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Published in: Breast Cancer 4/2020

Open Access 01-07-2020 | Breast Cancer | Original Article

High absolute lymphocyte counts are associated with longer overall survival in patients with metastatic breast cancer treated with eribulin—but not with treatment of physician’s choice—in the EMBRACE study

Authors: Yasuo Miyoshi, Yuta Yoshimura, Kenichi Saito, Kenzo Muramoto, Michiko Sugawara, Karenza Alexis, Kenichi Nomoto, Seigo Nakamura, Toshiaki Saeki, Junichiro Watanabe, Jose Manuel Perez-Garcia, Javier Cortes

Published in: Breast Cancer | Issue 4/2020

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Abstract

Background

Eribulin, a nontaxane synthetic inhibitor of microtubule dynamics, is widely used to manage locally advanced or metastatic breast cancer (MBC). Eribulin has demonstrated immunomodulatory activity on the tumour microenvironment. Baseline neutrophil-to-lymphocyte ratio (NLR), a marker of immune status, may predict progression-free survival in eribulin treatment. This post hoc analysis assessed predictors for overall survival (OS).

Methods

The phase 3 open-label study (EMBRACE) of eribulin versus treatment of physician’s choice (TPC) in patients with MBC provided source data. Baseline absolute lymphocyte counts (ALCs) and NLR were evaluable in 751 and 713 patients, respectively.

Results

Eribulin prolonged OS versus TPC in patients with baseline ALC ≥ 1500/µl (hazard ratio [HR] 0.586; 95% confidence interval [CI] 0.437–0.784; P < 0.001). There was no significant difference by treatment for ALC < 1500/µl (HR 1.002; 95% CI 0.800–1.253; P = 0.989). Univariate and multivariate analyses were performed and identified baseline ALC as a potential predictor of OS in eribulin-treated patients. Interaction analysis of OS supported 1500/µl as a potentially differential cutoff value. NLR at a cutoff value of 3 was associated with prolonged OS (eribulin group). However, similar results were also observed in the TPC group, without apparent interaction effect, suggesting that NLR may be a general prognostic marker rather than a specific predictor of OS for eribulin.

Discussion

This hypothesis-generating study speculates that baseline ALC may be an independent predictor for longer OS in eribulin-treated MBC patients and could be clinically impactful because it can be evaluated without the need for additional invasive procedures.

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Appendix
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Literature
1.
go back to reference Halaven (eribulin mesylate) [prescribing information]. Woodcliff Lake, NJ: Eisai Inc.; 2017. Halaven (eribulin mesylate) [prescribing information]. Woodcliff Lake, NJ: Eisai Inc.; 2017.
2.
go back to reference Halaven 0.44 mg/ml solution for injection [summary of product characteristics]. Hertfordshire, UK: Eisai Europe Limited; 2019. Halaven 0.44 mg/ml solution for injection [summary of product characteristics]. Hertfordshire, UK: Eisai Europe Limited; 2019.
3.
go back to reference Halaven [Japanese prescribing information]. Tokyo, Japan: Eisai Co., Ltd; 2016. Halaven [Japanese prescribing information]. Tokyo, Japan: Eisai Co., Ltd; 2016.
4.
go back to reference Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, et al. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377:914–23.CrossRef Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, et al. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377:914–23.CrossRef
5.
go back to reference Yoshida T, Ozawa Y, Kimura T, Sato Y, Kuznetsov G, Xu S, et al. Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states. Br J Cancer. 2014;110:1497–505.CrossRef Yoshida T, Ozawa Y, Kimura T, Sato Y, Kuznetsov G, Xu S, et al. Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states. Br J Cancer. 2014;110:1497–505.CrossRef
6.
go back to reference Funahashi Y, Okamoto K, Adachi Y, Semba T, Uesugi M, Ozawa Y, et al. Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models. Cancer Sci. 2014;105:1334–422.CrossRef Funahashi Y, Okamoto K, Adachi Y, Semba T, Uesugi M, Ozawa Y, et al. Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models. Cancer Sci. 2014;105:1334–422.CrossRef
7.
go back to reference Kashiwagi S, Asano Y, Goto W, Takada K, Takahashi K, Noda S, et al. Use of tumor-infiltrating lymphocytes (TILs) to predict the treatment response to eribulin chemotherapy in breast cancer. PLoS ONE. 2017;12:e0170634.CrossRef Kashiwagi S, Asano Y, Goto W, Takada K, Takahashi K, Noda S, et al. Use of tumor-infiltrating lymphocytes (TILs) to predict the treatment response to eribulin chemotherapy in breast cancer. PLoS ONE. 2017;12:e0170634.CrossRef
8.
go back to reference Miyagawa Y, Araki K, Bun A, Ozawa H, Fujimoto Y, Higuchi T, et al. Significant association between low baseline neutrophil-to-lymphocyte ratio and improved progression-free survival of patients with locally advanced or metastatic breast cancer treated with eribulin but not with nab-paclitaxel. Clin Breast Cancer. 2018;18:400–9.CrossRef Miyagawa Y, Araki K, Bun A, Ozawa H, Fujimoto Y, Higuchi T, et al. Significant association between low baseline neutrophil-to-lymphocyte ratio and improved progression-free survival of patients with locally advanced or metastatic breast cancer treated with eribulin but not with nab-paclitaxel. Clin Breast Cancer. 2018;18:400–9.CrossRef
9.
go back to reference Noh H, Eomm M, Han A. Usefulness of pretreatment neutrophil to lymphocyte ratio in predicting disease-specific survival in breast cancer patients. J Breast Cancer. 2013;16:55–9.CrossRef Noh H, Eomm M, Han A. Usefulness of pretreatment neutrophil to lymphocyte ratio in predicting disease-specific survival in breast cancer patients. J Breast Cancer. 2013;16:55–9.CrossRef
10.
go back to reference Ethier JL, Desautels D, Templeton A, Shah PS, Amir E. Prognostic role of neutrophil-to-lymphocyte ratio in breast cancer: a systematic review and meta-analysis. Breast Cancer Res. 2017;19:2.CrossRef Ethier JL, Desautels D, Templeton A, Shah PS, Amir E. Prognostic role of neutrophil-to-lymphocyte ratio in breast cancer: a systematic review and meta-analysis. Breast Cancer Res. 2017;19:2.CrossRef
11.
go back to reference Liu H, Zhang T, Ye J, Li H, Huang J, Li X, et al. Tumor-infiltrating lymphocytes predict response to chemotherapy in patients with advance non-small cell lung cancer. Cancer Immunol Immunother. 2012;61:1849–56.CrossRef Liu H, Zhang T, Ye J, Li H, Huang J, Li X, et al. Tumor-infiltrating lymphocytes predict response to chemotherapy in patients with advance non-small cell lung cancer. Cancer Immunol Immunother. 2012;61:1849–56.CrossRef
12.
go back to reference Kocián P, Šedivcová M, Drgáč J, Cerná K, Hoch J, Kodet R, et al. Tumor-infiltrating lymphocytes and dendritic cells in human colorectal cancer: their relationship to KRAS mutational status and disease recurrence. Hum Immunol. 2011;72:1022–8.CrossRef Kocián P, Šedivcová M, Drgáč J, Cerná K, Hoch J, Kodet R, et al. Tumor-infiltrating lymphocytes and dendritic cells in human colorectal cancer: their relationship to KRAS mutational status and disease recurrence. Hum Immunol. 2011;72:1022–8.CrossRef
13.
go back to reference Lee WS, Kang M, Baek JH, Lee JI, Ha SY. Clinical impact of tumor-infiltrating lymphocytes for survival in curatively resected stage IV colon cancer with isolated liver or lung metastasis. Ann Surg Oncol. 2013;20:697–702.CrossRef Lee WS, Kang M, Baek JH, Lee JI, Ha SY. Clinical impact of tumor-infiltrating lymphocytes for survival in curatively resected stage IV colon cancer with isolated liver or lung metastasis. Ann Surg Oncol. 2013;20:697–702.CrossRef
14.
go back to reference Araki K, Ito Y, Fukada I, Kobayashi K, Miyagawa Y, Imamura M, et al. Predictive impact of absolute lymphocyte counts for progression-free survival in human epidermal growth factor receptor 2-positive advanced breast cancer treated with pertuzumab and trastuzumab plus eribulin or nab-paclitaxel. BMC Cancer. 2018;18:982.CrossRef Araki K, Ito Y, Fukada I, Kobayashi K, Miyagawa Y, Imamura M, et al. Predictive impact of absolute lymphocyte counts for progression-free survival in human epidermal growth factor receptor 2-positive advanced breast cancer treated with pertuzumab and trastuzumab plus eribulin or nab-paclitaxel. BMC Cancer. 2018;18:982.CrossRef
15.
go back to reference Ueda S, Saeki T, Takeuchi H, Shigekawa T, Yamane T, Kuji I, et al. In vivo imaging of eribulin-induced reoxygenation in advanced breast cancer patients: a comparison to bevacizumab. Br J Cancer. 2016;114:1212–8.CrossRef Ueda S, Saeki T, Takeuchi H, Shigekawa T, Yamane T, Kuji I, et al. In vivo imaging of eribulin-induced reoxygenation in advanced breast cancer patients: a comparison to bevacizumab. Br J Cancer. 2016;114:1212–8.CrossRef
16.
go back to reference Ito K, Hamamichi S, Abe T, Akagi T, Shirota H, Kawano S, et al. Antitumor effects of eribulin depend on modulation of the tumor microenvironment by vascular remodeling in mouse models. Cancer Sci. 2017;108:2273–80.CrossRef Ito K, Hamamichi S, Abe T, Akagi T, Shirota H, Kawano S, et al. Antitumor effects of eribulin depend on modulation of the tumor microenvironment by vascular remodeling in mouse models. Cancer Sci. 2017;108:2273–80.CrossRef
17.
go back to reference Zhao S, Yu W, Ukon N, Tan C, Nishijima KI, Shimizu Y, et al. Elimination of tumor hypoxia by eribulin demonstrated by 18F-FMISO hypoxia imaging in human tumor xenograft models. EJNMMI Res. 2019;9:51.CrossRef Zhao S, Yu W, Ukon N, Tan C, Nishijima KI, Shimizu Y, et al. Elimination of tumor hypoxia by eribulin demonstrated by 18F-FMISO hypoxia imaging in human tumor xenograft models. EJNMMI Res. 2019;9:51.CrossRef
18.
go back to reference Goto W, Kashiwagi S, Asano Y, Takada K, Morisaki T, Fujita H, et al. Eribulin promotes antitumor immune responses in patients with locally advanced or metastatic breast cancer. Anticancer Res. 2018;38:2929–38.PubMed Goto W, Kashiwagi S, Asano Y, Takada K, Morisaki T, Fujita H, et al. Eribulin promotes antitumor immune responses in patients with locally advanced or metastatic breast cancer. Anticancer Res. 2018;38:2929–38.PubMed
19.
go back to reference Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol. 2006;24:99–146.CrossRef Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol. 2006;24:99–146.CrossRef
20.
go back to reference Muto Y, Kitano S, Tsutsumida A, Namikawa K, Takahashi A, Nakamura Y, et al. Investigation of clinical factors associated with longer overall survival in advanced melanoma patients treated with sequential ipilimumab. J Dermatol. 2019;46:498–506.CrossRef Muto Y, Kitano S, Tsutsumida A, Namikawa K, Takahashi A, Nakamura Y, et al. Investigation of clinical factors associated with longer overall survival in advanced melanoma patients treated with sequential ipilimumab. J Dermatol. 2019;46:498–506.CrossRef
21.
go back to reference Ku GY, Yuan J, Page DB, Schroeder SE, Panageas KS, Carvajal RD, et al. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer. 2010;116:1767–75.CrossRef Ku GY, Yuan J, Page DB, Schroeder SE, Panageas KS, Carvajal RD, et al. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer. 2010;116:1767–75.CrossRef
22.
go back to reference Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, et al. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211:781–90.CrossRef Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, et al. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211:781–90.CrossRef
23.
go back to reference Taylor MA, Lee YH, Schiemann WP. Role of TGF-β and the tumor microenvironment during mammary tumorigenesis. Gene Expr. 2011;15:117–32.CrossRef Taylor MA, Lee YH, Schiemann WP. Role of TGF-β and the tumor microenvironment during mammary tumorigenesis. Gene Expr. 2011;15:117–32.CrossRef
Metadata
Title
High absolute lymphocyte counts are associated with longer overall survival in patients with metastatic breast cancer treated with eribulin—but not with treatment of physician’s choice—in the EMBRACE study
Authors
Yasuo Miyoshi
Yuta Yoshimura
Kenichi Saito
Kenzo Muramoto
Michiko Sugawara
Karenza Alexis
Kenichi Nomoto
Seigo Nakamura
Toshiaki Saeki
Junichiro Watanabe
Jose Manuel Perez-Garcia
Javier Cortes
Publication date
01-07-2020
Publisher
Springer Japan
Published in
Breast Cancer / Issue 4/2020
Print ISSN: 1340-6868
Electronic ISSN: 1880-4233
DOI
https://doi.org/10.1007/s12282-020-01067-2

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