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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 
 BREAST CANCER RESEARCH, Vol.25(1) : 4, 2023-01 
Journal Title
Issue Date
Antineoplastic Combined Chemotherapy Protocols / adverse effects ; Breast Neoplasms* / metabolism ; Female ; Humans ; Letrozole / therapeutic use ; Lymphocytes / metabolism ; Neutrophils / metabolism ; Receptor, ErbB-2 / metabolism ; Retrospective Studies
Advanced breast cancer ; CDK4/6 inhibitor ; Neutrophil-to-lymphocyte ratio ; Palbociclib
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.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Gun Min(김건민) ORCID logo https://orcid.org/0000-0001-9167-8682
Kim, Min Hwan(김민환) ORCID logo https://orcid.org/0000-0002-1595-6342
Kim, Seul-gi(김슬기) ORCID logo https://orcid.org/0000-0003-1641-4059
Kim, Seung Il(김승일)
Kim, Jee Ye(김지예) ORCID logo https://orcid.org/0000-0003-3936-4410
Kim, Jee Hung(김지형) ORCID logo https://orcid.org/0000-0002-9044-8540
Kim, Chang Gon(김창곤)
Park, Byeong Woo(박병우) ORCID logo https://orcid.org/0000-0003-1353-2607
Park, Se Ho(박세호) ORCID logo https://orcid.org/0000-0001-8089-2755
Park, Hyung Seok(박형석) ORCID logo https://orcid.org/0000-0001-5322-6036
Sohn, Joo Hyuk(손주혁) ORCID logo https://orcid.org/0000-0002-2303-2764
Jeong, Joon(정준) ORCID logo https://orcid.org/0000-0003-0397-0005
Cho, Young Up(조영업) ORCID logo https://orcid.org/0000-0003-2936-410X
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