b.Role of tamoxifen:

For individuals with oestrogen receptor (ER)-positive breast cancer, antioestrogen tamoxifen has been the endocrine therapy of choice. Tamoxifen decreases the risk of recurrence following surgery when used as an adjuvant treatment. Tamoxifen provides an objective clinical response in half of the individuals with recurrent illness. The cancer, on the other hand, will eventually become hormoneindependent, meaning it will no longer respond to tamoxifen. Despite significant research, resistance mechanisms remain mostly understood [48].

Tamoxifen's hopeful profile spurred a slew of clinical studies and decades of anti-oestrogen research, which revealed new details about ER biology and its link to ER-dependent malignancies. There have been several randomised studies of adjuvant tamoxifen in early breast cancer patients. Before recurrence, information on

#### *The Future Perspectives of Drug Repurposing and Treatment for the Drug Resistant Breast… DOI: http://dx.doi.org/10.5772/intechopen.100143*

every woman in any randomised study of adjuvant tamoxifen versus no tamoxifen that began before 1990 was sought in 1995. The overall effects of tamoxifen proved to be minor among these women, therefore following studies of recurrence and total mortality are limited to the remaining women [49].

The effects of 1–2 years of tamoxifen and around 5 years of tamoxifen in the studies comparing tamoxifen vs. no adjuvant tamoxifen are summarised in Tamoxifen versus No Tamoxifen. The studies are separated by ER status, which is categorised as ER-poor, ERpositive, and ER-unknown, according to the recognised importance of the original tumour's hormone receptor status. Current and future assessments of receptor state may be more predictive of response as procedures for assessing receptor status advance. ER measures were, on average, extremely significant predictors of response to 5 years of adjuvant tamoxifen, despite the fact that it may be difficult to characterise the receptor assays employed in these studies many years ago. Many of the effects and side effects of tamoxifen in ER breast cancer patients are random [50].

### 2.Selective oestrogen receptor degraders (SERDs)

A selective oestrogen receptor degrader or downregulator (SERD) is a medication that binds to the oestrogen receptor (ER) and causes the ER to be degraded and therefore downregulated in the process. They're utilised with earlier types of medicines including selective oestrogen receptor modulators (SERMs) and aromatase inhibitors to treat oestrogen receptor-sensitive or progesterone receptor-sensitive breast cancer.

Selective oestrogen receptor degraders (SERDs) are oestrogen receptor antagonists that also cause proteasome-mediated ER degradation. Fulvestrant is a therapy for ER+ advanced breast cancer that has been authorised by the FDA [51].

### a.Fulvestrant

Fulvestrant is an oestrogen receptor antagonist that inhibits and destroys oestrogen receptors. This medication is not a SERM; rather, it works as an anti-oestrogen throughout the body. It's referred to be an oestrogen receptor degrader that's selective (SERD). Fulvestrant is at least as effective and safe as comparator endocrine treatments in postmenopausal women with advanced hormone-sensitive breast cancer. Fulvestrant is a safe and effective systemic medication that can be regarded as a viable therapeutic option for postmenopausal women with hormone-sensitive advanced breast cancer in the treatment sequence [52].

Fulvestrant is a steroidal ER antagonist that was developed for its lack of agonism in almost all types of tissues studied, but it was subsequently shown to be a SERD that causes ER to be ubiquitinated and destroyed by the proteasome. It is, in fact, the only FDA-approved treatment for postmenopausal women who have relapsed on hormone therapy and have advanced ER-positive breast cancer. Fulvestrant, on the other hand, has an unfavourable pharmacokinetic profile and requires a painful intramuscular injection to be administered (500 mg dose). Stable-state plasma concentrations require 3–6 months to achieve, even with improved loading-dosage regimens (500 mg dose on days 1, 15, and 29). Its overall therapeutic efficacy is limited by the poor ER turnover seen in patient cases (less than 50%), compared to complete receptor downregulation shown in in-vivo breast cell line investigations. As a result, there is still an unmet medical need for a potent orally available SERD capable of reaching higher levels of malignant exposure [53].

b.Mechanism associated with ER Suppression:

Resistance to oestrogen suppression or inactivation of ER by other methods (SERMs/SERDs) is linked to and/or caused by mechanisms. Although the phrase "endocrine resistance" technically refers to resistance to oestrogen suppression, we use it here to refer to oestrogen or ER suppression resistance.

In ER+ metastatic breast cancer, endocrine resistance is an unavoidable outcome (MBC), As a result, when CDK4/6 inhibitors (e.g., palbociclib, ribociclib, abemaciclib) are added to antiestrogens, progression-free survival in patients with ER+ MBC is significantly increased compared to antiestrogens alone. The addition of CDK4/6 inhibitors to antiestrogens abrogates some of the resistance mechanisms. However, in early-stage cancers, they might still be important drivers of hormone resistance. The **Figure 5** was indicating that the activation of HER2, EGFR, FGFR, and Other RTKs Promotes Endocrine Resistance, RTK activation is augmented by PI3K and MAPK signalling, which induces ER phosphorylation and promotes ligand-independent ER activation (most often by mutation or amplification). NF1 loss-of-function mutations activate Ras in a constitutive manner, which can activate the PI3K and MAPK pathways as well. In a ligand-independent way, ER phosphorylation increases transcription of ER-regulated genes. ER and oncogenic RTK signalling both target CCND1, the gene that encodes cyclin D1. RTKs activate additional transcription factors

**Figure 5.** *Activation of HER2, EGFR, FGFR, and other RTKs.*

*The Future Perspectives of Drug Repurposing and Treatment for the Drug Resistant Breast… DOI: http://dx.doi.org/10.5772/intechopen.100143*

that promote ER-independent survival in addition to ER. The combination of an ER antagonist with the appropriate RTK inhibitor CDK4/6 inhibitor might potentially overcome RTK-mediated endocrine resistance. Sensitivity to endocrine treatment and resistance to it in ER+ breast cancers are similar to other hormone-dependent malignancies including prostate cancer and endometrial cancer [54, 55].
