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xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EThis article highlights some important features of HER2-positive breast cancer. These include a review of some of the molecular mechanisms implicated in tumorigenesis, how certain therapies are used to interfere with these processes, the benefits of neoadjuvant therapy, and the treatment of patients with metastatic disease.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Emetastatic disease\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EHER2 signaling\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Etargeting\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eresistance\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Emolecular mechanism\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group drug\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Etrastuzumab\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Elapatinib\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Epertuzumab\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Etrastuzumab-emtansine\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ECLEOPATRA\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EVELVET\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EEMILIA\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ETH3RESA\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \n         \u003Cp id=\u0022p-2\u0022\u003EIn a session on HER2-positive breast cancer (BC), 3 presenters reviewed aspects of the disease and its management: basic mechanisms of HER2 signaling, targeting, and resistance; developments in neoadjuvant therapy; and the management of metastatic HER2-positive BC.\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EMark M. Moasser, MD, University of California, San Francisco, San Francisco, California, USA, discussed HER2, part of the HER family, which comprises 4 transmembrane receptors: epidermal growth factor receptor (EGFR), HER2, HER3, and HER4. In pathologic states, loss of regulatory mechanisms permits massive HER2 overexpression, and HER3 plays an essential part in this process, which is not yet fully understood [Vaught DB et al. \u003Cem\u003ECancer Res\u003C\/em\u003E. 2012; Lee-Hoeflich ST et al. \u003Cem\u003ECancer Res.\u003C\/em\u003E 2008; Holbro T et al. \u003Cem\u003EProc Natl Acad Sci USA.\u003C\/em\u003E 2003].\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EThere has been much interest in developing agents to target HER2 for the treatment of HER2-positive BC. Theoretically, inhibiting HER2 function is a reasonable strategy, and most studies have focused on the use of small-molecule inhibitors, such as lapatinib [Rusnak DW et al. \u003Cem\u003EMol Cancer Ther\u003C\/em\u003E. 2001], and antibodies, such as trastuzumab [Cho H-S et al. \u003Cem\u003ENature\u003C\/em\u003E. 2003]. However, this target has proven more difficult to inhibit than initially thought because of widespread and upfront resistance that is driven by a rapid compensatory increase in HER2-HER3 signaling output. However the strategy to home in on cancer cells via their massive surface HER2 expression using immunotherapy or immunodelivery approaches has proven far more impactful at this point with the introduction of trastuzumab, pertuzumab, and trastuzumab-emtansine introduced into clinical practice. Tumor PTEN and PIK3CA alterations have been extensively investigated but failed as potential predictive biomarkers of trastuzumab resistance (Loi S et al, \u003Cem\u003EJ Natl Cancer Inst\u003C\/em\u003E. 2013, Perez EA et al, \u003Cem\u003EJ Clin Oncol.\u003C\/em\u003E 2013, Pogue-Geile et al, \u003Cem\u003EJ Clin Oncol.\u003C\/em\u003E 2015). However biomarkers of immunologic signaling have proven powerful predictors of trastuzumab resistance (Perez EA et al, \u003Cem\u003EJ Clin Oncol.\u003C\/em\u003E 2015) and have identified an insufficient host immune response as a mechanistic basis for trastuzumab resistance. The development of more potent inhibitors of HER2-HER3 signaling is underway for more effective inactivation of oncogenic signaling, while the modulation of immune response may be a key next step in overcoming trastuzumab resistance.\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EAccording to Sibylle Loibl, MD, PhD, German Breast Group, Neu-Isenburg, Germany, pathologic complete response (pCR) rate has increased in recent years from about 20% using chemotherapy alone, to almost 70% using long-term anthracycline-taxane chemotherapy regimens and double HER2 blockade. In a pooled analysis, the gap between pCR and no pCR was much larger in hormone receptor (HR)\u2013negative compared with HR-positive patients [Cortazar P et al. \u003Cem\u003ELancet\u003C\/em\u003E. 2014]. In the NeoALTTO study [de Azambuja E et al. \u003Cem\u003ELancet Oncol.\u003C\/em\u003E 2014; Baselga J et al. \u003Cem\u003ELancet\u003C\/em\u003E. 2012], HER2 double-blockade using lapatinib and trastuzumab with taxane chemotherapy significantly increased both pCR (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E) and survival rates.\u003C\/p\u003E\n         \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/56\/17\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Pathologic Complete Response by HR Status in NeoALTTOHR, hormone receptor.Reprinted from The Lancet, Copyright 2012;379:633-640, Baselga J et al, Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. With permission from Elsevier.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1907051111\u0022 data-figure-caption=\u0022\u0026amp;lt;div xmlns=\u0026amp;quot;http:\/\/www.w3.org\/1999\/xhtml\u0026amp;quot;\u0026amp;gt;Pathologic Complete Response by HR Status in NeoALTTOHR, hormone receptor.Reprinted from \u0026amp;lt;em\u0026amp;gt;The Lancet\u0026amp;lt;\/em\u0026amp;gt;, Copyright 2012;379:633-640, Baselga J et al, Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. With permission from Elsevier.\u0026amp;lt;\/div\u0026amp;gt;\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/56\/17\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/56\/17\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/56\/17\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/11619\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-6\u0022 class=\u0022first-child\u0022\u003EPathologic Complete Response by HR Status in NeoALTTO\u003C\/p\u003E\n               \u003Cp id=\u0022p-7\u0022\u003EHR, hormone receptor.\u003C\/p\u003E\n               \u003Cp id=\u0022p-8\u0022\u003EReprinted from \u003Cem\u003EThe Lancet\u003C\/em\u003E, Copyright 2012;379:633-640, Baselga J et al, Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. With permission from Elsevier.\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EThe phase 3 NOAH trial [Gianni L et al. \u003Cem\u003ELancet Oncol\u003C\/em\u003E. 2014; Gianni L et al. \u003Cem\u003ELancet\u003C\/em\u003E. 2010] demonstrated short- and long-term benefits of adding neoadjuvant trastuzumab to chemotherapy.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EPredictive Biomarkers\u003C\/h2\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EPIK3CA (PIK3 catalytic subunit alpha) gene mutation occurs in about 20% of BC cases and is an independent predictor of pCR [Guarneri V et al. ESMO. 2014 (abstr 254O); Baselga J et al. ECC. 2013 (abstr 1859)]. Patients with PIK3CA mutation experience significantly lower pCR rates than those with wild-type PIK3 tumor [Loibl S et al. \u003Cem\u003EJ Clin Oncol.\u003C\/em\u003E 2014].\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EProf Loibl showed data from the FinHER study, demonstrating that tumor-infiltrating lymphocytes predict trastuzumab benefit [Loi S et al. \u003Cem\u003EAnn Oncol\u003C\/em\u003E. 2014].\u003C\/p\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EIan Krop, MD, PhD, Dana-Farber Cancer Institute, Boston, Massachusetts, USA, reviewed the treatment of metastatic HER2-positive BC.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-3\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EFirst-Line Therapy\u003C\/h2\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EPertuzumab is standard first-line therapy in patients with metastatic BC (MBC). The CLEOPATRA study [Baselga J et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E. 2012] showed an overall survival benefit of almost 16 months in patients who received pertuzumab in addition to chemotherapy and trastuzumab, and the objective response rate was 80% [Swain S et al. ESMO. 2014 (abstr 350O)]. Toxicity with this combined antibody approach typically involves only mild increases in diarrhea and rash.\u003C\/p\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EDocetaxel [Swain S et al. ESMO. 2014 (abstr 350O)] and paclitaxel [Datko F et al. SABCS. 2012 (abstr P5-18-20)] are acceptable chemotherapy partners to pertuzumab, said Dr Krop, and data from the VELVET study [Andersson M et al. ESMO. 2014 (abstr 361PD)] suggested that vinorelbine may also be suitable.\u003C\/p\u003E\n         \u003Cp id=\u0022p-15\u0022\u003EDr Krop indicated that an off-label pertuzumab-based regimen may be reasonable in patients who missed out on first-line pertuzumab therapy [Baselga J et al. \u003Cem\u003EJ Clin Oncol.\u003C\/em\u003E 2010].\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-4\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003ESecond-Line Therapy\u003C\/h2\u003E\n         \u003Cp id=\u0022p-16\u0022\u003ET-DM1 should be considered standard second-line therapy, said Dr Krop, since in the EMILIA study [Verma S et al. ESMO. 2012 (abstr LBA12)], T-DM1 demonstrated improved outcomes with favorable toxicity profiles, producing a median response of \u0026gt;\u20091 year. Randomized trials have also indicated its value as later-line therapy, including the TH3RESA study [Krop IE et al. \u003Cem\u003ELancet Oncol.\u003C\/em\u003E 2014] in which T-DM1 increased progression-free survival (6.2 vs 3.3 months; \u003Cem\u003EP\u003C\/em\u003E\u2009\u0026lt;\u2009.0001), with a trend toward overall survival benefit.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-5\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EThird and Later Lines of Therapy\u003C\/h2\u003E\n         \u003Cp id=\u0022p-17\u0022\u003EIn third-line and later therapy, combinations of trastuzumab or lapatinib and chemotherapy are active and should be continued, said Dr Krop, adding that while there are no preferred agents, he bases his choice on patient preferences.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-6\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EManagement of Central Nervous System Metastases\u003C\/h2\u003E\n         \u003Cp id=\u0022p-18\u0022\u003ECentral nervous system (CNS) disease occurs in up to 50% of patients with HER2-positive MBC. Radiation comprises the first-line therapy, and some patients benefit from resection. Single-agent lapatinib is of minimal benefit; this increases in combination with capecitabine, but duration of response is short [Sutherland S et al. \u003Cem\u003EBr J Cancer.\u003C\/em\u003E 2010]. Although Dr Krop noted that the American Society of Clinical Oncology guidelines recommend treatment of MBC based on standard algorithms [Ramakrishna N et al. \u003Cem\u003EJ Clin Oncol.\u003C\/em\u003E 2014], he emphasized that improved therapies in this setting are needed. Clinical studies are underway to investigate systemic therapies, such as neratinib, that can cross the blood\u2013brain barrier for the treatment of this challenging problem.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 SAGE Publications\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/56\/17.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzo8a1\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzo8a1\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}