Background/Objectives: In metastatic breast cancer (MBC) treated with CDK4/6 inhibitors, baseline neutrophil-to-lymphocyte ratio (NLR) is an established prognostic marker. On-treatment NLR dynamics have shown inconsistent associations with survival, and no prior study has decomposed change into neutrophil-driven and lymphocyte-driven components.Methods: We retrospectively analyzed 352 patients with HR+/HER2− MBC treated with ribociclib. Using paired neutrophil and lymphocyte counts at baseline and 4 months, a log-linear decomposition classified patients into four NLR-trajectory phenotypes by dominant driver of change. Associations with progression-free survival (PFS) and overall survival (OS) were assessed using a 4-month landmark approach with multivariable Cox models, with robustness evaluated across four thresholds, tertiles, and a continuous model. Secondarily, NLR change was related to discordance between 3-month and best overall response.Results: NLR trajectory was not associated with PFS in any specification (multivariable hazard ratio [HR] 1.15 per standard deviation [SD], 95% CI 0.97–1.37, p=0.12), but was independently associated with OS: each 1-SD increment carried an HR of 1.40 (95% CI 1.18–1.67, p< 0.001), confirmed on bootstrap resampling. Adding NLR trajectory to a baseline clinical model improved discrimination (C-index +0.04) and fit (likelihood-ratio p< 0.001). Proportional hazards was violated for the phenotype term, indicating a time-varying effect within two years post-landmark. NLR trajectory was unrelated to dose-limiting neutropenia or dose reduction (both p>0.24). Primary refractory patients showed blunted NLR decline versus responding or stable patients (p=0.008), independent of baseline NLR.Conclusions: On-treatment NLR trajectory is a PFS-independent, toxicity-independent correlate of OS in ribociclib-treated MBC, distinct from direct tumor control. Prospective external validation is warranted.

Background/Objectives: In metastatic breast cancer (MBC) treated with CDK4/6 inhibitors, baseline neutrophil-to-lymphocyte ratio (NLR) is an established prognostic marker. On-treatment NLR dynamics have shown inconsistent associations with survival, and no prior study has applied a dominant-driver decomposition to classify patients by whether NLR change is neutrophil- or lymphocyte-driven. Methods: We retrospectively analyzed 352 patients with HR+/HER2− MBC treated with ribociclib. Using paired neutrophil and lymphocyte counts at baseline and at approximately 12 weeks (before cycle 4), a log-linear decomposition classified patients into four NLR-trajectory phenotypes by the dominant driver of change. Associations with progression-free survival (PFS) and overall survival (OS) were assessed using a 4-month landmark approach with multivariable Cox models, with consistency evaluated across four thresholds, tertiles, and a continuous model. Secondarily, NLR change was compared across five response-trajectory groups. Results: NLR trajectory was not associated with PFS in any specification (multivariable hazard ratio [HR] 1.15 per standard deviation [SD], 95% CI 0.97–1.37, p = 0.12) but was independently associated with OS (HR 1.40 per SD, 95% CI 1.18–1.67, p < 0.001), confirmed on bootstrap resampling. Adding NLR trajectory improved discrimination (C-index +0.04) and fit (likelihood-ratio p < 0.001). The OS effect was time-varying, attenuating beyond 24 months. NLR trajectory was unrelated to dose-limiting neutropenia (p = 0.58) or dose reduction (p = 0.69). Primary refractory patients showed blunted NLR decline versus responding or stable patients (p = 0.005), independent of baseline NLR. Conclusions: On-treatment NLR trajectory is a correlate of OS, independent of PFS, dose-limiting neutropenia, and dose reduction, in ribociclib-treated MBC, distinct from direct tumor control. Prospective validation is warranted.