggests that the functional phenotype of TILs—and possibly their interaction with circadian immune modulation—may shape response to immunotherapy. Further studies incorporating spatial and functional profiling of the tumor immune microenvironment are warranted to clarify the clinical implications of circadian timing in ICI treatment. K. Nakamura, K. Saito, R. Ito, M. Yoshida, E. Hatakawa, R. Yamakado, M. Yoshikawa, S. Watanabe, N. Imai, M. Shibusawa, A. Noro, Y. Kozuka, K. Kawaguchi. Exploring the Impact of Circadian Timing and TIL Status on Immunotherapy Response in Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-07-01.
