**2. Characterization of the triple-negative breast cancer**

The TNBC is a subtype of breast cancer that lacks steroid receptors, i.e., estrogen and progesterone receptors, and does not overexpress the *HER2* gene. Eighty percent of patients with the TNBC have the basal type of breast cancer, according to the molecular classification [1, 3, 8]. About 15–20% of all patients with breast cancer have the TNBC, which is more common in patients younger than 50 years. The risk factors for the TNBC are as follows:


The TNBC has an aggressive course, grows fast, and metastasizes early, usually to the brain and lungs, and less commonly to the bones and liver. Compared with other breast cancers, the TNBC is poorly differentiated (G3) in the Bloom-Richardson classification [5, 6, 9]. In 2010, studies among 15,240 women with breast cancer, including 2500 with the TNBC, showed that patients with the TNBC had a worse prognosis than other patients [5, 6, 8–10].

The TNBC is also characterized by early recurrence, usually within 1–3 years after diagnosis [8]. Most patients with TNBCs have a poor prognosis because adjuvant therapy rarely leads to remission, and the presence of metastases is associated with a high resistance to chemotherapy and short survival [9]. Not all patients with TNBC, however, have a poor prognosis [6, 7, 9]. Numerous studies showed that the TNBC is related to the dysfunction of the *BRCA* genes and their protein products [9, 10]. According to Atchley et al. [10], TNBCs occur in 57% of patients with breast cancer and *BRCA1* mutations. Moreover, more than a half of TNBCs overexpress the MGFR receptor (c-Met growth factor receptor), which is associated with the signaling pathway initiating the epithelial-mesenchymal transformation [8, 9]. The TNBC is often associated with *P53* mutations, PTEN loss, activation of the PI3K/AKT signaling pathway, and loss of heterozygosity of the loci4p14, 4p15.3 m 5q11.1, 5q14, and 18q22–23 [11].

Although TNBC was initially detected in basal-like carcinoma, these two types of breast cancer are different from each other [12]. The basal-like carcinoma is diagnosed based on the immunohistochemical status of steroid receptors (ER, PR) and the HER2 receptor [4, 7, 9].

Molecularly, the TNBC comprises a heterogeneous group of tumors. Lehmann et al. [13] distinguished six types of the TNBC:


With modern techniques, we can distinguish many molecular forms of breast cancer [3], which is important because the molecular classification of breast cancer enables effective, individualized treatment [4]. Based on cDNA microarray and immunohistochemical analysis, five basic

• subtype with expression of genes typical for cells of the normal mammary gland (normal

• subtype with a decreased expression of genes coding proteins responsible for intercellular

On routine histology, breast cancer is defined based on immunohistochemical detection of three receptor proteins: estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor with additional gene status analysis of the *HER2* gene (*in situ* hybridization). This immunohistochemical profiling shows that 25% of breast cancers consist of type A luminal cells; 32%, of type B/HER2− cells; 18.5%, of luminal B/HER+ cells; and 7%, of cells that express solely the HER2 protein [7]. Cancers of the luminal subtype A and B express genes characteristic for glandular cells, which form the inner layer of normal ducts and lobules of the breast. Moreover, the luminal subtypes of breast cancer express cytokeratins typical for glandular cells, such as cytokeratins 8, 18, and 19, as well as α 6 integrins and Bcl-2, Ep-CAM, and MUC1 proteins. The luminal subtype A is characterized by a high expression of genes for estrogen receptors and progesterone receptors and genes regulating the function of these receptors, i.e., *FOX1*, *GATA3*, *LIV-*1, and *XBP1*. The luminal subtype A breast cancer typically occurs in young patients; in contrast to the luminal subtype B, the luminal subtype A breast cancer has a good prognosis [8–10]. In recent years, among all the molecular subtypes of breast cancer,

molecular subtypes of breast cancer have been distinguished:

• subtype with overexpression of the *HER2* gene (ER−, PR−, HER2+, CK5/6−)

junctions and adhesion of epithelial cells (claudin and cadherin E) [5, 6]

the triple-negative breast cancer (TNBC) has been studied most extensively.

patients younger than 50 years. The risk factors for the TNBC are as follows:

The TNBC is a subtype of breast cancer that lacks steroid receptors, i.e., estrogen and progesterone receptors, and does not overexpress the *HER2* gene. Eighty percent of patients with the TNBC have the basal type of breast cancer, according to the molecular classification [1, 3, 8]. About 15–20% of all patients with breast cancer have the TNBC, which is more common in

**2. Characterization of the triple-negative breast cancer**

• luminal subtype A (ER+ and/or PR+, HER2−, CK5/6−) • luminal subtype B (ER+ and/or PR+, HER2+, CK5/6−)

• basal-like subtype (ER−, PR−, HER2−, CK5/6+)

breast-like)

80 Breast Cancer and Surgery

• young age at menarche

• obesity in the menopausal age • family history of breast cancer Of all these TNBC subtypes, only the LAR TNBC does not express basal cytokeratins, such as CK5, CK6A, CK6B, CK14, CK16, CK17, CK23, and CK81, and it does not express proteins such as EGFR, p53, smooth muscle actin, P-cadherin, and c-Kit receptor [10, 11]. In contrast, the LAR TNBC expresses CK7, CK8, CK18, CK19, and the androgen receptor [12]. Moreover, the LAR TNBC expresses genes whose protein products regulate hormonal pathways and the gene for the androgen receptor and its co-activators [12, 13].

The BL1 TNBC expresses genes whose protein products are associated with cell cycle regulation, cell proliferation, repair process, and DNA replication [12].

The BL2 TNBC expresses genes whose protein products are involved in the signal transduction in the cell, through growth factors such as EGF, NGF, MET, Wnt/β-catenin, and IGF1R [12].

The IM TNBC is characterized by the expression of genes whose protein products are involved in immune reactions, such as signal transduction in Th1 and Th2 cells, natural killer cells, and dendritic cells [10, 12].

targets. Until this is achieved, chemotherapy remains the mainstay of systemic treatment for patients with stage I to stage III TNBC. Currently, none of the standard chemotherapy regimens is considered superior for patients with TNBCs, and treatment of these patients is based on the same principles as that in patients with other subtypes of breast cancer. Most guidelines recom-

Triple-Negative Breast Cancer: Expression of Hypoxia-Inducible Factor 1α in Triple-Negative…

http://dx.doi.org/10.5772/intechopen.75354

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The therapeutic strategies for the management of TNBC are targeting the DNA repair complex (platinum compounds and taxanes), P53 (taxanes), and cell proliferation (anthracycline-containing regimens) [21]. Despite the aggressive clinical course, the TNBC's response to chemotherapy is good. However, despite achieving high rates of pathological complete response (pCR) with conventional chemotherapy, the TNBC phenotype is associated with higher recurrence rates than the ER+ and HER2+ breast cancers. This is known as the triple-

Since the first application of taxanes, used in adjuvant therapy for over 20 years, relatively few new treatments have appeared in recent years for patients with the TNBC. New therapeutic methods are still lacking despite numerous ongoing clinical trials. Many retrospective studies have demonstrated that tumor infiltrating lymphocytes (TILs) are of prognostic importance in patients with early-stage TNBC. Increased TIL numbers within the neoplastic milieu correlate with a better response to the standard treatment regimen with anthracyclines

However, it has still not been shown whether the presence of TILs identifies tumors that are more susceptible to treatment, or whether the presence of lymphocytes itself increases the effectiveness of treatment [23]. There are numerous reports on the benefits of using platinum derivatives in chemotherapy, in particular in cancers with the *BRCA1* mutation, which is much more frequent in TNBCs (about 30%) than in other cancers. Nearly 80% of tumors that develop in carriers of the *BRCA1* mutation are triple-negative. The *BRCA* mutation status is increasingly therapeutically relevant beyond consideration of prophylactic mastectomy/ oophorectomy and surveillance. A recent randomized phase III trial demonstrated that in unselected patients with the metastatic TNBC, carboplatin and docetaxel were equal in effi-

However, in the *BRCA* mutation-associated TNBC, carboplatin yielded a superior response rate and progression-free survival compared with docetaxel. The improvement in pCR attained with the addition of carboplatin to anthracycline/taxane chemotherapy comes at the cost of increased toxicity. Because of the molecular variability of TNBCs, the platinum derivatives improve prognosis only in some patients. Therefore, it is very important to identify those patients with TNBC who will have the greatest benefit [25]. The current highest pCR rates, about 40–45%, are achieved by taxane/anthracycline sequential chemotherapy regimens and inclusion of platinum drugs with the taxane component. Inclusion or substitution of other chemotherapy drugs (capecitabine, gemcitabine, vinorelbine, or ixabepilone) resulted in little or no improvement in pCR rates [26, 27]. To date, all clinical trials showed that the neoadjuvant chemotherapy was the preferred option for patients with TNBC who required systemic therapy. Neoadjuvant chemotherapy studies have consistently reported higher response rates in TNBC than in non-TNBC, and pCR has been shown to predict improved long-term

mend a regimen based on the combination of an anthracycline with a taxane.

negative paradox [22].

in neoadjuvant therapy [23].

cacy as first-line treatments [24].

The M TNBC is characterized by the expression of genes whose protein products regulate cell mobility, interaction of cells with the extracellular matrix, and cell differentiation and growth [12].

The MSL TNBC expresses genes whose protein products are involved in angiogenesis and the signaling pathways of the ABC transporters [12, 13].

Most subtypes of the TNBC have the molecular profile typical for the basilar subtype of breast cancer, which lacks expression of ER, PR, and HER2 [8, 9, 12]. This molecular profile is observed mainly in subtypes BL1 (85%) and BL2 (31%), and subtypes IM (58%) and M (47%) [8, 12].

Usually, the LAR TNBC is a luminal A or B breast cancer (82%) [12–14]. Based on immunohistochemical studies, 50–80% of TNBCs are basal-like cancers, and conversely, 77–80% of basal-like breast cancers are TNBCs [9, 10, 12]. Molecular analyses indicate that TNBCs and the basal subtype of breast cancer are different cancers [13–15].

All the above-mentioned subtypes of the TNBC incur different prognoses; the longest recurrence-free survival is found in patients with the MSL TNBC, and the shortest recurrence-free survival, in patients with the LAR TNBC [15].

Histologically, the majority of TNBCs are luminal cancers (invasive carcinoma of no special type—IDC—NST) [15]. The TNBC occurs more commonly in patients with specific histological types of breast cancer, including the medullary breast cancer, metaplastic breast cancer, apocrine breast cancer, salivary gland-like breast cancer, secretory breast carcinoma, breast cancer derived from lipid-laded cells, and lobular breast carcinoma [16]. In patients with TNBCs, it is the histological type of the tumor that determines its biological properties; thus, patients with TNBCs do not always have rapid disease progression and poor prognosis [17, 18].

To identify a homogenous group of patients, Eiermann et al. [19] suggested that the tumors that become triple-negative after neoadjuvant treatment, and were not triple-negative before this treatment, should not be classified as TNBC. However, if the disease recurs as triplenegative metastases, the tumor should be considered as triple-negative although the primary tumor was not triple-negative [19]. According to these investigators, also rare histological subtypes of the TNBC, such as apocrine, glandular, or low-differentiated cancers, should be excluded from the group of triple-negative cancers [18, 20].
