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  • Review Article
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Towards personalized treatment for early stage HER2-positive breast cancer

Nature Reviews Clinical Oncology volume 17, pages 233–250 (2020)Cite this article

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Abstract

Advances in HER2-targeted therapies have improved the survival of patients with HER2-positive breast cancer. The standard-of-care treatment for localized disease has been chemotherapy and 1 year of adjuvant HER2-targeted therapy, typically with the anti-HER2 antibody trastuzumab. Despite the effectiveness of this treatment, disease relapse occurs in a subset of patients; thus, focus has been placed on escalating treatment by either combining different HER2-targeted agents or extending the duration of HER2-targeted therapy. Indeed, dual HER2-targeted therapies and extended-duration anti-HER2 therapy, as well as adjuvant therapy with the anti-HER2 antibody–drug conjugate T-DM1, have all been approved for clinical use. Emerging evidence suggests, however, that some patients do not derive sufficient benefit from these additional therapies to offset the associated toxicities and/or costs. Similarly, the universal use of chemotherapy might not benefit all patients, and treatment de-escalation through omission of chemotherapy has shown promise in clinical trials and is currently being explored further. The future of precision medicine should therefore involve tailoring of therapy based on the genetics and biology of each tumour and the clinical characteristics of each patient. Predictive biomarkers that enable the identification of patients who will benefit from either escalated or de-escalated treatment will be crucial to this approach. In this Review, we summarize the available HER2-targeted agents and associated mechanisms of resistance, and describe the current therapeutic landscape of early stage HER2-positive breast cancer, focusing on strategies for treatment escalation or de-escalation.

Key points

  • Advances in HER2-targeted therapy have improved the outcomes of patients with HER2-positive breast cancer; however, intrinsic and acquired resistance to such treatment remain a major clinical challenge.

  • Emerging preclinical and clinical evidence suggests that simultaneous therapeutic blockade of the HER2 and oestrogen receptor signalling pathways in tumours co-expressing both of these receptors should be considered in order to improve patient outcomes.

  • In the era of precision medicine, treatment based on the biological and molecular characteristics of the tumour and the clinical characteristics of the patient is a logical approach.

  • The development of a molecular approach to differentiate patients who are likely to benefit from HER2-targeted therapy with less or no chemotherapy (treatment de-escalation) from those who require chemotherapy or need additional treatment (escalation) remains an overarching challenge.

  • Prospective testing and validation of risk-stratified biomarker-driven treatment approaches will pave the way towards personalized therapy for patients with HER2-positive breast cancer.

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Fig. 1: Signalling by HER2 and other HER family members and the clinically approved HER2-targeted agents.
Fig. 2: Major mechanisms of resistance to HER2-targeted therapy.
Fig. 3: pCR rates stratified by ER status and treatment arm in clinical trials of neoadjuvant HER2-targeted therapy for HER2+ breast cancer.

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References

  1. 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  CAS  PubMed  Google Scholar 

  2. 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 

  3. Rimawi, M. F., Schiff, R. & Osborne, C. K. Targeting HER2 for the treatment of breast cancer. Annu. Rev. Med. 66, 111–128 (2015).

    Article  CAS  PubMed  Google Scholar 

  4. Gutierrez, C. & Schiff, R. HER2: biology, detection, and clinical implications. Arch. Pathol. Lab. Med. 135, 55–62 (2011).

    PubMed  PubMed Central  Google Scholar 

  5. Moasser, M. M. The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 26, 6469–6487 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Senkus, E. et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 26, v8–v30 (2015).

    Article  PubMed  Google Scholar 

  7. Wilson, F. R. et al. Herceptin(R) (trastuzumab) in HER2-positive early breast cancer: a systematic review and cumulative network meta-analysis. Syst. Rev. 7, 191 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  8. 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 

  9. Scheuer, W. et al. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res. 69, 9330–9336 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Yamashita-Kashima, Y. et al. Pertuzumab in combination with trastuzumab shows significantly enhanced antitumor activity in HER2-positive human gastric cancer xenograft models. Clin. Cancer Res. 17, 5060–5070 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. von Minckwitz, G. et al. Efficacy and safety of ABP 980 compared with reference trastuzumab in women with HER2-positive early breast cancer (LILAC study): a randomised, double-blind, phase 3 trial. Lancet Oncol. 19, 987–998 (2018).

    Article  Google Scholar 

  12. Pegram, M. D. et al. PF-05280014 (a trastuzumab biosimilar) plus paclitaxel compared with reference trastuzumab plus paclitaxel for HER2-positive metastatic breast cancer: a randomised, double-blind study. Br. J. Cancer 120, 172–182 (2019).

    Article  CAS  PubMed  Google Scholar 

  13. Pivot, X. et al. Three-year follow-up from a phase 3 study of SB3 (a trastuzumab biosimilar) versus reference trastuzumab in the neoadjuvant setting for human epidermal growth factor receptor 2-positive breast cancer. Eur. J. Cancer 120, 1–9 (2019).

    Article  CAS  PubMed  Google Scholar 

  14. Esteva, F. et al. 24 months results from a double-blind, randomized phase III trial comparing the efficacy and safety of neoadjuvant then adjuvant trastuzumab and its biosimilar candidate CT-P6 in HER2 positive early breast cancer (EBC) [abstract]. Cancer Res. 79 (Suppl. 4), P6-17-03 (2019).

    Google Scholar 

  15. Waller, C. F. et al. Biosimilar trastuzumab-dkst monotherapy versus trastuzumab monotherapy after combination therapy: final overall survival (OS) from the phase III HERITAGE trial [abstract]. J. Clin. Oncol. 37 (Suppl. 15), 1021 (2019).

    Article  Google Scholar 

  16. Kolberg, H. C., von Minckwitz, G. & Hanes, V. Phase 3 LILAC study sets standard for clinical evaluation of oncology biosimilars. Oncotarget 10, 8–9 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Lammers, P. E. et al. Neoadjuvant PF-05280014 (a potential trastuzumab biosimilar) versus trastuzumab for operable HER2+ breast cancer. Br. J. Cancer 119, 266–273 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pegram, M. et al. event-free survival by ADCC status from a follow-up study comparing SB3 (trastuzumab biosimilar) with reference trastuzumab for HER2 positive breast cancer in neoadjuvant setting [abstract]. Cancer Res. 79 (Suppl. 4), P6-17-09 (2019).

    Google Scholar 

  19. Jackisch, C. et al. Subcutaneous vs intravenous trastuzumab for patients with ERBB2-positive early breast cancer: final analysis of the HannaH phase 3 randomized clinical trial. JAMA Oncol. 5, e190339 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Cortes, J., Curigliano, G. & Dieras, V. Expert perspectives on biosimilar monoclonal antibodies in breast cancer. Breast Cancer Res. Treat. 144, 233–239 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Barbier, L. et al. The arrival of biosimilar monoclonal antibodies in oncology: clinical studies for trastuzumab biosimilars. Br. J. Cancer 121, 199–210 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Citri, A., Skaria, K. B. & Yarden, Y. The deaf and the dumb: the biology of ErbB-2 and ErbB-3. Exp. Cell Res. 284, 54–65 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Arpino, G. et al. Treatment of human epidermal growth factor receptor 2-overexpressing breast cancer xenografts with multiagent HER-targeted therapy. J. Natl. Cancer Inst. 99, 694–705 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Rimawi, M. F. et al. Reduced dose and intermittent treatment with lapatinib and trastuzumab for potent blockade of the HER pathway in HER2/neu-overexpressing breast tumor xenografts. Clin. Cancer Res. 17, 1351–1361 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. 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 

  26. Baselga, J. et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 379, 633–640 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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 

  28. von Minckwitz, G. et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N. Engl. J. Med. 377, 122–131 (2017).

    Article  Google Scholar 

  29. Chan, A. et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 17, 367–377 (2016).

    Article  CAS  PubMed  Google Scholar 

  30. Zuo, W. J. et al. Dual characteristics of novel HER2 kinase domain mutations in response to HER2-targeted therapies in human breast cancer. Clin. Cancer Res. 22, 4859–4869 (2016).

    Article  CAS  PubMed  Google Scholar 

  31. Boulbes, D. R. et al. HER family kinase domain mutations promote tumor progression and can predict response to treatment in human breast cancer. Mol. Oncol. 9, 586–600 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. 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 

  33. Yonemori, K. et al. Single agent activity of U3-1402, a HER3-targeting antibody-drug conjugate, in HER3-overexpressing metastatic breast cancer: updated results from a phase I/II trial [abstract 151O]. Ann. Oncol. 30 (Suppl. 3), mdz100.002 (2019).

    Google Scholar 

  34. Wang, X. et al. Humanized anti-EGFR antibody panitumumab inhibits tumor growth of inflammatory breast cancer by inducing antitumor immunity [abstract]. Cancer Res. 79 (Suppl. 13), 4492 (2019).

    Google Scholar 

  35. Mishra, R., Patel, H., Alanazi, S., Yuan, L. & Garrett, J. T. HER3 signaling and targeted therapy in cancer. Oncol. Rev. 12, 355 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Moasser, M. M., Basso, A., Averbuch, S. D. & Rosen, N. The tyrosine kinase inhibitor ZD1839 (“Iressa”) inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Res. 61, 7184–7188 (2001).

    CAS  PubMed  Google Scholar 

  37. Hirsh, V., Blais, N., Burkes, R., Verma, S. & Croitoru, K. Management of diarrhea induced by epidermal growth factor receptor tyrosine kinase inhibitors. Curr. Oncol. 21, 329–336 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hirsh, V. Managing treatment-related adverse events associated with EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer. Curr. Oncol. 18, 126–138 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Capri, G. et al. An open-label expanded access study of lapatinib and capecitabine in patients with HER2-overexpressing locally advanced or metastatic breast cancer. Ann. Oncol. 21, 474–480 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Paranjpe, R. et al. Neratinib in HER2-positive breast cancer patients. Ann. Pharmacother. 53, 612–620 (2019).

    Article  CAS  PubMed  Google Scholar 

  41. Parma, J. et al. Development of acneiform rash does not predict response to lapatinib treatment in patients with breast cancer. Pharmacotherapy 33, 1126–1129 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. Chiu, J. W. et al. Changing pattern of recurrences in patients with early HER2-positive breast cancer receiving neoadjuvant chemotherapy in the era of dual anti-HER2 therapy. Postgrad. Med. J. 95, 155–161 (2019).

    Article  PubMed  Google Scholar 

  43. Borges, V. F. et al. Efficacy results of a phase 1b study of ONT-380, a CNS-penetrant TKI, in combination with T-DM1 in HER2+metastatic breast cancer (MBC), including patients (pts) with brain metastases [abstract]. J. Clin. Oncol. 34 (Suppl. 15), 513 (2016).

    Article  Google Scholar 

  44. Seattle Genetics. Seattle Genetics announces positive topline results from pivotal trial of tucatinib in locally advanced or metastatic HER2-positive breast cancer. Seattle Genetics https://investor.seattlegenetics.com/press-releases/news-details/2019/Seattle-Genetics-Announces-Positive-Topline-Results-from-Pivotal-Trial-of-Tucatinib-in-Locally-Advanced-or-Metastatic-HER2-Positive-Breast-Cancer/default.aspx (2019).

  45. Rexer, B. N. & Arteaga, C. L. Intrinsic and acquired resistance to HER2-targeted therapies in HER2 gene-amplified breast cancer: mechanisms and clinical implications. Crit. Rev. Oncog. 17, 1–16 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Vernieri, C. et al. Resistance mechanisms to anti-HER2 therapies in HER2-positive breast cancer: current knowledge, new research directions and therapeutic perspectives. Crit. Rev. Oncol. Hematol. 139, 53–66 (2019).

    Article  PubMed  Google Scholar 

  47. Rimawi, M. F., De Angelis, C. & Schiff, R. Resistance to anti-HER2 therapies in breast cancer. Am. Soc. Clin. Oncol. Educ. Book 35, e157–e164 (2015).

    Article  Google Scholar 

  48. Gianni, L. et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 13, 25–32 (2012).

    Article  CAS  PubMed  Google Scholar 

  49. Llombart-Cussac, A. et al. HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial. Lancet Oncol. 18, 545–554 (2017).

    Article  CAS  PubMed  Google Scholar 

  50. Rimawi, M. F. et al. Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. J. Clin. Oncol. 31, 1726–1731 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Christianson, T. A. et al. NH2-terminally truncated HER-2/neu protein: relationship with shedding of the extracellular domain and with prognostic factors in breast cancer. Cancer Res. 58, 5123–5129 (1998).

    CAS  PubMed  Google Scholar 

  52. Kwong, K. Y. & Hung, M. C. A novel splice variant of HER2 with increased transformation activity. Mol. Carcinog. 23, 62–68 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Scaltriti, M. et al. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J. Natl. Cancer Inst. 99, 628–638 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Cocco, E. et al. Neratinib is effective in breast tumors bearing both amplification and mutation of ERBB2 (HER2). Sci. Signal. 11, eaat9773 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Mitra, D. et al. An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance. Mol. Cancer Ther. 8, 2152–2162 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wagle, N. et al. Whole exome sequencing (WES) of HER2+ metastatic breast cancer (MBC) from patients with or without prior trastuzumab (T): a correlative analysis of TBCRC003 [abstract]. Cancer Res. 75 (Suppl. 9), PD3-5 (2015).

    Google Scholar 

  58. 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 

  59. Eichhorn, P. J. et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res. 68, 9221–9230 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 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 

  61. Fujita, T. et al. PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer. Br. J. Cancer 94, 247–252 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. O’Brien, N. A. et al. Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib. Mol. Cancer Ther. 9, 1489–1502 (2010).

    Article  PubMed  CAS  Google Scholar 

  63. Faratian, D. et al. Systems biology reveals new strategies for personalizing cancer medicine and confirms the role of PTEN in resistance to trastuzumab. Cancer Res. 69, 6713–6720 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Schiff, R. et al. Cross-talk between estrogen receptor and growth factor pathways as a molecular target for overcoming endocrine resistance. Clin. Cancer Res. 10, 331S–336S (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Bender, L. M. & Nahta, R. Her2 cross talk and therapeutic resistance in breast cancer. Front. Biosci. 13, 3906–3912 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Yamaguchi, H., Chang, S. S., Hsu, J. L. & Hung, M. C. Signaling cross-talk in the resistance to HER family receptor targeted therapy. Oncogene 33, 1073–1081 (2014).

    Article  CAS  PubMed  Google Scholar 

  67. Qin, L. et al. Overexpression of insulin receptor substrate 4 can mediate acquired resistance to lapatinib-containing regimens in HER2+ breast cancer cells [abstract]. Cancer Res. 75 (Suppl. 9), P3-05-13 (2015).

    Google Scholar 

  68. Ikink, G. J., Boer, M., Bakker, E. R. & Hilkens, J. IRS4 induces mammary tumorigenesis and confers resistance to HER2-targeted therapy through constitutive PI3K/AKT-pathway hyperactivation. Nat. Commun. 7, 13567 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Shattuck, D. L., Miller, J. K., Carraway, K. L. 3rd & Sweeney, C. Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells. Cancer Res. 68, 1471–1477 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. Huang, C. et al. β1 integrin mediates an alternative survival pathway in breast cancer cells resistant to lapatinib. Breast Cancer Res. 13, R84 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Guo, W. et al. Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis. Cell 126, 489–502 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Mercogliano, M. F. et al. TNFα-induced mucin 4 expression elicits trastuzumab resistance in HER2-positive breast cancer. Clin. Cancer Res. 23, 636–648 (2017).

    Article  CAS  PubMed  Google Scholar 

  73. Chen, A. C. et al. Upregulation of mucin4 in ER-positive/HER2-overexpressing breast cancer xenografts with acquired resistance to endocrine and HER2-targeted therapies. Breast Cancer Res. Treat. 134, 583–593 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ingold Heppner, B. et al. Tumor-infiltrating lymphocytes: a predictive and prognostic biomarker in neoadjuvant-treated HER2-positive breast cancer. Clin. Cancer Res. 22, 5747–5754 (2016).

    Article  CAS  PubMed  Google Scholar 

  75. Salgado, R. et al. Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: a secondary analysis of the NeoALTTO trial. JAMA Oncol. 1, 448–454 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Bianchini, G. et al. Immune modulation of pathologic complete response after neoadjuvant HER2-directed therapies in the NeoSphere trial. Ann. Oncol. 26, 2429–2436 (2015).

    Article  CAS  PubMed  Google Scholar 

  77. De Angelis, C. et al. Evaluation of tumor immune infiltrate as a determinant of response to neo-adjuvant lapatinib and trastuzumab (LT) in HER2-positive (+) breast cancer (BC) [abstract]. J. Clin. Oncol. 34 (Suppl. 15), 608 (2016).

    Article  Google Scholar 

  78. Menendez, J. A. et al. Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proc. Natl Acad. Sci. USA 101, 10715–10720 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Blancafort, A. et al. Dual fatty acid synthase and HER2 signaling blockade shows marked antitumor activity against breast cancer models resistant to anti-HER2 drugs. PLOS ONE 10, e0131241 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Crocamo, S. et al. Neoadjuvant zoledronic acid for HER2-positive breast cancer: the Zo-NAnTax trial. Ther. Adv. Med. Oncol. 11, 1758835919853971 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Sethunath, V. et al. Targeting the mevalonate pathway to overcome acquired anti-HER2 treatment resistance in breast cancer. Mol. Cancer Res. https://doi.org/10.1158/1541-7786.MCR-19-0756 (2019).

  82. Halilovic, A. et al. HER2, chromosome 17 polysomy and DNA ploidy status in breast cancer; a translational study. Sci. Rep. 9, 11679 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Lal, P., Tan, L. K. & Chen, B. Correlation of HER-2 status with estrogen and progesterone receptors and histologic features in 3,655 invasive breast carcinomas. Am. J. Clin. Pathol. 123, 541–546 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Untch, M. et al. Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial. Ann. Oncol. 19, 1090–1096 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. Vici, P. et al. Triple positive breast cancer: a distinct subtype? Cancer Treat. Rev. 41, 69–76 (2015).

    Article  CAS  PubMed  Google Scholar 

  86. 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  CAS  PubMed  PubMed Central  Google Scholar 

  87. Giuliano, M. et al. Upregulation of ER signaling as an adaptive mechanism of cell survival in HER2-positive breast tumors treated with anti-HER2 therapy. Clin. Cancer Res. 21, 3995–4003 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Vaz-Luis, I., Winer, E. P. & Lin, N. U. Human epidermal growth factor receptor-2-positive breast cancer: does estrogen receptor status define two distinct subtypes? Ann. Oncol. 24, 283–291 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. Azim, H. A. Jr. & Piccart, M. J. Simultaneous targeting of estrogen receptor and HER2 in breast cancer. Expert Rev. Anticancer Ther. 10, 1255–1263 (2010).

    Article  CAS  PubMed  Google Scholar 

  90. Park, Y. H. et al. Patterns of relapse and metastatic spread in HER2-overexpressing breast cancer according to estrogen receptor status. Cancer Chemother. Pharmacol. 66, 507–516 (2010).

    Article  CAS  PubMed  Google Scholar 

  91. Lee, H. J. et al. Two histopathologically different diseases: hormone receptor-positive and hormone receptor-negative tumors in HER2-positive breast cancer. Breast Cancer Res. Treat. 145, 615–623 (2014).

    Article  CAS  PubMed  Google Scholar 

  92. Carey, L. A. et al. Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib. J. Clin. Oncol. 34, 542–549 (2016).

    Article  CAS  PubMed  Google Scholar 

  93. Spring, L. et al. Effectiveness and tolerability of neoadjuvant pertuzumab-containing regimens for HER2-positive localized breast cancer. Breast Cancer Res. Treat. 172, 733–740 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Untch, M. et al. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol. 13, 135–144 (2012).

    Article  CAS  PubMed  Google Scholar 

  95. Robidoux, A. et al. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 14, 1183–1192 (2013).

    Article  CAS  PubMed  Google Scholar 

  96. Schneeweiss, A. et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann. Oncol. 24, 2278–2284 (2013).

    Article  CAS  PubMed  Google Scholar 

  97. Cortazar, P. et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384, 164–172 (2014).

    Article  PubMed  Google Scholar 

  98. von Minckwitz, G. et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J. Clin. Oncol. 30, 1796–1804 (2012).

    Article  Google Scholar 

  99. Tanioka, M. et al. Integrated analysis of RNA and DNA from the phase III trial CALGB 40601 identifies predictors of response to trastuzumab-based neoadjuvant chemotherapy in HER2-positive breast cancer. Clin. Cancer Res. 24, 5292–5304 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Johnston, S. et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J. Clin. Oncol. 27, 5538–5546 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Kaufman, B. et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J. Clin. Oncol. 27, 5529–5537 (2009).

    Article  CAS  PubMed  Google Scholar 

  102. 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 

  103. 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: ALTERNATIVE. J. Clin. Oncol. 36, 741–748 (2018).

    Article  CAS  PubMed  Google Scholar 

  104. Rimawi, M. et al. A phase III trial evaluating pCR in patients with HR+, HER2-positive breast cancer treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) +/- estrogen deprivation: NRG Oncology/NSABP B-52 [abstract]. Cancer Res. 77 (Suppl. 4), S3-06 (2017).

    Google Scholar 

  105. Bedognetti, D. et al. Concurrent vs sequential adjuvant chemotherapy and hormone therapy in breast cancer: a multicenter randomized phase III trial. J. Natl. Cancer Inst. 103, 1529–1539 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Harbeck, N. et al. Final analysis of WSG-ADAPT HER2+/HR+ phase II trial: efficacy, safety, and predictive markers for 12-weeks of neoadjuvant TDM1 with or without endocrine therapy versus trastuzumab+endocrine therapy in HER2-positive hormone-receptor-positive early breast cancer [abstract]. Cancer Res. 76 (Suppl. 4), S5-03 (2016).

    Google Scholar 

  107. Rimawi, M. F. et al. TBCRC023: A randomized multicenter phase II neoadjuvant trial of lapatinib plus trastuzumab, with endcorine therapy and without chemotherapy, for 12 vs. 24 weeks in patients with HER2 overexpressing breast cancer [abstract]. Cancer Res. 75 (Suppl. 9), S6-02 (2015).

    Google Scholar 

  108. Rimawi, M. F. et al. TBCRC023: a randomized phase II neoadjuvant trial of lapatinib plus trastuzumab without chemotherapy for 12 vs. 24 weeks in patients with HER2-positive breast cancer. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-19-0851 (2019).

  109. Cameron, D. et al. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet 389, 1195–1205 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Perez, E. A. et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J. Clin. Oncol. 32, 3744–3752 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Huober, J. B. et al. Survival outcomes of the NeoALTTO study: updated results of a randomized multicenter phase III neoadjuvant trial [abstract]. J. Clin. Oncol. 35 (Suppl. 15), 512 (2017).

    Article  Google Scholar 

  112. Spring, L. et al. Pathological complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and mortality, stratified by breast cancer subtypes and adjuvant chemotherapy usage: individual patient-level meta-analyses of over 27,000 patients [abstract]. Cancer Res. 79 (Suppl. 4), GS2-03 (2019).

    Google Scholar 

  113. Piccart-Gebhart, M. et al. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial. J. Clin. Oncol. 34, 1034–1042 (2016).

    Article  CAS  PubMed  Google Scholar 

  114. Moreno-Aspitia, A. et al. Updated results from the phase III ALTTO trial (BIG 2-06; NCCTG (Alliance) N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L) or their combination (L+T) in the adjuvant treatment of HER2-positive early breast cancer [abstract]. J. Clin. Oncol. 35 (Suppl. 15), 502 (2017).

    Article  Google Scholar 

  115. Martin, M. et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 18, 1688–1700 (2017).

    Article  CAS  PubMed  Google Scholar 

  116. Cardoso, F. et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 30, 1194–1220 (2019).

    Article  CAS  PubMed  Google Scholar 

  117. von Minckwitz, G. et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N. Engl. J. Med. 380, 617–628 (2019).

    Article  Google Scholar 

  118. Joensuu, H. et al. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer Trial. J. Clin. Oncol. 27, 5685–5692 (2009).

    Article  CAS  PubMed  Google Scholar 

  119. Joensuu, H. et al. Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD randomized clinical trial. JAMA Oncol. 4, 1199–1206 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Pivot, X. et al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol. 14, 741–748 (2013).

    Article  CAS  PubMed  Google Scholar 

  121. Mavroudis, D. et al. Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann. Oncol. 26, 1333–1340 (2015).

    Article  CAS  PubMed  Google Scholar 

  122. Conte, P. et al. Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study. Ann. Oncol. 29, 2328–2333 (2018).

    Article  CAS  PubMed  Google Scholar 

  123. Pivot, X. et al. 6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): final analysis of a multicentre, open-label, phase 3 randomised trial. Lancet 393, 2591–2598 (2019).

    Article  CAS  PubMed  Google Scholar 

  124. Earl, H. M. et al. 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial. Lancet 393, 2599–2612 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Perez, E. A. et al. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J. Clin. Oncol. 29, 4491–4497 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Earl, H. M. et al. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results [abstract]. J. Clin. Oncol. 36 (Suppl. 15), 506 (2018).

    Article  Google Scholar 

  127. Ponde, N., Gelber, R. D. & Piccart, M. PERSEPHONE: are we ready to de-escalate adjuvant trastuzumab for HER2-positive breast cancer? NPJ Breast Cancer 5, 1 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Chen, L. et al. Short-duration versus 1-year adjuvant trastuzumab in early HER2 positive breast cancer: a meta-analysis of randomized controlled trials. Cancer Treat. Rev. 75, 12–19 (2019).

    Article  CAS  PubMed  Google Scholar 

  129. Tolaney, S. M. et al. Seven-year follow-up analysis of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2-positive breast cancer. J. Clin. Oncol. 37, 1868–1875 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. van Ramshorst, M. S. et al. Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 19, 1630–1640 (2018).

    Article  PubMed  Google Scholar 

  131. Bergh, J. C. S. et al. Docetaxel, trastuzumab, pertuzumab versus trastuzumab emtansine as neoadjuvant treatment of HER2-positive breast cancer: results from the Swedish PREDIX HER2 trial identifying a new potential de-escalation standard? [abstract]. J. Clin. Oncol. 37 (Suppl. 15), 501 (2019).

    Article  Google Scholar 

  132. Hurvitz, S. A. et al. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 19, 115–126 (2018).

    Article  CAS  PubMed  Google Scholar 

  133. Filho, O. M. et al. HER2 heterogeneity as a predictor of response to neoadjuvant T-DM1 plus pertuzumab: results from a prospective clinical trial [abstract]. J. Clin. Oncol. 37 (Suppl. 15), 502 (2019).

    Article  Google Scholar 

  134. Sawaki, M. et al. Evaluation of trastuzumab without chemotherapy as a post-operative adjuvant therapy in HER2-positive elderly breast cancer patients: randomized controlled trial [RESPECT (N-SAS BC07)]. Jpn. J. Clin. Oncol. 41, 709–712 (2011).

    Article  PubMed  Google Scholar 

  135. Nitz, U. A. et al. De-escalation strategies in HER2-positive early breast cancer (EBC): final analysis of the WSG-ADAPT HER2+/HR phase II trial: efficacy, safety, and predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab ± weekly paclitaxel. Ann. Oncol. 28, 2768–2772 (2017).

    Article  CAS  PubMed  Google Scholar 

  136. Guarneri, V. et al. De-escalated therapy for HR+/HER2+breast cancer patients with Ki67 response after 2-week letrozole: results of the PerELISA neoadjuvant study. Ann. Oncol. 30, 921–926 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 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 

  138. Fumagalli, D. et al. RNA sequencing to predict response to neoadjuvant anti-HER2 therapy: a secondary analysis of the NeoALTTO randomized clinical trial. JAMA Oncol. 3, 227–234 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Rimawi, M. F. et al. Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer. Breast Cancer Res. Treat. 167, 731–740 (2018).

    Article  CAS  PubMed  Google Scholar 

  140. Prat, A. et al. HER2-enriched subtype and ERBB2 expression in HER2-positive breast cancer treated with dual HER2 blockade. J. Natl. Cancer Inst. https://doi.org/10.1093/jnci/djz042 (2019).

  141. Bianchini, G. et al. Biomarker analysis of the NeoSphere study: pertuzumab, trastuzumab, and docetaxel versus trastuzumab plus docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel for the neoadjuvant treatment of HER2-positive breast cancer. Breast Cancer Res. 19, 16 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Ng, C. K. et al. Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification. Genome Biol. 16, 107 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Veeraraghavan, J. et al. A combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer. Ann. Oncol. 30, 927–933 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Veeraraghavan, J. et al. De-escalation of treatment in HER2-positive breast cancer: determinants of response and mechanisms of resistance. Breast 34, S19–S26 (2017).

    Article  PubMed  Google Scholar 

  145. Pogue-Geile, K. L. et al. Association of molecular signatures, mutations, and sTILs, with pCR in breast cancer patients in NRG Oncology/NSABP B-52 [abstract]. Cancer Res. 79 (Suppl. 13), 4064 (2019).

    Google Scholar 

  146. Triulzi, T., Bianchi, G. V. & Tagliabue, E. Predictive biomarkers in the treatment of HER2-positive breast cancer: an ongoing challenge. Future Oncol. 12, 1413–1428 (2016).

    Article  CAS  PubMed  Google Scholar 

  147. Weinstein, I. B. Cancer. Addiction to oncogenes–the Achilles heal of cancer. Science 297, 63–64 (2002).

    Article  CAS  PubMed  Google Scholar 

  148. Wolff, A. C. et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J. Clin. Oncol. 36, 2105–2122 (2018).

    Article  CAS  PubMed  Google Scholar 

  149. Fehrenbacher, L. et al. NSABP B-47 (NRG oncology): Phase III randomized trial comparing adjuvant chemotherapy with adriamycin (A) and cyclophosphamide (C) → weekly paclitaxel (WP), or docetaxel (T) and C with or without a year of trastuzumab (H) in women with node-positive or high-risk node-negative invasive breast cancer (IBC) expressing HER2 staining intensity of IHC 1+ or 2+ with negative FISH (HER2-Low IBC) [abstract]. Cancer Res. 78 (Suppl. 4), GS1-02 (2018).

    Google Scholar 

  150. Prat, A. et al. Molecular features and survival outcomes of the intrinsic subtypes within HER2-positive breast cancer. J. Natl. Cancer Inst. 106, dju152 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. 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 

  152. 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 

  153. Gori, S. et al. EGFR, pMAPK, pAkt and PTEN status by immunohistochemistry: correlation with clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab. Ann. Oncol. 20, 648–654 (2009).

    Article  CAS  PubMed  Google Scholar 

  154. Stern, H. M. et al. PTEN loss is associated with worse outcome in HER2-amplified breast cancer patients but is not associated with trastuzumab resistance. Clin. Cancer Res. 21, 2065–2074 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Perez, E. A. et al. Impact of PTEN protein expression on benefit from adjuvant trastuzumab in early-stage human epidermal growth factor receptor 2-positive breast cancer in the North Central Cancer Treatment Group N9831 trial. J. Clin. Oncol. 31, 2115–2122 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Dieci, M. V. et al. Association of tumor-infiltrating lymphocytes with distant disease-free survival in the ShortHER randomized adjuvant trial for patients with early HER2+ breast cancer. Ann. Oncol. 30, 418–423 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Ignatiadis, M. et al. Tumor-infiltrating lymphocytes in patients receiving trastuzumab/pertuzumab-based chemotherapy: a TRYPHAENA substudy. J. Natl. Cancer Inst. 111, 69–77 (2019).

    Article  PubMed  CAS  Google Scholar 

  158. 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 

  159. Luen, S. J., Savas, P., Fox, S. B., Salgado, R. & Loi, S. Tumour-infiltrating lymphocytes and the emerging role of immunotherapy in breast cancer. Pathology 49, 141–155 (2017).

    Article  CAS  PubMed  Google Scholar 

  160. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials. Lancet Oncol. 19, 27–39 (2018).

    Article  Google Scholar 

  161. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines®). Breast cancer (NCCN, 2019).

  162. Coates, A. S. et al. Tailoring therapies–improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann. Oncol. 26, 1533–1546 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Boughey, J. C. et al. Tumor biology correlates with rates of breast-conserving surgery and pathologic complete response after neoadjuvant chemotherapy for breast cancer: findings from the ACOSOG Z1071 (Alliance) Prospective Multicenter Clinical Trial. Ann. Surg. 260, 608–614; discussion 614–606 (2014).

    Article  PubMed  Google Scholar 

  164. 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 

  165. Jura, N., Shan, Y., Cao, X., Shaw, D. E. & Kuriyan, J. Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3. Proc. Natl Acad. Sci. USA 106, 21608–21613 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Rugo, H. S. et al. SOPHIA primary analysis: a phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx) [abstract]. J. Clin. Oncol. 37 (Suppl. 15), 1000 (2019).

    Article  Google Scholar 

  167. Lin, N. Abstract ES3-3: systemic therapy for breast cancer brain metastases [abstract]. Cancer Res. 79 (Suppl. 4), ES3-3 (2019).

    Google Scholar 

  168. Jiang, Z. et al. Pyrotinib combined with capecitabine in women with HER2+ metastatic breast cancer previously treated with trastuzumab and taxanes: a randomized phase III study [abstract]. J. Clin. Oncol. 37 (Suppl. 15), 1001 (2019).

    Article  Google Scholar 

  169. Verma, S., Shahidi, J., Lee, C., Wang, K. & Cortes, J. Trastuzumab deruxtecan (DS-8201a) vs ado-trastuzumab emtansine (T-DM1) for subjects with HER2-positive, unresectable and/or metastatic breast cancer who previously received trastuzumab and a taxane: a phase 3, randomized study [abstract]. Cancer Res. 79 (Suppl. 4), OT2-07-03 (2019).

    Google Scholar 

  170. Gianni, L. et al. Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study. Lancet Oncol. 19, 249–256 (2018).

    Article  CAS  PubMed  Google Scholar 

  171. Ciruelos, E. et al. SOLTI-1303 PATRICIA phase II trial (STAGE 1) – palbociclib and trastuzumab in postmenopausal patients with HER2-positive metastatic breast cancer. Cancer Res. 79 (Suppl. 4), PD3-03 (2019).

    Google Scholar 

  172. Metzger, O. et al. PATINA: a randomized, open label, phase III trial to evaluate the efficacy and safety of palbociclib + anti-HER2 therapy + endocrine therapy (ET) vs. anti-HER2 therapy + ET after induction treatment for hormone receptor positive (HR+)/HER2-positive metastatic breast cancer (MBC). Cancer Res. 79 (Suppl. 4), OT3-02-07 (2019).

    Google Scholar 

  173. Tolaney, S. M., Bourayou, N., Goel, S., Hossain, A. & Andre, F. A phase II randomized study to compare abemaciclib plus trastuzumab with or without fulvestrant to standard of care chemotherapy plus trastuzumab in hormone receptor positive, HER2-positive advanced breast cancer (monarcHER) [abstract]. J. Clin. Oncol. 35 (Suppl. 15), TPS1109 (2017).

    Article  Google Scholar 

  174. 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 

  175. McArthur, H. et al. Neoadjuvant Her2-targeted therapy +/- immunotherapy with pembrolizumab (neoHIP): an open label randomized phase II trial [abstract]. Cancer Res. 79 (Suppl. 4), OT3-04-02 (2019).

    Google Scholar 

  176. Emens, L. A. et al. Results from KATE2, a randomized phase 2 study of atezolizumab (atezo)+trastuzumab emtansine (T-DM1) vs placebo (pbo)+T-DM1 in previously treated HER2+ advanced breast cancer (BC) [abstract]. Cancer Res. 79 (Suppl. 4), PD3-01 (2019).

    Google Scholar 

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Acknowledgements

The work of the authors is supported, in part, by the Department of Defense grants W81XWH-17-1-0579 (to M.F.R.) and W81XWH-17-1-0580 (to R.S.), the NIH SPORE grant P50 CA186784 (to R.S., C.K.O. and M.F.R.); the Cancer Center grant P30 CA125123 (principal investigator C.K.O.); the Breast Cancer Research Foundation grant BCRF-17-143 (to R.S and C.K.O); the Cancer Prevention & Research Institute of Texas grant CPRIT RP 140102 (to C.De A.); and the Translational Breast Cancer Research Consortium (TBCRC).

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  1. These authors contributed equally: Kristina Goutsouliak, Jamunarani Veeraraghavan.

Authors and Affiliations

  1. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA

    Kristina Goutsouliak, Jamunarani Veeraraghavan, Vidyalakshmi Sethunath, Carmine De Angelis, C. Kent Osborne, Mothaffar F. Rimawi & Rachel Schiff

  2. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA

    Kristina Goutsouliak, Jamunarani Veeraraghavan, Vidyalakshmi Sethunath, Carmine De Angelis, C. Kent Osborne, Mothaffar F. Rimawi & Rachel Schiff

  3. Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Kristina Goutsouliak, Jamunarani Veeraraghavan, C. Kent Osborne, Mothaffar F. Rimawi & Rachel Schiff

  4. Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA

    Vidyalakshmi Sethunath

  5. Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

    Carmine De Angelis

  6. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    C. Kent Osborne & Rachel Schiff

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K.G., J.V., M.F.R., and R.S wrote the manuscript. All authors made substantial contributions to researching data for the manuscript and to discussions of content, and reviewed and/or edited the manuscript prior to submission.

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Correspondence to Mothaffar F. Rimawi or Rachel Schiff.

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Competing interests

C.K.O. has received research funding from AstraZeneca and GlaxoSmithKline, has served on advisory boards for AstraZeneca, Genentech and Tolmar Pharmaceuticals, has been a data monitoring committee member for Eli Lilly, and is a stockholder of GeneTex. M.F.R. receives research support from GlaxoSmithKline via his institution and has been a consultant for Daiichi, Genentech, Macrogenics and Novartis. R.S. has received research funding from AstraZeneca, Gilead Sciences, GlaxoSmithKline and PUMA Biotechnology, and has been a consultant or advisory committee member for Eli Lilly and Macrogenics. The other authors declare no competing interests.

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Goutsouliak, K., Veeraraghavan, J., Sethunath, V. et al. Towards personalized treatment for early stage HER2-positive breast cancer. Nat Rev Clin Oncol 17, 233–250 (2020). https://doi.org/10.1038/s41571-019-0299-9

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