Cancer Genetics and Epigenetics, 2025, Vol.13, No.3, 117-125 http://medscipublisher.com/index.php/cge 119 endocrine therapy from the very beginning (Lambertini et al., 2023). This kind of drug resistance usually occurs due to the characteristics of the tumor itself, such as the absence or malfunction of estrogen receptors, or it may be that there are some genetic and molecular changes in the tumor, resulting in the ineffectiveness of endocrine therapy (Figure 1) (Sutherland and Masgrove Press, 2009; Hartkopf et al., 2020; Sahin et al., 2021; Sewasew and Belachew, 2021). Figure 1 Ligand-dependent and ligand-independent mechanism of action of the estrogen receptor (Adopted from Sewasew and Belachew, 2021) Clinically, for patients with primary drug resistance, their condition usually deteriorates within the first 6 months of receiving adjuvant endocrine therapy, or within the first 6 months of receiving first-line endocrine therapy for patients with advanced breast cancer. The tumors of such patients are often more aggressive, manifested as higher tumor grade, more affected lymph nodes, and more prone to visceral metastasis during recurrence (Lambertini et al., 2023). 3.2 Acquired drug resistance: occurs after the initial treatment response Acquired endocrine resistance occurs in patients who initially respond to endocrine therapy but whose condition begins to deteriorate again after a period of continuous treatment This kind of drug resistance is usually associated with adaptive changes in tumor cells, such as mutations in the ESR1 gene, activation of other signaling pathways, or changes in the surrounding environment of the tumor (Tyson et al., 2015; Hanker et al., 2020; Hartkopf et al., 2020; Sewasew and Belachew, 2021; Sahin et al., 2021). Patients with acquired drug resistance may have a recurrence of the disease after 6 months of adjuvant endocrine therapy or after the initial control of metastatic breast cancer (Lambertini et al., 2023). Moreover, the longer the treatment duration, the higher the risk of acquired drug resistance, which has long been a major challenge in the treatment of estrogen receptor-positive breast cancer (Tyson et al., 2015; Hartkopf et al., 2020; Hanker et al., 2020; Sahin et al., 2021). 3.3 Clinical appraisal criteria and standards Clinically, the types of endocrine resistance are distinguished mainly based on the time and manifestations of the patient's condition deterioration during the process of endocrine therapy. According to internationally recognized
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