For a study, researchers sought to identify the molecular processes causing Endocrine therapy resistance (ETR) using a thorough genomic investigation of breast tumors. Pre-treatment and post-treatment tumor samples from 35 estrogen receptor-positive breast cancer patients who had neoadjuvant and adjuvant endocrine therapy revealed that 3 developed intrinsic resistance, 19 acquired resistance, and 13 remained susceptible. Neoadjuvant changes in tumor volume and adjuvant recurrence surveillance were utilized to evaluate the response. About 12 patients received endocrine therapy twice or more, with the second round starting after the first was determined to be ineffective. DNA whole-exome sequencing and RNA sequencing were performed on all samples, comprising 169 unique specimens. DNA mutations, copy-number alterations, and gene expression data were examined using supervised and unsupervised algorithms to identify molecular characteristics related to ETR. The alterations that occurred more frequently in ETR were those in GATA3 and ESR1. The well-known ESR1 D538G variant that causes ETR and the uncommon E380Q mutation that causes endocrine hypersensitivity was found. Resistance-developing tumors displayed distinct gene expression profiles from sensitive malignancies and were more enriched in the ER, HER2, GATA3, AKT, RAS, and p63 signaling pathways. Each patient’s data was carefully examined, displaying the range of ETR techniques. Because ETR has a variety of underlying mechanisms and diverse changes in somatic genetic and transcriptomic profiles that characterize them, it will be necessary to develop an individualized strategy using genomic and genetic biomarkers and medications tailored to each patient to overcome resistance.