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HR\u2010positive\/HER2\u2010negative MBC is characterized by a relatively prolonged, although variable, disease course and substantial intertumoral and intratumoral heterogeneity. Although endocrine\u2010based therapies remain the cornerstone of treatment, nearly all patients eventually develop resistance, which is increasingly addressed with biologically targeted agents and newer\u2010generation cytotoxic drugs. This review summarizes the current understanding of HR\u2010positive\/HER2\u2010negative MBC biology, highlighting mechanisms of intrinsic and acquired resistance, including driver genomic alterations that, along with clinical factors, help guide therapeutic choices and sequencing. The authors specify and discuss how\u00a0genomic and transcriptomic profiling inform treatment selection and how side effects and overall patient experience are considered in decision making. Advances in targeted therapies, such as CDK4\/6 (cyclin\u2010dependent kinase 4\/6), PI3K (phosphatidylinositol 3\u2010kinase), and AKT (protein kinase B) inhibitors, and next\u2010generation estrogen receptor degraders are reviewed along with the expanding role of antibody\u2013drug conjugates and biomarker\u2010guided tumor\u2010agnostic biologic therapies. The authors also explore evolving biologic concepts, including the impact of the tumor microenvironment on resistance and disease progression, and consider the distinct clinical behavior of invasive lobular carcinoma and current approaches. Emerging data from contemporary clinical trials promise to refine clinical and biomarker\u2010driven algorithms and improve outcomes for patients with HR\u2010positive\/HER2\u2010negative MBC. Ongoing multi\u2010omic research and adaptive clinical strategies will be essential to further the application of precision oncology in this most common subtype of MBC. Importantly, patient\u2010reported outcomes, shared decision making, and real\u2010world evidence are increasingly useful in formulating comprehensive care plans, guidelines, and policy. The modern treatment landscape features a personalized approach that integrates clinical features, biomarkers, and patient preferences across the disease continuum.<\/jats:p>","DOI":"10.3322\/caac.70055","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T14:43:29Z","timestamp":1768229009000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Personalizing therapies over the course of hormone receptor\u2010positive\/HER2\u2010negative metastatic breast cancer"],"prefix":"10.3322","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6425-4400","authenticated-orcid":false,"given":"Akshara","family":"Singareeka Raghavendra","sequence":"first","affiliation":[{"name":"Department of Breast Medical Oncology The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2470-0891","authenticated-orcid":false,"given":"Senthil","family":"Damodaran","sequence":"additional","affiliation":[{"name":"Department of Breast Medical Oncology The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5377-9167","authenticated-orcid":false,"given":"Carlos H.","family":"Barcenas","sequence":"additional","affiliation":[{"name":"Department of Breast Medical Oncology The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8886-5161","authenticated-orcid":false,"given":"Suzanne A.","family":"Fuqua","sequence":"additional","affiliation":[{"name":"Department of Medicine Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8663-0331","authenticated-orcid":false,"given":"Rachel M.","family":"Layman","sequence":"additional","affiliation":[{"name":"Department of Breast Medical Oncology The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5711-2404","authenticated-orcid":false,"given":"Debu","family":"Tripathy","sequence":"additional","affiliation":[{"name":"Department of Breast Medical Oncology The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,12]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.25881"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21863"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1701830"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21708"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/jncics\/pkab063"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.3747\/co.25.4000"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.19.02309"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2018.77.8738"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10549\u2010024\u201007524\u20102"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.47847"},{"key":"e_1_2_13_13_1","volume-title":"NCCN Guidelines\u00ae. 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