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Targeting HER2/3 in Breast Cancer

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References

  1. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–82.

    CAS  Article  PubMed  Google Scholar 

  2. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244(4905):707–12.

    CAS  Article  PubMed  Google Scholar 

  3. Ross JS, Fletcher JA. The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Stem Cells. 1998;16(6):413–28.

    CAS  Article  PubMed  Google Scholar 

  4. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783–92.

    CAS  Article  PubMed  Google Scholar 

  5. Denduluri N, et al. Selection of optimal adjuvant chemotherapy regimens for human epidermal growth factor receptor 2 (HER2) -negative and adjuvant targeted therapy for HER2-positive breast cancers. J Clin Oncol. 2016;34:2416–27.

    Article  PubMed  Google Scholar 

  6. Giordano SH, Temin S, Kirshner JJ, et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32:2078–99.

    CAS  Article  PubMed  Google Scholar 

  7. National Comprehensive Cancer Network. Clinical practice guidelines in oncology: Breast cancer version 2.2016. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.

  8. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2- positive advanced breast cancer. N Engl J Med. 2006;355:2733–43.

    CAS  Article  PubMed  Google Scholar 

  9. Cameron D, Casey M, Oliva C, et al. Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial. Oncologist. 2010;15:924.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge G, Aktan G, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2–positive metastatic breast cancer: final results from the EGF104900 study. J Clin Oncol. 2012;30:2585–92.

    CAS  Article  PubMed  Google Scholar 

  11. Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109–11.

    CAS  Article  PubMed  Google Scholar 

  12. Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372:724.

    CAS  Article  PubMed  Google Scholar 

  13. Gianni L, Pienkowski T, Im YH, 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. 2012;13:25–32.

    CAS  Article  PubMed  Google Scholar 

  14. Schneeweiss A, Chia S, Hickish T, 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. 2013;24:2278–84.

    CAS  Article  PubMed  Google Scholar 

  15. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Krop IE, Kim SB, González-Martín A, 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. 2014;15:689.

    CAS  Article  PubMed  Google Scholar 

  17. Wildiers H, Kim S-B, Gonzalez-Martin A, et al. Trastuzumab emtansine improves overall survival versus treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer: final overall survival results from the phase 3 TH3RESA study. SABCS. 2015:S5–05.

  18. Jhaveri K. MARIANNE: impact on current treatment of human epidermal growth factor receptor 2–positive metastatic breast cancer and implications for the future. J Clin Oncol. 2017 Jan 10;35(2):127–30.

    Article  PubMed  Google Scholar 

  19. Park JW, Liu MC, Yee D, et al. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016;375:11–22.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Jacobs SA, Robidoux A, Garcia JMP et al. NSABP FB-7: a phase II randomized trial evaluating neoadjuvant therapy with weekly paclitaxel (P) plus neratinib (N) or trastuzumab (T) or neratinib and trastuzumab (N+T) followed by doxorubicin and cyclophosphamide (AC) with postoperative T in women with locally advanced HER2-positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium. 2015 Dec 8–12. San Antonio, TX. Philadelphia (PA): AACR. Cancer Res. 2016;76(4 Suppl):Abstract nr PD5–04.

  21. Chan A, Delaloge S, Holmes FA, 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. 2016;17:367–77.

    CAS  Article  PubMed  Google Scholar 

  22. http://www.onclive.com/web-exclusives/neratinib-benefit-in-breast-cancer-sustained-in-5year-extenet-analysis. Accessed 22 Jan 2017.

  23. Saura C, Garcia-Saenz J, Xu B, Harb W, Moroose R, Pluard T. 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. 2014;32:3626–33.

    CAS  Article  PubMed  Google Scholar 

  24. US National Library of Medicine. ClinicalTrials.gov. Study of Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in Patients With HER2+ Metastatic Breast Cancer Who Have Received Two or More Prior HER2 Directed Regimens in the Metastatic Setting (NALA). https://clinicaltrials.gov/ct2/show/NCT01808573.

  25. Hyman D., Piha-Paul S., Rodón J., Saura C., Puzanov I., Shapiro G., et al. (2015) Neratinib for ERBB2 mutant, HER2 nonamplified, metastatic breast cancer: preliminary analysis from a multicenter, open-label, multi-histology phase II basket trial. Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium, 8–12 Dec 2015, San Antonio.

  26. US National Library of Medicine. ClinicalTrials.gov. Neratinib +/− Fulvestrant in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer. Cited Jan 2017 https://www.clinicaltrials.gov/ct2/show/NCT01670877.

  27. Efficacy Results of a Phase 1b Study of Tucatinib (ONT-380), an Oral HER2-Specific Inhibitor, in Combination with Capecitabine and Trastuzumab in HER2+ Metastatic Breast Cancer, Including Patients with Brain Metastases. Available from: http://www.cascadianrx.com/pdfs/ont-380/005_SABCS_Poster_Final.pdf. Accessed 03 Jan 2017.

  28. Borges VF 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. J Clin Oncol. 2016; 34 (suppl; abstr 513).

  29. Tamura K, Shitara K, Naito Y, et al. Single activity of DS-8201a, a HER2-targeting antibody-drug conjugate, in breast cancer patients previously treated with T-DM1: phase 1 dose escalation. Presented at: 2016 ESMO Congress; Oct 2016, Copenhagen, Denmark. Abstract LBA17.

  30. US National Library of Medicine. ClinicalTrials.gov. First-in-Human Study with the Antibody-Drug Conjugate SYD985 to Evaluate Safety and Efficacy in Cancer Patients. Cited Jan 2017 https://clinicaltrials.gov/ct2/show/NCT02277717.

  31. Miller K, Cortes J, Hurvitz SA, Krop IE, Tripathy D, Verma S. HERMIONE: a randomized phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician’s choice plus trastuzumab in patients with previously treated, anthracycline-naïve, HER2-positive, locally advanced/metastatic breast cancer. BMC Cancer. 2016;16:352.

    Article  PubMed  PubMed Central  Google Scholar 

  32. US National Library of Medicine. ClinicalTrials.gov. Open-Label Study Evaluating the Safety and Tolerability of LJM716, BYL719 and Trastuzumab in Patients with Metastatic HER2+ Breast Cancer. Cited Jan 2017 https://clinicaltrials.gov/ct2/show/NCT02167854.

  33. US National Library of Medicine. ClinicalTrials.gov. I-SPY 2 TRIAL: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer (I-SPY 2). Cited Jan 2017 https://clinicaltrials.gov/ct2/show/NCT01042379.

  34. Saura C, et al. Phase I/II study (NCT01132664) of buparlisib (pan-PI3K inhibitor) + trastuzumab in trastuzumab-resistant locally advanced/metastatic HER2+ breast cancer. Clin Cancer Res. 2014 Apr 1;20(7):1935–45.

    CAS  Article  PubMed  Google Scholar 

  35. US National Library of Medicine. ClinicalTrials.gov. NeoPHOEBE: Neoadjuvant Trastuzumab + BKM120 in Combination with Weekly Paclitaxel in HER2-positive Primary Breast Cancer. http://clinicaltrials.gov/ct2/show/NCT01816594.

  36. US National Library of Medicine. ClinicalTrials.gov. Phase Ib Dose-escalation Trial of Taselisib (GDC-0032) in Combination With Anti-HER2 Therapies in Participants With Advanced HER2+ Breast Cancer https://clinicaltrials.gov/ct2/show/NCT02390427.

  37. US National Library of Medicine. ClinicalTrials.gov. BYL719 + T-DM1 in HER2(+) Metastatic Breast Cancer Pts Who Progress on Prior Trastuzumab & Taxane Tx. https://clinicaltrials.gov/ct2/show/NCT02038010.

  38. US National Library of Medicine. ClinicalTrials.gov. Anti-PD-1 Monoclonal Antibody in Advanced, Trastuzumab-Resistant, HER2-Positive Breast Cancer (PANACEA). Cited Oct 2016. https://clinicaltrials.gov/ct2/show/NCT02129556.

  39. US National Library of Medicine. ClinicalTrials.gov. Pembrolizumab and Monoclonal Antibody Therapy in Advanced Cancer (PembroMab). Cited Oct 2016. https://clinicaltrials.gov/ct2/show/NCT02318901.

  40. US National Library of Medicine. ClinicalTrials.gov. Safety and pharmacokinetics of atezolizumab in combination with trastuzumab emtansine or with trastuzumab and pertuzumab in participants with HER2-positive breast cancer. Cited Oct 2016. https://clinicaltrials.gov/ct2/show/NCT02605915.

  41. Burstein HJ, Sun Y, Dirix LY, et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol. 2010;28:1301–7.

    CAS  Article  PubMed  Google Scholar 

  42. US National Library of Medicine. ClinicalTrials.gov. A Study Looking the Incidence and Severity of Diarrhea in Patients with Early-Stage HER2+ Breast Cancer Treated with Neratinib and Loperamide Cited Jan 2017 https://clinicaltrials.gov/show/NCT02400476.

  43. Cancer Genome Atlas Network T. Comprehensive molecular portraits of human breast tumors. Nature. 2012;490:61–70.

    Article  Google Scholar 

  44. Bose R, Kavuri SM, Searleman AC, Shen W, Shen D, Koboldt DC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 2013;3(2):224–37.

    CAS  Article  PubMed  Google Scholar 

  45. Ma CX et al. Phase II trial of neratinib for HER2 mutated, non-amplified metastatic breast cancer (HER2mut MBC). J Clin Oncol. 2016;34 (suppl; abstr 516).

  46. Wagle et al. A cancer precision medicine platform for multiple simultaneous genomic assays from metastatic biopsies (bx) in ER+ metastatic breast cancer. J Clin Oncol. 2016; 34(suppl; abstr 11513).

  47. Desmedt C, Zoppoli G, Gundem G, et al. Genomic characterization of primary invasive lobular breast cancer. J Clin Oncol. 2016;34:1872–81.

    CAS  Article  PubMed  Google Scholar 

  48. Cortes J, Dieras V, Ro J, Barriere J, Bachelot T, Hurvitz S, et al. Afatinib alone or afatinib plus vinorelbine versus investigator’s choice of treatment for HER2-positive breast cancer with progressive brain metastases after trastuzumab, lapatinib, or both (LUX-breast 3): a randomised, open-label, multicentre, phase 2 trial. Lancet Oncol. 2015;16:1700–10.

    CAS  Article  PubMed  Google Scholar 

  49. Barok M, Joensuu H, Isola J. Trastuzumab emtansine: mechanisms of action and drug resistance. Breast Cancer Res. 2014;16:209.

    Article  PubMed  PubMed Central  Google Scholar 

  50. der Lee V, 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. 2015;14(3):692–703.

    Article  PubMed  Google Scholar 

  51. Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12:395–402.

    CAS  Article  PubMed  Google Scholar 

  52. Rexer BN, Arteaga CL. Optimal targeting of HER2-PI3K signaling in breast cancer: mechanistic insights and clinical implications. Cancer Res. 2013;73:3817–20.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. André F, O’Regan R, Ozguroglu M, 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. 2014;15:580–91.

    Article  PubMed  Google Scholar 

  54. Hurvitz SA, Andre F, Jiang Z, et al. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol. 2015;16:816–29.

    CAS  Article  PubMed  Google Scholar 

  55. Rodrik-Outmezguine VS, Chandarlapaty S, Pagano NC, Poulikakos PI, Scaltriti M, Moskatel E, et al. mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Discov. 2011;1(3):248–59.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. Garrett JT, Olivares MG, Rinehart C, Granja-Ingram ND, Sanchez V, Chakrabarty A, et al. Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase. Proc Natl Acad Sci U S A. 2011;108:5021–6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. Chandarlapaty S, Sawai A, Scaltriti M, et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell. 2011;19(1):58–71.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. Garner AP, et al. An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin. Cancer Res. 2013 Oct 1;73(19):6024–35.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. Seock-Ah Im, Dejan Juric, Jose Baselga, Anthony Kong, Paloma Martin, Chia-Chi Lin et al. A phase 1 dose-escalation study of anti-HER3 monoclonal antibody LJM716 in combination with trastuzumab in patients with HER2-overexpressing metastatic breast or gastric cancer. J Clin Oncol. 2014;32:5s (suppl; abstr 2519).

  60. Mukai H, et al. Patritumab plus trastuzumab and paclitaxel in human epidermal growth factor receptor 2-overexpressing metastatic breast cancer. Cancer Sci. 2016 Oct;107(10):1465–70. doi:10.1111/cas.13017.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 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. 2016 Aug 1;22(15):3755–63.

    CAS  Article  PubMed  Google Scholar 

  62. Kim SB, 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. 2016 Nov 15;139(10):2336–42.

    CAS  Article  PubMed  Google Scholar 

  63. Stanton SE, Adams S, Disis ML. Variation in the incidence and magnitude of tumor-infiltrating lymphocytes in breast cancer subtypes: a systematic review. JAMA Oncol. 2016;2:1354–60.

    Article  PubMed  Google Scholar 

  64. Dushyanthen S, Beavis PA, Savas P, et al. Relevance of tumor infiltrating lymphocytes in breast cancer. BMC Med. 2015;13:202.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Salgado R, Denkert C, Campbell C, 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. 2015;1:448–54.

    Article  PubMed  Google Scholar 

  66. Bianchini G, Pusztai L, Pienkowski T, Im Y-H, Bianchi GV, Tseng L-M. Immune modulation of pathologic complete response after neoadjuvant HER2-directed therapies in the NeoSphere trial. Ann Oncol. 2015;26(12):2429–36.

    CAS  PubMed  Google Scholar 

  67. Rugo HS, Barve A, Waller CF, Hernandez-Bronchud M, Herson J, Yuan J, et al. Effect of a proposed trastuzumab biosimilar compared with trastuzumab on overall response rate in patients with ERBB2 (HER2)-positive metastatic breast cancer: a randomized clinical trial. JAMA. 2017;317(1):37–47.

    Article  PubMed  Google Scholar 

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Correspondence to Komal Jhaveri.

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A.H. and S.M. declare that they have no conflict of interest. K.J. declares personal fees from Novartis, ADC Therapeutics, and Pfizer.

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Hepner, A., Modi, S. & Jhaveri, K. Targeting HER2/3 in Breast Cancer. Curr Breast Cancer Rep 9, 61–69 (2017). https://doi.org/10.1007/s12609-017-0239-6

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Keywords

  • Human epidermal growth factor receptor 2
  • HER2
  • HER2+
  • HER3
  • Breast cancer
  • Commentary