Mechanisms and Therapeutic Strategies for Endocrine Resistance in Breast Cancer: A Comprehensive Review and Meta-Analysis.

As per recent scenarios, drug resistance is a significant challenge in treating breast cancer for several reasons, such as genetic mutations, altered signaling pathways, and tumor microenvironment. Endocrine resistance is one of the biggest significant barriers to treatment, particularly in hormone receptor-positive (HR+) breast cancers, which depends on estrogen or progesterone signaling for growth. While therapies such as tamoxifen, aromatase inhibitors, and selective estrogen receptor degraders (SERDs) have effectively targeted these pathways, many patients develop resistance, rendering them less effective over time, which is driving a need for innovative therapeutics to treat breast cancer and overcome drug resistance and better treatment outcomes. Recent studies suggest that combining the different therapies, including immunotherapy, targeted therapy, chemotherapy, etc., with endocrine therapy, may bypass the endocrine resistance. : We conducted a comprehensive systematic review and meta-analysis examining the molecular mechanisms of endocrine resistance and evaluating randomized clinical trial outcomes, overall survival and progression-free survival in endocrine-resistant breast cancer patients treated with endocrine therapy, targeted therapy, immunotherapy, or chemotherapy. : We have analyzed 35 randomized clinical trial studies for different therapies along with combination therapy, and our results demonstrated that supplementary or additional therapies in endocrine resistance breast cancer patients have better progression-free and overall survival. : The current study has demonstrated that combination therapies may have good survival results and patient outcomes in endocrine resistance. Also, This review sheds light on current challenges in drug resistance and the future direction of cancer treatment through a comprehensive analysis of these emerging treatment approaches to improve patient outcomes.