On-treatment derived neutrophil-to-lymphocyte ratio and survival with palbociclib and endocrine treatment: analysis of a multicenter retrospective cohort and the PALOMA-2/3 study with immune correlates

Abstract

Background Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have been established as a standard treatment for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC); however, predictive biomarkers with translational relevance have not yet been elucidated. Methods Data from postmenopausal women who received the CDK4/6 inhibitor palbociclib and letrozole for HR-positive, HER2-negative ABC from tertiary referral centers were analyzed (N = 221; exploratory cohort). Pre- and on-treatment neutrophil-to-lymphocyte ratio (NLR) and derived NLR (dNLR; neutrophil/[leukocyte-neutrophil]) were correlated with survival outcomes. Data from the PALOMA-2 (NCT01740427) and PALOMA-3 studies (NCT01942135) involving patients treated with endocrine treatment with or without palbociclib were also analyzed (validation cohort). Prospectively enrolled patients (N = 20) were subjected to immunophenotyping with circulating immune cells to explore the biological implications of immune cell dynamics. Results In the exploratory cohort, palbociclib administration significantly reduced leukocyte, neutrophil, and lymphocyte counts on day 1 of cycle 2. Although the baseline dNLR was not significantly associated with progression-free survival (PFS), higher on-treatment dNLRs were associated with worse PFS (hazard ratio = 3.337, P < 0.001). In the PALOMA-2 validation cohort, higher on-treatment dNLRs were associated with inferior PFS in patients treated with palbociclib and letrozole (hazard ratio = 1.498, P = 0.009), and reduction in the dNLR after treatment was predictive of a survival benefit (hazard ratio = 1.555, P = 0.026). On-treatment dNLRs were also predictive of PFS following palbociclib and fulvestrant treatment in the PALOMA-3 validation cohort. Using flow cytometry analysis, we found that the CDK4/6 inhibitor prevented T cell exhaustion and diminished myeloid-derived suppressor cell frequency. Conclusions On-treatment dNLR significantly predicted PFS in patients with HR-positive, HER2-negative ABC receiving palbociclib and endocrine treatment. Additionally, we observed putative systemic immune responses elicited by palbociclib, suggesting immunologic changes upon CDK4/6 inhibitor treatment.

Ratios of monocytes and neutrophils to lymphocytes in the blood predict benefit of CDK4/6 inhibitor treatment in metastatic breast cancer

“…Interestingly, Kim et al determined NLR after one treatment cycle with high NLR to predict a reduced PFS 49 , 50 . However, this strategy is not usable for therapy decision making, because a predictive marker has to be evaluated before therapy start.…”

The combination of baseline neutrophil to lymphocyte ratio and dynamic changes during treatment can better predict the survival of osteosarcoma patients

“…Standard treatment for osteosarcoma patients includes 2-3 cycles of neoadjuvant chemotherapy prior to surgery, which inevitably affects the patient's immune cell population (35). However, previous studies have shown that the degree of chemotherapy's impact on different immune cells is not consistent, with a greater reduction observed in neutrophils compared to lymphocytes (29). This leads to a decrease in delta NLR in most patients with high baseline NLR, and the poor prognosis of patients with high baseline NLR is already widely recognized.…”

“…Among these, NLR research is the most extensive and has been incorporated into the latest guidelines for the diagnosis and treatment of urological system tumors (15,(23)(24)(25)(26). Although most studies examining the role of NLR in cancer have focused on baseline values, recent evidence suggests that the dynamic changes in NLR during treatment may be more informative in predicting patient prognosis (27)(28)(29). Chronic inflammation and immune dysfunction are hallmarks of cancer, and NLR reflects the interaction between these two processes.…”

GX-I7(rhIL-7-hyFc, efineptakin alfa), a long-acting IL-7, safely and effectively increased peripheral CD8+and CD4+T cells and TILs in patients with solid tumors

“…However, with the emergence of immune therapies, such as immune checkpoint inhibitors (ICI), T cells have become a central focus in engaging the immune system in battle against cancer (1). Previous studies have revealed that lymphopenia (2), including anti-cancer treatment-induced lymphopenia, is associated with inferior survival outcomes (3)(4)(5). Furthermore, a low response to ICI therapy has been observed in patients with low lymphocyte count (6).…”