**1. Introduction**

Breast cancer is a common cancer in female with a high chance of recurrence even after curative treatment. The goal for treatment in metastatic disease is life prolongation and preservation of quality of life. Breast cancer is defined by the overexpression of hormone receptor (HR), either estrogen and/or progesterone receptors, and human epidermal growth factor receptor 2 (HER2) receptor. HR-positive HER2-negative (HR+ve/HER2−ve) breast cancer accounts for 70% of breast

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

cancer [1]. For patients with HR+ve/HER2−ve metastatic breast cancer (MBC), the choice between chemotherapy versus endocrine therapy depends on the disease load especially the presence of visceral crisis – patients with impending visceral crisis should be treated with systemic chemotherapy, whereas patients with stable condition should be given endocrine therapy. As hormonal stimulation is known to be the underlying driving force and these tumors tend to be slow growing, endocrine therapy is considered the mainstay of treatment for most patients.

targeted therapy that can help overcome this problem. The more clinically relevant mecha-

Management of Hormone Receptor-Positive Metastatic Breast Cancer

http://dx.doi.org/10.5772/intechopen.75759

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In mammalian cells, cell cycle progression is determined by the checkpoint regular retinoblastoma protein (Rb), which itself is controlled by a number of cyclin-dependent kinases (CDK) [8]. In quiescent state, Rb in its hypo-phosphorylated state suppresses the cell cycle progression from G1 phase into S (synthesis) phase. In proliferative state, CDK subtypes 4 and 6 complexes with cyclin D1, D2, or D3, triggering Rb phosphorylation [9]. Hyperphosphorylation of Rb leads to increased activity of the E2F family of transcription factors and promotes cell cycle progression. Cyclin D1 amplification is common in HR-positive breast cancer. Cyclin D1 is encoded by *CCDN1*. *CCND1* and cyclin D1 have been found to be amplified in 15–20 and 28–58% of luminal breast cancer respectively [10, 11]. Preclinical research suggested dysregulated cell cycle checkpoint regulation could lead to abnormal cell cycle progression and loss of endocrine responsiveness. Treatment of antiestrogen in breast cancer cells was associated with suppressed cyclin D1 expression, and emergence of endocrine resistance was accompanied by persistent cyclin D1 expression and Rb phosphorylation [12, 13]. Subsequent *in vitro* study further demonstrated that in breast cancer cell lines, CDK4/6 inhibitor palbociclib had preferential activity in reversing treatment resistance in luminal cells [14]. A number of CDK4/6 inhibitors have been tested clinically, and have become standard treatment of HR+ve/HER2−ve MBC.

Phosphatidylinositol-3-kinasd (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway is an important signal transduction system on which many growth factor receptors pathways converge. Crosstalk between the PI3K/Akt/mTOR pathway and growth factor receptors such as EGFR, HER2, HER2, FGFR1, and IGF1R have been described in endocrine resistance [15–18]. Abnormal activation of the PI3K pathway could result in factitious cell proliferation. The PI3K complex is composed of a regulatory subunit and a catalytic subunit p110. P110 has four isoforms – α, β, γ, and δ. *PIK3CA* mutation is found in up to 40% of breast cancer and is likely to be present in early cancer development [19, 20]. Abnormal PK3K signaling was found in up to 70% of breast cancers [21]. Besides *PIK3CA* mutation, hyperactivation of this pathway can result from aberration other PI3K subunits, mutation or phosphorylation of effectors Akt, loss of inhibitory signal from PTEN or INPPR4B, leading to activation of downstream effector mTOR protein. As hyperactivation of PI3K pathway could promote estrogen-independent ER transcriptional activation, inhibition of PI3K or its downstream effectors is an attractive target

Loss of HR expression, although uncommon, has been reported in hormone-resistant breast cancer. Study of paired primary and metastatic HR-positive breast cancer found a positive-tonegative change in HR status in 10% of metastatic breast tumor [23]. In the P024 neoadjuvant endocrine therapy trial that recruited 228 post-menopausal women with HR-positive stage 2 or 3 breast cancer, those who lost ER status after AI treatment had worse recurrence-free

**2.2. Crosstalk growth factor receptor and PI3K/AKT/mTOR pathway**

nisms are discussed as below.

**2.1. Dysregulation of cell cycle checkpoints**

to overcome endocrine resistance [21, 22].

**2.3. Changes in the estrogen receptor (ER) and HER2 status**

The first endocrine therapy described for treatment of MBC was tamoxifen which dated back in year 1971 [2]. It is a selective estrogen receptor modulator (SERMs) that binds competitively to estrogen receptors, and can have both antagonistic and agonistic effect depending on the tissue of action. Nowadays tamoxifen and raloxifen are the most commonly used SERMs clinically. SERMs can be used in both pre- and post-menopausal women. These drugs are well tolerated and have favorable toxicity profile. The use of aromatase inhibitor (AI) was started in early 2000s for post-menopausal women. AI blocks the action of peripheral aromatase, preventing conversion of androgens to estrogen. Letrozole and anastrozole are non-steroidal reversible AIs, whereas exemestane is a steroidal irreversible AI. The initial evidence to support the use of AI was by the TARGET trial, which showed equivalent efficacy of anastrozole and tamoxifen in the first line treatment of HR-positive MBC but with lower incidence of side effects such as thromboembolic events and vaginal bleeding [3]. Subsequently letrozole was demonstrated to have superior time to progression (9.4 versus 6.0 months, p < 0.0001), improved objective response rate (ORR) (32 versus 21%, p −0.0002) and a trend toward longer overall survival (OS) (34 versus 30 months) compared with tamoxifen [4]. The third class of endocrine therapy is selective estrogen-receptor degrader (SERD), and fulvestrant is the only SERD approved by the U.S. Food and Drug Administration (FDA) so far. In the CONFIRM trial, it has been defined that fulvestrant should be given at a higher dose of 500 mg instead of 250 mg for its better benefit in overall survival [5]. In the recently published phase 3 FALCON trial in which endocrine therapy-naïve patients were randomized to receive fulvestrant 500 mg monthly or anastrozole 1 mg daily [6]. The progression-free survival (PFS) in the fulvestrant group was 16.6 months compared with that of 13.8 months in the anastrozole group. The p-value was at a borderline of 0.0486 and the overall survival data is not available yet. As such, both AI and fulvestrant are acceptable option for initial treatment of HR+ve/HER2−ve MBC, yet the use of fulvestrant is often limited by the need for monthly intramuscular injection and its high cost.

Traditional endocrine therapy at the frontline setting achieves an overall response rate in the range of 25–45% and median PFS around 8–10 months [3, 4, 7]. Second line endocrine therapy often yields unfavorable response. With improving understanding in this disease, more and more evidence suggests that combining endocrine therapy with targeted therapy could overcome endocrine resistance and significantly prolong the time on endocrine therapy, delaying the needs for chemotherapy. This chapter will discuss the latest development in the targeted therapy for HR+ve/HER2−ve MBC and the future direction.
