Circadian Timing of Immunotherapy May Influence Outcomes in Triple-Negative Breast Cancer Based on Tumor Immune Microenvironment
核心洞察
The phase III A-BRAVE trial found that infusion timing alone (AM vs PM) was not associated with distant disease-free survival or overall survival in avelumab-treated patients with high-risk early-stage TNBC.
Exploratory analyses revealed a significant interaction between infusion timing and baseline tumor-infiltrating lymphocytes (搜索) (TILs), with AM dosing favoring immune-hot tumors and PM dosing favoring immune-cold tumors (DDFS p=0.001; OS p=0.002).
A separate retrospective case series of neoadjuvant pembrolizumab in early-stage TNBC suggested that late infusions may be associated with reduced pathological complete response rates, though sample size was limited.
The timing of immunotherapy administration—whether given in the morning or afternoon—may influence clinical outcomes in patients with early-stage triple-negative breast cancer (搜索) (TNBC), but the effect appears to depend critically on the tumor's baseline immune microenvironment, according to an exploratory analysis of the phase III A-BRAVE trial presented at the 2026 ASCO Annual Meeting.
Maria Vittoria Dieci and colleagues reported that while infusion timing alone showed no association with survival outcomes, a significant interaction emerged when patients were stratified by tumor-infiltrating lymphocyte (TIL) levels. The findings suggest that the circadian biology of the immune system may interact with the tumor immune milieu in ways that could eventually inform clinical scheduling—though investigators cautioned against changing practice without prospective validation.
No Overall Effect of Infusion Timing on Survival
The A-BRAVE trial randomized patients with high-risk early-stage TNBC to receive one year of adjuvant avelumab or observation. For the timing analysis, infusion data were available for 221 of 235 avelumab-treated patients (94%). The AM-rate was defined as the proportion of the first four avelumab infusions administered before 12:30 PM, the median treatment time in the cohort. Patients were classified as AM-dominant (AM-rate ≥50%; n=126, 57%) or PM-dominant (AM-rate <50%; n=95, 43%).
When the entire cohort was analyzed without biomarker stratification, no significant differences emerged. Three-year distant disease-free survival (DDFS) was 73.5% in AM-dominant patients versus 77.4% in PM-dominant patients (log-rank p=0.499). Three-year overall survival (OS) was 83.9% versus 86.0%, respectively (log-rank p=0.497).
Immune Microenvironment Defines Timing Effects
The picture changed substantially when investigators incorporated baseline immune biomarkers. TILs were evaluable in 188 patients (85%), and PD-L1 (搜索) expression was evaluable in 195 patients (88%). Exploratory interaction analyses demonstrated that the association between infusion timing and outcome varied according to the baseline immune milieu.
In patients with higher baseline TIL levels—so-called immune-hot tumors—earlier (AM) administration appeared to be associated with more favorable outcomes. Conversely, in patients with lower baseline TIL levels—immune-cold tumors—later (PM) administration appeared to be associated with more favorable outcomes.
The interaction signals were robust. When TILs were analyzed as high versus low groups, the AM-rate × TIL category interaction yielded p=0.001 for DDFS and p=0.002 for OS. The AM/PM-dominant × TIL category interaction produced p=0.002 for DDFS and p=0.001 for OS. Similar directional trends were observed in analyses incorporating PD-L1 (搜索) expression, and the findings remained consistent across multiple statistical approaches.
A Separate Case Series Adds Context
A separate retrospective case series, also examining timing effects in early-stage TNBC, evaluated ten patients who received neoadjuvant pembrolizumab per the KEYNOTE 522 regimen between July 2021 and July 2025. Using a cutoff of 12:27 PM (the median time of the first three immunotherapy infusions), patients receiving all first three infusions after that time were categorized as "late."
Among the five late-infusion patients, four failed to achieve pathological complete response (pCR) and one developed distant recurrence to the lung. In contrast, four of five early-infusion patients achieved pCR, and all five remained recurrence-free at the time of analysis. No treatment-related deaths or severe immunotherapy toxicities were reported. The authors acknowledged the sample size limitation and noted that further analysis of a larger dataset is underway.
Clinical Implications and Next Steps
The A-BRAVE investigators emphasized that these exploratory findings, while statistically compelling, require clinical and biological validation before any change in clinical practice can be recommended. The opposite timing effects observed in immune-hot versus immune-cold tumors suggest that a one-size-fits-all approach to immunotherapy scheduling may not be appropriate, and that baseline tumor immune profiling could eventually guide personalized infusion timing.
The growing body of circadian immuno-oncology evidence—spanning metastatic melanoma, renal cell carcinoma, non-small cell lung cancer, and now early-stage TNBC—underscores the need for prospective trials specifically designed to test timing hypotheses in biomarker-defined populations.