The Research Progress on the Prognostic Value of the Common Hematological Parameters in Peripheral Venous Blood in Breast Cancer

Abstract

Breast carcinoma is one of the most malignant tumors, severely influencing the physical and mental health of people. The latest epidemiological and clinical studies have found that breast tumor and inflammation are determinate relationships with each other. Inflammation is an essential component of the tumor microenvironment, and the change of inflammatory cells might influence tumor progression, such as neoplastic cell proliferation, migration, invasion, the collapse of antitumor immunity, metastasis and so forth. Peripheral blood tests at the time of diagnosis and treatment can reflect inflammatory conditions within the neoplasm. Evaluation of peripheral blood parameters including white blood cell, neutrophil, lymphocyte, monocyte, platelet counts, as well as neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (d-NLR) (neutrophil count divided by the result of white blood cell count minus neutrophil count), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR), which are indicators of systematic inflammatory response, have been widely proposed as prognostic factors for many malignancies. To intensively study the relationship between the common markers in peripheral blood and the treatment or prognosis of breast cancer will have critical clinical significance and application prospect, and can provide useful information for the clinicians. Herein, we review the research progress in the prognostic role of the peripheral blood in breast cancer to provide a new method for the treatment and prognosis of breast cancer.

Keywords: LMR; NLR; PLR; breast cancer; lymphocyte-to-monocyte ratio; neutrophil-to-lymphocyte ratio; platelet to lymphocyte ratio; prognosis.

Figure 1

Neutrophils enhance the migration, invasiveness and EMT of GC cells through IL-17a. (A) The effect of neutrophils on the migration ability of GC cells (MKN45 and MKN74) was determined 24 h when IL-17a neutralizing antibody or IgG isotype control antibody was added to Transwell co-culture chamber. Magnifications: × 100. *P < 0.05; **P < 0.001. (B) The effect of neutrophils on the invasion ability of GC cells (MKN45 and MKN74) was determined 24 h when IL-17a neutralizing antibody or IgG isotype control antibody was added to Transwell co-culture chamber. Magnifications: × 100. *, P < 0.05; **, P < 0.001. (C) Protein expression of E-cadherin, Vimentin, and ZEB1 in GC cells (MKN45 and MKN74) co-cultured with neutrophils was analyzed by Western blot when IL-17a neutralizing antibody or IgG isotype control antibody was added to the Transwell co-culture system. Densitometric analysis of E-cadherin, Vimentin, and ZEB1 expression was shown. **P < 0.001. Epithelial to mesenchymal transition (EMT) can contribute to gastric cancer (GC) progression and recurrence following therapy. The results indicated that neutrophils were widely distributed in gastric tissues of patients with GC and were enriched predominantly at the invasion margin, and was the independent predictor of poor disease-free survival (DFS) and disease-specific survival (DSS). Moreover, IL-17a was produced at the highest levels in co-culture compared with that in TANs not undergoing co-culture, and the TANs enhanced the migration, invasion and EMT of GC cells through the secretion of IL-17a. The conclusions prove that neutrophils correlate with tumor stage and predict poor prognosis in GC. TANs produce IL-17a and the IL-17a-targeted therapy might be used to treat patients with GC. Reprinted from Li et al. Copyright © The Author(s). 2019. (This work was published and licensed by BioMed Central).

Figure 2

Platelet releasates enhance cell proliferation without affecting apoptosis of breast cancer cells. Breast cancer cell lines MCF-7 and MDA-MB-231 were treated with or without 10% (final concentration) of PAR1-PR or PAR4-PR under a serum-free culture condition. (A) Cell proliferation rate was detected at indicated time points using a CCK assay. The fold increases of OD values, proportional to the increase of cell numbers, were referred to those at time 0. Data are presented as mean ± SEM from at least five independent experiments. ^#P<0.05, ^†P<0.001 vs control at corresponding time points. (B) CFSE fluorescence intensities of breast cancer cells were determined by flow cytometry after MCF-7 and MDA-MB-231 cells were cultured without (control; black solid lines) or with PAR1-PR (blue dash lines) or PAR4-PR (red dot lines) for 96 h. (C) Quantification of CFSE dilution. ^#P<0.05 vs control. (D) The MCF-7 and MDA-MB-231 cells were stained with FITC-conjugated Annexin V and PE-conjugated PI after 72 h of culture, and were examined using the Beckman Coulter F500 flow cytometer. Percentages of total apoptotic cells, that is, all Annexin-V-positive cells, were plotted. Images in (B and D) are the representatives from three independent experiments. A full color version of this figure is available at the British Journal of Cancer journal online. Selective platelet release of pro- or anti-angiogenic factors distinctly regulated angiogenesis. The results indicated that the PAR1-PR and PAR4-PR supplementation similarly enhanced cell proliferation of MCF-7 and MDA-MB-231 breast cancer cells, and the VEGF receptor blockade abolished PAR1-PR/PAR4-PR-enhanced cancer cell proliferation. Moreover, the Src and ERK inhibition diminished, and PI3K and PKC blockade abolished platelet releasate-enhanced cancer cell proliferation. The PAR1-PR enhanced tumour growth and angiogenesis more markedly than PAR4-PR. The conclusions prove that platelet releasate increases breast cancer cell proliferation through VEGF–integrin cooperative signaling, and proangiogenic factor-rich platelet releasate enhances cancer cell-induced angiogenesis more markedly. Reprinted from Jiang et al. Copyright © The Author(s). 2019. (This work was published and licensed by British Journal of Cancer.)

Figure 3

DFS and OS curves according to ratios. The comparison between the DFS of the groups classified by ratios revealed that those patients with both the patients with higher LMR and the ones with lower NLR had a better prognosis. The comparison between the OS of the groups classified by ratios revealed that those patients with low NLR had a better prognosis. Neoadjuvant chemotherapy in breast cancer is more and more standardized, and systemic inflammatory response is associated with the tumors. The results indicated that patients with high LMR and low NLR were associated with a lower percentage of relapse, and NLR was associated with a better survival. The conclusions prove that high LMR and low NLR can be considered as favourable prognostic factors in BC patients treated with neoadjuvant chemotherapy. Reprinted by permission from Springer Nature. Marín Hernández C, Piñero Madrona A, Gil Vázquez PJ, Galindo Fernández PJ, Ruiz Merino G, Alonso Romero JL, Parrilla Paricio P. Usefulness of lymphocyte-to-monocyte, neutrophil-to-monocyte and neutrophil-to-lymphocyte ratios as prognostic markers in breast cancer patients treated with neoadjuvant chemotherapy. Clin Transl Oncol. 2018; 20(4):476–483. Copyright © 2018, Clinical and Translational Oncology Available from: https://link.springer.com/journal/12094.

Figure 4

The relationship between NLR, PLR and ER, PR. (A) A higher ER-positive proportion was observed primarily in those patients with lower NLR before treatment; (B) A higher ER-positive proportion was observed primarily in those patients with lower PLR before treatment; (C) No statistical difference was found between the NLRlow group and the NLRhigh group in the expression of PR; (D) The patients with lower PLR (PLR < 159.01) showed higher PR-positive expression when compared to the patients with higher PLR. Proinflammatory markers, including neutrophil/lymphocyte ratio and platelet/lymphocyte ratio, are associated with many aspects of different malignancies. The results indicated that the proportion of ER-positive breast cancers before NAC was higher both in low NLR group and low PLR group. And the patients with low pretreatment NLR or PLR had better responses to NAC than those with high NLR or PLR. The conclusions prove that the patients with low pretreatment NLR or PLR had higher ER expression, and Pretreatment NLR and PLR may be important predictive indicators for neoadjuvant chemotherapy response in breast cancer patients. Reprinted by permission from Springer Nature. Xu J, Ni C, Ma C, Zhang L, Jing X, Li C, Liu Y, Qu X. Association of neutrophil/lymphocyte ratio and platelet/lymphocyte ratio with ER and PR in breast cancer patients and their changes after neoadjuvant chemotherapy. Clin Transl Oncol. 2017;19(8): 989–996. Copyright © 2017, Clinical and Translational Oncology. Available from: https://link.springer.com/journal/12094.

Figure 5

(A) Disease-free survival rates of 155 patients with hormone receptor-negative, HER2+ breast cancer according to low and high SII; (B) Distant metastasis-free survival rates of 155 patients with hormone receptor-negative, HER2+ breast cancer according to low and high SII; (C) Overall survival rates of 155 patients with hormone receptor-negative, HER2+ breast cancer according to low and high SII. The pretreatment systemic immune-inflammation index (SII) in hormone receptor-negative, human epidermal growth factor receptor 2+ (HER2+) breast cancer patients was used to predict the survival. The results showed that HER2+ patients with high and low SII had median DFS of 15.1 and 31.5 months, respectively; and the median OS of 54.5 and 71.1 months, respectively. The multivariate analysis had revealed increased SII independently linked to poor DFS. The conclusions prove that SII independently predicts poor survival for hormone receptor-negative, HER2+ breast cancer patients. Reprinted from Sun Y, Li W, Li AJ, Su H, Yue J, Yu J. Increased systemic immune-inflammation index independently predicts poor survival for hormone receptor-negative, HER2-positive breast cancer patients. Cancer Manag Res. 2019;11:3153–3162. © 2019 Sun et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/).