# Nanomedicine Interventions in Clinical Trials for the Treatment of Metastatic Breast Cancer
## 1 Introduction  
Cancer is one of the leading causes of death globally. Breast cancer is the most commonly diagnosed type of cancer in women (Figure 1) [1]. In the year 2018, 2.1 million women were diagnosed, and 626,679 women died due to this disease [2]. Its etiology is multifactorial, and some risk factors include age, family history, reproductive factors, use of certain contraceptives, and postmenopausal therapy. Despite the mortality rate remaining high, a declining trend has been observed for the last two decades due to early diagnosis, improved detection methods, and more sophisticated treatments [3]. Countries with premature implementation and high attendance of breast screenings have shown the highest decreases in mortality rate, despite the increasing incidence of cancers with low aggressive potential [4]. Still, a high mortality rate persists, possibly due the lack of therapeutic agents that act only on the target cells without damaging healthy cells [5]. Breast cancer is most commonly staged with the TMN system [2]. This system classifies the size of the primary tumor (T), the involvement of regional lymph nodes (N), and the presence or absence of metastasis (M) [6]. This classification creates five stages (0-IV) that describe the extent of the primary tumor and its metastasis [2]. Metastasis is a series of biological processes that start with the migration of tumor cells from the location of the primary tumor, followed by intravasation, survival, extravasation of the bloodstream, andcolonization of a distant site [7]. Metastatic breast cancer, despite being treatable, is a \"technically\" uncurable disease. In most patients with this condition, metastasis is the cause of death, with a median overall survival of 2-3 years [8]. Management of metastatic breast cancer differs according to its subtype [2]. There are more than 20 subtypes of breast cancer, according to the World Health Organization. The three major subtypes are hormone receptor-positive/HER2-negative (HR+/HER2-), HER2-positive (HER2+), and triple-negative [9]. Chemotherapy is generally used to prolong survival and to treat symptoms in patients with metastatic breast cancer. However, in monotherapy, it results in short survival and a brief response duration [10]. The management of these patients has evolved with the use of \"precision\" medicine, a technique that matches the treatment with the subtype of the tumor and patients' biomarkers [11]. For hormone receptor-positive/HER2-negative breast cancer, the initial therapeutical approach is endocrine treatment with or without targeted therapy. For all patients, first-line treatment consists of tamoxifen, an aromatase inhibitor, or fulvestrant. The addition of CDK 4/6 inhibitors improves PFS and overall survival [2]. Once endocrine resistance is achieved, a transition is made to chemotherapy with a single agent [9]. For HER2-positive, HER2-targeted agents, such as transtuzumab, and chemotherapy are first-line treatments [11]. In this subtype of breast cancer, brain metastasis is common and can be treated with both systemic and local therapy (radiation and surgery) [9]. Triple-negative breast cancer (TNBC) has one of the highest death rates, only second to HER2-positive breast cancer [2]. At a genetic level, TNBC is highly heterogeneous and tends to metastas to the brain and lungs [12]. Since TNBC does not express estrogen receptors, progesterone receptors or HER2, \"precision\" therapy is not established. In this type of tumor, chemotherapy with platinum is the preferred option for treatment. For TNBC with >1% programmed death-ligand 1 (PD-L1) staining, abraxane with atezolizumab showed a high progression-free survival [2]. Anticancer drugs are generally toxic to the healthy and tumor cells. Therefore, these treatments are restricted by their adverse effects (Table 1).