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

(2023) 25:4 Kim et al. Breast Cancer Research https://doi.org/10.1186/s13058-022-01601-4 Breast Cancer Research Open Access RESEARCH 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 Chang Gon Kim1†, Min Hwan Kim1†, Jee Hung Kim2,3†, Seul‑Gi Kim1, Gun Min Kim1, Tae Yeong Kim4, Won‑Ji Ryu4, Jee Ye Kim5, Hyung Seok Park5, Seho Park5, Young Up Cho5, Byeong Woo Park5, Seung Il Kim5, Joon Jeong3,6* and Joohyuk Sohn1* 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 lym‑ phocyte counts on day 1 of cycle 2. Although the baseline dNLR was not significantly associated with progressionfree 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 † Chang Gon Kim, Min Hwan Kim and Jee Hung Kim contributed equally to this article *Correspondence: Joon Jeong Joohyuk Sohn Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Kim et al. Breast Cancer Research (2023) 25:4 Page 2 of 16 a survival benefit (hazard ratio = 1.555, P = 0.026). On-treatment dNLRs were also predictive of PFS following palbo‑ ciclib 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 receiv‑ ing palbociclib and endocrine treatment. Additionally, we observed putative systemic immune responses elicited by palbociclib, suggesting immunologic changes upon CDK4/6 inhibitor treatment. Keywords Advanced breast cancer, CDK4/6 inhibitor, Neutrophil-to-lymphocyte ratio, Palbociclib Background The cyclin D-cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma (RB) pathway is a fundamental component of cell cycle regulation and is implicated in the initiation and progression of various malignancies [1, 2]. In particular, alterations in the cyclin D-CDK4/6Rb pathway contribute to both de novo and acquired resistance to endocrine treatment in patients with hormone receptor (HR)-positive breast cancer [3, 4]. Hence, this pathway is an important target for pharmacologic permutations to overcome endocrine resistance. Concordantly, CDK4/6 inhibitors exhibit robust and durable clinical activity in treating HR-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) [5–8]. Among CDK4/6 inhibitors, palbociclib demonstrates significant efficacy in combination with letrozole as first-line therapy (PALOMA-2) or fulvestrant as later-line therapy (PALOMA-3) in HRpositive, HER2-negative ABC [9–12]. Although phase III studies consistently show clinical benefits of CDK4/6 inhibitors irrespective of menopausal status, visceral metastasis, or ethnicity, a subset of patients treated with CDK4/6 inhibitors exhibit an early progression, warranting the identification of biomarkers to predict treatment outcome. Unfortunately, previously identified potential biomarkers are inconsistent, have limited clinical feasibility, and do not reflect the dynamic changes induced by CDK4/6 inhibitors [13, 14]. In addition to the essential role of CDK4/6 in cell cycle progression through RB phosphorylation, which underlies the proliferation of HR-positive breast cancer cells [15], novel functions have been discovered [16]. CDK6 is involved in the proliferation and differentiation of hematopoietic cells [17–19]. Consequently, hematologic adverse events, including neutropenia, commonly occur after CDK4/6 inhibitor administration [9, 20]. Moreover, CDK4/6 inhibitors enhance antitumor immunity through tumor infiltration and activation of T cells via transcriptional reprogramming [21, 22]. Combining immune checkpoint and CDK4/6 inhibitors synergistically delays tumor growth, providing a rationale for combination strategies comprising CDK4/6 inhibitors and immunotherapies. In this context, a series of clinical trials testing various combinations of CDK4/6 and immune checkpoint inhibitors are currently underway. Baseline and/or treatment-related lymphopenia is associated with poor clinical outcomes in patients with various malignancies, including metastatic breast cancer [23–25]. Meanwhile, neutrophilia is generally associated with poor outcomes [26], consistent with preclinical evidence that phenotypic and functional characteristic (...truncated)