**2.1. Dysregulation of cell cycle checkpoints**

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.

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.

Endocrine resistance is a major obstacle for treatment of HR+ve/HER2−ve MBC. Multiple mechanisms have been implicated. Based on these knowledge we now have a number of

**2. Endocrine resistance**

162 Breast Cancer and Surgery

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.

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

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 to overcome endocrine resistance [21, 22].

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

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 survival compared with those who had no change in ER status (HR of relapse = 2.4, p = 0.03) [24]. Another study of paired sample analysis of primary cancer and liver metastases posttreatment showed ER status and HER2 status change in 30% and 10% of patients [25]. How these changes in receptor status affect management and outcome is not well understood.

hormonal therapy, the type of recent hormonal therapy, or prior chemotherapy (HR ranges, 0.35–0.67). The ORR for all randomly assigned patients in palbociclib-letrozole group versus placebo-letrozole group was 42.1% (95% CI, 37.5–46.9) and 34.7% (95% CI, 28.4–41.3) (odds ratio 1.4, 95% CI, 0.98–2.01; p = 0.06). CBR among all patients randomized was 84.9% (95% CI, 81.2–88.1) for palbociclib-letrozole group and 70.3% (95% CI, 63.8–76.2) for placebo-letrozole group (odds ratio 2.39 (95% CI, 1.58–3.59; p < 0.0010). The most frequent grade 3 and 4 adverse event (AE) in the palbociclib-letrozole group was neutropenia (66%), but febrile neutropenia occurred in 1.8% of patients only. Other common AE included fatigue (37%), nausea (35%), arthralgia (33%), alo-

Management of Hormone Receptor-Positive Metastatic Breast Cancer

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

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PALAMO-3 is another indication-defining phase 3 study of palbociclib [30]. Patients with HR+ve/HER2−ve HER2-negative MBC who had relapsed or progressed during prior endocrine therapy were randomized to receive fulvestrant with placebo or fulvestrant with palbociclib. A total of 521 patients were randomized. The median PFS was 9.2 and 3.8 months in the fulvestrant-palbociclib and fulvestrant-placebo groups respectively (95% CI, 2.5–5.5) (HR 0.42, 95% CI, 0.32–0.56; p < 0.001). ORR was 10.4% with fulvestrant-palbociclib and 6.3% with fulvestrant-placebo, and the CBR was 34% with fulvestrant-palbociclib and 19% with fulvestrantplacebo. In the fulvestrant-palbociclib group, grade 3 or 4 neutropenia was found in 62%. Other common AEs were fatigue (38%), nausea (29%), anemia (26%), and headache (21%).

The results of PALOMA-2 echo those of PALOMA-1 that led to FDA approval. PALOMA-1 differs from PALOMA-2, besides being a phase 2 trial, in that it adopted a 1:1 randomization. There were also small differences in the subgroup analysis, such as inclusion of the newly diagnosed metastatic disease subgroup. Nevertheless, both studies showed significant sur-

Ribociclib is the second CDK 4/6 inhibitor received the U.S. FDA approval in March 2017. The first approval study was MONOLEESA-2 for first line setting. MONOLEESA-7, which is also a first line trial, had special interest in pre- and peri-menopausal women. The data also

MONOLEESA-2 is a double-blind, placebo-controlled, phase 3 study of ribociclib plus letrozole [31]. It mirrors PALOMA-2 for the target patient population. Patients were randomized 1:1 to ribociclib-letrozole or placebo-letrozole. The study demonstrated that the addition of ribociclib to letrozole significantly improved PFS from 14.5 months to over 25 months giving a HR of 0.56 for disease progression or death (95% CI, 0.43–0.72; p < 0.001). The ORR was 40.7% in the ribociclib group and 27.5% in the placebo group in the intention-to-treat population. The CBR was 79.6% in the ribociclib group and 72.8% in the placebo group (p = 0.02) respectively in the intention-to-treat population. The most common grade 3 and 4 AEs were neutropenia (60%), elevated alanine aminotransferase (9%), elevated aspartate aminotransferase

(6%), infection (4%) and vomiting (4%). Other common AEs were minor and mild.

pecia (33%) and diarrhea (26%) and all these were mild.

vival benefit of palbociclib and similar toxicity profiles.

*3.1.2.1. Key results of phase 3 MONOLEESA studies*

*3.1.2. Ribociclib*

became available recently.

### **2.4. Molecular changes secondary to the use of aromatase inhibitor**

Molecular changes in the target receptors after treatment causing treatment failure is a wellknown phenomenon in many malignancies. For HR-positive breast cancer, the target of interest is *ESR1*, which encodes for ERα. *ESR1* mutation has not been detected in sequencing analysis of 390 treatment-naïve primary breast cancer tissues in the Cancer Genome Atlas project [11]. In another study, tissue of patients with hormone-resistance breast cancer were sequenced, and showed 14 or 80 these cases showed *ESR1* mutations affecting the ligand-binding domain [26]. The mutations were the highly recurrent mutations encoding p.Tyr537Ser, p.Tyr537Asn and p.Asp538Gly alterations. p.Tyr537Ser and p.Asp538Gly play a role in hydrogen bonding of the mutant amino acid with Asp351 and favors the agonist conformation of the ER receptor. As a result the mutant ER becomes active in the absence of hormonal stimulation, and renders ER antagonists ineffective. The clinical significance of *ESR1* mutation will be further discussed in Section 3.4.
