Abstract
Breast cancer (BC) remains a significant healthcare challenge. Routinely, the treatment strategy is determined by immunohistochemistry (IHC)-based assessment of the key proteins such as estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67. However, it is estimated that over 75% of deaths result from metastatic tumors, indicating a need to develop more accurate protocols for intertumoral heterogeneity assessment and their consequences on prognosis. Therefore, the aim of this preliminary study was the identification of the expression profiles of routinely used biomarkers (ER, PR, HER2, Ki-67) and additional relevant proteins [Bcl-2, cyclin D1, E-cadherin, Snail+Slug, gross cystic disease fluid protein 15 (GCDFP-15), programmed death receptor 1 (PD-L1), and phosphatase of regenerating liver 3 (PRL-3)] in breast primary tumors (PTs) and paired synchronous axillary lymph node (ALN) metastases. A total of 67 tissue samples met the inclusion criteria for the study. The expression status of biomarkers was assessed in PTs and ALN metastases using tissue microarrays followed by IHC. In 11 cases, the shift of intrinsic molecular BC subtype was noticed between PTs and paired ALN metastases. Moreover, a significant disproportion in E-cadherin presence (p = 0.0002) was noted in both foci, and the expression status of all proteins except for HER2 demonstrated considerable variance (k = 1, p < 0.0001). Importantly, in around 30% of cases, the ALN metastases demonstrated discordance, i.e., loss/gain of expression, compared to the PTs. Intertumoral synchronous heterogeneity in both foci (primary tumor and node metastasis) is an essential phenomenon affecting the clinical subtype and characteristics of BC. Furthermore, a greater understanding of this event could potentially improve therapeutic efficacy.
Highlights
Breast carcinoma (BC) remains a healthcare challenge of high importance
We identified the profiles of expression of routinely used biomarkers (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67) and other proteins that play potential roles in BC carcinogenesis (Bcl-2, cyclin D1, E-cadherin, Snail and Slug, GCDFP-15, PD-L1, and phosphatase of regenerating liver 3 (PRL-3)) in the primary tumors (PTs) and paired axillary lymph node (ALN) metastases to demonstrate that such assessment may be insufficient to the potential detriment of the patients
Out of a total of 67 collected specimens, the following numbers of samples were subjected to a complete IHC assessment of paired breast PTs and ALN metastatic tumors: 47 samples for estrogen receptor (ER), 44 samples for PR, 49 samples for HER2, 43 samples for Ki-67, 23 samples for E-cadherin, 44 samples for cyclin D1, 42 samples for Bcl-2, 50 samples for GCDFP-15, samples for Snail+Slug, samples for PD-L1, and 21 samples for PRL-3 [other reports on the heterogeneity of GCDFP-15 and PRL-3 expression in BC have been previously published elsewhere [35, 36]]
Summary
Breast carcinoma (BC) remains a healthcare challenge of high importance. Each year, over 1,350,000 new cases are reported, with a mortality rate exceeding 500,000 [1, 2]. The mortality of BC remains stable, despite its increasing incidence, over 75% of deaths are caused by metastatic tumors that may express a different profile of clinically relevant biomarkers, such as estrogen receptor (ER), progesterone receptor (PR), and HER2, than the primary mass [3]. The major challenges originate from BC complexity of percolating genomic landscapes and compositional intratumoral and intertumoral heterogeneity reflected by the clinical behavior of breast tumors, as has been emphasized by Ellsworth et al [4] This compositional diversity within a tumor arises from the clonal selection driven by an acquired set of somatic mutations, and this plays a critical role in the initial diagnosis and the choice of a treatment strategy. Intertumoral heterogeneity, that observed between primary and metastatic tumors, has recently acquired growing significance in the management of BC
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