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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv 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 discusses discussed major advances in the treatment of human epidermal growth factor 2 (HER2)-positive breast cancer in the past decade, the current state of adjuvant therapy for HER2-positive breast cancer, as well as the therapeutic implications of neoadjuvant therapy for HER2-positive breast cancer.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EBreast Cancer\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EAdjuvant\/Neoadjuvant Therapy\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EOncology Genomics\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003ENancy U. Lin, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, USA, discussed major advances in the treatment of human epidermal growth factor 2 (HER2)-positive breast cancer in the past decade. Including the expansion of HER2-directed therapy into earlier disease stages, continuation of HER2-directed therapy after progression, and the use of combined targeted approaches.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EKey trials of first-line therapy for HER2-positive metastatic breast cancer (MBC) have demonstrated that trastuzumab plus chemotherapy is superior to chemotherapy alone [Slamon DJ et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2001], HER2-directed therapy plus endocrine therapy improves outcomes compared with endocrine therapy alone [Kaufman B et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2009; Johnston S et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2009], single-agent chemotherapy plus trastuzumab is comparable to a chemotherapy doublet plus trastuzumab [Forbes JF et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2006 (suppl; abstr LBA516); Pegram M et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2007 (suppl; abstr LBA1008)], and several chemotherapy agents are effective when paired with trastuzumab [Burstein HJ et al. \u003Cem\u003ECancer\u003C\/em\u003E 2007; Andersson M et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2010].\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003ERecent research has focused on new HER2-targeted agents. Pertuzumab, which binds to different regions on HER2 than trastuzumab, signficantly prolonged progression-free survival (PFS) in the CLEOPATRA trial of first-line pertuzumab plus trastuzumab plus docetaxel (18.5 months) versus trastuzumab plus docetaxel (12.4 months; HR for progression or death, 0.62; 95% CI, 0.51 to 0.75; p\u0026lt;0.001) [Baselga J et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2012].\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EStudy results have confirmed that HER2 is a valid target after progression on trastuzumab, with improved PFS [Geyer CE et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2006; von Minckwitz G et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2009; Blackwell KL et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2010] and overall survival (OS) [Blackwell KL et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2012].\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003ENovel HER2-directed agents under investigation include trastuzumab emtansine (T-DM1), neratinib, afatinib, MM-302, ertumaxomab, and AE37. T-DM1 is trastuzumab linked to DM1, a potent cytotoxic agent that selectively delivers DM1 to HER2 positive tumor cells. A first-line study found that median PFS was prolonged with T-DM1 versus trastuzumab plus docetaxel (14.2 vs 9.2 months; HR, 0.59; 95% CI, 0.36 to 0.97; p=0.035) [Hurvitz S et al. \u003Cem\u003EEur J Cancer\u003C\/em\u003E 2011 (suppl 1; abstr LBA3)]. The EMILIA study reported superior outcomes with T-DM1 versus lapatinib plus capecitabine for PFS (9.6 vs 6.4 months; HR for progression or death from any cause, 0.65; 95% CI, 0.55 to 0.77; p\u0026lt;0.001) and median OS (30.9 vs 25.1 months; HR for death from any cause, 0.68; 95% CI, 0.55 to 0.85; p\u0026lt;0.001) [Verma S et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2012].\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003ETremendous progress has been made with the approval of trastuzumab, lapatinib, and pertuzumab. Pertuzumab plus trastuzumab plus a taxane has been approved for first-line therapy, and T-DM1 approval is expected in 2013. HER2-directed therapy provides benefit for third-line treatment and beyond. Trials have shown that HER2 remains a valid target after progression on trastuzumab, and combinations of HER2-directed therapies can overcome trastuzumab resistance. However, HER2-positive MBC is still largely incurable and relapses can occur despite adjuvant therapy.\u003C\/p\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EAdjuvant Therapy\u003C\/h2\u003E\n         \u003Cp id=\u0022p-8\u0022\u003ETrastuzumab added to adjuvant chemotherapy has been the standard therapy for early HER2-positive breast cancer since 2005. Karen Gelmon, MD, University of British Columbia, Vancouver, British Columbia, Canada, discussed the current state of adjuvant therapy for HER2-positive breast cancer.\u003C\/p\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EThe PHARE and HERA trials that investigated trastuzumab duration found no significant difference in disease-free survival with 6 versus 12 months at 4 years of follow-up (84.9% vs 87.8%; HR, 1.28; 95% CI, 1.05 to 1.56; p=0.29; noninferiority not established) or 2 years versus 1 year with 8 years of follow-up (75.8% vs 76.0%; unadjusted HR, 0.99; 95% CI, 0.85 to 1.14; p=0.8588) of treatment, respectively [Pivot X et al. \u003Cem\u003EAnn Oncol\u003C\/em\u003E 2012 (suppl 9; abstr LBA5); Goldhirsch A et al. \u003Cem\u003EAnn Oncol\u003C\/em\u003E 2012 (suppl 9; abstr LBA6)]. The SOLD [\u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT00593697\u0026amp;atom=%2Fspmdc%2F12%2F20%2F22.atom\u0022\u003ENCT00593697\u003C\/a\u003E] and SHORT-HER [\u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT00629278\u0026amp;atom=%2Fspmdc%2F12%2F20%2F22.atom\u0022\u003ENCT00629278\u003C\/a\u003E] trials are investigating 9 weeks versus 12 months of combination therapy with trastuzumab.\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EThe ALTTO [\u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT00490139\u0026amp;atom=%2Fspmdc%2F12%2F20%2F22.atom\u0022\u003ENCT00490139\u003C\/a\u003E] trial is evaluating chemotherapy plus a year of trastuzumab or lapatinib, both agents sequentially, or both agents concurrently. The lapatinib monotherapy arm was discontinued when it was shown to be inferior, and final trial results are pending. Gelmon et al. [\u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2012 (suppl; abstr LBA671)] found that median PFS was shorter with lapatinib (9.0 months) versus trastuzumab (13.7 months) when both were combined with taxane-based therapy, and the centrally confirmed HER2-positive subgroup had an HR of 1.48 (95% CI, 1.15 to 1.92; p=0.003). The NeoALTTO trial [\u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT00553358\u0026amp;atom=%2Fspmdc%2F12%2F20%2F22.atom\u0022\u003ENCT00553358\u003C\/a\u003E] demonstrated improved pathologic complete response (pCR) with lapatinib plus trastuzumab (51.3%) compared with trastuzumab alone (29.5%; p=0.0001) [Baselga J et al. \u003Cem\u003ELancet\u003C\/em\u003E 2012].\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EResults of the AVEREL study [Gianni L et al. SABCS 2011 (abstr S4\u20138)] as assessed by independent review committee demonstrated a statistically significant benefit for the addition of bevacizumab to trastuzumab; the BETH Study [\u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT00625898\u0026amp;atom=%2Fspmdc%2F12%2F20%2F22.atom\u0022\u003ENCT00625898\u003C\/a\u003E] has not yet reported results for the adding bevacizumab to chemotherapy plus trastuzumab. The CLEOPATRA trial found significantly increased PFS with the addition of pertuzumab to trastuzumab plus docetaxel [Baselga J et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2012]. The ongoing APHINITY [\u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT01358877\u0026amp;atom=%2Fspmdc%2F12%2F20%2F22.atom\u0022\u003ENCT01358877\u003C\/a\u003E] trial is evaluating chemotherapy plus one year of trastuzumab with or without pertuzumab.\u003C\/p\u003E\n         \u003Cp id=\u0022p-12\u0022\u003ECardiac toxicity remains the most common long-term concern with trastuzumab treatment. Another issue is whether all HER2-positive cancers are the same or whether treatment can be tailored according to molecular features. Individualized treatment has the potential to decrease toxicity, improve quality of life, and improve outcomes.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003ENeoadjuvant Therapy\u003C\/h2\u003E\n         \u003Cp id=\u0022p-13\u0022\u003ENeoadjuvant therapy provides a unique platform to assess tumor response to treatment, obtain serial tumor biopsies, and understand tumor biology. Mothaffar Rimawi, MD, Baylor College of Medicine, Houston, Texas, USA, discussed the therapeutic implications of neoadjuvant therapy for HER2-positive breast cancer.\u003C\/p\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EThree neoadjuvant therapy trials demonstrated improved pCR with the addition of trastuzumab to chemotherapy versus chemotherapy alone (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E). Although the pCR rates were almost double with trastuzumab, considerable resistance to trastuzumab was evident. Lapatinib is a dual inhibitor of the HER2 and EGFR tyrosine kinases that should potently signal downstream of both their homo- and heterodimeric forms. Interestingly, the GeparQuinto trial reported a pCR rate of 30.3% with chemotherapy plus trastuzumab compared with 22.7% with chemotherapy plus lapatinib (OR, 0.68; 95% CI, 0.47 to 0.97; p=0.04) [Untch M et al. \u003Cem\u003ELancet Oncol\u003C\/em\u003E 2012]. Based on these data, Dr. Rimawi concluded that targeting HER2 with only one inhibitor is not the optimal strategy.\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\/12\/20\/22\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022BREAST-Q conceptual framework.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-79006326\u0022 data-figure-caption=\u0022BREAST-Q conceptual framework.\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\/12\/20\/22\/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\/12\/20\/22\/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\/12\/20\/22\/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\/14539\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 attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-15\u0022 class=\u0022first-child\u0022\u003EBREAST-Q conceptual framework.\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EBuzdar Au et al. \u003Cem\u003EJ Clin Onc\u003C\/em\u003E 2005; Gianni L et al. \u003Cem\u003ELancet\u003C\/em\u003E 2010; Untch et al. \u003Cem\u003EJ Clin Onc 2010.\u003C\/em\u003E\n            \u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-16\u0022\u003ENSABP B-41 reported 52.5% (p=0.9) pCR for its trastuzumab arm, 53.2% for its lapatinib arm, and 62.0% for its lapatinib plus trastuzumab arm (p=0.075) [Robidoux A et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2012 (suppl; abstr LBA506)]. The NeoSphere trial reported pCR rates of 45.8% with trastuzumab and pertuzumab plus docetaxel compared with 29.0% with trastuzumab plus docetaxel (p=0.0141); pCR was 24.0% with pertuzumab plus docetaxel and 16.8% with trastuzumab and pertuzumab [Gianni L et al. \u003Cem\u003ELancet Oncol\u003C\/em\u003E 2012]. The results of these studies indicate that multitargeted therapy inhibits the HER pathway more potently when combined with chemotherapy.\u003C\/p\u003E\n         \u003Cp id=\u0022p-17\u0022\u003EDr. Rimawi said that multitargeted approaches to blockade of HER2 signaling have improved outcomes in HER2-positive breast cancer. Some patients may not need chemotherapy, but further biomarker research and studies are needed to determine if they can be identified. An important question is whether targeting ER is important.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2013 MD Conference Express\u00ae\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\/12\/20\/22.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?nzo54q\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?nzo54q\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}