With almost 2.3 million new cases and 685 thousand fatal events in 2020 alone, breast cancer remains one of the main causes of morbidity and mortality in women worldwide. Despite the increasing prevalence of the disease in recent years, the number of deaths has dropped—this is mostly the result of better diagnostic and therapeutic opportunities, allowing to recognize and treat breast cancer earlier and more efficiently. However, metastatic disease still remains a therapeutic challenge. As mechanisms of tumor spread are being explored, new drugs can be implemented in clinical practice, improving the outcomes in patients with advanced disease. Formation of metastases is a complex process, which involves activation of angiogenesis, vasculogenesis, chemotaxis, and coagulation. The actions, which occur during metastatic spread are interrelated and complementary. This review summarizes their importance and mutual connections in formation of secondary tumors in breast cancer.

To date, lateral differences of invasive breast cancer (IBrC) with respect to the angiogenic and hemostatic profiles were never studied. Here, we aimed to determine the relationship of tumor laterality with various clinical and pathological parameters including angiogenic and hemostatic profiles. A total of 92 women that were initially non-metastatic and treated by surgery were included in this single-center prospective study. Patients were grouped according to tumor localization. A four-year follow-up was accomplished in all patients with a 15.22% recurrence rate. An immunoassay of selected angiogenic and hemostatic parameters, as well as immunohistochemistry of estrogen and progesterone receptors, human epidermal growth factor receptor 2 (HER2), and Ki67, was comparatively performed in groups with right- and left-sided IBrC. The same analysis was carried out in a subgroup of patients with luminal A molecular subtype of cancer. Patients with right-sided tumors free of nodal involvement had a significantly longer overall survival compared to their left-sided counterparts (p = 0.0491). Additionally, right-sided tumors had a higher predisposition to be a luminal-A subtype of IBrC (p = 0.0016). Furthermore, 10% of left-sided tumors exhibited an overexpression of HER2, while only 2% patients suffering right-sided tumors displayed a positive score (p = 0.0357). Our findings revealed a significantly higher concentration of vascular endothelial growth factor (VEGF)-A (p = 0.0136), lower anti-angiogenic ratios (sVEGFR1/VEGF-A (p = 0.0208) and sVEGFR2/VEGF-A (p = 0.0068)), and elevated plasminogen activator inhibitor type 1 (PAI-1) (p = 0.0229) in patients with breast cancer localized in the left breast, regardless of the molecular subtype of IBrC. Our study showed that left-sided breast tumors without lymph node metastases demonstrate worse overall survival. Laterality of IBrC is associated with pro-angiogenic and pro-thrombotic conditions. We propose to consider laterality as a prognostic factor of IBrC.