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Precision therapeutics and emerging strategies for HR-positive metastatic breast cancer

  • Review Article
  • Published:

From Nature Reviews Clinical Oncology

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Abstract

Anti-oestrogen-based therapies, often combined with a CDK4/6 inhibitor, are the current standard-of-care first-line therapy for patients with advanced-stage hormone receptor-positive (HR+) breast cancer. Resistance to anti-oestrogen agents inevitably occurs, mediated by oestrogen receptor (ER)-dependent or ER-independent mechanisms that drive tumour progression. Emerging endocrine therapies include, but are not limited to, next-generation oral ER degraders and proteolysis targeting chimeras, which might be particularly effective in patients with ESR1-mutant breast cancer. Furthermore, cancers harbouring driver alterations in oncogenic signalling pathways, including AKT and PI3K, might be susceptible to novel combination strategies involving targeted inhibitors. Next-generation CDK2/4 inhibitors are an area of active clinical investigation, and efforts are ongoing to evaluate the role of sequential CDK inhibition. Approved and emerging antibody–drug conjugates exploiting novel target antigens have also demonstrated promising clinical activity. These novel agents, as well as further identification and characterization of predictive biomarkers, will hopefully continue to improve clinical outcomes, reduce the incidence of toxicities, and limit the extent of overtreatment in this population. In this Review, we describe the evolving treatment paradigm for patients with metastatic HR+ breast cancer in light of the growing armamentarium of drugs and biomarkers that will help to shape the future therapeutic landscape. These strategies are expected to involve tumour molecular profiling to enable the delivery of precision medicine.

Key points

  • Emerging next-generation endocrine therapies, targeted agents and antibody–drug conjugates are changing the treatment landscape of advanced-stage hormone receptor-positive (HR+), HER2-negative breast cancer.

  • Personalized therapy is predicated on understanding the molecular factors that govern the progression of HR+ tumours and drug resistance, exemplified by the regulatory approvals of elacestrant and capivasertib for ESR1-mutant and AKT pathway-altered HR+, HER2-negative breast cancers, respectively.

  • Novel anti-oestrogen agents, including oral selective oestrogen receptor degraders and proteolysis targeting chimeras, and targeted therapies such as PI3K–AKT inhibitors and CDK2/4 inhibitors, have shown promise alone and/or in combination.

  • Leveraging a biomarker-guided approach to anti-oestrogen-resistant tumours is a priority for novel treatment strategies, including targeted doublet or triplet regimens that restore tumour dependence on oestrogen receptor signalling, or antibody–drug conjugates for endocrine-refractory disease.

  • Insights into the molecular and genomic mechanisms mediating resistance to current and emerging agents are expected to have an integral role in continued research efforts towards optimizing anticancer treatment.

  • Drug development and approvals are occurring in parallel for the large and heterogenous population of patients with HR+ breast cancer, and efforts to identify the optimal combination strategies and approach to treatment sequencing are underway.

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Fig. 1: Signalling pathways targeted by emerging therapies for advanced-stage HR+ breast cancer.
Fig. 2: Mechanisms of resistance to anti-oestrogen–CDK4/6 inhibitor combination regimens.
Fig. 3: Targeted selection of second-line or later-line therapies for patients with metastatic ER+ breast cancer.

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References

  1. Giaquinto, A. N. et al. Breast cancer statistics, 2022. CA Cancer J. Clin. 72, 524–541 (2022).

    Article  PubMed  Google Scholar 

  2. Łukasiewicz, S. et al. Breast cancer — epidemiology, risk factors, classification, prognostic markers, and current treatment strategies — an updated review. Cancers 13, 4287 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Clusan, L., Ferrière, F., Flouriot, G. & Pakdel, F. A basic review on estrogen receptor signaling pathways in breast cancer. Int. J. Mol. Sci. 24, 6834 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hortobagyi, G. N. et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann. Oncol. 29, 1541–1547 (2018).

    Article  CAS  PubMed  Google Scholar 

  6. Rugo, H. S. et al. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Res. Treat. 174, 719–729 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Johnston, S. et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer 5, 5 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hortobagyi, G. N. et al. Overall survival with ribociclib plus letrozole in advanced breast cancer. N. Engl. J. Med. 386, 942–950 (2022).

    Article  CAS  PubMed  Google Scholar 

  9. Slamon, D. J. et al. Overall survival with palbociclib plus letrozole in advanced breast cancer. J. Clin. Oncol. 42, 994–1000 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Goetz, M. P. et al. Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2- advanced breast cancer: final overall survival results of MONARCH 3. Ann Oncol 35, 718–727 (2024).

    Article  CAS  PubMed  Google Scholar 

  11. Chan, H. J., Petrossian, K. & Chen, S. Structural and functional characterization of aromatase, estrogen receptor, and their genes in endocrine-responsive and -resistant breast cancer cells. J. Steroid Biochem. Mol. Biol. 161, 73–83 (2016).

    Article  CAS  PubMed  Google Scholar 

  12. Farrar, M. C. & Jacobs, T. F. Tamoxifen. In: StatPearls https://www.ncbi.nlm.nih.gov/books/NBK532905/ (StatPearls, 2024).

  13. Ali, S. et al. Molecular mechanisms and mode of tamoxifen resistance in breast cancer. Bioinformation 12, 135–139 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Hernandez, R. K., Sørensen, H. T., Pedersen, L., Jacobsen, J. & Lash, T. L. Tamoxifen treatment and risk of deep venous thrombosis and pulmonary embolism: a Danish population-based cohort study. Cancer 115, 4442–4449 (2009).

    Article  CAS  PubMed  Google Scholar 

  15. Nabholtz, J.-M. A. Long-term safety of aromatase inhibitors in the treatment of breast cancer. Ther. Clin. Risk Manag. 4, 189–204 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet 386, 1341–1352 (2015).

    Article  Google Scholar 

  17. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in premenopausal women with oestrogen receptor-positive early-stage breast cancer treated with ovarian suppression: a patient-level meta-analysis of 7030 women from four randomised trials. Lancet Oncol. 23, 382–392 (2022).

    Article  Google Scholar 

  18. Peters, A. & Tadi, P. Aromatase inhibitors. In StatPearls https://www.ncbi.nlm.nih.gov/books/NBK557856/ (StatPearls, 2024).

  19. Guan, J. et al. Therapeutic ligands antagonize estrogen receptor function by impairing its mobility. Cell 178, 949–963.e18 (2019).

    Article  CAS  PubMed  Google Scholar 

  20. Wardell, S. E., Marks, J. R. & McDonnell, D. P. The turnover of estrogen receptor α by the selective estrogen receptor degrader (SERD) fulvestrant is a saturable process that is not required for antagonist efficacy. Biochem. Pharmacol. 82, 122–130 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Robertson, J. F. R. et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet 388, 2997–3005 (2016).

    Article  CAS  PubMed  Google Scholar 

  22. Osborne, C. K. et al. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J. Clin. Oncol. 20, 3386–3395 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Wang, L. & Sharma, A. The quest for orally available selective estrogen receptor degraders (SERDs). ChemMedChem 15, 2072–2097 (2020).

    Article  CAS  PubMed  Google Scholar 

  24. Farooq, M. & Patel, S. P. Fulvestrant. In StatPearls https://www.ncbi.nlm.nih.gov/books/NBK560854/ (StatPearls, 2024).

  25. Lloyd, M. R., Wander, S. A., Hamilton, E., Razavi, P. & Bardia, A. Next-generation selective estrogen receptor degraders and other novel endocrine therapies for management of metastatic hormone receptor-positive breast cancer: current and emerging role. Ther. Adv. Med. Oncol. 14, 17588359221113694 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ma, C. X., Reinert, T., Chmielewska, I. & Ellis, M. J. Mechanisms of aromatase inhibitor resistance. Nat. Rev. Cancer 15, 261–275 (2015).

    Article  CAS  PubMed  Google Scholar 

  27. Brett, J. O., Spring, L. M., Bardia, A. & Wander, S. A. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res. 23, 85 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jeselsohn, R., Buchwalter, G., De Angelis, C., Brown, M. & Schiff, R. ESR1 mutations — a mechanism for acquired endocrine resistance in breast cancer. Nat. Rev. Clin. Oncol. 12, 573–583 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Turner, N. C. et al. ESR1 mutations and overall survival on fulvestrant versus exemestane in advanced hormone receptor-positive breast cancer: a combined analysis of the phase III SoFEA and EFECT trials. Clin. Cancer Res. 26, 5172–5177 (2020).

    Article  CAS  PubMed  Google Scholar 

  30. Spoerke, J. M. et al. Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant. Nat. Commun. 7, 11579 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  31. O’Leary, B. et al. The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discov. 8, 1390–1403 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ferraro, E., Walsh, E. M., Tao, J. J., Chandarlapaty, S. & Jhaveri, K. Accelerating drug development in breast cancer: new frontiers for ER inhibition. Cancer Treat. Rev. 109, 102432 (2022).

    Article  CAS  PubMed  Google Scholar 

  33. Hanker, A. B., Sudhan, D. R. & Arteaga, C. L. Overcoming endocrine resistance in breast cancer. Cancer Cell 37, 496–513 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Razavi, P. et al. The genomic landscape of endocrine-resistant advanced breast cancers. Cancer Cell 34, 427–438.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Giltnane, J. M. et al. Genomic profiling of ER+ breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance. Sci. Transl. Med. 9, eaai7993 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Turner, N. C. et al. Capivasertib in hormone receptor-positive advanced breast cancer. N. Engl. J. Med. 388, 2058–2070 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. André, F. et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N. Engl. J. Med. 380, 1929–1940 (2019).

    Article  PubMed  Google Scholar 

  38. Fribbens, C. et al. Tracking evolution of aromatase inhibitor resistance with circulating tumour DNA analysis in metastatic breast cancer. Ann. Oncol. 29, 145–153 (2018).

    Article  CAS  PubMed  Google Scholar 

  39. Pearson, A. et al. Inactivating NF1 mutations are enriched in advanced breast cancer and contribute to endocrine therapy resistance. Clin. Cancer Res. 26, 608–622 (2020).

    Article  CAS  PubMed  Google Scholar 

  40. Miller, T. W. et al. A gene expression signature from human breast cancer cells with acquired hormone independence identifies MYC as a mediator of antiestrogen resistance. Clin. Cancer Res. 17, 2024–2034 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Khatpe, A. S., Adebayo, A. K., Herodotou, C. A., Kumar, B. & Nakshatri, H. Nexus between PI3K/AKT and estrogen receptor signaling in breast cancer. Cancers 13, 369 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wander, S. A. et al. The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor positive metastatic breast cancer. Cancer Discov. 10, 1174–1193 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Brett, J. O. et al. A gene panel associated with abemaciclib utility in ESR1-mutated breast cancer after prior cyclin-dependent kinase 4/6-inhibitor progression. JCO Precis. Oncol. 7, e2200532 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Garner, F., Shomali, M., Paquin, D., Lyttle, C. R. & Hattersley, G. RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models. Anticancer Drugs 26, 948–956 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bihani, T. et al. Elacestrant (RAD1901), a selective estrogen receptor degrader (SERD), has antitumor activity in multiple ER+ breast cancer patient-derived xenograft models. Clin. Cancer Res. 23, 4793–4804 (2017).

    Article  CAS  PubMed  Google Scholar 

  46. Patel, H. K. et al. Elacestrant (RAD1901) exhibits anti-tumor activity in multiple ER+ breast cancer models resistant to CDK4/6 inhibitors. Breast Cancer Res. 21, 146 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bardia, A. et al. Phase I study of elacestrant (RAD1901), a novel selective estrogen receptor degrader, in ER-positive, HER2-negative advanced breast cancer. J. Clin. Oncol. 39, 1360–1370 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bidard, F.-C. et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the randomized phase III EMERALD trial. J. Clin. Oncol. 40, 3246–3256 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bardia, A. et al. EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: updated results by duration of prior CDK4/6i in metastatic setting. Cancer Res. 83, abstr. GS3-01 (2023).

    Article  Google Scholar 

  50. Bardia, A. et al. Elacestrant vs standard-of-care in ER+/HER2− advanced or metastatic breast cancer (mBC) with ESR1 mutation: key biomarkers and clinical subgroup analyses from the phase 3 EMERALD trial. Cancer Res. 84, abstr. PS17-02 (2024).

    Article  Google Scholar 

  51. Scott, J. S. et al. Discovery of AZD9833, a potent and orally bioavailable selective estrogen receptor degrader and antagonist. J. Med. Chem. 63, 14530–14559 (2020).

    Article  CAS  PubMed  Google Scholar 

  52. Weir, H. M. et al. AZD9496: an oral estrogen receptor inhibitor that blocks the growth of ER-positive and ESR1-mutant breast tumors in preclinical models. Cancer Res. 76, 3307–3318 (2016).

    Article  CAS  PubMed  Google Scholar 

  53. Lawson, M. et al. The next-generation oral selective estrogen receptor degrader camizestrant (AZD9833) suppresses ER+ breast cancer growth and overcomes endocrine and CDK4/6 inhibitor resistance. Cancer Res. 83, 3989–4004 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hamilton, E. et al. A phase I dose escalation and expansion trial of the next-generation oral SERD camizestrant in women with ER-positive, HER2-negative advanced breast cancer: SERENA-1 monotherapy results. Ann. Oncol. 35, 707–717 (2024).

    Article  CAS  PubMed  Google Scholar 

  55. Oliveira, M. et al. Camizestrant, a next generation oral SERD vs fulvestrant in post-menopausal women with advanced ER-positive HER2-negative breast cancer: results of the randomized, multi-dose Phase 2 SERENA-2 trial. Cancer Res. 83, abstr. GS3-02 (2023).

    Article  Google Scholar 

  56. Oliveira, M. et al. Clinical activity of camizestrant, a next-generation SERD, versus fulvestrant in patients with a detectable ESR1 mutation: exploratory analysis of the SERENA-2 phase 2 trial. J. Clin. Oncol. 41, 1066 (2023).

    Article  Google Scholar 

  57. Bhagwat, S. V. et al. Preclinical characterization of LY3484356, a novel, potent and orally bioavailable selective estrogen receptor degrader (SERD). Cancer Res. 81, abstr. 1236 (2021).

    Article  Google Scholar 

  58. Jhaveri, K. et al. Imlunestrant monotherapy and in combination with abemaciclib, with or without an aromatase inhibitor, in estrogen receptor-positive (ER+), HER2-negative (HER2−) advanced breast cancer (aBC): updated results from the EMBER study. Cancer Res. 84, abstr. PS15-09 (2024).

    Article  Google Scholar 

  59. Jhaveri, K. et al. EMBER-3: a randomized phase 3 study of LY3484356, a novel, oral selective estrogen receptor degrader vs investigator’s choice of endocrine therapy of either fulvestrant or exemestane, in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced or metastatic breast cancer previously treated with endocrine-based therapy. Cancer Res. 82, abstr. OT2-11-01 (2022).

    Article  Google Scholar 

  60. Liang, J. et al. GDC-9545 (giredestrant): a potent and orally bioavailable selective estrogen receptor antagonist and degrader with an exceptional preclinical profile for ER+ breast cancer. J. Med. Chem. 64, 11841–11856 (2021).

    Article  CAS  PubMed  Google Scholar 

  61. Jhaveri, K. L. et al. Phase Ia/b study of giredestrant ± palbociclib and ± luteinizing hormone-releasing hormone agonists in estrogen receptor–positive, HER2-negative, locally advanced/metastatic breast cancer. Clin. Cancer Res. 30, 754–766 (2024).

    Article  CAS  PubMed  Google Scholar 

  62. Martín, M. et al. Giredestrant for estrogen receptor-positive, HER2-negative, previously treated advanced breast cancer: results from the randomized, phase II acelERA breast cancer study. J. Clin. Oncol. 42, 2149–2160 (2024).

    Article  PubMed  Google Scholar 

  63. Andreano, K. J. et al. The dysregulated pharmacology of clinically relevant ESR1 mutants is normalized by ligand-activated WT receptor. Mol. Cancer Ther. 19, 1395–1405 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Goldstein, S. R. et al. Postmenopausal evaluation and risk reduction with lasofoxifene (PEARL) trial: 5-year gynecological outcomes. Menopause 18, 17–22 (2011).

    Article  PubMed  Google Scholar 

  65. Cummings, S. R. et al. Lasofoxifene in postmenopausal women with osteoporosis. N. Engl. J. Med. 362, 686–696 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Goetz, M. P. et al. Lasofoxifene versus fulvestrant for ER+/HER2− metastatic breast cancer with an ESR1 mutation: results from the randomized, phase II ELAINE 1 trial. Ann. Oncol. 34, 1141–1151 (2023).

    Article  CAS  PubMed  Google Scholar 

  67. Snyder, L. B. et al. The discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer. Cancer Res. 81, abstr. 44 (2021).

    Article  Google Scholar 

  68. Hamilton, E. et al. First-in-human safety and activity of ARV-471, a novel PROTAC® estrogen receptor degrader, in ER+/HER2- locally advanced or metastatic breast cancer. Cancer Res. 82, abstr. PD13-08 (2022).

    Article  Google Scholar 

  69. Schott, A. F. et al. ARV-471, a PROTAC® estrogen receptor (ER) degrader in advanced ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer: phase 2 expansion (VERITAC) of a phase 1/2 study. Cancer Res. 83, abstr. GS3-03 (2023).

    Article  Google Scholar 

  70. Hamilton, E. P. et al. 390P vepdegestrant, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, in ER+/human epidermal growth factor receptor 2 (HER2)− advanced breast cancer: update of dose escalation results from a phase I/II trial. Ann. Oncol. 34, S344 (2023).

    Article  Google Scholar 

  71. Campone, M. et al. VERITAC-2: a global, randomized phase 3 study of ARV-471, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, vs fulvestrant in ER+/human epidermal growth factor receptor 2 (HER2)− advanced breast cancer. J. Clin. Oncol. 41, TPS1122 (2023).

    Article  Google Scholar 

  72. Parisian, A. D. et al. Palazestrant (OP-1250), a complete estrogen receptor antagonist, inhibits wild-type and mutant ER-positive breast cancer models as monotherapy and in combination. Mol. Cancer Ther. 23, 285–300 (2023).

    Article  PubMed Central  Google Scholar 

  73. Hodges-Gallagher, L. et al. OP-1250: a potent orally available complete antagonist of estrogen receptor-mediated signaling that shrinks wild type and mutant breast tumors. Eur. J. Cancer 138, S55 (2020).

    Article  Google Scholar 

  74. Lin, N. U. et al. 382MO updated results from the phase I/II study of OP-1250, an oral complete estrogen receptor (ER) antagonist (CERAN) and selective ER degrader (SERD) in patients (pts) with advanced or metastatic ER-positive, HER2-negative breast cancer. Ann. Oncol. 34, S338 (2023).

    Article  Google Scholar 

  75. Vidal, M. et al. Elacestrant in postmenopausal women with estrogen receptor positive and HER2-negative early breast cancer: primary efficacy and safety analysis of the preoperative, window of opportunity SOLTI-1905-ELIPSE trial. Cancer Res. 83, abstr. PD13-01 (2023).

    Article  Google Scholar 

  76. Robertson, J. F. et al. A randomized, pre-surgical study to investigate the biological effects of AZD9833 doses in women with ER-positive HER2-negative primary breast cancer (SERENA-3). Cancer Res. 81, abstr. OT-09-05 (2021).

    Article  Google Scholar 

  77. Neven, P. et al. 273P A preoperative window-of-opportunity (WOO) study of imlunestrant in ER+, HER2− early breast cancer (EBC): Final analysis from EMBER-2. Ann. Oncol. 34, S292–S293 (2023).

    Article  Google Scholar 

  78. Moore, H. M. et al. Evaluation of pharmacodynamic (PD) and biologic activity in a preoperative window-of-opportunity (WOO) study of giredestrant (GDC-9545) in postmenopausal patients (pts) with estrogen receptor-positive, HER2-negative (ER+/HER2−) operable breast cancer (BC). J. Clin. Oncol. 39, 577 (2021).

    Article  Google Scholar 

  79. Sherr, C. J. A new cell-cycle target in cancer — inhibiting cyclin D-dependent kinases 4 and 6. N. Engl. J. Med. 375, 1920–1923 (2016).

    Article  CAS  PubMed  Google Scholar 

  80. Finn, R. S., Aleshin, A. & Slamon, D. J. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. Breast Cancer Res. 18, 17 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Hortobagyi, G. N. et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N. Engl. J. Med. 375, 1738–1748 (2016).

    Article  CAS  PubMed  Google Scholar 

  82. Slamon, D. J. et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J. Clin. Oncol. 36, 2465–2472 (2018).

    Article  CAS  PubMed  Google Scholar 

  83. Tripathy, D. et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 19, 904–915 (2018).

    Article  CAS  PubMed  Google Scholar 

  84. Goetz, M. P. et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J. Clin. Oncol. 35, 3638–3646 (2017).

    Article  CAS  PubMed  Google Scholar 

  85. Finn, R. S. et al. Palbociclib and letrozole in advanced breast cancer. N. Engl. J. Med. 375, 1925–1936 (2016).

    Article  CAS  PubMed  Google Scholar 

  86. Slamon, D. J. et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N. Engl. J. Med. 382, 514–524 (2020).

    Article  CAS  PubMed  Google Scholar 

  87. Lu, Y.-S. et al. Updated overall survival of ribociclib plus endocrine therapy versus endocrine therapy alone in pre- and perimenopausal patients with HR+/HER2− advanced breast cancer in MONALEESA-7: a phase III randomized clinical trial. Clin. Cancer Res. 28, 851–859 (2022).

    Article  CAS  PubMed  Google Scholar 

  88. Morrison, L., Loibl, S. & Turner, N. C. The CDK4/6 inhibitor revolution — a game-changing era for breast cancer treatment. Nat. Rev. Clin. Oncol. 21, 89–105 (2024).

    Article  CAS  PubMed  Google Scholar 

  89. Lloyd, M. R., Spring, L. M., Bardia, A. & Wander, S. A. Mechanisms of resistance to CDK4/6 blockade in advanced hormone receptor-positive, HER2-negative breast cancer and emerging therapeutic opportunities. Clin. Cancer Res. 28, 821–830 (2021).

    Article  Google Scholar 

  90. Li, Z. et al. Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the hippo pathway. Cancer Cell 34, 893–905.e8 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  91. O’Leary, B. et al. Circulating tumor DNA markers for early progression on fulvestrant with or without palbociclib in ER+ advanced breast cancer. J. Natl Cancer Inst. 113, 309–317 (2021).

    Article  PubMed  Google Scholar 

  92. Herrera-Abreu, M. T. et al. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Res. 76, 2301–2313 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Costa, C. et al. PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Kα inhibitors in breast cancer. Cancer Discov. 10, 72–85 (2020).

    Article  CAS  PubMed  Google Scholar 

  94. Raimondi, L. et al. Assessment of resistance mechanisms and clinical implications in patients with KRAS mutated-metastatic breast cancer and resistance to CDK4/6 inhibitors. Cancers 13, 1928 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Nayar, U. et al. Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor-directed therapies. Nat. Genet. 51, 207–216 (2019).

    Article  CAS  PubMed  Google Scholar 

  96. Mao, P. et al. Acquired FGFR and FGF alterations confer resistance to estrogen receptor (ER) targeted therapy in ER+ metastatic breast cancer. Clin. Cancer Res. 26, 5974–5989 (2020).

    Article  CAS  PubMed  Google Scholar 

  97. Formisano, L. et al. Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer. Nat. Commun. 10, 1373 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Drago, J. Z. et al. FGFR1 amplification mediates endocrine resistance but retains TORC sensitivity in metastatic hormone receptor-positive (HR+) breast cancer. Clin. Cancer Res. 25, 6443–6451 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Ma, J. et al. MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation. Nat. Commun. 15, 1871 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Li, Q. et al. INK4 tumor suppressor proteins mediate resistance to CDK4/6 kinase inhibitors. Cancer Discov. 12, 356–371 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Baselga, J. et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 366, 520–529 (2012).

    Article  CAS  PubMed  Google Scholar 

  102. Kornblum, N. et al. Randomized phase II trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer resistant to aromatase inhibitor therapy: results of PrE0102. J. Clin. Oncol. 36, 1556–1563 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Piccart, M. et al. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2. Ann. Oncol. 25, 2357–2362 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Vasseur, A. et al. Fulvestrant and everolimus efficacy after CDK4/6 inhibitor: a prospective study with circulating tumor DNA analysis. Oncogene 43, 1214–1222 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).

    Article  CAS  PubMed  Google Scholar 

  106. Robson, M. et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N. Engl. J. Med. 377, 523–533 (2017).

    Article  CAS  PubMed  Google Scholar 

  107. Litton, J. K. et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N. Engl. J. Med. 379, 753–763 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Litton, J. K. et al. Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results from the EMBRACA trial. Ann. Oncol. 31, 1526–1535 (2020).

    Article  CAS  PubMed  Google Scholar 

  109. Robson, M. E. et al. OlympiAD final overall survival and tolerability results: olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann. Oncol. 30, 558–566 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Anderson, E. J. et al. A systematic review of the prevalence and diagnostic workup of PIK3CA mutations in HR+/HER2− metastatic breast cancer. Int. J. Breast Cancer 2020, 3759179 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Fritsch, C. et al. Characterization of the novel and specific PI3Kα inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol. Cancer Ther. 13, 1117–1129 (2014).

    Article  CAS  PubMed  Google Scholar 

  112. Bosch, A. et al. PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer. Sci. Transl. Med. 7, 283ra51 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  113. André, F. et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. Ann. Oncol. 32, 208–217 (2021).

    Article  PubMed  Google Scholar 

  114. Rugo, H. S. et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 22, 489–498 (2021).

    Article  CAS  PubMed  Google Scholar 

  115. De Laurentiis, M. et al. EPIK-B5: a phase III, randomized study of alpelisib (ALP) plus fulvestrant (FUL) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), PIK3CA-mutated advanced breast cancer (ABC) progressing on/after an aromatase inhibitor (AI) with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). J. Clin. Oncol. 40, TPS1109 (2022).

    Article  Google Scholar 

  116. Narayan, P. et al. FDA approval summary: alpelisib plus fulvestrant for patients with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer. Clin. Cancer Res. 27, 1842–1849 (2021).

    Article  CAS  PubMed  Google Scholar 

  117. Li, H., Prever, L., Hirsch, E. & Gulluni, F. Targeting PI3K/AKT/mTOR signaling pathway in breast cancer. Cancers 13, 3517 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Millis, S. Z., Ikeda, S., Reddy, S., Gatalica, Z. & Kurzrock, R. Landscape of phosphatidylinositol-3-kinase pathway alterations across 19784 diverse solid tumors. JAMA Oncol. 2, 1565–1573 (2016).

    Article  PubMed  Google Scholar 

  119. Howell, S. J. et al. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial. Lancet Oncol. 23, 851–864 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Hanan, E. J. et al. Discovery of GDC-0077 (inavolisib), a highly selective inhibitor and degrader of mutant PI3Kα. J. Med. Chem. 65, 16589–16621 (2022).

    Article  CAS  PubMed  Google Scholar 

  121. Bedard, P. L. et al. A phase I/Ib study evaluating GDC-0077 + palbociclib (palbo) + fulvestrant in patients (pts) with PIK3CA-mutant (mut), hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2− mBC). Cancer Res. 81, abstr. PD1-02 (2021).

    Article  Google Scholar 

  122. Juric, D. et al. A phase I/Ib study of inavolisib (GDC-0077) in combination with fulvestrant in patients (pts) with PIK3CA-mutated hormone receptor-positive/HER2-negative (HR+/HER2−) metastatic breast cancer. Cancer Res. 82, abstr. P5-17-05 (2022).

    Article  Google Scholar 

  123. Jhaveri, K. L. et al. Inavolisib or placebo in combination with palbociclib and fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer: phase III INAVO120 primary analysis. medically.gene.com, https://medically.gene.com/global/en/unrestricted/oncology/SABCS-2023/sabcs-2023-presentation-jhaveri-inavolisib-or-placebo-i.html (2023).

  124. Juric, D. et al. INAVO121: phase III study of inavolisib (INAVO) + fulvestrant (FUL) vs. alpelisib (ALP) + FUL in patients (pts) with hormone receptor-positive, HER2-negative (HR+, HER2−) PIK3CA-mutated (mut) locally advanced or metastatic breast cancer (LA/mBC). J. Clin. Oncol. 41, TPS1123 (2023).

    Article  Google Scholar 

  125. Tadesse, S. et al. Targeting CDK2 in cancer: challenges and opportunities for therapy. Drug Discov. Today 25, 406–413 (2020).

    Article  CAS  PubMed  Google Scholar 

  126. Turner, N. C. et al. Cyclin E1 expression and palbociclib efficacy in previously treated hormone receptor-positive metastatic breast cancer. J. Clin. Oncol. 37, 1169–1178 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Yap, T. A. et al. First-in-human phase 1/2a study of a potent and novel CDK2-selective inhibitor PF-07104091 in patients (pts) with advanced solid tumors, enriched for CDK4/6 inhibitor resistant HR+/HER2− breast cancer. J. Clin. Oncol. 41, 3010 (2023).

    Article  Google Scholar 

  128. Brown, V. et al. CDK2 inhibition with BLU-222 in combination with ribociclib demonstrates robust antitumor activity in pre-clinical models of CDK4/6 inhibitor-naïve and -resistant HR+/HER2− breast cancer. Cancer Res. 83, abstr. P6-10-07 (2023).

    Article  Google Scholar 

  129. Patel, M. R. et al. BLU-222, an oral, potent, and selective CDK2 inhibitor, in patients with advanced solid tumors: phase 1 monotherapy dose escalation. J. Clin. Oncol. 41, 3095 (2023).

    Article  Google Scholar 

  130. Dietrich, C. et al. INX-315, a selective CDK2 inhibitor, induces cell cycle arrest and senescence in solid tumors. Cancer Discov. 14, 446–467 (2024).

    Article  CAS  PubMed  Google Scholar 

  131. Yap, T. A. et al. First-in-human first-in-class phase 1/2a study of the next generation CDK4-selective inhibitor PF-07220060 in patients (pts) with advanced solid tumors, enriched for HR+ HER2− mBC who progressed on prior CDK4/6 inhibitors and endocrine therapy. J. Clin. Oncol. 41, 3009–3009 (2023).

    Article  Google Scholar 

  132. Yap, T. et al. 184MO — first-in-human phase I/IIa study of the first-in-class, next-generation CDK4-selective inhibitor PF-07220060 in combination with endocrine therapy (ET) in patients (pts) with HR+/HER2− metastatic breast cancer (mBC) who progressed on prior CDK4/6 inhibitors (CDK4/6i): safety and efficacy update. ESMO Open 9, 103206 (2024).

    Article  Google Scholar 

  133. Xie, Z. et al. Targeting resistance to current CDK4/6 therapies by RGT-419B, an inhibitor with optimized kinase activity spectrum. Cancer Res. 81, abstr. PS16-22 (2021).

    Article  Google Scholar 

  134. Wander, S. et al. First-in-human phase 1A study of RGT-419B, a next generation CDK4 inhibitor, in patients (pts) with hormone receptor positive (HR+) HER2- advanced/metastatic breast cancer (ABC) who progressed on prior CDK4/6 inhibitors (CDK4/6i). Cancer Res. 84, abstr. PO3-18–06 (2024).

    Article  Google Scholar 

  135. Turner, N. et al. SERENA-1: updated analyses from a phase 1 study of the next generation oral selective estrogen receptor degrader camizestrant (AZD9833) combined with abemaciclib, in women with ER-positive, HER2-negative advanced breast cancer. Cancer Res. 83, abstr. P3-07-28 (2023).

    Article  Google Scholar 

  136. Oliveira, M. et al. Serena-1: updated analyses from a phase 1 study (parts C/D) of the next-generation oral SERD camizestrant (AZD9833) in combination with palbociclib, in women with ER-positive, HER2-negative advanced breast cancer. J. Clin. Oncol. 40, 1032–1032 (2022).

    Article  Google Scholar 

  137. Jhaveri, K. et al. Imlunestrant, an oral selective estrogen receptor degrader, in combination with abemaciclib with or without an aromatase inhibitor, in estrogen receptor-positive advanced breast cancer: results from the phase 1a/b EMBER study. Cancer Res. 83, abstr. PD13-12 (2023).

    Article  Google Scholar 

  138. Oliveira, M. et al. Interim analyses (IA) of the giredestrant (G), G + abemaciclib (A), and G + ribociclib (R) arms in MORPHEUS breast cancer (BC): a phase I/II study of G treatment (tx) combinations in patients (pts) with estrogen receptor-positive, HER2-negative locally advanced/metastatic BC (ER+, HER2− LA/mBC). J. Clin. Oncol. 41, 1061 (2023).

    Article  Google Scholar 

  139. Damodaran, S. et al. Open-label, phase II, multicenter study of lasofoxifene plus abemaciclib for treating women with metastatic ER+/HER2− breast cancer and an ESR1 mutation after disease progression on prior therapies: ELAINE 2. Ann. Oncol. 34, 1131–1140 (2023).

    Article  CAS  PubMed  Google Scholar 

  140. Rugo, H. et al. ELEVATE: a phase 1b/2, open-label, umbrella study evaluating elacestrant in various combinations in women and men with metastatic breast cancer (mBC). Cancer Research 83, abstr. OT2-01-03 (2023).

    Article  Google Scholar 

  141. Im, S.-A. et al. SERENA-4: a phase 3 comparison of AZD9833 (camizestrant) plus palbociclib, versus anastrozole plus palbociclib, for patients with ER-positive, HER2-negative advanced breast cancer who have not previously received systemic treatment for advanced disease. J. Clin. Oncol. 39, TPS1101 (2021).

    Article  Google Scholar 

  142. Turner, N. C. et al. persevERA breast cancer (BC): phase III study evaluating the efficacy and safety of giredestrant (GDC-9545) + palbociclib versus letrozole + palbociclib in patients (pts) with estrogen-receptor-positive, HER2-negative locally advanced or metastatic BC (ER+/HER2− LA/mBC). J. Clin. Oncol. 39, TPS1103 (2021).

    Article  Google Scholar 

  143. Mayer, E. L. et al. evERA breast cancer (BC): phase III study of giredestrant + everolimus vs exemestane + everolimus in patients (pts) with estrogen receptor-positive, HER2-negative locally advanced or metastatic BC (ER+, HER2− LA/mBC). J. Clin. Oncol. 41, TPS1119 (2023).

    Article  Google Scholar 

  144. Layman, R. M. et al. TACTIVE-U: phase 1b/2 umbrella study of ARV-471, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, combined with other anticancer treatments in ER+ advanced or metastatic breast cancer. J. Clin. Oncol. 41, TPS1121 (2023).

    Article  Google Scholar 

  145. Kalinsky, K. et al. Randomized phase II trial of endocrine therapy with or without ribociclib after progression on cyclin-dependent kinase 4/6 inhibition in hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: MAINTAIN trial. J. Clin. Oncol. 41, 4004–4013 (2023).

    Article  CAS  PubMed  Google Scholar 

  146. Llombart-Cussac, A. et al. Second-line endocrine therapy (ET) with or without palbociclib (P) maintenance in patients (pts) with hormone receptor-positive (HR[+])/human epidermal growth factor receptor 2-negative (HER2[−]) advanced breast cancer (ABC): PALMIRA trial. J. Clin. Oncol. 41, 1001 (2023).

    Article  Google Scholar 

  147. Mayer, E. L. et al. PACE: a randomized phase II study of fulvestrant, palbociclib, and avelumab after progression on cyclin-dependent kinase 4/6 inhibitor and aromatase inhibitor for hormone receptor-positive/human epidermal growth factor receptor-negative metastatic breast cancer. J. Clin. Oncol. 42, 2050–2060 (2024).

    Article  CAS  PubMed  Google Scholar 

  148. Wander, S. A. et al. Clinical outcomes with abemaciclib after prior cdk4/6 inhibitor progression in breast cancer: a multicenter experience. J. Natl Compr. Canc. Netw. https://doi.org/10.6004/jnccn.2020.7662 (2021).

  149. Kalinsky, K. et al. Abemaciclib plus fulvestrant vs fulvestrant alone for HR+, HER2− advanced breast cancer following progression on a prior CDK4/6 inhibitor plus endocrine therapy: primary outcome of the phase 3 postMONARCH trial. J. Clin. Oncol. 42, LBA1001 (2024).

    Article  Google Scholar 

  150. Yap, T. et al. CT014 - PETRA: first-in-human phase 1/2a trial of the first-in-class new generation poly(ADP-ribose) polymerase-1 selective inhibitor (PARP1i) saruparib (AZD5305) in patients (pts) with advanced solid tumors with BRCA1/2, PALB2 or RAD51C/D mutations. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT014, abstractsonline.com https://www.abstractsonline.com/pp8/#!/20272/presentation/11430 (2024).

  151. Mark, C., Lee, J. S., Cui, X. & Yuan, Y. Antibody–drug conjugates in breast cancer: current status and future directions. Int. J. Mol. Sci. 24, 13726 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Khongorzul, P., Ling, C. J., Khan, F. U., Ihsan, A. U. & Zhang, J. Antibody-drug conjugates: a comprehensive review. Mol. Cancer Res. 18, 3–19 (2020).

    Article  CAS  PubMed  Google Scholar 

  153. Ogitani, Y. et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin. Cancer Res. 22, 5097–5108 (2016).

    Article  CAS  PubMed  Google Scholar 

  154. Modi, S. et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N. Engl. J. Med. 387, 9–20 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Modi, S. et al. Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: results from a phase Ib study. J. Clin. Oncol. 38, 1887–1896 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. FDA. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-low breast cancer. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-her2-low-breast-cancer (2022).

  157. Curigliano, G. et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): primary results from DESTINY-Breast06 (DB-06). J. Clin. Oncol. 42, LBA1000 (2024).

    Article  Google Scholar 

  158. Goldenberg, D. M., Cardillo, T. M., Govindan, S. V., Rossi, E. A. & Sharkey, R. M. Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC). Oncotarget 6, 22496–22512 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Vidula, N., Yau, C. & Rugo, H. Trophoblast cell surface antigen 2 gene (TACSTD2) expression in primary breast cancer. Breast Cancer Res. Treat. 194, 569–575 (2022).

    Article  CAS  PubMed  Google Scholar 

  160. Bardia, A. et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N. Engl. J. Med. 384, 1529–1541 (2021).

    Article  CAS  PubMed  Google Scholar 

  161. Rugo, H. S. et al. Sacituzumab govitecan in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J. Clin. Oncol. 40, 3365–3376 (2022).

    Article  CAS  PubMed  Google Scholar 

  162. Rugo, H. S. et al. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet 402, 1423–1433 (2023).

    Article  CAS  PubMed  Google Scholar 

  163. Center for Drug Evaluation and Research. FDA approves sacituzumab govitecan-hziy for HR-positive breast cancer. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sacituzumab-govitecan-hziy-hr-positive-breast-cancer (2023).

  164. Okajima, D. et al. Datopotamab deruxtecan, a novel TROP2-directed antibody-drug conjugate, demonstrates potent antitumor activity by efficient drug delivery to tumor cells. Mol. Cancer Ther. 20, 2329–2340 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Meric-Bernstam, F. et al. Phase 1 TROPION-pantumor01 study evaluating datopotamab deruxtecan (Dato-DXd) in unresectable or metastatic hormone receptor-positive/HER2-negative breast cancer (BC). Cancer Res. 83, abstr. PD13-08 (2023).

    Article  Google Scholar 

  166. Bardia, A. et al. LBA11 datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2−) breast cancer (BC): primary results from the randomised phase III TROPION-Breast01 trial. Ann. Oncol. 34, S1264–S1265 (2023).

    Article  Google Scholar 

  167. Koyama, K. et al. Patritumab deruxtecan (HER3-DXd), a novel HER3 directed antibody drug conjugate, exhibits in vitro activity against breast cancer cells expressing HER3 mutations with and without HER2 overexpression. PLoS ONE 17, e0267027 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Pistilli, B. et al. 189O a phase II study of patritumab deruxtecan (HER3-DXd), in patients (pts) with advanced breast cancer (ABC), with biomarker analysis to characterize response to therapy (ICARUS-BREAST01). ESMO Open 8, 101378 (2023).

    Article  Google Scholar 

  169. Velimirovic, M. et al. Rising circulating tumor DNA as a molecular biomarker of early disease progression in metastatic breast cancer. JCO Precis. Oncol. 4, 1246–1262 (2020).

    Article  PubMed  Google Scholar 

  170. Bidard, F.-C. et al. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 23, 1367–1377 (2022).

    Article  CAS  PubMed  Google Scholar 

  171. Turner, N. et al. Design of SERENA-6, a phase III switching trial of camizestrant in ESR1-mutant breast cancer during first-line treatment. Future Oncol. 19, 559–573 (2023).

    Article  CAS  PubMed  Google Scholar 

  172. Cornell, L., Wander, S. A., Visal, T., Wagle, N. & Shapiro, G. I. MicroRNA-mediated suppression of the TGF-β pathway confers transmissible and reversible CDK4/6 inhibitor resistance. Cell Rep. 26, 2667–2680.e7 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Wander, S. A. et al. Real-world (RW) outcomes of patients (pts) with advanced breast cancer (aBC) with and without resistance alterations (alts) detected in cell-free circulating tumor DNA (ctDNA) prior to CDK4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) treatment. J. Clin. Oncol. 41, 1081 (2023).

    Article  Google Scholar 

  174. Hamilton, E. P. et al. Phase I/II study of H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2−) advanced breast cancer. J. Clin. Oncol. 39, 1018 (2021).

    Article  Google Scholar 

  175. Jhaveri, K. et al. 383MO imlunestrant with or without everolimus or alpelisib, in ER+, HER2− advanced breast cancer (aBC): results from the phase Ia/b EMBER study. Ann. Oncol. 34, S338–S339 (2023).

    Article  Google Scholar 

  176. Hamilton, E. P. et al. 218P vepdegestrant, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, plus palbociclib (palbo) in ER+/human epidermal growth factor receptor 2 (HER2)− advanced breast cancer: updated phase Ib cohort results. ESMO Open 9, 103240 (2024).

    Article  Google Scholar 

  177. Borges, V. F. et al. 212P a phase Ib/II study of palazestrant (OP-1250) in combination with ribociclib in patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative (ER+, HER2−) metastatic breast cancer. ESMO Open https://doi.org/10.1016/j.esmoop.2024.103234 (2024).

  178. Tsuji, J. et al. Clinical efficacy and whole-exome sequencing of liquid biopsies in a phase IB/II study of bazedoxifene and palbociclib in advanced hormone receptor-positive breast cancer. Clin. Cancer Res. 28, 5066–5078 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Johnston, S. R. D. et al. H3B-6545 + palbociclib in patients (pts) with locally advanced/metastatic estrogen receptor-positive (ER+), HER2 negative (−) breast cancer (BC). J. Clin. Oncol. 42, 1051 (2024).

    Article  Google Scholar 

  180. Krop, I. E. et al. Patritumab deruxtecan (HER3-DXd), a human epidermal growth factor receptor 3-directed antibody-drug conjugate, in patients with previously treated human epidermal growth factor receptor 3-expressing metastatic breast cancer: a multicenter, phase I/II trial. J. Clin. Oncol. 41, 5550–5560 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Beth Israel Deaconess Medical Center, Boston, MA, USA

    Maxwell R. Lloyd

  2. Memorial Sloan Kettering Evelyn H. Lauder Breast Center, New York, NY, USA

    Komal Jhaveri

  3. Winship Cancer Institute at Emory University, Atlanta, GA, USA

    Kevin Kalinsky

  4. UCLA Health Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA

    Aditya Bardia

  5. Massachusetts General Hospital Cancer Center, Boston, MA, USA

    Seth A. Wander

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M.R.L. and S.A.W. researched data for the article and wrote the manuscript. All authors substantially contributed to discussion of content and reviewed or edited the manuscript before submission.

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K.J. has had consultant or advisory board roles for AbbVie, AstraZeneca, Blueprint Medicine, Daiichi Sankyo, Eisai, Genentech, Gilead, Lilly/Loxo Oncology, Menarini/Stemline, Novartis, Pfizer, Scorpion Therapeutics, Sun Pharma Advanced Research Company Ltd, Taiho Oncology and Zymeworks, and has received research funding support through their institution from AstraZeneca, Blueprint Medicines, Context Therapeutics, Genentech, Immunomedics/Gilead, Lilly/Loxo Oncology, Merck Pharmaceuticals, Novartis, Pfizer, Puma Biotechnology, Scorpion Therapeutics and Zymeworks. K.K. has had consultant or advisory board roles for Astra Zeneca, Daiichi Sankyo, eFFECTOR Therapeutics, Genentech/Roche, Gilead, Lilly, Menarini Silicon Biosystems, Merck, Mersana, Myovant Sciences, Novartis, Prelude Therapeutics, Puma Biotechnology, RayzeBio, Regor, Relay Therapeutics, Seattle Genetics and Takeda; has received research funding support through their institution from Ascentage, AstraZeneca, Daichi Sankyo, Genentech/Roche, Lilly, Novartis and Seattle Genetics; and has a spouse who owns stock from ADC Therapeutics and EQRX (as a prior employee). A.B. has had consultant or advisory board roles for Astra Zeneca, Daiichi Pharma, Eli Lilly, Foundation Medicine, Genentech, Immunomedics/Gilead, Merck, Novartis, Pfizer, Phillips, Radius Health and Sanofi, and has received research funding support through their institution from AstraZeneca, Daiichi Pharma, Eli Lilly, Genentech, Immunomedics/Gilead, Merck, Novartis, Pfizer, Radius Health and Sanofi. S.A.W. has had consultant or advisory board roles for AstraZeneca, Biovica, Eli Lilly, Foundation Medicine, Genentech, Hologic, Novartis, Pfizer, Puma Biotechnology and Veracyte; has education or speaking roles for 2ndMD, Eli Lilly and Guardant Health; and has received research funding support through their institution from Eli Lilly, Genentech, Nuvation Bio, Pfizer, Regor Therapeutics and Sermonix. M.R.L. declares no competing interests.

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Lloyd, M.R., Jhaveri, K., Kalinsky, K. et al. Precision therapeutics and emerging strategies for HR-positive metastatic breast cancer. Nat Rev Clin Oncol 21, 743–761 (2024). https://doi.org/10.1038/s41571-024-00935-6

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