Research ArticleClinical Studies

Absolute Lymphocyte Count Is an Independent Prognostic Factor for ER-positive HER2-negative Advanced Breast Cancer Patients Treated With CDK4/6 Inhibitors

HARUKA KANAOKA, MASAYUKI NAGAHASHI, YUSA ATAKE, AKIRA HATTORI, AYAKO BUN, REIKO FUKUI, HIROMI OZAWA, YUKIE FUJIMOTO, TOMOKO HIGUCHI, KEIKO NATORI, MICHIKO IMAMURA, KEIKO MURASE, YUICHI TAKATSUKA and YASUO MIYOSHI
Anticancer Research October 2022, 42 (10) 4867-4878; DOI: https://doi.org/10.21873/anticanres.15992

Abstract

Background/Aim: The aim of this study was to elucidate the clinical significance of peripheral blood biomarkers, including absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and C-reactive protein (CRP) in patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative advanced breast cancer treated with the CDK4/6 inhibitors, abemaciclib and palbociclib. Patients and Methods: A total of 83 patients treated with fulvestrant plus abemaciclib or palbociclib were included in this study. Progression-free survival (PFS) and overall survival (OS) were compared in relation to baseline levels of ALC, NLR, PLR and CRP. Results: The cut-off values of ALC, NLR, PLR, and CRP for PFS were determined from the receiver operating characteristic curve using the Youden index for area under the curve and set at 1,212/μl, 1.964, 170 and 0.220 mg/dl, respectively. In the abemaciclib-treated group, ALC-high patients showed significantly better PFS than ALC-low patients (p=0.0151) and multivariate analysis revealed that ALC was an independent prognostic factor for PFS (p=0.0085). In the palbociclib-treated group, there was no significant relationship between any peripheral blood biomarkers and PFS. In both treatment groups, ALC-high patients showed significantly better OS than ALC-low patients (p=0.0169 and 0.0290, respectively). Multivariate analysis revealed ALC was an independent prognostic factor for OS in both abemaciclib- and palbociclib-treated groups (p=0.0112 and 0.0202, respectively). Conclusion: ALC is an independent prognostic factor for estrogen receptor-positive human epidermal growth factor receptor 2-negative advanced breast cancer patients treated with the CDK4/6 inhibitors abemaciclib and palbociclib.

Key Words:

Cyclin-dependent-kinase 4-6 (CDK4/6) inhibitors have significantly improved the treatment of estrogen receptor (ER)-positive human epidermal growth factor receptor 2 (HER2)-negative relapsed or unresectable advanced breast cancer (1-7). While three CDK4/6 inhibitors have been approved by the U.S. Food and Drug Administration to treat these advanced breast cancer patients, only palbociclib and abemaciclib are approved for use in Japan (8). Clinical trials and real-world data from our clinical experience have revealed that the clinical outcomes and side effects with palbociclib and abemaciclib appear to differ in every detail (8-10). Clinicians can maximize patient benefit through the proper use of each CDK4/6 inhibitor, which will require a deeper understanding of the characteristics of each.

Biomarkers can help to understand the mechanism by which a drug works and to identify patients that may benefit from its use. However, the only definitive predictive or prognostic factor for CDK4/6 inhibitors that has been established to date is ER status (11, 12). Peripheral blood biomarkers are highly versatile markers that reflect various conditions in a patient. For instance, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are biomarkers associated with systematic inflammation, while absolute lymphocyte count (ALC) is considered as a marker of the host immune condition (13). These peripheral blood biomarkers have also proven to be useful in a variety of cancer patients (13). For breast cancer patients, ALC and NLR have shown predictive and/or prognostic value in several situations (14-20). The significance of peripheral blood markers in relation to and between different CDK4/6 inhibitors has not yet been fully investigated.

The aim of this study was to elucidate the clinical significance of peripheral blood biomarkers in patients treated with CDK4/6 inhibitors and to clarify the differences in the roles of biomarkers between patients treated with abemaciclib or palbociclib to obtain a better understanding of the biology of patients undergoing these treatments.

Patients and Methods

Patient eligibility. A total of 89 patients who were treated with abemaciclib or palbociclib in addition to fulvestrant for unresectable breast cancer between December 2017 and February 2022 at Hyogo College of Medicine Hospital were consecutively screened for recruitment into this study. Of the 89 patients, six patients who were treated with abemaciclib or palbociclib for less than 21 days were excluded. This resulted in 83 patients being included in this retrospective study. The Institutional Review Board of the Hyogo College of Medicine has approved this study (No. 1969), which was planned in accordance with the Declaration of Helsinki. Since this study collected only retrospective clinical data and offered no risk to the patients, they were not asked for their written informed consent.

All patients included in this study were diagnosed with breast cancer by histological analysis. All cases were classified as ER-positive and HER2-negative, where cancers were considered ER-positive with nuclear staining of 1% or more, and HER2-negative with either an immunohistochemistry score of zero/1+ or 2+ with no HER2 amplification, as confirmed by in situ hybridization. The number of patients with de novo stage IV and recurrent tumors were 31 and 52, respectively, and the number of patients with and without visceral metastasis were 52 and 31, respectively.

Treatment procedures and evaluation of outcome. Patients received an intramuscular injection of 500 mg fulvestrant on days 1 and 15 of cycle one and then on day 1 of each subsequent cycle (28 days). For treatment with palbociclib, patients also received 125 mg oral palbociclib once daily for 3 weeks, followed by a week off in a 28-day cycle. For treatment with abemaciclib, patients received 150 mg abemaciclib twice daily during each 28-day cycle. Treatment was discontinued with disease progression, unacceptable toxic effects, or death. If a patient experienced toxic effects related to any of these drugs, they underwent dose interruption, reduction or delay as per a predefined dose-modification strategy under the consideration of physicians. Of the 83 patients, 43 patients were treated with abemaciclib, 26 patients were treated with palbociclib, and 14 patients were treated with both abemaciclib and palbociclib. Among these latter 14 patients, 12 were initially treated with palbociclib followed by abemaciclib, and two were initially treated with abemaciclib followed by palbociclib. Thus, in this study, a total of 57 patients were treated with abemaciclib (abemaciclib group) and 40 patients were treated with palbociclib (palbociclib group), including the patients who received both treatments.

Progression-free survival (PFS) was defined as the period from the start of abemaciclib or palbociclib treatment until disease progression or death due to any reason (median, 8.4 months; range=0.7-46.3 months). Similarly, overall survival (OS) was defined as the period from the start of abemaciclib or palbociclib treatment to death from any reason (median, 22.5 months; range=4.0-48.3 months).

Measurements of ALC, NLR, PLR, and CRP. Neutrophil, lymphocyte, and platelet counts were automatically measured using Sysmex hematology analyzers XN-9000 (Sysmex Corporation, Kobe, Japan) in the Hyogo College of Medicine Hospital. The NLR was calculated by dividing the number of neutrophils by the number of lymphocytes in each patient. Similarly, the PLR was calculated by dividing the number of platelets by the number of lymphocytes in each patient. C-reactive protein (CRP) was measured with LABOSPECT008 (Hitachi High-Technologies Corporation, Tokyo Japan) in the Hyogo College of Medicine Hospital, where the normal range of CRP was ≤0.3 mg/dl. Blood was collected immediately before the first administration of abemaciclib or Palbociclib.

Statistical analysis. The cut-off value of the peripheral blood biomarkers, ALC, NLR, PLR, and CRP, for PFS was calculated from the receiver operating characteristic curve using the Youden index for areas under the curve (AUC). Kaplan–Meier plots and log-rank tests for PFS or OS were applied for each group. Univariate and multivariate analyses for PFS or OS were performed using a Cox proportional-hazards model to obtain the hazard ratio (HR) and 95% confidence interval (95%CI). Statistical significance was set at p<0.05 with a two-tailed test and statistical calculations were performed using JMP Pro 11 (SAS Institute Inc., Cary, NC, USA).

Results

Determination of optimal cut-off values of ALC, NLR, PLR, and CRP for PFS. Based on the receiver operating characteristic curve calculated using the Youden index for AUC, the optimal cut-off values for PFS ≥12 months were determined as 1,212/μl (AUC=0.655; sensitivity=0.729; specificity=0.563) for ALC, 1.964 mg/dl (AUC=0.562; sensitivity=0.540; specificity=0.616) for NLR, 170 mg/dl (AUC=0.611; sensitivity=0.680; specificity=0.579) for PLR, and 0.220 mg/dl (AUC=0.561; sensitivity=0.784; specificity=0.420) for CRP.

PFS of patients according to baseline ALC, NLR, PLR, and CRP levels. Among the 83 patients in the study, patients defined as CRP-low exhibited significantly better PFS than CRP-high patients (p=0.0150, Figure 1D). Neither ALC, NLR nor PLR was significantly associated with PFS among the 83 patients (Figure 1A-C). We next examined the impact of these markers on PFS in the subgroups of patients treated with abemaciclib or palbociclib. In the subgroup of patients treated with abemaciclib, ALC-high patients showed significantly better PFS than ALC-low patients (p=0.0151, Figure 2A). Neither NLR, PLR nor CRP was significantly associated with PFS in this subgroup (Figure 2B-D). In the subgroup of patients treated with palbociclib, there was no significant relationship between any peripheral blood biomarker and PFS (Figure 2E-H).

Figure 1.
Figure 1.

Kaplan–Meier plot of progression-free survival (PFS) in 83 patients according to baseline levels of (A) absolute lymphocyte count (ALC), (B) neutrophil-to-lymphocyte ratio (NLR), (C) platelet-to-lymphocyte ratio (PLR) and (D) C-reactive protein (CRP).

Figure 2.
Figure 2.

Kaplan–Meier plot of progression-free survival (PFS) in patients treated with abemaciclib (A-D) or palbociclib (E-F). PFS in patients treated with abemaciclib is shown according to baseline levels of (A) absolute lymphocyte count (ALC), (B) neutrophil-to-lymphocyte ratio (NLR), (C) platelet-to-lymphocyte ratio (PLR) and (D) C-reactive protein (CRP). PFS in patients treated with palbociclib is shown according to baseline levels of (E) ALC, (F) NLR, (G) PLR and (H) CRP.

Univariable and multivariable analyses for PFS in patients treated with abemaciclib or palbociclib. In the subgroup of patients treated with abemaciclib, univariate analysis revealed that ALC was a significant prognostic factor for PFS (p=0.0160, Table I). Among those patients, multivariate analysis including ALC and other clinical parameters (menopausal status, primary advanced or recurrence, metastatic sites, prior chemotherapy, treatment line) revealed that ALC was an independent prognostic factor for PFS (p=0.0085, Table I). In the subgroup of patients treated with palbociclib, univariate analysis revealed that none of the peripheral biomarkers were a significant prognostic factor for PFS (Table II). Among the clinical parameters, treatment line was a significant prognostic factor for PFS (p=0.0026, Table II). In this subgroup, multivariate analysis including treatment line and other clinical parameters revealed that treatment line was an independent prognostic factor for PFS (p=0.0031, Table II).

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Table I.

Univariate and multivariate analyses of progression-free survival for patients treated with abemaciclib.

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Table II.

Univariate and multivariate analyses of progression-free survival for patients treated with Palbociclib.

Subgroup analyses of PFS in patients treated with abemaciclib according to clinical factors. Since ALC levels were significantly associated with PFS in the subgroup of patients treated with abemaciclib, the relationship between ALC levels and PFS was further investigated in this subgroup (Figure 3). ALC-high patients showed consistently longer PFS than ALC-low patients, irrespective of menopausal status, metastatic sites, prior chemotherapy, or treatment line (Figure 3). In patients with recurrence (HR=0.360; 95%CI=0.156-0.787), but not patients with primary advanced disease (HR=0.987, 95%CI=0.321-2.878), PFS was better in ALC-high patients than ALC-low patients (Figure 3). ALC-high patients also showed consistently longer PFS than ALC-low patients in the subgroups of non-visceral metastasis (HR=0.197, 95%CI=0.052-0.639), NLR-low (HR=0.359, 95%CI=0.145-0.890), and CRP-low (H=0.317, 95%CI=0.114-0.771), as compared with the subgroups of visceral metastasis (HR=0.568, 95%CI=0.249-1.228), NLR-high (HR=0.761, 95%CI=0.246-1.992), and CRP-high (HR=0584, 95%CI=0.204-1.632) (Figure 3).

Figure 3.
Figure 3.

Forest plots of absolute lymphocyte count (ALC) levels for progression free survival. The dashed line shows a hazard ratio of 0.463 and a 95% confidence interval of 0.241-0.867 in all patients. NLR: Neutrophil-to-lymphocyte ratio; PLR: platelet-to-lymphocyte ratio; CRP: C-reactive protein.

OS of patients according to baseline ALC, NLR, PLR and CRP levels. Among the 83 patients studied, OS in ALC-high patients was significantly better than in ALC-low patients (p=0.0068, Figure 4A). OS in PLR-low patients was also significantly better than in PLR-high patients (p=0.0367, Figure 4C). Neither NLR nor CRP was significantly associated with OS (Figure 4B and D). In the subgroup of patients treated with abemaciclib, OS in ALC-high patients was significantly better than in ALC-low patients (p=0.0169, Figure 5A). Neither NLR, PLR nor CRP was significantly associated with OS in patients in this subgroup (Figure 5B-D). In the subgroup of patients treated with palbociclib, OS in ALC-high patients was significantly better than in ALC-low patients (p=0.0290, Figure 5E). OS in PLR-low patients was also significantly better than in PLR-high patients (p=0.0210, Figure 5G). Neither NLR nor CRP was significantly associated with OS (Figure 5F and H).

Figure 4.
Figure 4.

Kaplan–Meier plot of overall survival (OS) in 83 patients according to baseline levels of (A) absolute lymphocyte count (ALC), (B) neutrophil-to-lymphocyte ratio (NLR), (C) platelet-to-lymphocyte ratio (PLR) and (D) C-reactive protein (CRP).

Figure 5.
Figure 5.

Kaplan–Meier plot of overall survival (OS) in patients treated with abemaciclib (A-D) or palbociclib (E-F). OS in patients treated with abemaciclib is shown according to baseline levels of (A) absolute lymphocyte count (ALC), (B) neutrophil-to-lymphocyte ratio (NLR), (C) platelet-to-lymphocyte ratio (PLR) and (D) C-reactive protein (CRP). OS in patients treated with palbociclib is shown according to baseline levels of (E) ALC, (F) NLR, (G) PLR and (H) CRP.

Univariable and multivariable analyses for OS in patients treated with abemaciclib according to clinical factors. In the subgroup of patients treated with abemaciclib, univariate analysis revealed that ALC was a significant prognostic factor for OS (p=0.0136, Table III). Among these patients, multivariate analysis including ALC and other clinical parameters revealed ALC was an independent prognostic factor for OS (p=0.0112, Table III).

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Table III.

Univariate and multivariate analyses of overall survival for patients treated with abemaciclib.

In the subgroup of patients treated with palbociclib, univariate analysis revealed that ALC and PLR were significant prognostic factors for OS (p=0.0463 and p=0.0265, respectively, Table IV). Among these patients, multivariate analysis including ALC and other clinical parameters revealed ALC was an independent prognostic factor for OS (p=0.0202, Table IV). Similarly, multivariate analysis including PLR and other clinical parameters revealed PLR was also an independent prognostic factor for OS (p=0.0053, Table IV).

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Table IV.

Univariate and multivariate analyses of overall survival for patients treated with Palbociclib.

Discussion

In the current study, we revealed the clinical significance of peripheral blood biomarkers, including ALC, in patients with ER-positive HER2-negative advanced breast cancer treated with the CDK4/6 inhibitors, abemaciclib and palbociclib. Our study found ALC is an independent prognostic factor in advanced breast cancer patients treated with both abemaciclib and palbociclib. Furthermore, we found that the roles of the peripheral blood biomarkers slightly differ between the abemaciclib-treated group and the palbociclib-treated group. These findings indicate that the mechanisms of action of abemaciclib and palbociclib differ despite both drugs being effective in ER-positive HER2-negative advanced breast cancer patients. To our knowledge, this is the first study to show the clinical impact of ALC in breast cancer patients treated with palbociclib or abemaciclib. We believe that these are important and suggestive findings when considering the effective usage of these drugs.

Our study revealed that ALC is an independent prognostic factor for OS for both abemaciclib and palbociclib treatments. Previously, it was suggested that baseline ALC may have prognostic value when assessing potential response to hormone therapy in breast cancer patients (21). More recently, it was reported that OS in ALC-high patients was significantly better than in ALC-low patients among ER-positive HER2-negative advanced breast cancer patients treated with palbociclib (22), which agrees with our results. Based on previous reports, a low lymphocyte count in peripheral blood may reflect both a weak immunological condition of the host and a high tumor burden (23). Considering the action of CDK4/6 inhibitors may be exerted in cooperation with tumor immunity, such as CD8-positive T cells (24), CDK4/6 inhibitors may be less effective in patients presenting a low-ALC baseline due to an insufficient immune system to work cooperatively with the drugs.

The current study also showed that ALC is an independent prognostic factor for PFS in patients treated with abemaciclib but not palbociclib. These findings indicate that ALC may be not only a prognostic factor, but also a predictive factor among patients treated with abemaciclib. It has been reported that CDK4/6 inhibitors are able to modulate the immune condition of the host (25). Previous preclinical and clinical evidence indicates that the anticancer activity of CDK4/6 inhibitors is not only due to blockade of the cell cycle but also due to a range of immunostimulatory effects, such as enhancement of antigen presentation, activation of effector T cells and suppression of regulatory T cells (26, 27). The PFS and OS analyses in the current study suggest the influence of baseline ALC on drug effectiveness is more prominent in the abemaciclib-treated group than the palbociclib-treated group. This difference in the degree of influence of baseline ALC between abemaciclib and palbociclib treatment may reflect differences in immunostimulatory effects.

The subgroup analysis for patients treated with abemaciclib revealed that ALC-high patients showed consistently longer PFS in the subgroups of recurrence, non-visceral metastasis, NLR-low and CRP-low, compared with the subgroups of primary advanced disease, visceral metastasis, NLR-high and CRP-high. Considering recurrence and non-visceral metastasis may theoretically have a lower tumor burden compared with primary advanced disease and visceral metastasis (28), and that NLR-low and CRP-low usually indicate lower inflammation (29), a lower tumor burden or lower inflammation are considered favorable conditions for anti-tumor immunity. Taking everything into account, the clinical impact of ALC in patients treated with abemaciclib may reflect an immunomodulatory function of abemaciclib.

The main limitations of this study are the retrospective nature of the analysis and the low number of patients included. Nevertheless, the current study revealed the clinical significance of ALC in patients treated with either abemaciclib or palbociclib. Another implication of the current study is that the differences observed between patients treated with abemaciclib and palbociclib may reflect differences in immunostimulatory effects between these drugs. These findings need to be verified in larger prospective studies.

In conclusion, ALC is an independent prognostic factor for ER-positive HER2-negative advanced breast cancer patients treated with CDK4/6 inhibitors, including abemaciclib and palbociclib. Our findings suggest an immunomodulatory function of CDK4/6 inhibitors, which is important for understanding the mechanisms of action of these drugs and considering the treatment strategy for cancer patients.

Acknowledgements

The Authors thank ClearScience (http://www.clearscience.net/) for English language editing.

Footnotes

  • Authors’ Contributions

    All Authors contributed to the study conception and design. HK, YA, AH, AB, RF, HO, YF, TH, KN, MI, KM, and YT contributed to data collection. HK, MN and YM contributed to statistical analysis. YM supervised the entire study. HK and MN wrote the first draft of the manuscript and all authors commented on previous versions of manuscript. All Authors read and approved the final manuscript.

  • Conflicts of Interest

    M Nagahashi received honoraria from Chugai, AstraZeneca, Eli Lilly, Pfizer, Novartis, Taiho, Daiichi Sankyo, Esai, Kyowa-Kirin, and Denka. Y Miyoshi received research funding and honoraria from Esai, Chugai, AstraZeneca, Eli Lilly, Pfizer, MSD, Kyowa-Kirin, Daiichi-Sankyo, and Taiho. H Kanaoka, A Bun, R Fukui, H Ozawa, T Higuchi, K Natori, M Imamura, and Y Takatsuka have no conflict of interest.

  • Funding

    This work was supported by the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research Grant Number 22H03140 and 21K19522 for MN, 22K08764 for YM.

  • Received July 24, 2022.
  • Revision received August 8, 2022.
  • Accepted August 9, 2022.

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Absolute Lymphocyte Count Is an Independent Prognostic Factor for ER-positive HER2-negative Advanced Breast Cancer Patients Treated With CDK4/6 Inhibitors
HARUKA KANAOKA, MASAYUKI NAGAHASHI, YUSA ATAKE, AKIRA HATTORI, AYAKO BUN, REIKO FUKUI, HIROMI OZAWA, YUKIE FUJIMOTO, TOMOKO HIGUCHI, KEIKO NATORI, MICHIKO IMAMURA, KEIKO MURASE, YUICHI TAKATSUKA, YASUO MIYOSHI
Anticancer Research Oct 2022, 42 (10) 4867-4878; DOI: 10.21873/anticanres.15992
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