RBC Balanced Immuno-inflammatory Signatures Identify Advanced Breast Cancer Patients on CDK4/6 Inhibitors at Increased Risk of Progression and Death

Recent studies show red blood cell (RBC) plays an essential role in regulating immunity. Nevertheless, the association of immuno-inflammatory parameters, especially RBC balanced signatures, with survival outcomes and adverse events still require investigation for advanced breast cancer (ABC) patients receiving cyclin-dependent kinases 4/6 inhibitor (CDKI). Herein, the predictive and prognostic performance of novel RBC balanced immuno-inflammatory (RBC-IMM) parameters is evaluated relative to classical-IMM ones. A total of 100 CDKI-treated ABC patients are included. The RBC-IMM score prominently recognizes patients at high risk of progression-free survival (PFS) events (P < 0.001), death (P < 0.001), grade 3/4 leukopenia (P = 0.010) and increased aspartate aminotransferase (P = 0.049). Interestingly, RBC-IMM score predicts the PFS more accurately than classical-IMM score (AUC = 0.766 and 0.596, P = 0.005). Clinico+RBC_index exhibits superior performance to clinico_index in terms of PFS with the addition of RBC-IMM score to clinical features. Furthermore, metabolomics analysis identifies phosphatidylcholine (PtdCho) notably involved in the interplay between RBC-mediated immuno-inflammation and CDKI efficacy, based on which clinico+PtdCho_index is developed to optimize PFS prediction of clinico_index. All these findings indicate that novel RBC-IMM related parameters have the advantage of identifying benefit and safety in CDKI-treated ABC patients over classical indicators, offering clinical implications of underlying mechanisms for erythroid lineage specific differential metabolites.