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 Kim, Min Hwan Kim, Jee Hung Kim, Seul Gi Kim, Gun Min Kim, Tae Yeong Kim, Won Ji Ryu, Jee Ye Kim, Hyung Seok Park, Seho Park, Young Up Cho, Byeong Woo Park, Seung Il Kim, Joon Jeong, Joohyuk Sohn

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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.

Original languageEnglish
Article number4
JournalBreast Cancer Research
Issue number1
Publication statusPublished - 2023 Dec

Bibliographical note

Funding Information:
This study was supported by the Industrial Core Technology Development Program of the Ministry of Trade, Industry & Energy of the Republic of Korea (20003773 to J.S.); the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF2020R1C1C1005934 to M.H.K.); the Yonsei University College of Medicine (6-2020-0128 to M.H.K.); and a Young Medical Scientist Research Grant Program of the Daewoong Foundation (DY20206P to C.G.K.).

Funding Information:
This publication uses data from Pfizer, Inc., that have been made available through Vivli, Inc. Vivli has not contributed to or approved, and is not in any way responsible for, the contents of this publication. The authors wish to thank the participants, the investigators, and the site personnel who participated in this study.

Publisher Copyright:
© 2023, The Author(s).

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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