Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Management of patients with advanced-stage HER2-positive breast cancer: current evidence and future perspectives

Nature Reviews Clinical Oncology volume 21, pages 185–202 (2024)Cite this article

Subjects

Abstract

Amplification and/or overexpression of ERBB2, the gene encoding HER2, can be found in 15–20% of invasive breast cancers and is associated with an aggressive phenotype and poor clinical outcomes. Relentless research efforts in molecular biology and drug development have led to the implementation of several HER2-targeted therapies, including monoclonal antibodies, tyrosine-kinase inhibitors and antibody–drug conjugates, constituting one of the best examples of bench-to-bedside translation in oncology. Each individual drug class has improved patient outcomes and, importantly, the combinatorial and sequential use of different HER2-targeted therapies has increased cure rates in the early stage disease setting and substantially prolonged survival for patients with advanced-stage disease. In this Review, we describe key steps in the development of the modern paradigm for the treatment of HER2-positive advanced-stage breast cancer, including selecting and sequencing new-generation HER2-targeted therapies, and summarize efficacy and safety outcomes from pivotal studies. We then outline the factors that are currently known to be related to resistance to HER2-targeted therapies, such as HER2 intratumoural heterogeneity, activation of alternative signalling pathways and immune escape mechanisms, as well as potential strategies that might be used in the future to overcome this resistance and further improve patient outcomes.

Key points

  • The discovery of ERBB2 and the clinical characterization of HER2, the protein it encodes, as a biomarker and therapeutic target have been key milestones in breast cancer treatment.

  • The development of several HER2-targeted agents, including monoclonal antibodies, tyrosine-kinase inhibitors and antibody–drug conjugates, has increased cure rates in patients with early stage HER2-positive (HER2+) breast cancer and substantially improved survival for patients with advanced-stage HER2+ breast cancer.

  • Incorporating novel HER2-targeted therapies into treatment algorithms for patients with metastatic HER2+ breast cancer to optimize selection and sequencing of these agents is currently a clinical challenge.

  • Several mechanisms, such as intratumoural heterogeneity, activation of alternative signalling pathways and immune escape mechanisms, can reduce the efficacy of HER2-targeted agents.

  • Future research on treatments for patients with HER2+ breast cancer is focusing on developing novel drugs that can specifically target cancer cells with minimal side effects as well as on the implementation of novel technologies, such as artificial intelligence for integrating clinical and genomic data, liquid biopsy assays for minimal residual disease monitoring and treatment escalation/de-escalation, and single-cell sequencing for a more precise assessment of HER2 heterogeneity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Timeline of the relevant discoveries related to HER2 and breast cancer.
Fig. 2: Treatment algorithm for patients with advanced-stage HER2-positive breast cancer.
Fig. 3: Selected treatment-related adverse events from HER2-targeted agents in breast cancer.
Fig. 4: Common mechanisms of resistance to HER2-targeted agents.

Similar content being viewed by others

References

  1. Carpenter, G., King, L. Jr & Cohen, S. Epidermal growth factor stimulates phosphorylation in membrane preparations in vitro. Nature 276, 409–410 (1978).

    Article  ADS  CAS  PubMed  Google Scholar 

  2. Schechter, A. L. et al. The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature 312, 513–516 (1984).

    Article  ADS  CAS  PubMed  Google Scholar 

  3. Slamon, D. J. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177–182 (1987).

    Article  ADS  CAS  PubMed  Google Scholar 

  4. Yarden, Y. & Sliwkowski, M. X. Untangling the ErbB signalling network. Nat. Rev. Mol. Cell Biol. 2, 127–137 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Schlam, I. & Swain, S. M. HER2-positive breast cancer and tyrosine kinase inhibitors: the time is now. NPJ Breast Cancer 7, 56 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Coussens, L. et al. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 230, 1132–1139 (1985).

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Kraus, M. H., Issing, W., Miki, T., Popescu, N. C. & Aaronson, S. A. Isolation and characterization of ERBB3, a third member of the ERBB/epidermal growth factor receptor family: evidence for overexpression in a subset of human mammary tumors. Proc. Natl Acad. Sci. USA 86, 9193–9197 (1989).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  8. Plowman, G. D. et al. Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. Proc. Natl Acad. Sci. USA 90, 1746–1750 (1993).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  9. Di Fiore, P. P. et al. erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science 237, 178–182 (1987).

    Article  ADS  PubMed  Google Scholar 

  10. Hudziak, R. M., Schlessinger, J. & Ullrich, A. Increased expression of the putative growth factor receptor p185HER2 causes transformation and tumorigenesis of NIH 3T3 cells. Proc. Natl Acad. Sci. USA 84, 7159–7163 (1987).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  11. Slamon, D. J. et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244, 707–712 (1989).

    Article  ADS  CAS  PubMed  Google Scholar 

  12. Drebin, J. A., Stern, D. F., Link, V. C., Weinberg, R. A. & Greene, M. I. Monoclonal antibodies identify a cell-surface antigen associated with an activated cellular oncogene. Nature 312, 545–548 (1984).

    Article  ADS  CAS  PubMed  Google Scholar 

  13. Drebin, J. A., Link, V. C., Weinberg, R. A. & Greene, M. I. Inhibition of tumor growth by a monoclonal antibody reactive with an oncogene-encoded tumor antigen. Proc. Natl Acad. Sci. USA 83, 9129–9133 (1986).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. Drebin, J. A., Link, V. C., Stern, D. F., Weinberg, R. A. & Greene, M. I. Down-modulation of an oncogene protein product and reversion of the transformed phenotype by monoclonal antibodies. Cell 41, 697–706 (1985).

    Article  CAS  PubMed  Google Scholar 

  15. Fendly, B. M. et al. Characterization of murine monoclonal antibodies reactive to either the human epidermal growth factor receptor or HER2/neu gene product. Cancer Res. 50, 1550–1558 (1990).

    CAS  PubMed  Google Scholar 

  16. Carter, P. et al. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc. Natl Acad. Sci. USA 89, 4285–4289 (1992).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cho, H. S. et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 421, 756–760 (2003).

    Article  ADS  CAS  PubMed  Google Scholar 

  18. Hudis, C. A. Trastuzumab-mechanism of action and use in clinical practice. N. Engl. J. Med. 357, 39–51 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Clynes, R. A., Towers, T. L., Presta, L. G. & Ravetch, J. V. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat. Med. 6, 443–446 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Petricevic, B. et al. Trastuzumab mediates antibody-dependent cell-mediated cytotoxicity and phagocytosis to the same extent in both adjuvant and metastatic HER2/neu breast cancer patients. J. Transl. Med. 11, 307 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Collins, D. M. et al. Trastuzumab induces antibody-dependent cell-mediated cytotoxicity (ADCC) in HER-2-non-amplified breast cancer cell lines. Ann. Oncol. 23, 1788–1795 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Varchetta, S. et al. Elements related to heterogeneity of antibody-dependent cell cytotoxicity in patients under trastuzumab therapy for primary operable breast cancer overexpressing Her2. Cancer Res. 67, 11991–11999 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Stagg, J. et al. Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proc. Natl Acad. Sci. USA 108, 7142–7147 (2011).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  24. Klapper, L. N., Waterman, H., Sela, M. & Yarden, Y. Tumor-inhibitory antibodies to HER-2/ErbB-2 may act by recruiting c-Cbl and enhancing ubiquitination of HER-2. Cancer Res. 60, 3384–3388 (2000).

    CAS  PubMed  Google Scholar 

  25. Baselga, J. et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J. Clin. Oncol. 14, 737–744 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Pegram, M. D. et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J. Clin. Oncol. 16, 2659–2671 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Cobleigh, M. A. et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J. Clin. Oncol. 17, 2639–2648 (1999).

    Article  CAS  PubMed  Google Scholar 

  28. Baselga, J. Phase I and II clinical trials of trastuzumab. Ann. Oncol. 12, S49–S55 (2001).

    Article  PubMed  Google Scholar 

  29. Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Piccart-Gebhart, M. J. et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl. J. Med. 353, 1659–1672 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Howlader, N., Cronin, K. A., Kurian, A. W. & Andridge, R. Differences in breast cancer survival by molecular subtypes in the United States. Cancer Epidemiol. Biomark. Prev. 27, 619–626 (2018).

    Article  CAS  Google Scholar 

  32. Sundquist, M., Brudin, L. & Tejler, G. Improved survival in metastatic breast cancer 1985-2016. Breast 31, 46–50 (2017).

    Article  PubMed  Google Scholar 

  33. Grinda, T. et al. Evolution of overall survival and receipt of new therapies by subtype among 20 446 metastatic breast cancer patients in the 2008-2017 ESME cohort. ESMO Open. 6, 100114 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Baselga, J. et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N. Engl. J. Med. 366, 109–119 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Franklin, M. C. et al. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 5, 317–328 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Junttila, T. T. et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 15, 429–440 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Swain, S. M. et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N. Engl. J. Med. 372, 724–734 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Swain, S. M. et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 21, 519–530 (2020).

    Article  CAS  PubMed  Google Scholar 

  39. Bachelot, T. et al. Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE). Ann. Oncol. 30, 766–773 (2019).

    Article  CAS  PubMed  Google Scholar 

  40. Miles, D. et al. Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication. Ann. Oncol. 32, 1245–1255 (2021).

    Article  CAS  PubMed  Google Scholar 

  41. Rimawi, M. et al. First-line trastuzumab plus an aromatase inhibitor, with or without pertuzumab, in human epidermal growth factor receptor 2-positive and hormone receptor-positive metastatic or locally advanced breast cancer (PERTAIN): a randomized, open-label phase II trial. J. Clin. Oncol. 36, 2826–2835 (2018).

    Article  CAS  PubMed  Google Scholar 

  42. Johnston, S. R. D. et al. Phase III, randomized study of dual human epidermal growth factor receptor 2 (HER2) blockade with lapatinib plus trastuzumab in combination with an aromatase inhibitor in postmenopausal women with HER2-positive, hormone receptor-positive metastatic breast cancer: updated results of ALTERNATIVE. J. Clin. Oncol. 39, 79–89 (2021).

    Article  CAS  PubMed  Google Scholar 

  43. Arpino, G. et al. Pertuzumab, trastuzumab, and an aromatase inhibitor for HER2-positive and hormone receptor-positive metastatic/locally advanced breast cancer: PERTAIN final analysis. Clin. Cancer Res. 14, 1468–1476 (2023).

    Article  Google Scholar 

  44. Hua, X. et al. Trastuzumab plus endocrine therapy or chemotherapy as first-line treatment for patients with hormone receptor-positive and HER2-positive metastatic breast cancer (SYSUCC-002). Clin. Cancer Res. 28, 637–645 (2022).

    Article  CAS  PubMed  Google Scholar 

  45. Perez, E. A. et al. Safety and efficacy of vinorelbine in combination with pertuzumab and trastuzumab for first-line treatment of patients with HER2-positive locally advanced or metastatic breast cancer: VELVET Cohort 1 final results. Breast Cancer Res. 18, 126 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Andersson, M. et al. Efficacy and safety of pertuzumab and trastuzumab administered in a single infusion bag, followed by vinorelbine: VELVET cohort 2 final results. Oncologist 22, 1160–1168 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wildiers, H. et al. Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2-positive metastatic breast cancer (EORTC 75111-10114): an open-label, randomised, phase 2 trial from the Elderly Task Force/Breast Cancer Group. Lancet Oncol. 19, 323–336 (2018).

    Article  CAS  PubMed  Google Scholar 

  48. Bazan, J. G., Holbrook, A., Jhawar, S. & White, J. R. Abstract P4-12-03: patterns of progression in metastatic breast cancer: does oligoprogression exist? Cancer Res. 80, P4-12-03–P14-12-03 (2020).

    Article  Google Scholar 

  49. Lievens, Y. et al. Defining oligometastatic disease from a radiation oncology perspective: an ESTRO-ASTRO consensus document. Radiother. Oncol. 148, 157–166 (2020).

    Article  PubMed  Google Scholar 

  50. Patel, P. H., Palma, D., McDonald, F. & Tree, A. C. The dandelion dilemma revisited for oligoprogression: treat the whole lawn or weed selectively? Clin. Oncol. 31, 824–833 (2019).

    Article  CAS  Google Scholar 

  51. Tsai, C. J. et al. Final analysis of consolidative use of radiotherapy to block (CURB) oligoprogression trial - a randomized study of stereotactic body radiotherapy for oligoprogressive metastatic lung and breast cancers. Int. J. Radiat. Oncol. Biol. Phys. 114, 1061 (2022).

    Article  Google Scholar 

  52. Perez, E. A. et al. Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE study. J. Clin. Oncol. 35, 141–148 (2017).

    Article  CAS  PubMed  Google Scholar 

  53. Geyer, C. E. et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N. Engl. J. Med. 355, 2733–2743 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Blackwell, K. L. et al. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J. Clin. Oncol. 28, 1124–1130 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. Yamamoto, Y. et al. Pertuzumab retreatment for HER2-positive advanced breast cancer: a randomized, open-label phase III study (PRECIOUS). Cancer Sci. 113, 3169–3179 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Cameron, D. et al. Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial. Oncologist 15, 924–934 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. von Minckwitz, G. et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study. J. Clin. Oncol. 27, 1999–2006 (2009).

    Article  Google Scholar 

  58. Lewis Phillips, G. D. et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 68, 9280–9290 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Verma, S. et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 367, 1783–1791 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Dieras, V. et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 18, 732–742 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Marchio, C. et al. Evolving concepts in HER2 evaluation in breast cancer: heterogeneity, HER2-low carcinomas and beyond. Semin. Cancer Biol. 72, 123–135 (2021).

    Article  CAS  PubMed  Google Scholar 

  62. Modi, S. et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N. Engl. J. Med. 382, 610–621 (2020).

    Article  CAS  PubMed  Google Scholar 

  63. Saura Manich, C. et al. 279P Trastuzumab deruxtecan (T-DXd) in patients with HER2-positive metastatic breast cancer (MBC): updated survival results from a phase II trial (DESTINY-Breast01). Ann. Oncol. 32, S485–S486 (2021).

    Article  Google Scholar 

  64. 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 

  65. Tamura, K. et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. Lancet Oncol. 20, 816–826 (2019).

    Article  CAS  PubMed  Google Scholar 

  66. Cortes, J. et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N. Engl. J. Med. 386, 1143–1154 (2022).

    Article  CAS  PubMed  Google Scholar 

  67. Hurvitz, S. A. et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet 401, 105–117 (2023).

    Article  CAS  PubMed  Google Scholar 

  68. Andre, F. et al. Trastuzumab deruxtecan versus treatment of physician’s choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. Lancet 401, 1773–1785 (2023).

    Article  CAS  PubMed  Google Scholar 

  69. Powell, C. A. et al. Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies. ESMO Open. 7, 100554 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Swain, S. M. et al. Multidisciplinary clinical guidance on trastuzumab deruxtecan (T-DXd)-related interstitial lung disease/pneumonitis-Focus on proactive monitoring, diagnosis, and management. Cancer Treat. Rev. 106, 102378 (2022).

    Article  CAS  PubMed  Google Scholar 

  71. Tarantino, P. et al. Interstitial lung disease induced by anti-ERBB2 antibody-drug conjugates: a review. JAMA Oncol. 7, 1873–1881, (2021).

    Article  PubMed  Google Scholar 

  72. Conte, P. et al. Drug-induced interstitial lung disease during cancer therapies: expert opinion on diagnosis and treatment. ESMO Open. 7, 100404 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Rugo, H. S., Bianchini, G., Cortes, J., Henning, J. W. & Untch, M. Optimizing treatment management of trastuzumab deruxtecan in clinical practice of breast cancer. ESMO Open. 7, 100553 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Huang, L., Jiang, S. & Shi, Y. Tyrosine kinase inhibitors for solid tumors in the past 20 years (2001-2020). J. Hematol. Oncol. 13, 143 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Moulder, S. L. et al. Phase I study of ONT-380, a HER2 inhibitor, in patients with HER2+-advanced solid tumors, with an expansion cohort in HER2+ metastatic breast cancer (MBC). Clin. Cancer Res. 23, 3529–3536 (2017).

    Article  CAS  PubMed  Google Scholar 

  76. Metzger Filho, O. et al. Phase I dose-escalation trial of tucatinib in combination with trastuzumab in patients with HER2-positive breast cancer brain metastases. Ann. Oncol. 31, 1231–1239 (2020).

    Article  CAS  PubMed  Google Scholar 

  77. Murthy, R. K. et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N. Engl. J. Med. 382, 597–609 (2020).

    Article  CAS  PubMed  Google Scholar 

  78. Curigliano, G. et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis. Ann. Oncol. 33, 321–329 (2022).

    Article  CAS  PubMed  Google Scholar 

  79. Lin, N. U. et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J. Clin. Oncol. 38, 2610–2619 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Lin, N. U. et al. Tucatinib vs placebo, both in combination with trastuzumab and capecitabine, for previously treated ERBB2 (HER2)-positive metastatic breast cancer in patients with brain metastases: updated exploratory analysis of the HER2CLIMB randomized clinical trial. JAMA Oncol. 9, 197–205, (2023).

    Article  PubMed  Google Scholar 

  81. Gennari, A. et al. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann. Oncol. 32, 1475–1495 (2021).

    Article  CAS  PubMed  Google Scholar 

  82. Frenel, J.-S. et al. Efficacy of tucatinib+trastuzumab+capecitabine (TTC) after trastuzumab-deruxtecan (T-DXd) exposure in Her2-positive metastatic breast cancer: a French multicentre retrospective study. J. Clin. Oncol. 41, 1014–1014 (2023).

    Article  ADS  Google Scholar 

  83. Saura, C. et al. Safety and efficacy of neratinib in combination with capecitabine in patients with metastatic human epidermal growth factor receptor 2-positive breast cancer. J. Clin. Oncol. 32, 3626–3633 (2014).

    Article  ADS  CAS  PubMed  Google Scholar 

  84. Freedman, R. A. et al. TBCRC 022: a phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J. Clin. Oncol. 37, 1081–1089 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Awada, A. et al. Neratinib plus paclitaxel vs trastuzumab plus paclitaxel in previously untreated metastatic ERBB2-positive breast cancer: the NEfERT-T randomized clinical trial. JAMA Oncol. 2, 1557–1564, (2016).

    Article  PubMed  Google Scholar 

  86. Saura, C. et al. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: phase III NALA trial. J. Clin. Oncol. 38, 3138–3149 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hurvitz, S. A. et al. Efficacy of neratinib plus capecitabine in the subgroup of patients with central nervous system involvement from the NALA trial. Oncologist 26, e1327–e1338 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Barcenas, C. H. et al. Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: the CONTROL trial. Ann. Oncol. 31, 1223–1230 (2020).

    Article  CAS  PubMed  Google Scholar 

  89. Xu, B. et al. Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 22, 351–360 (2021).

    Article  CAS  PubMed  Google Scholar 

  90. Xu, B. et al. Abstract GS3-02: updated overall survival (OS) results from the phase 3 PHOEBE trial of pyrotinib versus lapatinib in combination with capecitabine in patients with HER2-positive metastatic breast cancer. Cancer Res. 82, GS3-02–GS03-02 (2022).

    Article  Google Scholar 

  91. Ma, F. et al. Pyrotinib versus placebo in combination with trastuzumab and docetaxel as first line treatment in patients with HER2 positive metastatic breast cancer (PHILA): randomised, double blind, multicentre, phase 3 trial. BMJ 383, e076065 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  92. van der Lee, M. M. et al. The preclinical profile of the duocarmycin-based her2-targeting ADC SYD985 predicts for clinical benefit in low HER2-expressing breast cancers. Mol. Cancer Ther. 14, 692–703 (2015).

    Article  PubMed  Google Scholar 

  93. Saura Manich, C. et al. LBA15 primary outcome of the phase III SYD985.002/TULIP trial comparing [vic-]trastuzumab duocarmazine to physician’s choice treatment in patients with pre-treated HER2-positive locally advanced or metastatic breast cancer. Ann. Oncol. 32, S1288 (2021).

    Article  Google Scholar 

  94. Nordstrom, J. L. et al. Anti-tumor activity and toxicokinetics analysis of MGAH22, an anti-HER2 monoclonal antibody with enhanced Fcgamma receptor binding properties. Breast Cancer Res. 13, R123 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Bang, Y. J. et al. First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors. Ann. Oncol. 28, 855–861 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Rugo, H. S. et al. Efficacy of margetuximab vs trastuzumab in patients with pretreated ERBB2-positive advanced breast cancer: a phase 3 randomized clinical trial. JAMA Oncol. 7, 573–584, (2021).

    Article  PubMed  Google Scholar 

  97. Rugo, H. S. et al. Margetuximab versus trastuzumab in patients with previously treated HER2-positive advanced breast cancer (SOPHIA): final overall survival results from a randomized phase 3 trial. J. Clin. Oncol. 41, 198–205 (2023).

    Article  CAS  PubMed  Google Scholar 

  98. Malmgren, J., Hurlbert, M., Atwood, M. & Kaplan, H. G. Examination of a paradox: recurrent metastatic breast cancer incidence decline without improved distant disease survival: 1990-2011. Breast Cancer Res. Treat. 174, 505–514 (2019).

    Article  PubMed  Google Scholar 

  99. Gallicchio, L., Devasia, T. P., Tonorezos, E., Mollica, M. A. & Mariotto, A. Estimation of the number of individuals living with metastatic cancer in the United States. J. Natl Cancer Inst. 114, 1476–1483 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Konecny, G. et al. Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J. Natl Cancer Inst. 95, 142–153 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Dowsett, M. et al. Relationship between quantitative estrogen and progesterone receptor expression and human epidermal growth factor receptor 2 (HER-2) status with recurrence in the Arimidex, Tamoxifen, Alone or in Combination trial. J. Clin. Oncol. 26, 1059–1065 (2008).

    Article  CAS  PubMed  Google Scholar 

  102. Gutierrez, M. C. et al. Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J. Clin. Oncol. 23, 2469–2476 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Xia, W. et al. A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer. Proc. Natl Acad. Sci. USA 103, 7795–7800 (2006).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  104. Wang, Y. C. et al. Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast cancers-role of estrogen receptor and HER2 reactivation. Breast Cancer Res. 13, R121 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Marra, A. & Curigliano, G. Are all cyclin-dependent kinases 4/6 inhibitors created equal? NPJ Breast Cancer 5, 27 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Miller, T. W. et al. ERalpha-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov. 1, 338–351 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Landis, M. W., Pawlyk, B. S., Li, T., Sicinski, P. & Hinds, P. W. Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis. Cancer Cell 9, 13–22 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Finn, R. S. et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 11, R77 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Goel, S. et al. Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors. Cancer Cell 29, 255–269 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ciruelos, E. et al. Palbociclib and trastuzumab in HER2-positive advanced breast cancer: results from the phase II SOLTI-1303 PATRICIA trial. Clin. Cancer Res. 26, 5820–5829 (2020).

    Article  CAS  PubMed  Google Scholar 

  111. Tolaney, S. M. et al. Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial. Lancet Oncol. 21, 763–775 (2020).

    Article  CAS  PubMed  Google Scholar 

  112. Tolaney, S. M. et al. Overall survival and exploratory biomarker analyses of abemaciclib plus trastuzumab with or without fulvestrant vs trastuzumab plus chemotherapy in HR+, HER2+ metastatic breast cancer patients. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-23-1209 (2023).

  113. Vance, G. H. et al. Genetic heterogeneity in HER2 testing in breast cancer: panel summary and guidelines. Arch. Pathol. Lab. Med. 133, 611–612 (2009).

    Article  PubMed  Google Scholar 

  114. Bernasconi, B., Chiaravalli, A. M., Finzi, G., Milani, K. & Tibiletti, M. G. Genetic heterogeneity in HER2 testing may influence therapy eligibility. Breast Cancer Res. Treat. 133, 161–168 (2012).

    Article  PubMed  Google Scholar 

  115. Bartlett, J. M. et al. HER2 testing in the UK: recommendations for breast and gastric in-situ hybridisation methods. J. Clin. Pathol. 64, 649–653 (2011).

    Article  CAS  PubMed  Google Scholar 

  116. Wolff, A. C. et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J. Clin. Oncol. 31, 3997–4013 (2013).

    Article  PubMed  Google Scholar 

  117. Hanna, W. M. et al. HER2 in situ hybridization in breast cancer: clinical implications of polysomy 17 and genetic heterogeneity. Mod. Pathol. 27, 4–18 (2014).

    Article  CAS  PubMed  Google Scholar 

  118. Marusyk, A., Janiszewska, M. & Polyak, K. Intratumor heterogeneity: the Rosetta stone of therapy resistance. Cancer Cell 37, 471–484 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Perez, E. A. et al. Relationship between tumor biomarkers and efficacy in MARIANNE, a phase III study of trastuzumab emtansine ± pertuzumab versus trastuzumab plus taxane in HER2-positive advanced breast cancer. BMC Cancer 19, 517 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Hou, Y. et al. HER2 intratumoral heterogeneity is independently associated with incomplete response to anti-HER2 neoadjuvant chemotherapy in HER2-positive breast carcinoma. Breast Cancer Res. Treat. 166, 447–457 (2017).

    Article  CAS  PubMed  Google Scholar 

  121. Rye, I. H. et al. Intratumor heterogeneity defines treatment-resistant HER2+ breast tumors. Mol. Oncol. 12, 1838–1855 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Hurvitz, S. A. et al. Neoadjuvant trastuzumab emtansine and pertuzumab in human epidermal growth factor receptor 2-positive breast cancer: three-year outcomes from the phase III KRISTINE study. J. Clin. Oncol. 37, 2206–2216 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Caswell-Jin, J. L. et al. Clonal replacement and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy. Nat. Commun. 10, 657 (2019).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  124. Filho, O. M. et al. Impact of HER2 heterogeneity on treatment response of early-stage HER2-positive breast cancer: phase II neoadjuvant clinical trial of T-DM1 combined with pertuzumab. Cancer Discov. 11, 2474–2487 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Drago, J. Z., Modi, S. & Chandarlapaty, S. Unlocking the potential of antibody-drug conjugates for cancer therapy. Nat. Rev. Clin. Oncol. 18, 327–344 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  126. 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 

  127. Mosele, F. et al. Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial. Nat. Med. 29, 2110–2120 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Fruman, D. A. et al. The PI3K pathway in human disease. Cell 170, 605–635 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. She, Q. B. et al. Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling. PLoS ONE 3, e3065 (2008).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  130. Berns, K. et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12, 395–402 (2007).

    Article  CAS  PubMed  Google Scholar 

  131. Esteva, F. J. et al. PTEN, PIK3CA, p-AKT, and p-p70S6K status: association with trastuzumab response and survival in patients with HER2-positive metastatic breast cancer. Am. J. Pathol. 177, 1647–1656 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Chandarlapaty, S. et al. Frequent mutational activation of the PI3K-AKT pathway in trastuzumab-resistant breast cancer. Clin. Cancer Res. 18, 6784–6791 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).

    Article  ADS  Google Scholar 

  134. Razavi, P. et al. The genomic landscape of endocrine-resistant advanced breast cancers. Cancer Cell 34, 427–438.e426 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Loibl, S. et al. PIK3CA mutations are associated with reduced pathological complete response rates in primary HER2-positive breast cancer: pooled analysis of 967 patients from five prospective trials investigating lapatinib and trastuzumab. Ann. Oncol. 27, 1519–1525 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Baselga, J. et al. Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer. J. Clin. Oncol. 32, 3753–3761 (2014).

    Article  CAS  PubMed  Google Scholar 

  137. Baselga, J. et al. Relationship between tumor biomarkers and efficacy in EMILIA, a phase III study of trastuzumab emtansine in HER2-positive metastatic breast cancer. Clin. Cancer Res. 22, 3755–3763 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Andre, F. et al. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 15, 580–591 (2014).

    Article  CAS  PubMed  Google Scholar 

  139. Andre, F. et al. Molecular alterations and everolimus efficacy in human epidermal growth factor receptor 2-overexpressing metastatic breast cancers: combined exploratory biomarker analysis from BOLERO-1 and BOLERO-3. J. Clin. Oncol. 34, 2115–2124 (2016).

    Article  PubMed  Google Scholar 

  140. Jhaveri, K. et al. A phase I study of alpelisib in combination with trastuzumab and LJM716 in patients with PIK3CA-mutated HER2-positive metastatic breast cancer. Clin. Cancer Res. 27, 3867–3875 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Solit, D. B. et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature 439, 358–362 (2006).

    Article  ADS  CAS  PubMed  Google Scholar 

  142. Smith, A. E. et al. HER2+ breast cancers evade anti-HER2 therapy via a switch in driver pathway. Nat. Commun. 12, 6667 (2021).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  143. Ferraro, E. et al. Abstract P4-02-01: efficacy of HER2 ADCs against HER2 inhibitor resistance alterations in the PI3K and MAPK pathways in HER2-positive breast cancer. Cancer Res. 83, P4-02-01–P04-02-01 (2023).

    Article  Google Scholar 

  144. Kancha, R. K. et al. Differential sensitivity of ERBB2 kinase domain mutations towards lapatinib. PLoS ONE 6, e26760 (2011).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  145. Xu, X. et al. HER2 reactivation through acquisition of the HER2 L755S mutation as a mechanism of acquired resistance to HER2-targeted therapy in HER2+ breast cancer. Clin. Cancer Res. 23, 5123–5134 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Kingston, B. et al. Genomic profile of advanced breast cancer in circulating tumour DNA. Nat. Commun. 12, 2423 (2021).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  147. Hyman, D. M. et al. HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature 554, 189–194 (2018).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  148. Holbro, T. et al. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc. Natl Acad. Sci. USA 100, 8933–8938 (2003).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  149. Krishnamurthy, A. & Jimeno, A. Bispecific antibodies for cancer therapy: a review. Pharmacol. Ther. 185, 122–134 (2018).

    Article  CAS  PubMed  Google Scholar 

  150. Geuijen, C. A. W. et al. Unbiased combinatorial screening identifies a bispecific IgG1 that potently inhibits HER3 signaling via HER2-guided ligand blockade. Cancer Cell 33, 922–936.e910 (2018).

    Article  CAS  PubMed  Google Scholar 

  151. Hamilton, E. P. et al. Clinical activity of MCLA-128 (zenocutuzumab), trastuzumab, and vinorelbine in HER2 amplified metastatic breast cancer (MBC) patients (pts) who had progressed on anti-HER2 ADCs. J. Clin. Oncol. 38, 3093–3093 (2020).

    Article  Google Scholar 

  152. Swain, S. M., Shastry, M. & Hamilton, E. Targeting HER2-positive breast cancer: advances and future directions. Nat. Rev. Drug. Discov. 22, 101–126 (2023).

    Article  CAS  PubMed  Google Scholar 

  153. Krop, I. E. et al. Results from the phase 1/2 study of patritumab deruxtecan, a HER3-directed antibody-drug conjugate (ADC), in patients with HER3-expressing metastatic breast cancer (MBC). J. Clin. Oncol. 40, 1002–1002 (2022).

    Article  Google Scholar 

  154. Savas, P. et al. Clinical relevance of host immunity in breast cancer: from TILs to the clinic. Nat. Rev. Clin. Oncol. 13, 228–241 (2016).

    Article  CAS  PubMed  Google Scholar 

  155. Denkert, C. et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 19, 40–50 (2018).

    Article  PubMed  Google Scholar 

  156. Luen, S. J. et al. Tumour-infiltrating lymphocytes in advanced HER2-positive breast cancer treated with pertuzumab or placebo in addition to trastuzumab and docetaxel: a retrospective analysis of the CLEOPATRA study. Lancet Oncol. 18, 52–62 (2017).

    Article  CAS  PubMed  Google Scholar 

  157. Hills, R. K. et al. Do tumor infiltrating lymphocytes (TILs) predict benefits from trastuzumab therapy for HER2 positive breast cancer? Meta-analysis of individual patient data from 4097 women in 5 trials. J. Clin. Oncol. 41, 508 (2023).

    Article  Google Scholar 

  158. Datta, J. et al. Progressive loss of anti-HER2 CD4(+) T-helper type 1 response in breast tumorigenesis and the potential for immune restoration. Oncoimmunology 4, e1022301 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Dirix, L. Y. et al. Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study. Breast Cancer Res. Treat. 167, 671–686 (2018).

    Article  CAS  PubMed  Google Scholar 

  160. Chia, S. et al. A phase Ib trial of durvalumab in combination with trastuzumab in HER2-positive metastatic breast cancer (CCTG IND.229). Oncologist 24, 1439–1445 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Loi, S. et al. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial. Lancet Oncol. 20, 371–382 (2019).

    Article  CAS  PubMed  Google Scholar 

  162. Emens, L. A. et al. Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial. Lancet Oncol. 21, 1283–1295 (2020).

    Article  CAS  PubMed  Google Scholar 

  163. Adams, S. et al. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study. Ann. Oncol. 30, 397–404 (2019).

    Article  CAS  PubMed  Google Scholar 

  164. Cortes, J. et al. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N. Engl. J. Med. 387, 217–226 (2022).

    Article  CAS  PubMed  Google Scholar 

  165. Geyer, J. C. E. et al. Abstract OT2-16-05: safety analyses of NRG BR004: a randomized, double-blind, phase III trial of taxane/trastuzumab/pertuzumab with atezolizumab or placebo in first-line HER2-positive metastatic breast cancer (MBC). Cancer Res. 83, OT2-16-05–OT12-16-05 (2023).

    Article  Google Scholar 

  166. Gil Del Alcazar, C. R., Aleckovic, M. & Polyak, K. Immune escape during breast tumor progression. Cancer Immunol. Res. 8, 422–427 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Gil Del Alcazar, C. R. et al. Immune escape in breast cancer during in situ to invasive carcinoma transition. Cancer Discov. 7, 1098–1115 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Linde, N. et al. Macrophages orchestrate breast cancer early dissemination and metastasis. Nat. Commun. 9, 21 (2018).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  169. Shi, Y. et al. Trastuzumab triggers phagocytic killing of high HER2 cancer cells in vitro and in vivo by interaction with Fcgamma receptors on macrophages. J. Immunol. 194, 4379–4386 (2015).

    Article  CAS  PubMed  Google Scholar 

  170. Betancur, P. A. et al. A CD47-associated super-enhancer links pro-inflammatory signalling to CD47 upregulation in breast cancer. Nat. Commun. 8, 14802 (2017).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  171. Upton, R. et al. Combining CD47 blockade with trastuzumab eliminates HER2-positive breast cancer cells and overcomes trastuzumab tolerance. Proc. Natl Acad. Sci. USA 118, e2026849118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Messaoudene, M. et al. T-cell bispecific antibodies in node-positive breast cancer: novel therapeutic avenue for MHC class I loss variants. Ann. Oncol. 30, 934–944 (2019).

    Article  CAS  PubMed  Google Scholar 

  173. Blanco, B., Dominguez-Alonso, C. & Alvarez-Vallina, L. Bispecific immunomodulatory antibodies for cancer immunotherapy. Clin. Cancer Res. 27, 5457–5464 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. van Hall, T. et al. Monalizumab: inhibiting the novel immune checkpoint NKG2A. J. Immunother. Cancer 7, 263 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Geurts, V. C. M. et al. Unleashing NK- and CD8 T cells by combining monalizumab and trastuzumab for metastatic HER2-positive breast cancer: results of the MIMOSA trial. Breast 70, 76–81 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Echle, A. et al. Deep learning in cancer pathology: a new generation of clinical biomarkers. Br. J. Cancer 124, 686–696 (2021).

    Article  PubMed  Google Scholar 

  177. Boehm, K. M., Khosravi, P., Vanguri, R., Gao, J. & Shah, S. P. Harnessing multimodal data integration to advance precision oncology. Nat. Rev. Cancer 22, 114–126 (2022).

    Article  CAS  PubMed  Google Scholar 

  178. Moding, E. J., Nabet, B. Y., Alizadeh, A. A. & Diehn, M. Detecting liquid remnants of solid tumors: circulating tumor DNA minimal residual disease. Cancer Discov. 11, 2968–2986 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Krop, I. E. et al. Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol. 15, 689–699 (2014).

    Article  CAS  PubMed  Google Scholar 

  180. Krop, I. E. et al. Trastuzumab emtansine versus treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol. 18, 743–754 (2017).

    Article  CAS  PubMed  Google Scholar 

  181. Perez, E. A. et al. Incidence of adverse events with therapies targeting HER2-positive metastatic breast cancer: a literature review. Breast Cancer Res. Treat. 194, 1–11 (2022).

    Article  CAS  PubMed  Google Scholar 

  182. Battisti, N. M. L., Tong, D., Ring, A. & Smith, I. Long-term outcome with targeted therapy in advanced/metastatic HER2-positive breast cancer: the Royal Marsden experience. Breast Cancer Res. Treat. 178, 401–408 (2019).

    Article  CAS  PubMed  Google Scholar 

  183. Yeo, B., Kotsori, K., Mohammed, K., Walsh, G. & Smith, I. E. Long-term outcome of HER2 positive metastatic breast cancer patients treated with first-line trastuzumab. Breast 24, 751–757 (2015).

    Article  CAS  PubMed  Google Scholar 

  184. Tripathy, D. et al. De novo versus recurrent HER2-positive metastatic breast cancer: patient characteristics, treatment, and survival from the SystHERs registry. Oncologist 25, e214–e222 (2020).

    Article  CAS  PubMed  Google Scholar 

  185. Wong, Y. et al. Long-term survival of de novo stage IV human epidermal growth receptor 2 (HER2) positive breast cancers treated with HER2-targeted therapy. Oncologist 24, 313–318 (2019).

    Article  CAS  PubMed  Google Scholar 

  186. den Brok, W. D. et al. Survival with metastatic breast cancer based on initial presentation, de novo versus relapsed. Breast Cancer Res. Treat. 161, 549–556 (2017).

    Article  Google Scholar 

  187. Harano, K. et al. Clinicopathological and surgical factors associated with long-term survival in patients with HER2-positive metastatic breast cancer. Breast Cancer Res. Treat. 159, 367–374 (2016).

    Article  CAS  PubMed  Google Scholar 

  188. Hopkins, A. M., Rowland, A., McKinnon, R. A. & Sorich, M. J. Predictors of long-term disease control and survival for HER2-positive advanced breast cancer patients treated with pertuzumab, trastuzumab, and docetaxel. Front. Oncol. 9, 789 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  189. Yardley, D. A. et al. Long-term survivor characteristics in HER2-positive metastatic breast cancer from registHER. Br. J. Cancer 110, 2756–2764 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Witzel, I. et al. Long-term tumor remission under trastuzumab treatment for HER2 positive metastatic breast cancer - results from the HER-OS patient registry. BMC Cancer 14, 806 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  191. Veitch, Z. et al. No evidence of disease versus residual disease in long-term responders to first-line HER2-targeted therapy for metastatic breast cancer. Br. J. Cancer 126, 881–888 (2022).

    Article  CAS  PubMed  Google Scholar 

  192. Kim, S. B. et al. Relationship between tumor biomarkers and efficacy in TH3RESA, a phase III study of trastuzumab emtansine (T-DM1) vs. treatment of physician’s choice in previously treated HER2-positive advanced breast cancer. Int. J. Cancer 139, 2336–2342 (2016).

    Article  CAS  PubMed  Google Scholar 

  193. Burris, H. A. 3rd et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J. Clin. Oncol. 29, 398–405 (2011).

    Article  CAS  PubMed  Google Scholar 

  194. Braso-Maristany, F. et al. HER2DX ERBB2 mRNA expression in advanced HER2-positive breast cancer treated with T-DM1. J. Natl Cancer Inst. 115, 332–336 (2023).

    Article  CAS  PubMed  Google Scholar 

  195. Garcia-Murillas, I. et al. Assessment of molecular relapse detection in early-stage breast cancer. JAMA Oncol. 5, 1473–1478 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  196. Ponde, N. F., Lambertini, M. & de Azambuja, E. Twenty years of anti-HER2 therapy-associated cardiotoxicity. ESMO Open. 1, e000073 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  197. Giordano, S. H. et al. Systemic therapy for advanced human epidermal growth factor receptor 2-positive breast cancer: ASCO guideline update. J. Clin. Oncol. 40, 2612–2635 (2022).

    Article  CAS  PubMed  Google Scholar 

  198. Pantel, K. & Alix-Panabieres, C. Liquid biopsy and minimal residual disease - latest advances and implications for cure. Nat. Rev. Clin. Oncol. 16, 409–424 (2019).

    Article  CAS  PubMed  Google Scholar 

  199. Sammons, S., Van Swearingen, A. E. D., Chung, C. & Anders, C. K. Advances in the management of breast cancer brain metastases. Neurooncol Adv. 3, v63–v74 (2021).

    PubMed  PubMed Central  Google Scholar 

  200. Martin, A. M. et al. Brain metastases in newly diagnosed breast cancer: a population-based study. JAMA Oncol. 3, 1069–1077 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  201. Brufsky, A. M. et al. Central nervous system metastases in patients with HER2-positive metastatic breast cancer: incidence, treatment, and survival in patients from registHER. Clin. Cancer Res. 17, 4834–4843 (2011).

    Article  CAS  PubMed  Google Scholar 

  202. Pestalozzi, B. C. et al. CNS relapses in patients with HER2-positive early breast cancer who have and have not received adjuvant trastuzumab: a retrospective substudy of the HERA trial (BIG 1-01). Lancet Oncol. 14, 244–248 (2013).

    Article  CAS  PubMed  Google Scholar 

  203. Olson, E. M. et al. Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the post-trastuzumab era. Breast 22, 525–531 (2013).

    Article  PubMed  Google Scholar 

  204. Lin, N. U. et al. Abstract P2-13-05: central nervous system metastases as a site of first recurrence in adjuvant therapy trials of HER2+ early breast cancer (EBC). Cancer Res. 82, P2-13-05–P12-13-05 (2022).

    Article  Google Scholar 

  205. Swain, S. M. et al. Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel: results from the randomized phase III study CLEOPATRA. Ann. Oncol. 25, 1116–1121 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Krop, I. E. et al. Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA. Ann. Oncol. 26, 113–119 (2015).

    Article  CAS  PubMed  Google Scholar 

  207. Duchnowska, R., Loibl, S. & Jassem, J. Tyrosine kinase inhibitors for brain metastases in HER2-positive breast cancer. Cancer Treat. Rev. 67, 71–77 (2018).

    Article  CAS  PubMed  Google Scholar 

  208. Nader-Marta, G. et al. Efficacy of tyrosine kinase inhibitors for the treatment of patients with HER2-positive breast cancer with brain metastases: a systematic review and meta-analysis. ESMO Open. 7, 100501 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Lin, N. U. et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin. Cancer Res. 15, 1452–1459 (2009).

    Article  CAS  PubMed  Google Scholar 

  210. Bachelot, T. et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 14, 64–71 (2013).

    Article  CAS  PubMed  Google Scholar 

  211. Freedman, R. A. et al. Translational breast cancer research consortium (TBCRC) 022: a phase II trial of neratinib for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J. Clin. Oncol. 34, 945–952 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Freedman, R. et al. Abstract PD7-03: translational breast cancer research consortium trial 022: neratinib and trastuzumab-emtansine for HER2+ breast cancer brain metastases (BCBM). Cancer Res. 83, PD7-03–PD07-03 (2023).

    Article  ADS  Google Scholar 

  213. Dijkers, E. C. et al. Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin. Pharmacol. Ther. 87, 586–592 (2010).

    Article  CAS  PubMed  Google Scholar 

  214. Lin, N. U. et al. Pertuzumab plus high-dose trastuzumab in patients with progressive brain metastases and HER2-positive metastatic breast cancer: primary analysis of a phase II study. J. Clin. Oncol. 39, 2667–2675 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Hurvitz, S. et al. Abstract GS3-01: Trastuzumab deruxtecan (T-DXd; DS-8201a) vs. trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Cancer Res. 82, GS3-01–GS03-01 (2022).

    Article  Google Scholar 

  216. Bartsch, R. et al. Trastuzumab deruxtecan in HER2-positive breast cancer with brain metastases: a single-arm, phase 2 trial. Nat. Med. 28, 1840–1847 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Perez-Garcia, J. M. et al. Trastuzumab deruxtecan in patients with central nervous system involvement from HER2-positive breast cancer: The DEBBRAH trial. Neuro Oncol. 25, 157–166 (2023).

    Article  CAS  PubMed  Google Scholar 

  218. Kabraji, S. et al. Preclinical and clinical efficacy of trastuzumab deruxtecan in breast cancer brain metastases. Clin. Cancer Res. 29, 174–182 (2023).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

All authors acknowledge support from the Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute (grant no P30CA008748). A.M. is supported by the European Society for Medical Oncology José Baselga Fellowship for Clinician Scientists founded by AstraZeneca (2023–2025). S.C. is supported by the Breast Cancer Research Foundation. The authors thank and appreciate the helpful comments and suggestions provided by the journal editors and reviewers.

Author information

Authors and Affiliations

  1. Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy

    Antonio Marra

  2. Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Sarat Chandarlapaty

  3. Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Sarat Chandarlapaty & Shanu Modi

  4. Weill Cornell Medical College, New York, NY, USA

    Sarat Chandarlapaty & Shanu Modi

Authors
  1. Antonio Marra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sarat Chandarlapaty
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shanu Modi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors made a substantial contribution to each stage of the preparation of this manuscript.

Corresponding author

Correspondence to Shanu Modi.

Ethics declarations

Competing interests

A.M. has received honoraria as a consultant, adviser or speaker from Roche and Menarini/Stemline. S.C. receives institutional grants and/or funding from AstraZeneca, Daiichi Sankyo and Lilly; has shares and/or ownership interests in Odyssey Biosciences and Totus Medicines; and has received honoraria as a consultant or adviser from AstraZeneca, Lilly, Prelude Therapeutics, Neogenomics, Novartis, Nuvalent and SAGA Diagnostics Effector Therapeutics. S.M. receives institutional funding for clinical research from AstraZeneca, Daiichi Sankyo, Genentech and Seagen; and has received honoraria as a consultant, adviser or speaker from AstraZeneca, Daiichi Sankyo, Eli Lilly, Genentech, Gilead, GlaxoSmithKline, Macrogenics, Puma Biotechnology, Seagen and Zymeworks.

Peer review

Peer review information

Nature Reviews Clinical Oncology thanks J. Cortes; H. Iwata, who co-reviewed with K. Nozawa; and P. Tarantino, who co-reviewed with O. Martínez-Sáez, for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Marra, A., Chandarlapaty, S. & Modi, S. Management of patients with advanced-stage HER2-positive breast cancer: current evidence and future perspectives. Nat Rev Clin Oncol 21, 185–202 (2024). https://doi.org/10.1038/s41571-023-00849-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-023-00849-9

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer