The evidence for the use of peripheral blood indices in the diagnosis of breast cancer

Abstract

Diagnosis at early stages is critical for achieving favorable outcomes in patients with breast cancer. However, early breast cancer is characterized by atypical clinical and imaging manifestations, which are misdiagnosed as benign breast disease. This misdiagnosis may affect the choice of treatment, delay the patient’s condition, and affect survival. Therefore, identifying an effective and simple screening method to supplement existing screening methods is of considerable importance for improving diagnostic efficacy. Peripheral blood indices are simple, economical, and readily accessible that include routine blood indices, lipid indices, and coagulation indices. With in-depth research on tumor pathogenesis, the relationships between these indices and tumor development have been gradually revealed, suggesting their potential as diagnostic factors for breast cancer. This narrative review explores the development of peripheral blood indices for diagnosing breast cancer and their potential use in early diagnosis.

Introduction

Breast cancer is the most common malignancy among women worldwide, ¹ considerably affecting survival and quality of life. Diagnosing and treating breast cancer at an early stage via screening can reduce the disease burden on patients to some extent and enhance survival rates. ² Currently, pathological biopsy is the gold standard for diagnosing breast cancer. However, due to its invasive nature and challenges associated with obtaining samples repeatedly, clinical breast examination and imaging modalities are required as supplementary tools before establishing a final diagnosis. The accuracy of clinical breast examinations is relatively low, ³ which may be because early signs of breast cancer are not typical. Imaging modalities include breast ultrasound (BUS), mammography (MMG), and magnetic resonance imaging (MRI), each of which carries a risk of missed diagnosis. BUS has relatively low specificity, resulting in high recall and biopsy rates,^4,5 and its findings may be influenced by the operator. MMG has a relatively poor screening effect in patients with dense breast tissue; as breast density increases, both the sensitivity and specificity of MMG decrease. ⁶ MRI has the highest sensitivity among imaging examinations for the detection of breast cancer. ⁷ However, it is not routinely prioritized due to its high cost and long examination time. Consequently, there remains an urgent need to develop a breast cancer diagnostic method that has high sensitivity and specificity, is easy to operate, and can complement existing approaches for early detection and attainment of accurate, personalized medical care.

Peripheral blood indices include hematological and biochemical indices, providing a comprehensive overview of various body functions. Acquiring these indices is straightforward, and recent studies on tumor development and progression have gradually revealed associations between these indices and tumors. Studies indicate the significant role of the tumor microenvironment (TME) in tumor progression. The TME refers to the environment in which tumor cells reside, comprising cancer cells, a range of other body cells such as immune cells and adipocytes, the extracellular matrix, cytokines, and numerous other signaling molecules. ⁸ Tumor cells interact with their surrounding cellular environment. These cells influence the microenvironment by releasing signals that promote angiogenesis, among other processes, whereas the cellular microenvironment impacts tumor development and progression.^9–11 Evaluating indices related to the TME can, to some extent, reflect its status and predict the biological activity of tumors. These indices include routine blood indices for neutrophils and lymphocytes, lipid indices related to adipocytes and signaling molecules, and coagulation indices associated with coagulation factors, among others. Many of these indices have been studied to evaluate the diagnosis and prognosis of tumors.^12,13 However, in real-world clinical settings, healthcare professionals rely not just on a single diagnostic marker, as single indices fail to fully capture the complex biological characteristics of tumors. To the best of our knowledge, there are relatively few review articles on the application of peripheral blood indices in tumor diagnosis and treatment. In this narrative review, we selected three common clinical markers: blood counts, blood lipids, and coagulation indices. PubMed, Web of Science, and the Cochrane Library were independently searched. For example, in PubMed, free-text terms were added to subject headings using Boolean operators: (“breast cancer”) and (“peripheral blood indices”) and (“blood counts” or “neutrophils” or “lymphocytes” or “platelets” or “blood lipids” or “coagulation”) and (“diagnosis” or “diagnostic”). We aimed to expand on the theoretical underpinnings and clinical diagnostic significance of breast cancer, providing scientifically backed, evidence-based support for comprehensive, personalized breast cancer therapy.

Correlation between peripheral blood indices and breast cancer

Cancerous growth exhibits complex biological characteristics. Tumorigenesis is widely understood to involve a multifaceted signaling system comprising tumor cells, various cell types in the body, and their production of numerous cytokines, chemokines, and growth factors.^14,15 This signaling network facilitates multiple pathological and physiological processes, including inflammation, blood clotting, and energy metabolism, with additional effects on the patient. ¹⁶ Collectively, these insights provide a basis for the clinical selection of predictive markers in tumor diagnosis.

Correlation between blood cell counts and breast cancer

Blood cell count is a specific category assessed in routine blood tests. It is widely used alongside other routine blood indices and is cost-effective. The significance of blood cell counts in breast cancer originates from examining the link between tumors and inflammation. Studies have shown that interactions between cancer cells and inflammatory cells promote tumor growth and metastasis.^17,18 Subsequent studies have primarily focused on the interactions of neutrophils, lymphocytes, and platelets with tumors. Therefore, we have provided a detailed description of these three types of cells.

Neutrophils and tumors primarily interact by promoting both normal and abnormal angiogenesis, which in turn facilitates tumor growth and invasion. ¹⁹ The primary mechanism underlying this phenomenon is the suppression of tumor necrosis factor-α secretion by elevated neutrophil levels, resulting in increased release of vascular endothelial growth factor (VEGF) into the bloodstream. ²⁰ Concurrently, interactions between neutrophils and the TME may result in an increase in neutrophil count. Kwantwi et al ²¹ confirmed this mechanism through in vitro experiments, demonstrating that tumor-associated neutrophils (TANs), which are transformed from healthy neutrophils under the influence of tumor tissue, can effectively suppress T-cell immune responses. High TAN density is associated with poor prognosis in patients with breast cancer. ²² In addition, some studies have indicated that the TME in breast cancer promotes the transformation of neutrophils into TANs, which can be classified into two types: TAN1 and TAN2. In the early stages of tumors, TAN1 can prevent cancer cell metastasis by producing chemokines; however, as the tumor progresses, TAN1 gradually differentiates into TAN2, which promotes tumor growth.^23,24

Lymphocytes, particularly CD8+ T lymphocytes, are key cells in anticancer immune responses. Their effects on cancer cells can be mediated through the acceleration of apoptosis and other mechanisms. ²⁵ This process is primarily associated with the expression of immune checkpoint inhibitors or markers. ²⁶ Nevertheless, multiple lymphocyte subtypes exist, each playing distinct roles in tumor development and progression. For instance, T-helper (Th) 17 (Th17) and Th22 cells within these subgroups have been proposed to contribute to tumor development. ²⁷ Studies in patients with breast cancer indicate differences in lymphocyte levels among the disease’s molecular variants. Compared with triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2) + breast cancer, which are usually characterized by higher number of lymphocytes in the TME, luminal breast cancer often demonstrates reduced lymphocyte levels in the tumor area, ²⁸ with limited impact on overall tumor status. Although the precise relationship between different lymphocyte subtypes and tumors remains unclear, current evidence suggests a substantial lymphocyte presence in the TME associated with tumorigenesis.

An elevated platelet count is observed in approximately 20%–60% of patients with cancer, particularly in advanced stages of the disease. ²⁹ It is widely accepted that platelets contribute to tumor development and dissemination.^30,31 This process is supported by platelet-derived factors that promote angiogenesis, thereby contributing to tumor angiogenesis.^32–34 Simultaneously, when tumor cells activate platelets, receptors on the platelet membrane can interact with tissue cells, ³⁵ leading to disruption of the vascular basement membrane ³⁶ and subsequently promoting tumor growth and metastasis. Furthermore, patients with cancer frequently experience elevated blood coagulation due to multiple factors associated with coagulation dysregulation. The platelets, triggered by the tumor, become active and aggregate in the bloodstream, contributing to these processes.^37,38

Correlation between lipid indices and breast cancer

Aberrant energy metabolism is a well-recognized biological characteristic of cancer cells. In addition to the classical Warburg effect, unpredictable lipid metabolism may play a crucial role in the progression of cancer.^39,40 Common lipid assessments in clinical practice include total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). Studies have shown that elevated LDL-C levels are associated with an increased risk of breast cancer and can affect cell proliferation, potentially mediated by activation of cytochrome P450 enzymes, including sterol 27 hydroxylase and cholesterol 27-hydroxylase (CYP27A1), in breast cancer cells. ⁴¹ LDL-C can also upregulate the expression of various cancer-related gene products, thereby promoting the proliferation, migration, and invasion of cancer cells.^42,43 Regarding HDL-C, it can carry nonlipid components, including proteins, micro ribonucleic acids (microRNAs), hormones, and metabolites, through its metabolic pathways, a function considered important for tumor cell survival.^44,45 This is further supported by studies indicating that blocking relevant lipid metabolic pathways may inhibit tumor development.^46–48

Cholesterol processing is essential for lipid metabolism, and it has been proposed that cholesterol can activate the phosphatidylinositol 3-kinase/protein kinase B and Wnt signaling pathways, thereby promoting tumor cell growth and proliferation.^49,50 Given the pivotal role of estrogen in the progression of breast cancer, it has been suggested that blood lipids, particularly cholesterol, may influence the proliferation and progression of breast cancer cells by modulating estrogen levels. ⁵¹ This may occur because elevated cholesterol levels compete with sex hormone–binding globulin, resulting in increased endogenous estrogen levels and subsequently affecting the development and differentiation of breast epithelial cells. The relationship between molecular subtypes of breast cancer and cholesterol metabolism varies. In TNBC, endosulfine alpha (ENSA) as an important regulator of cholesterol biosynthesis activates signal transducer and activator of transcription 3 (STAT3), which can bind to the promoter of sterol regulatory element-binding transcription factor 2 (SREBP2) to enhance its transcription, and this process depends on protein phosphatase 2A (PP2A), a serine/threonine phosphatase. Ultimately, the increase in cholesterol biosynthesis promotes tumor growth. ⁵² In patients with hormone receptor–positive breast cancer, studies indicate that 27-hydroxycholesterol, a cholesterol metabolite, can promote tumor cell growth and proliferation. ⁵³ Luo et al. ⁵⁴ confirmed this finding and further demonstrated that zinc finger MYND-type containing 8 (ZMYND8) plays a key role in converting cholesterol into 27-hydroxycholesterol, an essential step in this process.

There remain differing views regarding the association between TG levels and breast cancer. Some studies suggest that TG contributes to the development of breast cancer through multiple pathways; for example, it may promote the proliferation, differentiation, and apoptosis of breast epithelial cells as well as increase the expression of estrogen receptors (ER). ⁵⁵ Subsequent studies have shown that, compared with adjacent normal tissues, the rate-limiting enzyme Lipin-1 in the TG synthesis pathway is expressed at significantly higher levels in breast cancer tissues, and that inhibiting its activity can reduce tumor cell migration and proliferation. ⁵⁶ Cho et al. ⁵⁷ reported that, during TG degradation, inhibition of the G0S2 gene suppressed the proliferation, migration, and invasion of breast cancer cells. However, other studies suggest that there is no direct association between TG levels and the risk of breast cancer.^58,59

Correlation between coagulation indices and breast cancer

The widespread presence of tumor cells affects multiple organ systems; in the hematologic system, it manifests as an increased risk of venous thromboembolism in patients with cancer, ⁶⁰ leading to excessive clot formation. Studies suggest that both hypercoagulable states and inconsistent fibrinolytic activity contribute significantly to the growth and progression of breast cancer. ⁶¹ Coagulation is initiated by abnormal activation of the coagulation cascade, in which tissue factor (TF) triggers downstream processes. Studies have shown aberrant TF expression in the TME by inflammatory and stromal cells. ⁶² Simultaneously, these cells release various coagulation factors, elements that promote angiogenesis, and coagulation particles, thereby resulting in a hypercoagulable state. ⁶³ Apart from their role in blood clotting, cancer cells contribute to fibrinolysis, as shown by their generation of fibrinogen activator inhibitor-1, elevating fibrinogen activator inhibitor-1 antigen levels and related plasma function. ⁶⁴ Additionally, the formation of blood hypercoagulability is associated with neutrophil extracellular traps (NETs), complexes formed from DNA, histones, and neutrophil elastase following neutrophil activation during coagulation. This process promotes platelet aggregation induced by tumors, with toll-like receptor 4 (TLR4) and high-mobility group box (HMGB) molecules from activated platelets acting as links between tumor cells and NETs, thereby facilitating coagulation. ⁶⁵ Through these mechanisms, tumors induce a hypercoagulable state, which in turn can further promote tumor growth and angiogenesis,^66,67 and help tumors evade immune surveillance by forming microthrombi, thereby facilitating metastasis.^68,69 This creates a self-perpetuating cycle within the body.

Diagnostic value of peripheral blood indices in breast cancer

Utilization of blood cell counts in the diagnosis of breast cancer

In real-world situations, a single blood routine index, such as neutrophil counts, may be influenced by patients’ overall health conditions. Therefore, previous studies have attempted to reduce this inconsistency by using ratios of individual blood cell counts. Currently, a variety of studies commonly use these ratios: neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and lymphocyte/monocyte ratio (LMR). In past studies, indicators such as NLR, PLR, and LMR have been investigated to assess treatment outcomes of breast cancer and predict the expected survival time of patients.^70–72 However, in recent years, emerging evidence has revealed their role in the diagnostic process. In studies using the NLR indicator for diagnosis, Alizamir et al. ⁷³ analyzed the levels of peripheral blood indices in patients with breast cancer and those with benign breast diseases. The findings demonstrated that patients with breast cancer have significantly higher NLR levels than those with benign breast diseases, with a diagnostic sensitivity of 73.79% and specificity of 80.85%. When conducting clinical diagnosis of breast cancer, it is necessary to clarify the status of the sentinel lymph node (SLN), and NLR is also considered a relevant reference indicator in this context. Yang et al. ¹³ found that the prevalence of SLN metastasis was substantially higher in patients with high NLR than in those with low NLR. Philip et al. ⁷⁴ conducted a retrospective analysis of cases of TNBC, and the findings demonstrated a significant correlation between NLR and pathological lymph node stage in patients with TNBC. Specifically, in the high NLR group, the diagnosis of SLN metastasis accounted for 75%, whereas in the low NLR group, this proportion was only 36%. These findings confirm that NLR can serve as an evaluation index to enhance the precision of early diagnosis of breast malignancies.

As previously mentioned, in the process of tumor metastasis, platelets play a crucial role.^30,31 Axillary lymph nodes are the first site of metastasis in breast cancer; therefore, in the clinical application of PLR, we focused more on its relationship with lymph node metastasis. Some studies have reported that an elevated PLR is correlated with lymph node metastasis in breast cancer.^75,76 Additionally, studies suggest that patients with negative axillary lymph nodes exhibit a greater PLR than those with positive nodes, leading to ongoing debate over its effectiveness in breast cancer diagnosis. ⁷⁷

In terms of the LMR in breast cancer, there is variation in research outcomes. It is widely accepted that LMR is less effective in diagnosing breast cancer compared with other indicators and may be limited to certain molecular subtypes. ⁷⁸ Subsequent studies have used it to predict outcomes in breast cancer and assess the efficacy of neoadjuvant treatments, with some studies demonstrating that higher LMR levels are associated with longer survival and a higher likelihood of complete pathological remission.^79,80

These findings indicate that blood markers might predict breast cancer diagnosis and clinical stages; however, their diagnostic applicability requires more extensive research with larger sample sizes.

Utilization of lipid indices in the diagnosis of breast cancer

Even with advances in understanding the theoretical link between lipids and breast cancer, correlation studies between clinical lipid indices and breast cancer have primarily focused on assessing incidence risk and prognosis. However, there is some controversy in this area of research. A comprehensive meta-analysis underscored an inverse correlation between TC and HDL-C with respect to the occurrence of breast cancer; however, the interconnection between LDL-C and breast cancer remained ambiguous. ⁸¹ Furthermore, a comprehensive review identified HDL-C as a protective factor for women experiencing perimenopause. ⁵¹ However, Narii et al. ⁵⁹ included 956,390 women in a prospective study to examine the association of LDL-C, HDL-C, and TG with the development of breast cancer. The study indicated a certain level of positive association between LDL-C levels and breast cancer, whereas the association between HDL-C and TG with breast cancer development was not significant. In addition, studies have also reported no association between breast cancer and either HDL-C or LDL-C.^82,83 In terms of prognosis, the predictive value of lipid markers remains controversial. One study found that elevated TG levels are associated with the occurrence of breast cancer, and patients with breast cancer with high TG levels have a worse prognosis. ⁵⁵ However, another study suggested that there is no correlation between TG levels and the risk of breast cancer. ⁵⁹

Additionally, some researchers have attempted to use lipid indices directly for the clinical detection and treatment of breast cancer. Agnoli et al. ⁸⁴ reported a clear connection between TG levels and the probability of axillary lymph node metastasis in patients with breast cancer, potentially serving as a basis for clinical diagnosis. However, it has also been observed that no such correlation exists between these two factors. ⁸⁵

Therefore, there remains significant debate over whether lipid indicators are applicable to the clinical diagnosis of breast cancer. Further comprehensive investigation is needed into their role in diagnosing and treating breast cancer.

Utilization of coagulation indices in the diagnosis of breast cancer

Currently, essential coagulation metrics in medical centers include activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen (Fib), and D-dimer. Traditionally and in contemporary medical settings, coagulation indices have been frequently used to monitor the overall occurrence of venous thrombosis in patients with cancer, a common complication in these tumors, occurring in about 4%–20% of cases. ⁸⁶ This finding is attributable to the hypercoagulability of blood in patients with cancer, associated with clotting and fibrinolysis processes. ⁶⁷ However, in the early stage of cancer development, the absence of distinct clinical signs in patients results in limited studies using this technique for early tumor detection, unlike its more frequent application in advanced breast cancer cases. For example, Rhone et al. ⁸⁷ reported a significant increase in PT in patients with distant metastatic breast cancer compared to those without such metastases. Considering the expectation of a hypercoagulable state in patients with cancer, numerous researchers have attempted to use this feature for rapid diagnosis. As a precursor to fibrin, Fib responds to alterations in plasma viscosity, ⁸⁸ and its levels may be elevated, thereby increasing thrombosis risk and potentially affecting tumor spread or metastasis, which affects patient prognosis. ⁸⁹ A meta-analysis revealed an association between high plasma D-dimer levels in patients with breast cancer and tumor–node–metastasis (TNM) stage and metastasis, serving as a potential reference indicator for early detection and staging of the disease. ⁹⁰

Conclusion

Currently, precision and individualized treatment are key directions of development in breast cancer diagnosis and therapy. The analysis of relevant indices in peripheral blood is considered efficient, economical, and readily accessible. Therefore, the use of these indices in the diagnosis of breast cancer is worthy of affirmation. However, current studies primarily focus on single research institutions, with limited research indicators, which do not adequately reflect the complex biological characteristics of tumors. Moreover, although these indices have been shown to be associated with the formation and progression of breast cancer, their underlying mechanisms of action in breast tumors have not yet been fully elucidated. Therefore, more studies are warranted in the future to provide a stronger basis and reference for clinical studies. At the same time, further comprehensive prospective studies are needed regarding the clinical application of these indices before peripheral blood indices can be widely used in the diagnosis of breast cancer.