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Drugs 2012; 72 (9): 1175-1193 LEADING ARTICLE 0012-6667/12/0009-1175/$55.55/0 Adis ª 2012 Springer International Publishing AG

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Drugs 2012; 72 (9): 1175-1193 LEADING ARTICLE 0012-6667/12/0009-1175/$55.55/0 Adis ª 2012 Springer International Publishing AG This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. Terms and Conditions for Use of PDF The provision of PDFs for authors’ personal use is subject to the following Terms & Conditions: The PDF provided is protected by copyright. All rights not specifi cally granted in these Terms & Conditions are expressly reserved. Printing and storage is for scholarly research and educational and personal use. Any copyright or other notices or disclaimers must not be removed, obscured or modifi ed. The PDF may not be posted on an open-access website (including personal and university sites). The PDF may be used as follows: • to make copies of the article for your own personal use, including for your own classroom teaching use (this includes posting on a closed website for exclusive use by course students); • to make copies and distribute copies (including through e-mail) of the article to research colleagues, for the personal use by such colleagues (but not commercially or systematically, e.g. via an e-mail list or list serve); • to present the article at a meeting or conference and to distribute copies of such paper or article to the delegates attending the meeting; • to include the article in full or in part in a thesis or dissertation (provided that this is not to be published commercially). Drugs 2012; 72 (9): 1175-1193 LEADING ARTICLE 0012-6667/12/0009-1175/$55.55/0 Adis ª 2012 Springer International Publishing AG. All rights reserved. Overcoming Treatment Resistance in HER2-Positive Breast Cancer Potential Strategies Fabio Puglisi,1,2 Alessandro Marco Minisini,1 Carmine De Angelis3 and Grazia Arpino3 1 DepartmentThis of Oncology, University material Hospital of Udine, Udine, Italy is 2 Department of Medical and Biological Sciences, University of Udine, Udine, Italy 3 Department of Clinical and Molecular Oncology and Endocrinology, University of Naples, Federico II, Naples,the Italy copyright of the Abstract Human epidermal growth factor receptor (HER)-2 overexpression or amplification occurs in about 20% of all breast cancers and results in a worse prognosis. Nevertheless, anti-HER2 treatments have recently been devel- originaloped, resulting in dramaticpublisher. improvements in the clinical outcome of patients with HER2-positive breast cancer. Trastuzumab has shown efficacy in early and advanced breast cancer treatment and lapatinib is currently approved for the treatment of advanced disease. Other anti-HER2 agents are being in- vestigated. Mechanisms of resistance to trastuzumab treatment include Unauthorisedcrosstalk with heterologous receptors andcopying amplification of HER2 signalling; amplification of the phosphoinositide 3-kinase (PI3K)/AKT pathway; alter- ation in binding of trastuzumab to HER2; and loss of HER2 expression. Pro- posed mechanisms of resistance to lapatinib involve derepression and/or activation of compensatory survival pathways through increased PI3K/AKT andor estrogen distribution receptor (ER) signalling. Several strategies to overcome resistance to anti-HER2 treatment are in different phases of development and include treatment with pertuzumab, T-DM1 and mammalian target of rapamycin is(mTOR) prohibited. inhibitors. 1. Introduction oncogene and/or overexpression of its protein is evident.[2] These characteristics are associated In the past decades, insights into the genomic with an increased propensity for metastases and heterogeneity of breast cancer and the underlying clinically translate into reduced disease-free sur- biology have led to an individualized treatment vival (DFS) and overall survival (OS).[2-7] However, approach due to the ability to identify in advance although HER2 positivity (i.e. gene amplification those patients who are most likely to respond to a or protein overexpression) confers a poor prognosis particular therapy.[1] to patients with such tumours, it predicts response to Notably, in about 20% of all primary invasive anti-HER2 targeted agents. In other words, HER2 breast cancers, amplification of the human epi- positivity is an unfavourable prognostic factor and a dermal growth factor receptor (HER)-2 proto- favourable predictive factor at the same time. 1176 Puglisi et al. Trastuzumab is a humanized IgG1k monoclonal 2. State of the Art Treatment for HER2- antibody, specifically targeted against the extra- Positive Breast Cancer cellular domain (ECD) of HER2, where it binds 2.1 Early Disease with high affinity. In 1998, trastuzumab was ap- proved in combination with chemotherapy for the 2.1.1 Adjuvant Treatment treatment of HER2-overexpressing metastatic In HER2-positive EBC, trastuzumab showed breast cancer (MBC), mainly based on the re- consistent results in four landmark phase III trials sults of two randomized controlled trials (RCTs) comparing trastuzumab-containing versus chemo- showing a benefit in terms of OS with the addition of therapy alone regimens. Both DFS and OS were trastuzumab to chemotherapy.[8,9] Unfortunately, significantly prolonged by 1 year of trastuzumab. although trastuzumab plus chemotherapy has At a median follow-up of 3.9 years, the joint anal- improved theThis prognosis of patients material with HER2- ysis of the NCCTG N9831is (see table I for defi- positive MBC,[6] almost all patients eventually nitions of study names used in this article, where succumb to progressive disease, with a median OS available) and NSABP B-31 trials showed a highly of about 2–3 years in the majority of randomized significant advantage in DFS (hazard ratio [HR] = trials. 0.52, 95% CI 0.45, 0.6) and in OS (HR = 0.61, 95% the copyrightCI 0.50, 0.75) of for the trastuzumab-containingthe In 2005, the efficacy of trastuzumab was also [12] demonstrated in the adjuvant setting, where four arms. Similarly, an updated analysis of the randomized trials reported a significant reduction HERA trial at a median follow-up of 4 years con- in the rates of recurrence and death in patients firmed the significant advantage in DFS for the with HER2-positiveoriginal early breast cancer (EBC)publisher.trastuzumab-containing arm (HR = 0.76, 95% CI treated with trastuzumab and chemotherapy.[10] 0.66, 0.87) although the initial advantage in OS Again, although it is anticipated that many pa- was not more statistically significant, mainly be- [13] tients treated with adjuvant trastuzumab will be cause of a high percentage of crossover. cured of their disease, it is also expected that In the BCIRG 006 trial, trastuzumab showed Unauthorisedmany will experience a recurrence.[11] an improvement copying in DFS and OS even with a non- Thus, a large proportion of patients with HER2- anthracycline-containing regimen (HR = 0.75, 95% positive tumours either do not respond to tras- CI 0.63, 0.90 and HR = 0.77, 95% CI 0.60, 0.99, [14] tuzumab or develop tolerance to the antibody, respectively). suggesting both de novo and acquired mecha- At present, the standard duration of adjuvant nisms of drugand resistance. distributiontrastuzumab is 1 year, either in combination or Besides trastuzumab, other anti-HER2 agents after completing adjuvant chemotherapy. (such as lapatinib) are currently available in the The optimal duration of trastuzumab treatment clinical setting, while others are still being devel- is still under investigation. Results of the 2-year oped in clinical trials.[12] trastuzumab arm in the HERA trial are awaited This review focusesis on potentialprohibited. mechanisms of resistance to anti-HER2 treatment, examining Table I. Trial acronyms and definitions studies that have evaluated signalling from recep- ALTTO Adjuvant Lapatinib and/or Trastuzumab Treatment tor tyrosine kinases (RTKs) outside of the HER Optimisation family, increased phosphoinositide 3-kinase (PI3K) BCIRG Breast Cancer International Research Group signalling, amplification of signalling by other CALGB Cancer and Leukemia Group B receptors of the HER family and the presence of FinHER FINland HERceptin altered forms of HER2 that are not recognized or HERA Herceptin adjuvant bound by trastuzumab. In addition, major results NCCTG North Central Cancer Treatment Group of clinical studies on novel anti-HER2 agents are Neo-ALTTO Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation also described in order to support the proof of NSABP National Surgical Adjuvant Breast and Bowel Project concept that underlies the strategy to overcome PHARE Protocol of Herceptin Adjuvant with Reduced Exposure resistance to trastuzumab. Adis ª 2012 Springer International Publishing AG. All rights reserved. Drugs 2012; 72 (9) Treatment Resistance in HER2-Positive Breast Cancer 1177 and data from the FinHER (FINland HERcep- In both of these studies, trastuzumab was ad- tinstudy (short 9-week course of trastuzumab) ministered concomitantly with anthracycline- and need to be taken into consideration.[15] In addition, taxane-based chemotherapy. Safety data show a two other trials will investigate shorter trastuzu- favourable profile, with a low incidence of clini- mab therapy: the PHARE trial[16] will compare cally significant cardiac adverse events. 6 versus 12 months and SHORTHER[17] will com- Several preclinical and clinical data strongly pare 3 versus 12 months. Moreover, although suggest that combination of different HER2 tar- concomitant administration of trastuzumab with get agents working with different mechanisms of chemotherapy showed an improved DFS benefit action may improve the outcome in patients with compared with the sequential arm in the N9831 HER2-positive disease, as trastuzumab
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