Original Study| Volume 23, ISSUE 3, e68-e76, April 2023

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Absolute Lymphocyte Count Changes During Neoadjuvant Chemotherapy are Associated With Prognosis of Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Patients

Published:January 11, 2023DOI:



      Some reports have shown that absolute lymphocyte count (ALC) is associated with prognosis in breast cancer; however, the impact of ALC changes remains unclear. This study aimed to investigate the relationship between ALC changes during neoadjuvant chemotherapy for human epidermal growth factor receptor-2 (HER2)-positive breast cancer patients and disease prognosis.

      Patients and Methods

      This retrospective cohort study January 2010 to September 2020) included patients diagnosed with HER2-positive breast cancer and treated with trastuzumab-based neoadjuvant chemotherapy. The ALC ratio was defined as the ALC value after administration of the anti-HER2 drug divided by the ALC value before administration. The optimal ALC ratio cut-off value was identified using the receiver operating characteristic curve analysis and Youden's index. The relationship between the ALC ratio and disease-free survival was assessed using the Kaplan–Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards model.


      Data from a total of 100 HER2-positive breast cancer patients were analyzed. The cut-off value of the ALC ratio was set as 1.142. The median follow-up period was 52.0 (range: 5.1-123.7) months. The 5-year disease-free survival rates were 88.4% and 60.9% in the high-and low-ALC ratio groups, respectively, and were significantly higher in the high-ALC ratio group (p = .0031). The ALC ratio was an independent prognostic factor in multivariate Cox proportional hazards analysis (p = .0032).


      HER2-positive breast cancer patients with a higher ALC ratio during trastuzumab-based neoadjuvant chemotherapy may have a better prognosis than their counterparts.



      NAC (neoadjuvant chemotherapy), HER-2 (human epidermal growth factor receptor-2), TNBC (triple-negative breast cancer), pCR (pathological complete response), NLR (neutrophil-to-lymphocyte ratio), PLR (platelet-to-lymphocyte ratio), ALC (absolute lymphocyte count), ADCC (antibody-dependent cell-mediated cytotoxicity), NK (natural killer cells), DFS (disease-free survival), HR (hazard ratio), CI (confidence interval), TIL (tumor-infiltrating lymphocytes)
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        • Kaufmann M
        • von Minckwitz G
        • Bear HD
        • et al.
        Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: new perspectives 2006.
        Ann Oncol. 2007; 18: 1927-1934
        • Untch M
        • Konecny GE
        • Paepke S
        • von Minckwitz G.
        Current and future role of neoadjuvant therapy for breast cancer.
        Breast. 2014; 23: 526-537
        • von Minckwitz G
        • Untch M
        • Blohmer JU
        • et al.
        Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes.
        J Clin Oncol. 2012; 30: 1796-1804
        • Kuerer HM
        • Newman LA
        • Smith TL
        • et al.
        Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy.
        J Clin Oncol. 1999; 17: 460-469
        • Cortazar P
        • Zhang L
        • Untch M
        • et al.
        Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.
        Lancet. 2014; 384: 164-172
        • Berruti A
        • Amoroso V
        • Gallo F
        • et al.
        Pathologic complete response as a potential surrogate for the clinical outcome in patients with breast cancer after neoadjuvant therapy: a meta-regression of 29 randomized prospective studies.
        J Clin Oncol. 2014; 32: 3883-3891
        • Masood S.
        Prognostic/predictive factors in breast cancer.
        Clin Lab Med. 2005; 25 (viii): 809-825
        • Hanahan D
        • Weinberg RA.
        Hallmarks of cancer: the next generation.
        Cell. 2011; 144: 646-674
        • Hong J
        • Chen X
        • Gao W
        • et al.
        A high absolute lymphocyte count predicts a poor prognosis in HER-2- positive breast cancer patients treated with trastuzumab.
        Cancer Manag Res. 2019; 11: 3371-3379
        • 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
        • Krenn-Pilko SK
        • Langsenlehner U
        • Thurner EM
        • et al.
        The elevated preoperative platelet-to-lymphocyte ratio predicts poor prognosis in breast cancer patients.
        Br J Cancer. 2014; 110: 2524-2530
        • Valachis A
        • Mauri D
        • Polyzos NP
        • Chlouverakis G
        • Mavroudis D
        • Georgoulias V.
        Trastuzumab combined to neoadjuvant chemotherapy in patients with HER2-positive breast cancer: a systematic review and meta-analysis.
        Breast. 2011; 20: 485-490
        • Buzdar AU
        • Valero V
        • Ibrahim NK
        • et al.
        Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen.
        Clin Cancer Res. 2007; 13: 228-233
        • Dawood S
        • Broglio K
        • Buzdar AU
        • Hortobagyi GN
        • Giordano SH.
        Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review.
        J Clin Oncol. 2010; 28: 92-98
        • Muntasell A
        • Cabo M
        • Servitja S
        • et al.
        Interplay between natural killer cells and anti-HER2 antibodies: perspectives for breast cancer immunotherapy.
        Front Immunol. 2017; 8: 1544
        • Valabrega G
        • Montemurro F
        • Aglietta M.
        Trastuzumab: mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer.
        Ann Oncol. 2007; 18: 977-984
        • Andre F
        • Dieci MV
        • Dubsky P
        • et al.
        Molecular pathways: involvement of immune pathways in the therapeutic response and outcome in breast cancer.
        Clin Cancer Res. 2013; 19: 28-33
        • Chen DS
        • Mellman I.
        Oncology meets immunology: the cancer-immunity cycle.
        Immunity. 2013; 39: 1-10
        • Leslie HS
        • Mary KG
        • Christian W.
        TNM Classification of Malignant Tumours.
        7th ed. Hodoken, NJ2009
        • Wolff AC
        • Hammond MEH
        • Allison KH
        • et al.
        Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline focused update.
        Arch Pathol Lab Med. 2018; 142: 1364-1382
        • Tiainen S
        • Rilla K
        • Hämäläinen K
        • Oikari S
        • Auvinen P.
        The prognostic and predictive role of the neutrophil-to-lymphocyte ratio and the monocyte-to-lymphocyte ratio in early breast cancer, especially in the HER2+ subtype.
        Breast Cancer Res Treat. 2021; 185: 63-72
        • Guo W
        • Lu X
        • Liu Q
        • et al.
        Prognostic value of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio for breast cancer patients: an updated meta-analysis of 17079 individuals.
        Cancer Med. 2019; 8: 4135-4148
        • De Giorgi U
        • Mego M
        • Scarpi E
        • et al.
        Relationship between lymphocytopenia and circulating tumor cells as prognostic factors for overall survival in metastatic breast cancer.
        Clin Breast Cancer. 2012; 12: 264-269
        • Che Y-Q
        • Zhang Y
        • Wang D
        • Liu HY
        • Shen D
        • Luo Y.
        Baseline lymphopenia: a predictor of poor outcomes in HER2 positive metastatic breast cancer treated with trastuzumab.
        Drug Des Dev Ther. 2019; 13: 3727-3734
        • Manuel M
        • Tredan O
        • Bachelot T
        • et al.
        Lymphopenia combined with low TCR diversity (divpenia) predicts poor overall survival in metastatic breast cancer patients.
        Oncoimmunology. 2012; 1: 432-440
        • Group French Adjuvant Study
        Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05 randomized trial.
        J Clin Oncol. 2001; 19: 602-611
        • Lo Nigro CL
        • Macagno M
        • Sangiolo D
        • Bertolaccini L
        • Aglietta M
        • Merlano MC.
        NK-mediated antibody-dependent cell-mediated cytotoxicity in solid tumors: biological evidence and clinical perspectives.
        Ann Transl Med. 2019; 7: 105
        • Eccles SA.
        Monoclonal antibodies targeting cancer: “magic bullets” or just the trigger?.
        Breast Cancer Res. 2001; 3: 86-90
        • Bianchini G
        • Gianni L.
        The immune system and response to HER2-targeted treatment in breast cancer.
        Lancet Oncol. 2014; 15: e58-e68
        • Loi S
        • Sirtaine N
        • Piette F
        • et al.
        Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98.
        J Clin Oncol. 2013; 31: 860-867
        • Inoue H
        • Horii R
        • Ito Y
        • Iwase T
        • Ohno S
        • Akiyama F.
        Tumor-infiltrating lymphocytes affect the efficacy of trastuzumab-based treatment in human epidermal growth factor receptor 2-positive breast cancer.
        Breast Cancer. 2018; 25: 268-274
        • Zhang L
        • Dermawan K
        • Jin M
        • et al.
        Differential impairment of regulatory T cells rather than effector T cells by paclitaxel-based chemotherapy.
        Clin Immunol. 2008; 129: 219-229
        • Ménétrier-Caux C
        • Curiel T
        • Faget J
        • Manuel M
        • Caux C
        • Zou W.
        Targeting regulatory T cells.
        Target Oncol. 2012; 7: 15-28