Advances and Future Directions in the Targeting of HER2-positive Breast Cancer: Implications for the Future
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The natural history of HER2-positive breast cancer significantly changed in the past 15 years. Form being the most aggressive type of breast cancer, it became treatable with important cure rates. However, with new and successful drugs, resistance emerges. Progress in research and drug development continues to make available effective anti-HER2 therapies. Our challenge today is to use these tools correctly by looking at the data that support the indications of each compound and to continue clinical trial participation.
KeywordsHER2-positive breast cancer Trastuzumab resistance Pertuzumab T-DM1 PI3K signaling Immunotherapy
Conflict of Interest
Ishwaria M. Subbiah declares no conflict of interest.
Ana Maria Gonzalez-Angulo has research funding and paid consultancy to Genentech, Novartis and GlaxoSmithKline.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
This work was supported in part by National Cancer Institute 1K23CA121994 (AMG) ASCO Career Development Award (AMG), Komen for the Cure Catalystic Award KG090341 (AMG), American Cancer Society Research Scholar Grant 121329-RSG-11-187-01-TBG (AMG), National Cancer Institute through The University of Texas MD Anderson’s Cancer Center Support Grant (P30 CA016672).
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 9.Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005;23:4265–74.PubMedCrossRefGoogle Scholar
- 10.Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999;17:2639–48.PubMedGoogle Scholar
- 19.Seidman AD, Berry D, Cirrincione C, et al. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008;26:1642–9.PubMedCrossRefGoogle Scholar
- 31.Kang JY, Dolled-Filhart M, Ocal IT, et al. Tissue microarray analysis of hepatocyte growth factor/Met pathway components reveals a role for Met, matriptase, and hepatocyte growth factor activator inhibitor 1 in the progression of node-negative breast cancer. Cancer Res. 2003;63:1101–5.PubMedGoogle Scholar
- 40.••Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-19, 2012. Original data from the CLEOPATRA study showing the benefit of additional pertuzumab to trastuzumab in advanced breast cancer.Google Scholar
- 41.•Swain SM, Kim SB, Cortes J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14:461–71. Confirmatory data from CLEOPATRA expanding on overall survival benefit of additional pertuzumab to trastuzumab.Google Scholar
- 42.••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. Original data from the NEOSPHERE trial showing improvement in pathological complete responses when adding trastuzumab to trastuzumab in the neoadjuvant setting.Google Scholar
- 43.ClinicalTrials.gov: A Study of Pertuzumab in Addition to Chemotherapy and Herceptin (Trastuzumab) as Adjuvant Therapy in Patients With HER2-Positive Primary Breast Cancer, U.S. National Institutes of HealthGoogle Scholar
- 48.Krop IE, LoRusso P, Miller KD, et al. A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2012;30:3234–41.PubMedCrossRefGoogle Scholar
- 50.••Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783–91. Original data of the EMILIA trial demonstrating the superiority of TDM-1 to standard of care in advanced HER2-positive breast cancer.Google Scholar
- 51.ClinicalTrials.gov: A Study of Trastuzumab Emtansine Versus Trastuzumab as Adjuvant Therapy in Patients With HER2-Positive Breast Cancer Who Have Residual Tumor in the Breast or Axillary Lymph Nodes Following Preoperative Therapy (KATHERINE),Google Scholar
- 52.ClinicalTrials.gov: A Study of Trastuzumab Emtansine (T-DM1) Plus Pertuzumab/Pertuzumab Placebo Versus Trastuzumab [Herceptin] Plus a Taxane in Patients With Metastatic Breast Cancer (MARIANNE),Google Scholar
- 53.ClinicalTrials.gov: A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Patients With HER2-Positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-Directed Therapy (TH3RESA),Google Scholar
- 56.ClinicalTrials.gov: Everolimus in Combination With Trastuzumab and Paclitaxel in the Treatment of HER2 Positive Locally Advanced or Metastatic Breast Cancer (BOLERO-1),Google Scholar
- 57.•O’Regan R: Phase 3, Randomized, Double-blind, Placebo-controlled Multicenter Trial of Daily Everolimus Plus Weekly Trastuzumab and Vinorelbine in Trastuzumab-resistant, Advanced Breast Cancer (BOLERO-3), Phase 3, Randomized, Double-blind, Placebo-controlled Multicenter Trial of Daily Everolimus Plus Weekly Trastuzumab and Vinorelbine in Trastuzumab-resistant, Advanced Breast Cancer (BOLERO-3). Chicago, IL, 2013. BOLERO3 data showing the role of mTOR inhibition to overcome trastuzumab therapy resistance.Google Scholar
- 61.Murray JL, Gillogly ME, Przepiorka D, et al. Toxicity, immunogenicity, and induction of E75-specific tumor-lytic CTLs by HER-2 peptide E75 (369-377) combined with granulocyte macrophage colony-stimulating factor in HLA-A2+ patients with metastatic breast and ovarian cancer. Clin Cancer Res. 2002;8:3407–18.PubMedGoogle Scholar
- 62.•Peoples GE, Holmes JP, Hueman MT, et al. Combined clinical trial results of a HER2/neu (E75) vaccine for the prevention of recurrence in high-risk breast cancer patients: U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02. Clin Cancer Res. 2008;14:797–803. Randomized trial showing the benefit of an anti-HER2 vaccine in patients with early breast cancer.Google Scholar