Divergent Impact of Breast Cancer Laterality on Clinicopathological, Angiogenic, and Hemostatic Profiles: A Potential Role of Tumor Localization in Future Outcomes

Abstract

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.

Prognostic significance of tumor laterality in advanced ovarian cancer

“…Second, considering the fact that bilateral ovarian cancer develops through synchronous tumorigenesis or metastasis from one side to the other, ovarian cancer involving bilateral ovaries may have more subclinical metastases to the lymph nodes or visceral organs than those involving a unilateral ovary. In colorectal or breast cancer, several investigations have suggested that the survival differences can be attributed to the differences in the molecular and clinical characteristics of right-sided and left-sided tumors [5][6][7][8][9][10]. In the current study, we did not perform such mechanistic investigations.…”

“…In colorectal P A G E cancers, it has been reported that right-sided tumors have poorer survival than left-sided tumors [5][6][7]. Similarly, in breast cancer, several reports have suggested that left-sided breast cancers have poorer survival than right-sided tumors [8][9][10]. In ovarian cancer, two studies reported that patients with left-sided ovarian cancer had a more favorable prognosis than those with right-sided ovarian cancer, presumably because of flow pattern dynamics in the peritoneal cavity or differential flow patterns of the right and left ovarian veins [11,12].…”

“…Previous studies have suggested that tumor laterality in paired organs is predictive of patient survival, and patients with left testicular cancer, right lung cancer, and right breast cancer showed significantly better survival than those P A G E with contralateral disease [5][6][7][8][9][10][11]. So far, three studies have investigated the prognostic significance of tumor laterality in patients with ovarian cancer [11][12][13] but have produced conflicting results.…”

Incidence and laterality of breast carcinoma among patients who attended Aminu Kano Specialist Hospital, Kano State, Nigeria

“…Previous studies from Nigeria, Africa and the western world reported similar patterns (Amer, 2014). Generally, the laterality of invasive breast cancer is proposed to associate with several factors including pro-angiogenic, and pro-thrombotic conditions, and suggested to consider laterality as a prognostic factor of invasive breast cancer (Barbara et al, 2020). The majority of women are right-handed, so it might be easier to detect a palpable lump in the left breast compared with the right (Senie et al, 1980).…”

Delineation of Pathogenomic Insights of Breast Cancer in Young Women

“…Numerous studies have suggested a higher percentage of BC in the left breast than in the right breast [ 63 , 64 , 65 ], including in the cases of bilateral BC [ 66 ]. Furthermore, studies have shown a poor OS of patients with tumors in the left breast and that such tumors were highly angiogenic in nature [ 67 ]. Moreover, certain aspects of BC laterality have been validated in a transgenic EERB2 murine model [ 68 ], showing differences in gene expression in both control and transgenic tumor-bearing mice.…”