{"markup":"\u003C?xml version=\u00221.0\u0022 encoding=\u0022UTF-8\u0022 ?\u003E\n    \u003Chtml version=\u0022HTML+RDFa+MathML 1.1\u0022\n    xmlns:content=\u0022http:\/\/purl.org\/rss\/1.0\/modules\/content\/\u0022\n    xmlns:dc=\u0022http:\/\/purl.org\/dc\/terms\/\u0022\n    xmlns:foaf=\u0022http:\/\/xmlns.com\/foaf\/0.1\/\u0022\n    xmlns:og=\u0022http:\/\/ogp.me\/ns#\u0022\n    xmlns:rdfs=\u0022http:\/\/www.w3.org\/2000\/01\/rdf-schema#\u0022\n    xmlns:sioc=\u0022http:\/\/rdfs.org\/sioc\/ns#\u0022\n    xmlns:sioct=\u0022http:\/\/rdfs.org\/sioc\/types#\u0022\n    xmlns:skos=\u0022http:\/\/www.w3.org\/2004\/02\/skos\/core#\u0022\n    xmlns:xsd=\u0022http:\/\/www.w3.org\/2001\/XMLSchema#\u0022\n    xmlns:mml=\u0022http:\/\/www.w3.org\/1998\/Math\/MathML\u0022\u003E\n  \u003Chead\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/js\/js_itu2PgFdrjV-docKmLK8Jn5oXe_05RgvQh73eOhI_mE.js\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_at_symbol.js?nzo8de\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_article_reference_popup.js?nzo8de\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/js\/js_I8yX6RYPZb7AtMcDUA3QKDZqVkvEn35ED11_1i7vVpc.js\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022\u003E\n\u003C!--\/\/--\u003E\u003C![CDATA[\/\/\u003E\u003C!--\n(function(i,s,o,g,r,a,m){i[\u0022GoogleAnalyticsObject\u0022]=r;i[r]=i[r]||function(){(i[r].q=i[r].q||[]).push(arguments)},i[r].l=1*new Date();a=s.createElement(o),m=s.getElementsByTagName(o)[0];a.async=1;a.src=g;m.parentNode.insertBefore(a,m)})(window,document,\u0022script\u0022,\u0022\/\/www.google-analytics.com\/analytics.js\u0022,\u0022ga\u0022);ga(\u0022create\u0022, \u0022UA-15605596-27\u0022, {\u0022cookieDomain\u0022:\u0022auto\u0022});ga(\u0022set\u0022, \u0022page\u0022, location.pathname + location.search + location.hash);ga(\u0022send\u0022, \u0022pageview\u0022);ga(\u0027create\u0027, \u0027UA-189672-26\u0027, \u0027auto\u0027, {\u0027name\u0027: \u0027hwTracker\u0027});\r\nga(\u0027hwTracker.send\u0027, \u0027pageview\u0027);\n\/\/--\u003E\u003C!]]\u003E\n\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022\u003E\n\u003C!--\/\/--\u003E\u003C![CDATA[\/\/\u003E\u003C!--\njQuery.extend(Drupal.settings, {\u0022basePath\u0022:\u0022\\\/\u0022,\u0022pathPrefix\u0022:\u0022\u0022,\u0022highwire\u0022:{\u0022markup\u0022:[{\u0022requested\u0022:\u0022full-text\u0022,\u0022variant\u0022:\u0022full-text\u0022,\u0022view\u0022:\u0022full\u0022,\u0022pisa\u0022:\u0022spmdc;14\\\/56\\\/19\u0022},{\u0022requested\u0022:\u0022long\u0022,\u0022variant\u0022:\u0022full-text\u0022,\u0022view\u0022:\u0022full\u0022,\u0022pisa\u0022:\u0022spmdc;14\\\/56\\\/19\u0022}],\u0022ac\u0022:{\u0022spmdc;14\\\/56\\\/19\u0022:{\u0022access\u0022:{\u0022reprint\u0022:true,\u0022full\u0022:true},\u0022pisa_id\u0022:\u0022spmdc;14\\\/56\\\/19\u0022,\u0022atom_uri\u0022:\u0022\u0022,\u0022jcode\u0022:\u0022spmdc\u0022}}},\u0022googleanalytics\u0022:{\u0022trackOutbound\u0022:1,\u0022trackMailto\u0022:1,\u0022trackDownload\u0022:1,\u0022trackDownloadExtensions\u0022:\u00227z|aac|arc|arj|asf|asx|avi|bin|csv|doc(x|m)?|dot(x|m)?|exe|flv|gif|gz|gzip|hqx|jar|jpe?g|js|mp(2|3|4|e?g)|mov(ie)?|msi|msp|pdf|phps|png|ppt(x|m)?|pot(x|m)?|pps(x|m)?|ppam|sld(x|m)?|thmx|qtm?|ra(m|r)?|sea|sit|tar|tgz|torrent|txt|wav|wma|wmv|wpd|xls(x|m|b)?|xlt(x|m)|xlam|xml|z|zip\u0022,\u0022trackUrlFragments\u0022:1},\u0022ajaxPageState\u0022:{\u0022js\u0022:{\u0022sites\\\/all\\\/libraries\\\/cluetip\\\/jquery.cluetip.js\u0022:1,\u0022sites\\\/all\\\/libraries\\\/cluetip\\\/lib\\\/jquery.hoverIntent.js\u0022:1,\u0022sites\\\/all\\\/libraries\\\/cluetip\\\/lib\\\/jquery.bgiframe.min.js\u0022:1,\u0022sites\\\/all\\\/modules\\\/highwire\\\/highwire\\\/plugins\\\/highwire_markup_process\\\/js\\\/highwire_at_symbol.js\u0022:1,\u0022sites\\\/all\\\/modules\\\/highwire\\\/highwire\\\/plugins\\\/highwire_markup_process\\\/js\\\/highwire_article_reference_popup.js\u0022:1,\u0022sites\\\/all\\\/modules\\\/contrib\\\/google_analytics\\\/googleanalytics.js\u0022:1,\u00220\u0022:1}}});\n\/\/--\u003E\u003C!]]\u003E\n\u003C\/script\u003E\n\u003Clink 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 highlights some key aspects about neoadjuvant treatment of endocrine receptor-positive breast cancer, including its use in postmenopausal women, the use of biomarkers for clinical management, and clinical trials investigating the use of novel targeted agents in this setting.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Eefficacy\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Ebiomarkers\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Enovel targeted agent\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Epostmenopausal women\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eendocrine therapy\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group drug\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Eletrozole\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Etamoxifen\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eanastrozole\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eeverolimus\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eexemestane\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Ebuparlisib\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 neoadjuvant treatment of patients with estrogen receptor (ER)-positive breast cancer (BC), 3 presenters reviewed its efficacy, predictive biomarkers, and clinical trials evaluating novel targeted agents.\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EDavid A. Cameron, MD, University of Edinburgh, Edinburgh, United Kingdom, provided clinical insights on the neoadjuvant therapy of ER-positive BC in postmenopausal women. Although neoadjuvant therapy has historically been chemotherapy based, Prof Cameron advocates a similar approach to that of the adjuvant setting, which focuses on avoiding chemotherapy based on cancer biology. Not all women with BC need chemotherapy, since endocrine therapy can induce effective responses.\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EIn the P024 study, for example, letrozole therapy was more effective than tamoxifen in terms of clinical, mammography, ultrasonography, and breast conservation responses [Ellis MJ, Ma C. \u003Cem\u003EBreast Cancer Res Treat.\u003C\/em\u003E 2007]. In the IMPACT study, which compared the efficacy of anastrozole, tamoxifen, and a combination of both, anastrozole produced the highest improvement rate for conversion to breast-conserving surgery [Smith IE et al. \u003Cem\u003EJ Clin Oncol.\u003C\/em\u003E 2005] and the highest antiproliferative effect [Dowsett M et al. \u003Cem\u003EJ Clin Oncol.\u003C\/em\u003E 2005].\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EProf Cameron also emphasized the need for patience when treating ER-positive BCs because they respond more slowly to chemotherapy and endocrine therapy. A recent study showed that overall response rate (ORR; 95% vs 45%) and pathologic complete response (pCR) rate (17.5% vs 2.5%) increased in patients who received 1 year of neoadjuvant therapy, compared with 4 months [Allevi G et al. \u003Cem\u003EBr J Cancer.\u003C\/em\u003E 2013]. In the TEAM IIa trial [Fontein DBY et al. \u003Cem\u003EEur J Cancer.\u003C\/em\u003E 2014], proliferation continued to decrease between 3 and 6 months of therapy, and the breast conservation rate also increased (62% vs 71%).\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EAlthough the optimal duration of neoadjuvant therapy is unknown, Prof Cameron added that the traditional 3 or 4 months\u2019 duration is suboptimal, and 5 to 10 years, as in the adjuvant setting, may be more realistic.\u003C\/p\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EWhile pCR rates are lower with endocrine therapy and chemotherapy in ER-positive BCs, particularly those that are human epidermal growth factor receptor 2 (HER2)-negative [Cortazar P et al. \u003Cem\u003ELancet\u003C\/em\u003E. 2014], he stressed that pCR is not the goal of neoadjuvant therapy\u2014it is the clinical effects and long-term patient benefits that matter.\u003C\/p\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EWith respect to choice of neoadjuvant therapy, Prof Cameron emphasized that the data on aromatase inhibitors clearly highlight why they have become the de facto treatment. However, he believes it is reasonable to choose the same agents as would be used in the adjuvant setting.\u003C\/p\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EMitchell Dowsett, PhD, FMedSci, Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom, discussed biomarkers in the endocrine and chemotherapy settings.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EEndocrine Therapy\u003C\/h2\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EEndocrine therapy predominantly suppresses tumor cell proliferation without an increase in apoptosis, and this correlates with the slow response to this form of therapy, said Prof Dowsett. Data from the IMPACT study [Dowsett M et al. \u003Cem\u003EClin Cancer Res.\u003C\/em\u003E 2005] showed the power of Ki67 to predict treatment benefit; anastrozole produced more significant reductions in Ki67 expression, compared with tamoxifen, after 2 and 12 weeks (\u003Cem\u003EP\u003C\/em\u003E\u2009=\u2009.004 and \u003Cem\u003EP\u003C\/em\u003E\u2009\u0026lt;\u2009.001), with near-maximal responses at 2 weeks.\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EThe degree of downregulation of proliferation also predicts treatment benefit. After 12 weeks of endocrine therapy, Ki67 levels increased in some patients after an initial decrease, suggestive of acquired treatment resistance [Dowsett M et al. \u003Cem\u003EJ Natl Cancer Inst\u003C\/em\u003E. 2011]. Levels initially decreased minimally in others, suggestive of de novo resistance. In the long term, these patients with acquired or de novo resistance experienced equally poor outcomes, compared with those who experienced and maintained more significant Ki67 reductions.\u003C\/p\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EAt the time of surgery, the proliferation rate of the residual cancer cells also predicts recurrence risk, he added.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-3\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EChemotherapy\u003C\/h2\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EConversely, chemotherapy leads to decreased cellular proliferation, which may be driven by increased apoptosis. Increases in apoptosis have been shown to occur quickly\u2014within 24 hours of primary chemotherapy [Archer CD et al. \u003Cem\u003EBr J Cancer\u003C\/em\u003E. 2003]. Patients treated with chemotherapy typically experience rapid regressions, and the degree of cell death may predict the response to treatment, said Prof Dowsett.\u003C\/p\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EThe proliferation rate of residual cancer cells at surgery also predicts the risk of recurrence, with poorer outcomes associated with a higher residual cancer burden (RCB) [Symmans WF et al. \u003Cem\u003EJ Clin Oncol.\u003C\/em\u003E 2007], and high post-chemotherapy Ki67 levels [von Minckwitz G et al. \u003Cem\u003EClin Cancer Res\u003C\/em\u003E. 2013; Jones RL et al. \u003Cem\u003EBreast Cancer Res Treat.\u003C\/em\u003E 2009].\u003C\/p\u003E\n         \u003Cp id=\u0022p-15\u0022\u003ECombining Ki67 with RCB to create the residual proliferative cancer burden can also enhance the prediction of long-term recurrence risk [Sheri A et al. \u003Cem\u003EAnn Oncol\u003C\/em\u003E. 2014].\u003C\/p\u003E\n         \u003Cp id=\u0022p-16\u0022\u003EAccording to Ingrid A. Mayer, MD, MSCI, Vanderbilt University, Nashville, Tennessee, USA, neoadjuvant endocrine therapy trials comprise a valid alternative for patients with ER-positive BC and provide insights into the biological basis for therapeutic responses to ER-targeting agents.\u003C\/p\u003E\n         \u003Cp id=\u0022p-17\u0022\u003EShe shared preclinical data on the role of different signaling pathways, such as P13K and ErbB pathways, in mediating resistance to endocrine therapy, which supported the combination of endocrine therapy with specific pathway inhibitors in an attempt to maximize efficacy and minimize therapeutic resistance.\u003C\/p\u003E\n         \u003Cp id=\u0022p-18\u0022\u003ESeveral examples of clinical trials in the metastatic setting were shown as a proof of concept of the clinical benefit provided by the addition of P13K\/mTOR pathway inhibitors, such as BOLERO-2 [Yardley et al. \u003Cem\u003EAd Ther\u003C\/em\u003E. 2013], which evaluated the efficacy of combined everolimus and exemestane, and a recent phase 1b study [Mayer IA et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E. 2014] that investigated the combination of letrozole and the pan-phosphoinositide-3-kinase (PIK3) inhibitor buparlisib in patients with ER-positive, HER2-negative BC refractory to previous endocrine therapies.\u003C\/p\u003E\n         \u003Cp id=\u0022p-19\u0022\u003ECurrently, phase II neoadjuvant trials exploring the addition of inhibitors of the P13K\/AKT\/mTOR pathway to endocrine therapy are underway. A phase 2 randomized trial [\u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT01923168\u0026amp;atom=%2Fspmdc%2F14%2F56%2F19.atom\u0022\u003ENCT01923168\u003C\/a\u003E] is also currently ongoing to investigate the efficacy of letrozole with or without 1 of 2 PI3K inhibitors, BYL719 and buparlisib, in patients with mutated and wild-type \u003Cem\u003EPIK3CA\u003C\/em\u003E gene, said Dr Mayer.\u003C\/p\u003E\n         \u003Cp id=\u0022p-20\u0022\u003EAs an example of genomically driven clinical trial design platform, patients with ER-positive, HER2-negative, stage 2 or 3 BC undergo a biopsy for sequencing purposes, and the ones with a \u003Cem\u003EPIK3CA\u003C\/em\u003E mutation will enter a trial involving the Akt inhibitor MK-2206 plus anastrozole [\u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT01776008\u0026amp;atom=%2Fspmdc%2F14%2F56%2F19.atom\u0022\u003ENCT01776008\u003C\/a\u003E], while those without will enter a trial involving the Cdk4\/6 inhibitor PD0332991plus anastrozole [\u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT01723774\u0026amp;atom=%2Fspmdc%2F14%2F56%2F19.atom\u0022\u003ENCT01723774\u003C\/a\u003E].\u003C\/p\u003E\n         \u003Cp id=\u0022p-21\u0022\u003EDr Mayer emphasized that neoadjuvant endocrine therapy trials also serve as discovery platforms that enhance understanding of the molecular mechanisms of resistance to estrogen deprivation. This may facilitate development of effective mechanism-based treatments for endocrine therapy-resistant disease.\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\/19.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_openurl.js?nzo8de\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}