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.

HER2-targeted therapies — a role beyond breast cancer

Nature Reviews Clinical Oncology volume 17, pages 33–48 (2020)Cite this article

Subjects

Abstract

HER2 is an established therapeutic target in a large subset of women with breast cancer; a variety of agents including trastuzumab, pertuzumab, lapatinib, neratinib and trastuzumab emtansine (T-DM1) have been approved for the treatment of HER2-positive breast cancer. HER2 is also overexpressed in subsets of patients with other solid tumours. Notably, the addition of trastuzumab to first-line chemotherapy has improved the overall survival of patients with HER2-positive gastric cancer, and has become the standard-of-care treatment for this group of patients. However, trials involving pertuzumab, lapatinib and T-DM1 have failed to provide significant improvements in the outcomes of patients with HER2-positive gastric cancer. HER2-targeted therapies are also being tested in patients with other solid tumours harbouring HER2 overexpression, and/or amplifications or other mutations of the gene encoding HER2 (ERBB2), including biliary tract, colorectal, non-small-cell lung and bladder cancers. The experience with gastric cancer suggests that the successes observed in HER2-positive breast cancer might not be replicated in these other tumour types, owing to differences in the level of HER2 overexpression and other aspects of disease biology. In this Review, we describe the current role of HER2-targeted therapies beyond breast cancer and also highlight the potential of novel HER2-targeted agents that are currently in clinical development.

Key points

  • HER2 alterations, including overexpression, amplifications and other mutations, are found in a variety of solid tumours.

  • Trastuzumab plus chemotherapy is the standard-of-care first-line therapy for patients with HER2-positive gastric cancer, although trials involving pertuzumab, lapatinib and T-DM1 have failed to reveal any improvements in outcomes.

  • HER2-targeted therapies are being tested in other tumour types, including HER2-positive biliary tract, colorectal, non-small-cell lung and bladder cancers.

  • Novel antibody–drug conjugates and bispecific antibodies targeting HER2, and HER2-targeted therapies in combination with immune-checkpoint inhibition are all under investigation in clinical trials.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Fig. 1: Mechanism of action of agents targeting HER2.
Fig. 2: Frequency of HER2 alterations across tumour types.
Fig. 3: HER2 expression in breast cancer and gastric cancer.

References

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

    CAS  PubMed  Google Scholar 

  2. Klapper, L. N. et al. 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 

  3. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  5. Romond, E. H. et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N. Engl. J. Med. 353, 1673–1684 (2005).

    CAS  PubMed  Google Scholar 

  6. Slamon, D. et al. Adjuvant trastuzumab in HER2-positive breast cancer. N. Engl. J. Med. 365, 1273–1283 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Sakai, K. et al. Pertuzumab, a novel dimerization inhibitor, inhibits the growth of human lung cancer cells mediated by the HER3 signaling pathway. Cancer Sci. 98, 1498–1503 (2007).

    CAS  PubMed  Google Scholar 

  8. Mendoza, N. et al. Inhibition of ligand-mediated HER2 activation in androgen independent prostate cancer. Cancer Res. 62, 5485–5488 (2002).

    CAS  PubMed  Google Scholar 

  9. Mann, M. et al. Targeting cyclooxygenase 2 and HER-2/neu pathways inhibits colorectal carcinoma growth. Gastroenterology 120, 1713–1719 (2001).

    CAS  PubMed  Google Scholar 

  10. Mullen, P., Cameron, D. A., Hasmann, M., Smyth, J. F. & Langdon, S. P. Sensitivity to pertuzumab (2C4) in ovarian cancer models: cross-talk with estrogen receptor signaling. Mol. Cancer Ther. 6, 93–100 (2007).

    CAS  PubMed  Google Scholar 

  11. Nahta, R., Hung, M. C. & Esteva, F. J. The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res. 64, 2343–2346 (2004).

    CAS  PubMed  Google Scholar 

  12. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  16. Chab, 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).

    Google Scholar 

  17. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Google Scholar 

  20. Chmielecki, J. et al. Oncogenic alterations in ERBB2/HER2 represent potential therapeutic targets across tumors from diverse anatomic sites of origin. Oncologist 20, 7–12 (2015).

    CAS  PubMed  Google Scholar 

  21. Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat. Med. 23, 703–713 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Schram, A. et al. Landscape of somatic ERBB2 mutations: findings from AACR GENIE and comparison to ongoing ERBB2 mutant basket study [abstract]. Cancer Res. 77 (13 Suppl.), LB-103 (2017).

    Google Scholar 

  23. Pahuja, K. B. et al. Actionable activating oncogenic ERBB2/HER2 transmembrane and juxtamembrane domain mutations. Cancer Cell. 34, 792–806 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Profiling differential responses to Pan-HER inhibition. Cancer Discov. 7, OF12 (2017).

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

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Bang, Y. J. et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for the treatment of HER2-positive advanced gastric or gastro-esophageal cancer (ToGA): a phase 3, open-label, randomized controlled trial. Lancet. 376, 687–697 (2010).

    CAS  PubMed  Google Scholar 

  27. Van Cutsem, E. et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer 18, 476–484 (2015).

    PubMed  Google Scholar 

  28. Bang, Y. J. Advances in the management of HER2-positive advanced gastric and gastroesophageal junction cancer. J. Clin. Gastroenterol. 46, 637–648 (2012).

    CAS  PubMed  Google Scholar 

  29. Cappellesso, R. et al. HER2 status in gastroesophageal cancer: a tissue microarray study of 1040 cases. Hum. Pathol. 46, 665–672 (2015).

    CAS  PubMed  Google Scholar 

  30. Matsusaka, S. et al. Clinicopathological factors associated with HER2 status in gastric cancer: results from a prospective multicenter observational cohort study in a Japanese population (JFMC44-1101). Gastric Cancer 19, 839–851 (2016).

    CAS  PubMed  Google Scholar 

  31. Hofmann, M. et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology 52, 797–805 (2008).

    CAS  PubMed  Google Scholar 

  32. Rüschoff, J. et al. HER2 testing in gastric cancer: a practical approach. Mod. Pathol. 25, 637–650 (2012).

    PubMed  Google Scholar 

  33. Cho, J. et al. A large cohort of consecutive patients confirmed frequent HER2 positivity in gastric carcinomas with advanced stages. Ann. Surg/ Oncol. 20, S477–S484 (2013).

    Google Scholar 

  34. Yoon, H. H. et al. Association of HER2/ErbB2 expression and gene amplification with pathologic features and prognosis in esophageal adenocarcinomas. Clin. Cancer Res. 18, 546–554 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Cho, E. Y. et al. Heterogeneity of ERBB2 in gastric carcinomas: a study of tissue microarray and matched primary and metastatic carcinomas. Mod. Pathol. 26, 677–684 (2013).

    CAS  PubMed  Google Scholar 

  36. Kim, K. M. et al. Human epidermal growth factor receptor 2 testing in gastric cancer: recommendations of an Asia-Pacific Task Force. Asia Pac. J. Clin. Oncol. 10, 297–307 (2014).

    PubMed  PubMed Central  Google Scholar 

  37. Kim, S. Y. et al. Trastuzumab inhibits the growth of human gastric cancer cell lines with HER2 amplification synergistically with cisplatin. Int. J. Oncol. 32, 89–95 (2008).

    PubMed  Google Scholar 

  38. Fujimoto-Ouchi, K. et al. Antitumor activity of trastuzumab in combination with chemotherapy in human gastric cancer xenograft models. Cancer Chemother. Pharmacol. 59, 795–805 (2007).

    CAS  PubMed  Google Scholar 

  39. Yang, J. et al. The combination of exposure-response and case-control analyses in regulatory decision making. J. Clin. Pharmacol. 53, 160–166 (2013).

    PubMed  Google Scholar 

  40. Shah, M. A. et al. HELOISE: phase IIIb randomized multicenter study comparing standard-of-care and higher-dose trastuzumab regimens combined with chemotherapy as first-line therapy in patients with human epidermal growth factor receptor 2-positive metastatic gastric or gastroesophageal junction adenocarcinoma. J. Clin. Oncol. 35, 2558–2567 (2017).

    CAS  PubMed  Google Scholar 

  41. 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).

    CAS  PubMed  Google Scholar 

  42. Tabernero, J. et al. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol. 19, 1372–1384 (2018).

    CAS  PubMed  Google Scholar 

  43. Kang, Y. K. et al. A phase IIa dose-finding and safety study of first-line pertuzumab in combination with trastuzumab, capecitabine and cisplatin in patients with HER2-positive advanced gastric cancer. Br. J. Cancer 111, 660–666 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Hecht, J. R. et al. Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013/LOGiC–a randomized phase III trial. J. Clin. Oncol. 34, 443–451 (2016).

    CAS  PubMed  Google Scholar 

  45. Makiyama, A. et al. A randomized phase II study of weekly paclitaxel ± trastuzumab in patients with HER2-positive advanced gastric or gastro-esophageal junction cancer refractory to trastuzumab combined with fluoropyrimidine and platinum: WJOG7112G (T-ACT) [abstract]. J. Clin. Oncol. 36 (15 Suppl.), 4011 (2018).

    Google Scholar 

  46. Ignatov, T., Gorbunow, F., Eggemann, H., Ortmann, O. & Ignatov, A. Loss of HER2 after HER2-targeted treatment. Breast. Cancer Res. Treat. 175, 401–408 (2019).

    CAS  Google Scholar 

  47. Mittendorf, E. A. et al. Loss of HER2 amplification following trastuzumab-based neoadjuvant systemic therapy and survival outcomes. Clin. Cancer Res. 15, 7381–7388 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Satoh, T. et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN–a randomized, phase III study. J. Clin. Oncol. 32, 2039–2049 (2014).

    CAS  PubMed  Google Scholar 

  49. Thuss-Patience, P. C. et al. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 18, 640–653 (2017).

    CAS  PubMed  Google Scholar 

  50. Janjigian, Y. Y. et al. A phase II study of afatinib in patients (pts) with metastatic human epidermal growth factor receptor (HER2)-positive trastuzumab refractory esophagogastric (EG) cancer [abstract]. J. Clin. Oncol. 33 (3 Suppl.), 59 (2015).

    Google Scholar 

  51. Hofheinz, R. et al. HER-FLOT: Trastuzumab in combination with FLOT as perioperative treatment for patients with HER2-positive locally advanced esophagogastric adenocarcinoma: A phase II trial of the AIO Gastric Cancer Study Group [abstract]. J. Clin. Oncol. 32 (15 Suppl.), 4073 (2014).

    Google Scholar 

  52. Wagner, A. D. et al. EORTC-1203-GITCG – the “INNOVATION”-trial: Effect of chemotherapy alone versus chemotherapy plus trastuzumab, versus chemotherapy plus trastuzumab plus pertuzumab, in the perioperative treatment of HER2 positive, gastric and gastroesophageal junction adenocarcinoma on pathologic response rate: a randomized phase II-intergroup trial of the EORTC-Gastrointestinal Tract Cancer Group, Korean Cancer Study Group and Dutch Upper GI-Cancer Group. BMC Cancer 19, 494 (2019).

    PubMed  PubMed Central  Google Scholar 

  53. Nam, A. R. et al. Therapeutic implication of HER2 in advanced biliary tract cancer. Oncotarget 7, 58007–58021 (2016).

    PubMed  PubMed Central  Google Scholar 

  54. Sohal, D. P. et al. Molecular characteristics of biliary tract cancer. Crit Rev. Oncol. Hematol. 107, 111–118 (2016).

    PubMed  Google Scholar 

  55. Harder, J. et al. EGFR and HER2 expression in advanced biliary tract cancer. World J. Gastroenterol. 15, 4511–4517 (2009).

    PubMed  PubMed Central  Google Scholar 

  56. Shafizadeh, N., Grenert, J. P., Sahai, V. & Kakar, S. Epidermal growth factor receptor and HER-2/neu status by immunohistochemistry and fluorescence in situ hybridization in adenocarcinomas of the biliary tree and gallbladder. Hum. Pathol 41, 485–492 (2010).

    CAS  PubMed  Google Scholar 

  57. Nakazawa, K. et al. Amplification and overexpression of c-erbB-2, epidermal growth factor receptor, and c-met in biliary tract cancers. J. Pathol. 206, 356–365 (2005).

    CAS  PubMed  Google Scholar 

  58. Kalekou, H. & Miliaras, D. Immunohistochemical study of microvessel density, CD44 (standard form), p53 protein and c-erbB2 in gallbladder carcinoma. J. Gastroenterol. Hepatol. 19, 812–818 (2004).

    PubMed  Google Scholar 

  59. Javle, M. et al. Molecular characterization of gallbladder cancer using somatic mutation profiling. Hum. Pathol. 45, 701–708 (2014).

    CAS  PubMed  Google Scholar 

  60. Yoshida, H. et al. A significant subgroup of resectable gallbladder cancer patients has an HER2 positive status. Virchows Arch. 468, 431–439 (2016).

    CAS  PubMed  Google Scholar 

  61. Li, M. et al. Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. Nat. Genet. 46, 872–876 (2014).

    CAS  PubMed  Google Scholar 

  62. Yamashita-Kashima, Y. et al. Molecular targeting of HER2-overexpressing biliary tract cancer cells with trastuzumab emtansine, an antibody-cytotoxic drug conjugate. Cancer Chemother. Pharmacol. 83, 659–671 (2019).

    CAS  PubMed  Google Scholar 

  63. Kawamoto, T. et al. Overexpression and gene amplification of EGFR, HER2, and HER3 in biliary tract carcinomas, and the possibility for therapy with the HER2-targeting antibody pertuzumab. J. Gastroenterol. 50, 467–479 (2015).

    CAS  PubMed  Google Scholar 

  64. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Javle, M. et al. HER2/neu-directed therapy for biliary tract cancer. J. Hematol. Oncol. 8, 58 (2015).

    PubMed  PubMed Central  Google Scholar 

  66. Hainsworth, J. D. et al. Targeted therapy for advanced solid tumors on the basis of molecular profiles: results from MyPathway, an open-label, phase IIa multiple basket study. J. Clin. Oncol. 36, 536–542 (2018).

    CAS  PubMed  Google Scholar 

  67. Meric-Bernstam, F. et al. Single agent activity of ZW25, a HER2-targeted bispecific antibody, in heavily pretreated HER2-expressing cancers [abstract]. J. Clin. Oncol. 36 (15 Suppl.), 2500 (2018).

    Google Scholar 

  68. Seo, A. N. et al. HER2 status in colorectal cancer: its clinical significance and the relationship between HER2 gene amplification and expression. PLOS ONE. 9, e98528 (2014).

    PubMed  PubMed Central  Google Scholar 

  69. El-Deiry, W. S. et al. Molecular profiling of 6,892 colorectal cancer samples suggests different possible treatment options specific to metastatic sites. Cancer Biol. Ther. 16, 1726–1737 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Kavuri, S. M. et al. HER2 activating mutations are targets for colorectal cancer treatment. Cancer Discov. 5, 832–841 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Yonesaka, K. et al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci. Transl. Med. 3, 99ra86 (2011).

    PubMed  PubMed Central  Google Scholar 

  72. Mohan, S. et al. Changes in colorectal carcinoma genomes under anti-EGFR therapy identified by whole-genome plasma DNA sequencing. PLOS Genet. 10, e1004271 (2014).

    PubMed  PubMed Central  Google Scholar 

  73. Bertotti, A. et al. A molecularly annotated platform of patient-derived xenografts (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov. 1, 508–523 (2011).

    CAS  PubMed  Google Scholar 

  74. Ramanathan, R. K. et al. Low overexpression of HER-2/neu in advanced colorectal cancer limits the usefulness of trastuzumab (Herceptin) and irinotecan as therapy. A phase II trial. Cancer Invest. 22, 858–865 (2004).

    CAS  PubMed  Google Scholar 

  75. Clark, J. W., Niedzwiecki, D., Hollis, D. & Mayer, R. Phase II trial of 5-fluorouracil (5-FU), leucovorin (LV), oxaliplatin (Ox), and trastuzumab (T) for patients with metastatic colorectal cancer (CRC) refractory to initial therapy [abstract]. Proc. Am. Soc. Clin. Oncol. 22, (3584 (2003).

    Google Scholar 

  76. Sartore-Bianchi, A. et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol. 17, 738–746 (2016).

    CAS  PubMed  Google Scholar 

  77. Grothey, A. et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381, 303–312 (2013).

    CAS  PubMed  Google Scholar 

  78. Li, J. et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 16, 619–629 (2015).

    CAS  PubMed  Google Scholar 

  79. Mayer, R. J. et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N. Engl. J. Med. 372, 1909–1919 (2015).

    PubMed  Google Scholar 

  80. Xu, J. et al. Results of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: the TERRA study. J. Clin. Oncol. 36, 350–358 (2018).

    CAS  PubMed  Google Scholar 

  81. Hurwitz, H. et al. Targeted therapy for gastrointestinal tumors based on molecular profiles: early results from MyPathway, an open-label phase IIa basket study in patients with advanced solid tumors [abstract]. Proc. Am. Soc. Clin. Oncol. 34 (Suppl. 4S), 653 (2016).

    Google Scholar 

  82. Yoshizawa, A. et al. HER2 status in lung adenocarcinoma: a comparison of immunohistochemistry, fluorescence in situ hybridization (FISH), dual-ISH, and gene mutations. Lung Cancer 85, 373–378 (2014).

    PubMed  Google Scholar 

  83. Kris, M. G. et al. Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors. Ann. Oncol. 26, 1421–1427 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Eng, J. et al. Outcomes of chemotherapies and HER2 directed therapies in advanced HER2-mutant lung cancers. Lung Cancer 99, 53–56 (2016).

    PubMed  PubMed Central  Google Scholar 

  85. Robichaux, J. P. et al. Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer. Nat. Med. 24, 638–646 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Oh, I. J. et al. Clinical activity of pan-HER inhibitors against HER2-mutant lung adenocarcinoma. Clin. Lung Cancer 19, 775–781 (2018).

    Google Scholar 

  87. Koga, T. et al. Activity of a novel HER2 inhibitor, poziotinib, for HER2 exon 20 mutations in lung cancer and mechanism of acquired resistance: an in vitro study. Lung Cancer 126, 72–79 (2018).

    PubMed  Google Scholar 

  88. Wang, Y. et al. HER2 exon 20 insertions in non-small cell lung cancer are sensitive to the irreversible pan-HER receptor tyrosine kinase inhibitor pyrotinib. Ann. Oncol. 30, 447–455 (2019).

    CAS  PubMed  Google Scholar 

  89. Lai, W. V. et al. Afatinib in patients with metastatic or recurrent HER2-mutant lung cancers: a retrospective international multicentre study. Eur. J. Cancer 109, 28–35 (2019).

    CAS  PubMed  Google Scholar 

  90. Heymach, J. V. et al. A phase II study of poziotinib in EGFR in exon 20 mutant advanced non small cell lung cancer (NSCLC) [abstract OA02.06]. J. Thorac. Oncol. 13, S323–S324 (2018).

    Google Scholar 

  91. Peters, S. et al. Trastuzumab emtansine (T-DM1) in patients with previously treated HER2-overexpressing metastatic non-small cell lung cancer: efficacy, safety, and biomarkers. Clin. Cancer Res. 25, 64–72 (2019).

    PubMed  Google Scholar 

  92. Li, B. T. et al. Ado-trastuzumab emtansine for patients with HER2-mutant lung cancers: results from a phase II basket trial. J. Clin. Oncol. 36, 2532–2537 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Li, B. T., et al. Updated results of phase 1 study of DS-8201a in HER2-expressing or -mutated advanced non-small cell lung cancer. In Proc. IASLC 19th World Conference on Lung Cancer (2018).

  94. Modi, S. et al. Trastuzumab deruxtecan (DS-8201a) in subjects with HER2-low expressing breast cancer: updated results of a large phase 1 study [abstract]. Cancer Res. 79 (4 Suppl.), P6-17-02 (2019).

    Google Scholar 

  95. Rinnerthaler, G. et al. HER2 directed antibody-drug-conjugates beyond T-DM1 in breast cancer. Int. J. Mol. Sci. 20, 1115 (2019).

    CAS  PubMed Central  Google Scholar 

  96. Yan, M. et al. HER2 expression status in diverse cancers: review of results from 37,992 patients. Cancer Metastasis Rev. 34, 157–164 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Kiss, B. et al. Her2 alterations in muscle-invasive bladder cancer: patient selection beyond protein expression for targeted therapy. Sci. Rep. 7, 42713 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Krüger, S. et al. HER2 overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic implications. Int. J. Cancer 102, 514–518 (2002).

    PubMed  Google Scholar 

  99. Hussain, M. H. et al. Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: results of a multicenter phase II National Cancer Institute trial. J. Clin. Oncol. 25, 2218–2224 (2007).

    CAS  PubMed  Google Scholar 

  100. Ross, J. S. et al. A high frequency of activating extracellular domain ERBB2 (HER2) mutation in micropapillary urothelial carcinoma. Clin. Cancer Res. 20, 68–75 (2014).

    CAS  PubMed  Google Scholar 

  101. Hayashi, T. et al. Targeting HER2 with T-DM1, an antibody cytotoxic drug conjugate, is effective in HER2 over expressing bladder cancer. J. Urol. 194, 1120–1131 (2015).

    CAS  PubMed  Google Scholar 

  102. Grivas, P. D. et al. Evaluation of the antitumor activity of dacomitinib in models of human bladder cancer. Mol. Med. 19, 367–376 (2013).

    PubMed  PubMed Central  Google Scholar 

  103. De Martino, M. et al. Impact of ERBB2 mutations on in vitro sensitivity of bladder cancer to lapatinib. Cancer Biol. Ther. 15, 1239–1247 (2014).

    PubMed  PubMed Central  Google Scholar 

  104. Powles, T. et al. Phase III, double-blind, randomized trial that compared maintenance lapatinib versus placebo after first-line chemotherapy in patients with human epidermal growth factor receptor 1/2-positive metastatic bladder cancer. J. Clin. Oncol. 35, 48–55 (2017).

    CAS  PubMed  Google Scholar 

  105. Saeki, H. et al. Re-evaluation of HER2 status in patients with HER2-positive advanced or recurrent gastric cancer refractory to trastuzumab (KSCC1604). Eur J. Cancer 105, 41–49 (2018).

    CAS  PubMed  Google Scholar 

  106. Ferris, R. L. et al. Tumor antigen-targeted, monoclonal antibody-based immunotherapy: clinical response, cellular immunity, and immunoescape. J. Clin. Oncol. 28, 4390–4399 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Musolino, A. et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J. Clin. Oncol. 26, 1789–1796 (2008).

    CAS  PubMed  Google Scholar 

  108. Zhang, X. L. et al. Comparative study on overexpression of HER2/neu and HER3 in gastric cancer. World J. Surg. 33, 2112–2118 (2009).

    PubMed  Google Scholar 

  109. Tang, D. et al. Assessment and prognostic analysis of EGFR, HER2, and HER3 protein expression in surgically resected gastric adenocarcinomas. Onco. Targets Ther. 8, 7–14 (2014).

    PubMed  PubMed Central  Google Scholar 

  110. Ema, A. et al. Immunohistochemical analysis of RTKs expression identified HER3 as a prognostic indicator of gastric cancer. Cancer Sci. 105, 1591–1600 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Yoon, H. H. et al. HER-2/neu gene amplification in relation to expression of HER2 and HER3 proteins in patients with esophageal adenocarcinoma. Cancer 120, 415–424 (2014).

    CAS  PubMed  Google Scholar 

  112. Paterson, A. L. et al. Characterisation of the timing and prevalence of receptor tyrosine kinase expression changes in esophageal carcinogenesis. J. Pathol. 230, 118–128 (2013).

    CAS  PubMed  Google Scholar 

  113. Lédel, F. et al. HER3 expression in patients with primary colorectal cancer and corresponding lymph node metastases related to clinical outcome. Eur J. Cancer 50, 656–662 (2014).

    PubMed  Google Scholar 

  114. Lee, H. J. et al. HER3 overexpression is a prognostic indicator of extrahepatic cholangiocarcinoma. Virchows Arch. 461, 521–530 (2012).

    CAS  PubMed  Google Scholar 

  115. Yang, X. et al. Characterization of EGFR family gene aberrations in cholangiocarcinoma. Oncol. Rep. 32, 700–708 (2014).

    CAS  PubMed  Google Scholar 

  116. Gallardo, A. et al. Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas. Br. J. Cancer 106, 1367–1373 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Shattuck, D. L. et al. Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells. Cancer Res. 68, 1471–1477 (2008).

    CAS  PubMed  Google Scholar 

  118. Zhuang, G. et al. Elevation of receptor tyrosine kinase EphA2 mediates resistance to trastuzumab therapy. Cancer Res. 70, 299–308 (2010).

    CAS  PubMed  Google Scholar 

  119. Jin, M. H. et al. Resistance mechanism against trastuzumab in HER2-positive cancer cells and its negation by Src inhibition. Mol. Cancer Ther. 16, 1145–1154 (2017).

    CAS  PubMed  Google Scholar 

  120. Arribas, J. et al. p95HER2 and breast cancer. Cancer Res. 71, 1515–1519 (2011).

    CAS  PubMed  Google Scholar 

  121. 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).

    CAS  PubMed  Google Scholar 

  122. Sperinde, J. et al. Quantitation of p95HER2 in paraffin sections by using a p95-specific antibody and correlation with outcome in a cohort of trastuzumab-treated breast cancer patients. Clin. Cancer Res. 16, 4226–4235 (2010).

    CAS  PubMed  Google Scholar 

  123. Duman, B. B. et al. PTEN, Akt, MAPK, p53 and p95 expression to predict trastuzumab resistance in HER2 positive breast cancer. J. BUON. 18, 44–50 (2013).

    CAS  PubMed  Google Scholar 

  124. Loibl, S. et al. Validation of p95 as a predictive marker for trastuzumab-based therapy in primary HER2-positive breast cancer: a translational investigation from the neoadjuvant GeparQuattro study. [abstract]. J. Clin. Oncol. 29 (15 Suppl.), 530 (2011).

    Google Scholar 

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

    Google Scholar 

  126. Stransky, N. et al. The landscape of kinase fusions in cancer. Nat. Commun. 5, 4846 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Mertens, F. et al. The emerging complexity of gene fusions in cancer. Nat. Rev. Cancer 15, 371–381 (2015).

    CAS  PubMed  Google Scholar 

  128. Ock, C. Y. et al. Optimal patient selection for trastuzumab treatment in her2-positive advanced gastric cancer. Clin. Cancer Res. 21, 2520–2529 (2015).

    CAS  PubMed  Google Scholar 

  129. An, E. et al. Quantitative proteomic analysis of HER2 expression in the selection of gastric cancer patients for trastuzumab treatment. Ann. Oncol. 28, 110–115 (2017).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  131. Iwata, T. N. et al. A HER2-targeting antibody-drug conjugate, trastuzumab deruxtecan (DS-8201a), enhances antitumor immunity in a mouse model. Mol. Cancer Ther. 17, 1494–1503 (2018).

    CAS  PubMed  Google Scholar 

  132. Doi, T. et al. Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study. Lancet Oncol. 18, 1512–1522 (2017).

    CAS  PubMed  Google Scholar 

  133. 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).

    CAS  PubMed  Google Scholar 

  134. Shitara, K. et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study. Lancet Oncol. 20, 827–836 (2019).

    CAS  PubMed  Google Scholar 

  135. ZW25 Effective in HER2-Positive Cancers. Cancer Discov. 9, 8(2019).

  136. Sternberg, A. HER2-targeted antibody ZW25 earns FDA fast track designation in GEA. Targeted Oncology https://www.targetedonc.com/news/her2targeted-antibody-zw25-earns-fda-fast-track-designation-in-gea (2019).

  137. 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).

    CAS  PubMed  Google Scholar 

  138. 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).

    CAS  PubMed  Google Scholar 

  139. Catenacci, D. V. T. et al. Antitumor activity of margetuximab (M) plus pembrolizumab (P) in patients (pts) with advanced HER2+ (IHC3+) gastric carcinoma (GC) [abstract]. J. Clin. Oncol. 37 (4 Suppl.), 65 (2019).

    Google Scholar 

  140. Janjigian, Y. Y. et al. First-line pembrolizumab (P), trastuzumab (T), capecitabine (C) and oxaliplatin (O) in HER2-positive metastatic esophagogastric adenocarcinoma (mEGA) [abstract]. J. Clin. Oncol. 37 (4 Suppl.), 62 (2019).

    Google Scholar 

  141. Ackerman, S. E. et al. TLR7/8 immune-stimulating antibody conjugates elicit robust myeloid activation leading to enhanced effector function and anti-tumor immunity in pre-clinical models [abstract]. Cancer Res. 79 (13 Suppl.), 1559 (2019).

    Google Scholar 

  142. Williams, J. Boltbody™ immune-stimulating antibody conjugates (ISAC) demonstrate tumor clearance and generation of immunological memory in preclinical tumor models. Bolt Biotherapeutics https://boltbio.com/wp-content/uploads/2019/04/4-1-19-Bolt-AACR-Data-Press-Release.pdf (2019).

  143. Meric-Bernstam, F. et al. Advances in HER2-targeted therapy: novel agents and opportunities beyond breast and gastric cancer. Clin. Cancer Res. 25, 2033–2041 (2019).

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors’ research is supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (grant number 2016R1D1A1A09918133).

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea

    Do-Youn Oh & Yung-Jue Bang

Authors
  1. Do-Youn Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yung-Jue Bang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors made a substantial contribution to all aspects of the preparation of this manuscript.

Corresponding author

Correspondence to Yung-Jue Bang.

Ethics declarations

Competing interests

Y.-J.B. has acted as a consultant or advisor for Astellas, AstraZeneca, Bayer, BeiGene, BMS, Daiichi-Sankyo, Eli Lilly, Genentech/Roche, Genexine, GreenCross, Hanmi, Merck Serano, MSD, Novartis, Samyang Biopharm and Taiho. D.-Y.O. has acted as a consultant or advisor for ASLAN, AstraZeneca, Bayer, Genentech/Roche, Halozyme, Merck Serono, Novartis, Taiho and Zymeworks, and received research grants from Arraly, AstraZeneca, Eli Lilly and Novartis.

Additional information

Publisher’s note

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Oh, DY., Bang, YJ. HER2-targeted therapies — a role beyond breast cancer. Nat Rev Clin Oncol 17, 33–48 (2020). https://doi.org/10.1038/s41571-019-0268-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-019-0268-3

This article is cited by

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