Analysis of the Main Directions in the Development of Mono and Combination Pharmacotherapy Acting on Hormonal Signaling Pathways of Breast Cancer According to the FDA Databases and Clinicaltrials.gov.

Background: Hormone signaling plays a significant role in cancerogenesis. This review presents a comprehensive analysis of FDA-approved drugs, as well as recent clinical trials of drugs acting on hormone signaling pathways. It discusses traditional methods of hormonal cancer therapy and identifies new mechanisms in cancer hormonal signaling. The review has made use of the databases Clinicaltrials.gov and PubMed to find new trends in the development of anti-cancer drugs and related hormonal-dependent mechanisms of breast cancer.

Methods: A search of the Drugs@FDA database was conducted to identify pharmaceutical agents approved by the FDA for the treatment of hormone-dependent breast tumors. The clinical trials for these drugs were obtained from ClinicalTrials.gov. The search was expanded from 2018 to early 2024. The keywords used in the search for information were breast cancer, hormonal signaling pathways, luminal types of breast cancer, and hormone-dependent breast cancer. The drug targets, pharmacological information, and clinical data were obtained from the PubMed database.

Results: An analysis of the ClinicalTrials.gov database revealed that the pharmacokinetic direction has significant potential for the discovery of new drugs. The metabolites of SERMs metabolites and their combination have the potential to enhance the efficiency of prodrug. Small molecules can penetrate through the blood-brain-barrier, making them a promising avenue for treating brain metastasis. New SERDs, such as ZB716, exhibit superior oral bioavailability compared to fulvestrant, which is solely administered via injection. The investigation of the signaling hormonal pathways of BC allows for the enhancement of personalised anti-cancer therapy and the overcoming of resistance. Consequently, the specific mechanism of action of ARV-471 (the PROTAC group) enhances sensitivity to drug-resistant targets and affects non-enzymatic functions. Furthermore, PROTACs exhibit markedly enhanced target selectivity in comparison to traditional inhibitors. The combination of endocrine therapy for breast cancer with compounds that target mTOR, PI3K, CDK4/6, and other pathways holds considerable promise. The combination of letrozole with everolimus demonstrated the most promising outcome, with a median progression-free survival period of 22 months, a significant improvement over the 9-month median progression-free survival observed in monotherapy with letrozole.

Conclusion: It is evident that traditional endocrine treatments play a pivotal role in the management of HR+ BC. However, the emergence of resistance necessitates the development of novel therapeutic strategies. These strategies should be based on pharmacokinetics, further investigation of the molecular signaling pathways of BC, such as new SERMs, SERDs, PROTACs, as well as new drug groups, like SERCAs, CERANs, SHERPAs. Combination therapy represents the most promising avenue for BC treatment. While PROTAC combination with new monotherapeutic agents for BC treatment has yet to be investigated, we believe that such combinations have the potential to make the treatment more selective, effective, and personalised in the future.