Lead Investigator: Min Hwan Kim, Yonsei University College of Medicine
Title of Proposed Research: Analysis of neutrophil to lymphocyte ratio (NLR) in ER+ breast cancer patients to predict palbociclib clinical response
Vivli Data Request: 5925
Funding Source: None
Potential Conflicts of Interest: None
Summary of the Proposed Research:
The PALOMA-2,3 study are randomized multicenter trials to test the efficacy and safety of Palbociclib in combination with endocrine therapy in advanced estrogen receptor (ER) + breast cancer patients, and showed superior efficacy of palbocicilb combination therapy compared to endocrine monotherapy. The cyclin dependent kinase (CDK) 4/6 selective inhibitor, palbociclib showed robust clinical benefit as both front-line (PALOMA-2) and later-line (PALOMA-3) therapy in ER+ breast cancer patients. However, the resistance to palbociclib develops after 2 years of therapy in average, and reliable clinical predictors are needed to predict palbociclib response. Recent studies showed that CDK4/6 inhibitor exhibit anti-tumor effect not only by inducing cell cycle arrest, but also by modifying tumor microenvironment and promoting anti-tumor immune response. In the preliminary analysis of palbociclib-treated patients in our institution (Yonsei Cancer Center), The high neutrophil-to-lymphocyte (NLR) ratio after 1 cycle of palbociclib treatment was significantly associated with progression-free survival of palbociclib + endocrine therapy, demonstrating immunologic biomarkers from peripheral blood can predict palbociclib response. It would be a significant advance if we can predict favorable and durable response to palbociclib using NLR in peripheral blood analysis. We propose a pooled analysis of palbociclib phase III trials (PALOMA-2 and PALOMA-3) to establish peripheral NLR or lymphocyte count as predictors for palbociclib response. The results of this study will affect treatment of all ER+ advanced breast cancer patients world wide, approxmately 300,000~400,000 patients per year worldwide and 20,000~30,000 patients per year in US. If the result can affect the adjuvant CDK4/6 treatment in the future, the result will affects ~ 1,000,000 cases worldwide ~100,000 cases in US every year.
Statistical Analysis Plan:
The absolute white blood cell (WBC) count and neutrophil counts at baseline, Day 15, Day 28, and later cycles will be collected in all patients. The student t-test and chi-square test will be performed to compare the categorical variables and continuous variables between the dNLR-low and dNLR-high patients, respectively. The Kaplan-Meier analysis will be performed to compare recurrence-free survival (RFS) and overall survival (OS) of patients, according to lymphocyte counts.
We will perform pooled analysis of all patients and 1st/2nd line therapy patients in PALOMA-2 and -3 data, and we will also analyze the impact of dNLR in PALOMA-2 and -3 patients separately, In the pooled analysis, hazard ratio for dNLR will be adjusted for combination partner (fulvestrant or letrozole) and line of therapy.
The patients with complete data of key variables (WBC count, neutrophil, and survival outcomes) will be included in the final analysis set, excluding patients with missing data. The balanced distribution of baseline characteristics (e.g., age, visceral metastasis, or endocrine resistance status) will be inspected in the final analysis set. The proper adjustment method will be incorporated (e.g., propensity matching) if needed, otherwise, the data set will be analyzed per se. The statistical analysis will be performed using R 3.5.2 on Vivli platform using proper R packages (e.g., survival, gglot2, etc.)
Study of Palbociclib (PD-0332991) + Letrozole vs. Letrozole For 1st Line Treatment Of Postmenopausal Women With ER+/HER2- Advanced Breast Cancer (PALOMA-2)
Study ID: NCT01740427
Palbociclib (PD-0332991) Combined With Fulvestrant In Hormone Receptor+ HER2-Negative Metastatic Breast Cancer After Endocrine Failure (PALOMA-3)
Study ID: NCT01942135
On-treatment derived neutrophil-to-lymphocyte ratio and response to palbociclib and letrozole: Analysis of a multicenter retrospective cohort and the PALOMA-2 study.
Chang Gon Kim, Min Hwan Kim, Jee Hung Kim, Seul-Gi Kim, Gun Min Kim, Tae Yeong Kim, Won-Ji Ryu, Jeeye Kim, Hyung Seok Park, Seho Park, Youngup Cho, Byeong-Woo Park, Seung Il Kim, Joon Jeong, and Joohyuk Sohn. Journal of Clinical Oncology 2021 39:15_suppl, 1066-1066.