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Newer therapeutic classes include PI3K\/AKT inhibitors, oral selective estrogen receptor degraders, proteolysis-targeting chimeras, PARP inhibitors, and antibody-drug conjugates. The development and regulatory approval of these new therapies to treat HR+ HER2\u2013 breast cancer raises the question of how to use and sequence this fast-growing armamentarium to maximize benefit for individual patients. Disease progression and resistance mechanisms emerging on treatment (therapeutic pressure) add further complexity by inducing molecular alterations; thus, a clear understanding of the mechanisms behind resistance to both endocrine and CDK4\/6 inhibitor therapies and their implications for subsequent treatment is critical. In principle, the most effective and tolerable drugs should be used first with the goals of delaying chemotherapy and offering patients the best quality and duration of life. This review aims to explain the evolving treatment landscape for HR+ HER2\u2013 ABC and provides the scientific background for developing future treatment algorithms driven by preclinical and clinical results.<\/jats:p>","DOI":"10.1093\/oncolo\/oyag215","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T11:20:05Z","timestamp":1780917605000},"source":"Crossref","is-referenced-by-count":0,"title":["Navigating first- and second-line treatment options in hormone receptor-positive HER2-negative advanced breast cancer"],"prefix":"10.1093","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6256-7083","authenticated-orcid":false,"given":"Jose","family":"Sandoval","sequence":"first","affiliation":[{"name":"Geneva University and Department of Medical Oncology, Geneva University Hospitals Faculty of Medicine, , Geneva, 1205,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1434-9460","authenticated-orcid":false,"given":"Patrick","family":"Neven","sequence":"additional","affiliation":[{"name":"Department of Oncology, Gynecologic Oncology and Multidisciplinary Breast Center, University Hospitals Leuven , Leuven, 3000,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Emde","sequence":"additional","affiliation":[{"name":"Eli Lilly Israel International Business Unit Oncology, , Ra\u2019anana, 4366411,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois-Cl\u00e9ment","family":"Bidard","sequence":"additional","affiliation":[{"name":"Institut Curie, UVSQ and Paris Saclay University , Saint Cloud, 92210,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Aftimos","sequence":"additional","affiliation":[{"name":"Institut Jules Bordet, Universit\u00e9 Libre de Bruxelles , Brussels, 1070,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Llombart","sequence":"additional","affiliation":[{"name":"Valencia Hospital Arnau Vilanova and Universidad CEU Cardenal Herrera , Moncada, 46015,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2796-1042","authenticated-orcid":false,"given":"Eva","family":"Ciruelos","sequence":"additional","affiliation":[{"name":"Hospital Universitario 12 de Octubre Medical Oncology Department, Breast Cancer Unit, , Madrid, 28041,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter A","family":"Fasching","sequence":"additional","affiliation":[{"name":"University Hospital Erlangen Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg , Erlangen, 91054,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiping","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Breast Oncology, Peking University Cancer Hospital & Institute , Beijing, 100142,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5196-5908","authenticated-orcid":false,"given":"Mario","family":"Campone","sequence":"additional","affiliation":[{"name":"Institut de Canc\u00e9rologie de l'Ouest (ICO) , Angers\/Saint Herblain, 49055\/44805,","place":["France"]},{"name":"CRCI2NA \u2013 Inserm U1307, CNRS UMR6075 , Nantes Universit\u00e9, Universit\u00e9 d'Angers , Nantes, 44805,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique","family":"Coersmeyer","sequence":"additional","affiliation":[{"name":"Eli Lilly (Suisse) S.A. 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