Hematological and biochemical indicators show growing value in breast cancer management

Breast cancer remains a predominant global health challenge for women, with late-stage diagnosis being a key contributor to its high mortality. This is particularly pronounced in low-resource settings where access to advanced, costly diagnostic tools is limited. There is a pressing need for affordable, non-invasive, and accessible diagnostic strategies. This review underscores the significant potential of hematological and biochemical serum markers as pivotal tools to bridge this diagnostic gap, offering insights into diagnosis, prognosis, and therapeutic monitoring for breast cancer.

Hematological markers associated with breast cancer

Hematological markers, derived from routine and inexpensive tests like the complete blood count (CBC), provide a window into the body's physiological and pathological state, including systemic inflammation and immune response, which are hallmarks of cancer.

• Formed elements: Studies consistently show significant alterations in the cellular components of blood in breast cancer patients. These include decreases in hemoglobin (Hb) and red blood cell (RBC) counts (indicating anemia), and changes in white blood cell (WBC) populations. Notably, levels of lymphocytes, neutrophils, and monocytes often show statistically significant differences compared to healthy individuals, reflecting the tumor's interaction with the immune system.

• Neutrophil-to-lymphocyte ratio (NLR): The NLR has emerged as a robust prognostic indicator. A higher NLR is consistently associated with poorer outcomes, including shorter disease-free and overall survival, particularly in aggressive subtypes like HER2-positive and triple-negative breast cancer. Its value lies in reflecting a pro-tumor inflammatory environment.

• Platelet-to-lymphocyte ratio (PLR): Elevated PLR is another key marker linked to more aggressive tumor characteristics, such as lymph node involvement and higher tumor grade. Platelets are thought to promote tumor growth and metastasis by releasing growth factors and shielding cancer cells from immune surveillance.

• Erythrocyte sedimentation rate (ESR): As a nonspecific marker of inflammation, ESR levels are significantly elevated in breast cancer patients compared to healthy controls, and high levels have been correlated with a worse prognosis.

Biochemical serum markers associated with breast cancer

Serum biochemical markers offer complementary information on metabolic and organ function, which can be perturbed by cancer progression and metastasis.

• Enzymes: Lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) are particularly significant. Elevated LDH is associated with tumor progression and metastasis, while a rise in ALP often serves as an important indicator of bone or liver metastasis.

• Creatine kinase-BB: This isoenzyme may not be a reliable marker for malignancy itself but shows promise as an indicator of hormone dependency in breast cancer.

• Serum uric acid (SUA): The role of SUA is complex and dualistic, acting as both an antioxidant and a pro-inflammatory agent. The relationship between SUA levels and breast cancer risk appears to be J-shaped, where both very low and very high levels may be detrimental.

• C-reactive protein (CRP): As a sensitive marker of systemic inflammation, CRP levels are markedly elevated in breast cancer patients and are linked to increased tumor burden and poorer survival outcomes.

• Cancer antigens (CA 15-3 & CA 27.29): These are among the most reliable serum markers for monitoring disease in advanced-stage breast cancer, effectively tracking treatment response, recurrence, and metastatic spread.

• D-dimer: Elevated plasma D-dimer levels are associated with advanced disease, larger tumor size, and metastasis, reflecting the activation of coagulation pathways in cancer progression.

• Oxidative stress markers: Reactive oxygen species (ROS) play a pivotal role in breast cancer. Markers like 4-hydroxynonenal (4-HNE) are elevated, while antioxidant enzymes like catalase are decreased in patients, offering a non-invasive glimpse into the oxidative stress associated with tumorigenesis.

Systemic biomarkers for breast cancer management

The true value of these markers lies in their integration into a systemic, multi-modal diagnostic framework. While individually they may lack specificity for early detection, their combined use can significantly enhance risk stratification, prognosis, and monitoring. For instance, combining NLR and PLR with tumor immune features can improve prognostic accuracy. However, challenges remain, including low specificity, susceptibility to influence by non-cancerous conditions (e.g., infection, obesity), and the need for technical simplification for markers like those related to oxidative stress. Therefore, they are best utilized as complementary tools alongside clinical examination and imaging, rather than as stand-alone diagnostics.

Future directions

Future research should focus on standardizing assessment protocols and leveraging emerging technologies like liquid biopsy and machine learning to analyze multiple biomarkers simultaneously. Exploring the interplay between hematological markers, oxidative stress, and genetic factors could uncover novel therapeutic targets. Expanding access to these affordable tools is crucial for reducing global disparities in breast cancer outcomes.

Conclusions

Hematological and serum-based biomarkers represent a promising avenue for improving breast cancer care, especially in resource-limited settings. Markers such as NLR, PLR, CA 15-3, and oxidative stress indicators provide valuable, cost-effective, and non-invasive insights into tumor-associated inflammation and disease progression. Their integration into structured, multi-modal diagnostic strategies holds the potential to enable earlier detection, guide personalized treatment, and ultimately contribute to more equitable breast cancer management worldwide.