Tumor Microenvironment Associated Biomarkers

Pathogenesis and aggressive behavior of IBC are closely related to tumor surrounding inflammatory and immune cells, blood vessels, and extracellular matrix, which are all components of the tumor microenvironment. The tumor microenvironment has a crucial role in the local immune response.7 Term “inflammatory” breast cancer is based on clinical characteristics of IBC, that comprise inflammatory appeared breast, however, activated inflammatory pathways are not specific biological aspects of IBC. Nonetheless, accumulating data suggest specific composition of TME in IBC.7

The tumor microenvironment contains increased mammary stem cells and macrophages, which may influence the phenotype of IBC. Tumor surrounding tissue of the normal breast expresses a higher level of markers of the stem cells CD44, CD49f, CD133/2, and of the macrophages CD68 compared to non-IBC normal breast tissue.63

IBC cells induce the polarisation of macrophages into alternatively activated M2 tumor-associated macrophages (TAMs). TAMs antagonize the antitumor activity of CD8 T-cells, support survival, and proliferation of tumor cells and contribute to metastasis process and angiogenesis by the production of inflammatory mediators, immunosuppression, and by mediating tumor extracellular matrix remodeling.64–66 Macrophage colony-stimulating factor 1 is a cytokine involved in M2 macrophage polarization. Its inhibition by antibody reduced the aggressive clinical phenotype of IBC. It was shown, that TAM isolated from TME of IBC patients produce several cytokines that facilitate metastatic potential of IBC cells.

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Mesenchymal stem cells (MSCs) also induce polarisation of M2 TAMs by the production of macrophage colony-stimulating factor 1 (CSF1) and interleukin family proteins. In vitro and in vivo experiments demonstrated reduction of the aggressive clinical phenotype of IBC by using an antibody antiCSF1 and modulation of the effect of interleukins on TAMs by anti-IL6 antibodies.7 Other in vitro study suggests that inhibition of M2 polarisation of macrophages by phosphopeptide mimetic PM37, targeting the SH2 domain of STAT6, can prevent radioresistance of IBC.67

T-cells infiltration and regulation of them are also an important component of TME. Infiltration of the healthy tumor-infiltrating lymphocytes (TILs) plays an important role in a good response to chemotherapy.7 Aggregates of CD8-positive T cells in the intratumoral and peritumoral desmoplastic stroma were identified in approximately half of women with IBC.59 The infiltrates of CD8 T-cells participate in immune regulation of tumor growth. TILs in IBC have often poor effector function, which is typically associated with the expression of immune checkpoint inhibitor programmed cell death ligand 1 (PDL1) on TILs and tumor cells.68,69 Recent studies describe the importance of PDL1, which was overexpressed in 38% IBC (versus 10–30% in non-IBC). High levels of PDL1 may negatively regulate the function of T-cells. Anti-PDL1 therapies may reverse, in IBC tumors with overexpression of PDL1, Tcells exhaustion. In patients with PDL1 upregulation was interestingly reported a better response to chemotherapy.70–72 PDL1 status in IBC patients remained a statistically independent predictor of OS (36,4% 5 years OS in PDL1-positive versus 47.3% in PDL1-negative IBC).73

B cells have also a critical role in the antitumor immune response. Arial-Pulido et al evaluated protein expression od PD-L1 and CD20 as prognostic biomarkers in IBC tumors. CD20+TILs/PD-L1+TILs status was an independent favorable prognostic factor for DFS and breast cancer-specific survival (BCSS) in IBC and TN IBC.74

Other important cells in TME are antigen-presenting cells – dendritic cells (DCs), which participate in T-cells activation. DCs are often suppressed in the peripheral blood of women with IBC leading in decreased tumor necrosis factor (TNF) secretion, thus novel therapeutics with DC agonistic activity may lead to a better outcome in patients with IBC by direct secretion of TNF. DCs also secrete interleukin 12 (IL12), which plays a role in T helper cells maturation, thus IL12 agonists may also be a new therapeutic option in IBC treatment.7,75–77

The communication between intrinsic and extrinsic components of IBC and the abundance of cytokines and chemokines in the TME strongly contribute to the aggressiveness and high angiogenic potential of this tumor. Critical modes of interaction are cytokine-mediated communication and direct intercellular contact between cancer cells and tumor microenvironment with a variety of pathway crosstalk.7

For clinical practice, TME biomarkers with clinical utility are the same as for non-IBC, a most useful are presence of TILs and PD-L1 expression in TNBC, while other biomarkers help us to better characterize the biology of IBC without direct effect for clinical decision making.

Blood-Based Biomarkers

Circulating tumor cells (CTC) count is an independent prognostic factor in primary and metastatic breast cancer patients.75,78 In the pooled analysis of two prospective trials in nonmetastatic IBC patients treated with neoadjuvant chemotherapy combined with neoadjuvant and adjuvant bevacizumab (BEVERLY-1, BEVERLY-2), prognostic values of circulating tumor cells (CTC) were evaluated. At baseline 39% of patients had detectable CTC, which was associated with shorter 3-year DFS (39% versus 70% in CTC negative patients) and shorter 3-year OS with a suggestion that CTC count could have a role in stratification of IBC patients.79 In a retrospective study of 147 patients with newly diagnosed IBC, patients with fewer than 5 CTCs had significantly better PFS and OS than patients with five or more CTCs detected before the start with chemotherapy. CTCs were a strong predictor of worse prognosis in these women.80 Their detection by the FDA-approved CellSearch system showed clinical validity in IBC as well as in non-IBC patients.

CTC counts also correlate with the blood dendritic cells (DC) immunophenotypes and the function of IBC. Patients with high levels of CTCs (≥5) have lower levels of myeloid-DCs (mDCs) capable of producing TNF-α and IL-12 through the toll-like receptor (TLR), which suggests general dysfunction of the immune system in IBC patients with a high number of CTCs.75 Patients with high levels of CTCs have a lower percentage of CD3+ and CD4+ T cells in peripheral blood, a lower percentage of CD8+ T cells, and a higher percentage of T-regulatory lymphocytes compared to patients without CTCs.81 Moreover, a high percentage of mDCs, which could induce a pro-inflammatory TME, is independently associated with worse OS in IBC patients.75

Also, prognostic impact of circulating levels of matrix metalloproteinases (MMP) 2 and 9 were examined in BEVERLY-2 IBC patients with HER2-positive IBC treated with the addition of bevacizumab to trastuzumab-based chemotherapy. High baseline MMP2 and low baseline MMP9 were correlated with better DFS and OS with a significant increase in MMP2 and a decrease in MMP9 levels during treatment.82

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