**3. Treatment of patients with TNBC**

Patients with the TNBC do not benefit from hormonal treatment or treatment with anti-HER2 antibodies (trastuzumab) because their tumors do not express the ER, PR, and HER2 receptors. Therefore, surgery, radiation therapy, and chemotherapy, used alone or in various combinations, are currently the only reliable therapeutic options for patients with TNBCs. However, recent research on TNBC has identified many receptors that could be used as future therapeutic 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 recommend a regimen based on the combination of an anthracycline with a taxane.

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

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

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

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

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

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

Patients with the TNBC do not benefit from hormonal treatment or treatment with anti-HER2 antibodies (trastuzumab) because their tumors do not express the ER, PR, and HER2 receptors. Therefore, surgery, radiation therapy, and chemotherapy, used alone or in various combinations, are currently the only reliable therapeutic options for patients with TNBCs. However, recent research on TNBC has identified many receptors that could be used as future therapeutic

TNBCs do not always have rapid disease progression and poor prognosis [17, 18].

dendritic cells [10, 12].

82 Breast Cancer and Surgery

signaling pathways of the ABC transporters [12, 13].

survival, in patients with the LAR TNBC [15].

the basal subtype of breast cancer are different cancers [13–15].

excluded from the group of triple-negative cancers [18, 20].

**3. Treatment of patients with TNBC**

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 triplenegative paradox [22].

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 in neoadjuvant therapy [23].

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 efficacy as first-line treatments [24].

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 outcomes for patients with TNBC. The specific adjuvant regimens that may be effective for TNBC are still being determined. Many large randomized trials have established the benefit of adjuvant anthracyclines and taxanes in breast cancer [28].

been studied most extensively. In 2008, the Food and Drug Administration (FDA) approved bevacizumab in combination with a taxane (paclitaxel) as first-line therapy for metastatic HER2-negative breast cancer, including the TNBC [30]. A meta-analysis of phase III studies with bevacizumab showed an improvement in progression-free survival but not in overall survival in these patients. However, the addition of bevacizumab considerably increased

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

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Based on these data, in 2011, the FDA withdrew bevacizumab as the treatment for metastatic

Because we know more and more about the interaction of inflammatory cells with cancer cells, in future, immunotherapy might be introduced for the treatment of breast cancer. Cancer cells use many mechanisms to avoid immune responses. For instance, in the TNBC, cancer cells express the PD-1 antigen and its ligands on cell surface. These proteins induce T lymphocyte tolerance. Preclinical studies showed that blocking the activity of the PD-1/PD-L1 might be used as treatment for TNBC. Both anti PD-1 antibodies (pembrolizumab and nivolumab) and

Poly-ADP-ribose polymerases (PARPs) are enzymes that are essential for cell survival. Cell damage activates PARPs, which, in turn, induces cell repair systems that maintain genome stability and regulation of transcription. Preclinical studies showed that PARPs are inhibited in cancer cells with pre-existing DNA repair defects, e.g. with the *BRCA1* mutations. The FDA has recently approved monotherapy with olaparib, a PARPi, as a first-in-class drug to treat germline *BRCA* mutation-associated advanced refractory breast cancer. Several ongoing studies are assessing the activity of PARPi alone or in combination with chemotherapy for germline BRCA-associated metastatic and early-stage breast cancers. Because a substantial proportion of TNBCs are thought to harbor DNA repair defects, it might be possible to extend the observation of PARPi sensitivity of germline BRCA-associated tumors to *BRCA* wild-type TNBCs that harbor a BRCAness phenotype. Accordingly, PARPi are being explored in the

The high frequency (about 50%) of PI3K pathway alterations in the TNBC makes this pathway a promising target for therapeutics, and inhibitors of PI3K, AKT, and/or mTOR are in clinical development. PI3K blockade promotes HR deficiency by downregulating BRCA1/2 and thus

These drugs modulate gene expression through epigenetic regulation and can induce cell cycle arrest, differentiation, and apoptosis. Panobinostat is a potent pan-histone deacetylase inhibitor with preclinical activity in the TNBC. Several histone deacetylase inhibitors are

an anti-PD-L1 antibody (atezolizumab) showed promise in preclinical studies [32].

treatment toxicity [31].

**4.2. Immune checkpoint inhibitors**

general population of patients with the TNBC [33].

sensitizing BRCA-proficient tumors to PARP inhibition [34].

**4.4. PI3K/AKT/mTOR pathway inhibitors**

**4.5. Histone deacetylase inhibitors**

breast cancer.

**4.3. PARPi**

The evidence consistently shows that 10–20% of patients with TNBC who would not experience pCR following treatment with a current third-generation taxane and anthracycline will achieve pCR when a platinum drug is added to the regimen. However, because of the substantial added toxicity and predicted modest overall survival benefit across patient subgroups, carboplatin and cisplatin have not been routinely incorporated into neoadjuvant treatment [29].

The principles of local treatment in breast cancer, i.e., surgery and radiotherapy, are the same for the TNBC and all other types of breast cancer. Over the last several years, the percentage of patients operated on for breast cancer has increased; this trend has also been observed in patients with TNBC.

In patients with the TNBC, radiation therapy is given as in other types of breast cancer, i.e., after mastectomy or breast-conserving surgery. However, this approach to radiation therapy remains controversial because more and more patients have TNBCs, which has a fast local growth. The general rule that breast-conserving surgery followed by radiation therapy in early stage cancers (T1-2 N<sup>0</sup> ) is the equivalent of mastectomy, in this case, has many limitations. Also the general consensus that post-mastectomy radiation therapy is not indicated for patients with node-negative tumors less than 5 cm in diameter should not be oversimplified in patients with triple-negative tumors [28].
