Biomarkers for Inflammatory Breast Cancer: Diagnostic and Therapeutic Utility

Abstract: Inflammatory breast cancer (IBC) is a rare and highly aggressive subtype of advanced breast cancer. The aggressive behavior, resistance to chemotherapy, angiogenesis, and high metastatic potential are key intrinsic characteristics of IBC caused by many specific factors. Pathogenesis and 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 (TME). The tumor microenvironment has a crucial role in the local immune r09esponse. 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. This review aimed to summarize current knowledge of predictive and prognostic biomarkers in IBC.

Keywords: inflammatory breast neoplasms, biomarkers, tumor microenvironment, targeted therapy

INTRODUCTION

Inflammatory breast cancer (IBC) is rare and highly aggressive subtype of locally advanced breast cancer. The primary tumor of IBC is classified by The 2017 American Joint Committee on Cancer and the International Union for Cancer Control (AJCC-UICC) Tumor, Node, Metastasis (TNM) as T4d and characterized by the presence of many dermal tumor emboli in the papillary and reticular dermis of the skin overlying the breast, diffuse dermatologic erythema and edema (peau d’orange). IBC accounts for about 2.5% of all diagnosed breast cancers, in the United States is estimated to account for 1% to 6% cases.^1,2 Actually, in some parts of the Middle East and northern Africa, this incidence can be as high as 10%.³ Younger and African-American women are especially affected by IBC. The average age is 59 years, which is less than that of patients with non-IBC breast cancer.^1,2

In general, patients with non-metastatic IBC are treated similarly to those with others LABC. There are only two main differences – breast conservation therapy (BCT) and sentinel lymph node biopsy (SNB) are inappropriate for IBC.⁴

IBC is a very aggressive type of breast cancer. The aggressive behavior, resistance to chemotherapy, angiogenesis, and high metastatic potential are key intrinsic characteristics of IBC caused by many specific factors. Accordingly, contributions of the tumor microenvironment (TME) to the pathogenesis and aggressive behavior of IBC was declared in many studies. This review aimed to summarize current knowledge of predictive and prognostic biomarkers in IBC, including tumor tissue and tumor microenvironment associated biomarkers including blood circulation.

Tumor-Associated Biomarkers

IBC is a clinicopathologic entity. Typical clinical presentation with duration no more than six months occupying at least one-third of the breast and histology of invasive breast cancer obtained from a biopsy of the affected breast are mandatory for the diagnosis of IBC. Mammographic findings of IBC and mastitis could have a similar appearance; therefore, breast imaging could be more useful in disease monitoring.

Staging evaluations include routine laboratory tests, computed tomography of the chest, abdomen, and pelvis, a bone scan, and ultrasound-guided biopsy of the nodes in patients with suspicious lymph nodes.⁵

IBC cells are histopathologically similar to non-IBC cells. The tumor is not a specific histologic subtype of breast cancer, IBC is usually of the ductal type with pleomorphic cells and a high histologic grade.⁶ Cancer cells are typically distributed diffusely in clusters throughout the skin and breast. In IBC tumors have been reported cytokine-mediated infiltration of the lymphocytes or tumor-associated macrophages. Tumor biomarkers are in most cases evaluated in main tumor rather than in the lymphatic emboli. However, there might be a discrepancy between these two types of tumor tissue with clinical implications as non-IBC tumors can recur with IBC features and vice versa.

The classic histologic finding on biopsy is a dermal lymphatic invasion, which is found in approximately 75% of all cases, but it can also be an incidental finding in patients with non-IBC. Therefore, this finding is not necessary for the diagnosis. Within the dermal-lymphatic vessels are found formation and invasion of tumor emboli, which are responsible for the local signs and rapid metastatic potential.^6–11 Several markers have been identified in preclinical tumors emboli models, such as zinc finger E-box-binding homeobox 1 (ZEB1), E-cadherin, aldehyde dehydrogenase 1 (ALDH1) and NOTCH3.^12–14

The hallmark if IBC are tumor emboli (TE) formed by aggregates of tumor, immune and stromal cells, which caused blockage of dermal lymph vessels with the typical clinical presentation of “peau d’orange” appearance of the skin. Variable intercellular contact, both between cancer cells and TME and cancer cells, is responsible for the formation of a unique emboli structure. Caveolin1 and RhoC overexpression modulates these junctions and contributes to invasion of tumor emboli into the vascular structure. The emboli cells can survive despite hypoxia and direct exposure to the immune system and to form small cell clusters with high metastatic potential.¹⁵ A better understanding of the biology of tumor emboli is important to developing novel opportunities for treatment.⁷ Intracellular translocation of E-cadherin causes modulation of intercellular junctions and cancer cells migration into surrounding tumor microenvironment, which contributes to the special structure of IBC.⁷ Recent reports have linked IBC to display a hybrid epithelial/mesenchymal phenotype based on its levels of E-cadherin and its ability to migrate collectively as tumor emboli. On a molecular level, hybrid E/M cells have been shown to coexpress CD24 and CD44 (CD24hi CD44hi signature). This subpopulation resembles features of chemoresistance and have metastasis initiation properties.^16,17

IBC tumors are characterized by downregulation of hormone receptors – estrogen receptor and/or progesterone receptor (ER/PR) and amplification of human epidermal growth factor receptor 2 (HER2) more frequently than non-IBC (HR-positive subtypes 30% in IBC versus 60–80% in non-IBC; HER2-positive 40% in IBC versus 25% in non-IBC). Also, incidence rates of triple-negative breast cancer (TNBC) subtypes are higher in IBC (30% versus 10–15% in non-IBC). These subtypes are generally associated with a worse prognosis and shorter disease-free survival.^2,18–20

In clinical practice, the most important tumor-associated biomarkers are LE, even not present in all patients, while there is no other specific IBC-related biomarker with clinical utility, while all other biomarkers the same as in non-IBC setting.

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