Association of anemia and neutrophil-lymphocyte ratio with overall survival in breast cancer patients

Objective: The neutrophil-lymphocyte ratio (NLR) has been shown to correlate with disease progression and survival in a number of cancers. In this study we explore this ratio and a number of other blood-derived factors, including platelet-lymphocyte ratio (PLR) and hemoglobin levels, for their prognostic value with overall survival in breast cancer patients. Methods: A retrospective study was conducted with data from the medical records of patients with breast cancer (n = 303) collected from a breast cancer treatment and research clinic. The data included clinical staging at diagnosis, tumor size, axillary lymph node involvement, presence or absence of metastases, tumor histology, tumor grade, hormone receptor, treatments received (surgery, chemotherapy, hormonotherapy), overall survival, NLR, PLR, anemia, leukocytosis, neutrophilia, and lymphopenia. Cox regression was used to verify the influence of the variables on five-year overall survival of patients following their initial diagnosis. Results: Patients with NLR >4 showed association with staging >II (p < 0.05), with the presence of metastasis (p < 0.0001), and with negative hormone receptor (p < 0.0001). A hemoglobin <12 g/dL associated with staging >II (p < 0.0001), with the presence of metastasis (p < 0.0001), and with negative hormone receptor (p < 0.05). High values of NLR and PLR were associated with shorter overall survival by Kaplan-Meier survival curves (p < 0.001 and p = 0.021, respectively). After multivariate regression, tumor size, lymph node status, metastasis, NLR and anemia remained as factors that independently influenced mortality at 5 years. NLR >4 increased the risk of death by 7.76 times (p < 0.001) and hemoglobin <12 mg/d increased the risk of death by 2.47 times (p = 0.037). Conclusions: NLR and anemia are factors that independently correlate with overall survival in breast cancer patients. These factors have the advantage of being derived from simple and inexpensive blood testing.

Neutrophil-lymphocyte ratio; Anemia; Hemoglobin; Overall survival; Breast cancer

[1] International Agency for Research on Cancer (IARC). Cancer causes. 2020. Available at: http://gco.iarc.fr/today/data/factsheets/cancers/20-Breast-fact-sheet.pdf (Accessed: 24 October 2021).

[2] Brazil. Ministerio da Saúde. Estimativa 2021: incidência de câncer no Brasil. Instituto Nacional de Câncer José Alencar Gomes da Silva. 2021. Available at: https://www.inca.gov.br/tipos-de-cancer/cancer-de-mama (Accessed: 24 October 2021).

[3] Soerjomataram I, Louwman MWJ, Ribot JG, Roukema JA, Coebergh JWW. An overview of prognostic factors for long-term survivors of breast cancer. Breast Cancer Research and Treatment. 2008; 107: 309–330.

[4] Bundred NJ. Prognostic and predictive factors in breast cancer. Cancer Treatment Reviews. 2001; 27: 137–142.

[5] Cupp MA, Cariolou M, Tzoulaki I, Aune D, Evangelou E, Berlanga-Taylor AJ. Neutrophil to lymphocyte ratio and cancer prognosis: an um-brella review of systematic reviews and meta-analyses of observational studies. BMC Medicine. 2020; 18: 360.

[6] Paramanathan A, Saxena A, Morris DL. A systematic review and meta-analysis on the impact of pre-operative neutrophil lymphocyte ratio on long term outcomes after curative intent resection of solid tumours. Surgical Oncology. 2014; 23: 31–39.

[7] Koh C, Bhoo-Pathy N, Ng K, Jabir RS, Tan G, See M, et al. Utility of pre-treatment neutrophil–lymphocyte ratio and platelet–lymphocyte ratio as prognostic factors in breast cancer. British Journal of Cancer. 2015; 113: 150–158.

[8] Ethier J, 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 Research. 2017; 19: 2.

[9] Krenn-Pilko S, Langsenlehner U, Thurner E, Stojakovic T, Pichler M, Gerger A, et al. The elevated preoperative platelet-to-lymphocyte ratio predicts poor prognosis in breast cancer patients. British Journal of Cancer. 2014; 110: 2524–2530.

[10] Zhang Y, Chen Y, Chen D, Jiang Y, Huang W, Ouyang H, et al. Impact of preoperative anemia on relapse and survival in breast cancer patients. BMC Cancer. 2014; 14: 844.

[11] Dirican A, Kucukzeybek BB, Alacacioglu A, Kucukzeybek Y, Erten C, Varol U, et al. Do the derived neutrophil to lymphocyte ratio and the neutrophil to lymphocyte ratio predict prognosis in breast cancer?International Journal of Clinical Oncology. 2015; 20: 70–81.

[12] Azab B, Shah N, Radbel J, Tan P, Bhatt V, Vonfrolio S, et al. Pretreatment neutrophil/lymphocyte ratio is superior to platelet/lymphocyte ratio as a predictor of long-term mortality in breast cancer patients. Medical Oncology. 2013; 30: 432.

[13] Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proceedings of the National Academy of Sciences. 2001; 98: 10869–10874.

[14] Zhu Y, Si W, Sun Q, Qin B, Zhao W, Yang J. Platelet-lymphocyte ratio acts as an indicator of poor prognosis in patients with breast cancer. Oncotarget. 2017; 8: 1023–1030.

[15] Zhou X, Du Y, Huang Z, Xu J, Qiu T, Wang J, et al. Prognostic value of PLR in various cancers: a meta-analysis. PLoS ONE. 2014; 9: e101119.

[16] Kandemir E, Mayadagli A, Turken O, Yaylaci M, Ozturk A. Pre-treatment Haemoglobin Concentration is a Prognostic Factor in Patients with Early-stage Breast Cancer. Journal of International Medical Research. 2005; 33: 319–328.

[17] Lee C, Tsai C, Yeh D, Lin C, Li Y, Tzeng H. Hemoglobin level trajectories in the early treatment period are related with survival outcomes in patients with breast cancer. Oncotarget. 2016; 8: 1569–1579.

[18] Wan S, Lai Y, Myers RE, Li B, Palazzo JP, Burkart AL, et al. Post-diagnosis hemoglobin change associates with overall survival of multiple malignancies – results from a 14-year hospital-based cohort of lung, breast, colorectal, and liver cancers. BMC Cancer. 2013; 13: 340.

[19] Eichbaum MH, Weiss LM, Bruckner T, Schneeweiss A, Sinn HP, Gebauer G, et al. Prognostic impact of hemoglobin levels before and during carboplatin/taxane- based chemotherapy in patients with primary invasive epithelial ovarian cancer. Medical Science Monitor. 2009; 15: CR156–CR163.

[20] Pongsanon K, Benjapibal M, Ruengkhachorn I. Prognostic significance of hemoglobin levels in patients with primary epithelial ovarian carcinoma undergoing platinumbased chemotherapy. Asian Pacific Journal of Cancer Prevention. 2011; 12: 131–136.

[21] Nomelini RS, de Carvalho Oliveira LJ, Tavares-Murta BM, Murta EFC. Parameters of blood count and tumor markers: a retrospective analysis and relation to prognostic factors in ovarian cancer. European Journal of Gynaecological Oncology. 2017; 38: 364–367.

[22] Nomelini RS, da Silva TM, Tavares Murta BM, Murta EFC. Parameters of Blood Count and Tumor Markers in Patients with Borderline Ovarian Tumors: a Retrospective Analysis and Relation to Staging. ISRN Oncology. 2012; 2012: 947831.

[23] Bryne M, Eide GE, Lilleng R, Langmark F, Thrane PS, Dabelsteen E. A multivariate study of the prognosis of oral squamous cell carcinomas. are blood group and hemoglobin new prognostic factors? Cancer. 1991; 68: 1994–1998.

[24] Zhu W, Xu B. Association of pretreatment anemia with pathological response and survival of breast cancer patients treated with neoadjuvant chemotherapy: a population-based study. PLoS ONE. 2015; 10: e0136268.

[25] Lamy P, Durigova A, Jacot W. Iron homeostasis and anemia markers in early breast cancer. Clinica Chimica Acta. 2014; 434: 34–40.

[26] Candido J, Hagemann T. Cancer-Related Inflammation. Journal of Clinical Immunology. 2013; 33: 79–84.

[27] Bailur JK, Pawelec G, Hatse S, Brouwers B, Smeets A, Neven P, et al. Immune profiles of elderly breast cancer patients are altered by chemotherapy and relate to clinical frailty. Breast Cancer Research. 2017; 19: 20.

[28] Coffelt SB, Wellenstein MD, de Visser KE. Neutrophils in cancer: neutral no more. Nature Reviews Cancer. 2016; 16: 431–446.

[29] Gay LJ, Felding-Habermann B. Contribution of platelets to tumour metastasis. Nature Reviews Cancer. 2011; 11: 123–134.

[30] Criscitiello C, Esposito A, Trapani D, Curigliano G. Prognostic and predictive value of tumor infiltrating lymphocytes in early breast cancer. Cancer Treatment Reviews. 2016; 50: 205–207.

[31] Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008; 454: 436–444.