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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\u003Cp id=\u0022p-1\u0022\u003EAromatase inhibitors are important agents used for the adjuvant treatment of early hormone receptor-positive breast cancer in postmenopausal women. Studies in early stage breast cancer are ongoing to determine if the cellular proliferation biomarker Ki67 predicts patient response to therapy. Genetic analysis of biopsy specimens may help identify resistance mechanisms.\u003C\/p\u003E\u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Ehormone receptor-positive\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Epostmenopausal women\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Ebreast cancer\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eclinical research\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Ebiomarker analysis\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group drug\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Eanastrozole\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Etamoxifen\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EArimidex, Tamoxifen Alone or in Combination\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EATAC\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ENCT00894030\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EImmediate Preoperative \u201cArimidex\u201d (anastrozole), Tamoxifen, or Arimidex Combined with Tamoxifen\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EIMPACT\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ETrial of Perioperative Endocrine Therapy \u2013 Individualising Care\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EPOETIC\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ENCT02338310\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\u003Cp id=\u0022p-2\u0022\u003EMitchell Dowsett, PhD, Royal Marsden Hospital, London, United Kingdom, gave a brief history of the development of aromatase inhibitors (AIs) and an overview of ongoing research seeking to further elucidate the role of hormones in breast cancer (BC). Developed in the 1990s, AIs are approved for the adjuvant treatment of early hormone receptor-positive BC in postmenopausal women. A timeline of AI development according to Dr Dowsett\u2019s lab is illustrated in \u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E.\u003C\/p\u003E\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\/16\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Timeline of Aromatase Inhibitor Development4-OHA, 4-hydroxyandrostenedione; AG, aminoglutethimide; AI, aromatase inhibitor; ER, estradiol; PD, pharmacodynamics.Reproduced with permission from M Dowsett, PhD.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1332938980\u0022 data-figure-caption=\u0022Timeline of Aromatase Inhibitor Development4-OHA, 4-hydroxyandrostenedione; AG, aminoglutethimide; AI, aromatase inhibitor; ER, estradiol; PD, pharmacodynamics.Reproduced with permission from M Dowsett, PhD.\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\/16\/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\/16\/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\/16\/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\/11617\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 \u003Cp id=\u0022p-3\u0022 class=\u0022first-child\u0022\u003ETimeline of Aromatase Inhibitor Development\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003E4-OHA, 4-hydroxyandrostenedione; AG, aminoglutethimide; AI, aromatase inhibitor; ER, estradiol; PD, pharmacodynamics.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EReproduced with permission from M Dowsett, PhD.\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-6\u0022\u003EThe availability of pharmacodynamic biomarkers helped to accelerate the development of AIs. Plasma estradiol assays with high sensitivity and specificity were particularly useful in letrozole and anastrozole research. According to Dr Dowsett, biomarker analyses of these agents demonstrated that the extreme suppression of estrogen levels would lead to clinical responses that no true phase 2 trials had been studied. It is estimated that this reduced the development time by 12 to 18 months.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EIn the ATAC trial [Baum M et al. \u003Cem\u003ELancet\u003C\/em\u003E. 2002], anastrozole was compared with tamoxifen and a combination of anastrozole plus tamoxifen as adjuvant therapy in \u0026gt;\u20099000 patients with estrogen receptor (ER)-positive early BC. At 3 years, there was a significant improvement in the anastrozole group compared with the tamoxifen group (HR, 0.83; 95% CI, 0.71 to 0.96; \u003Cem\u003EP\u003C\/em\u003E\u2009=\u2009.013). This benefit was shown to persist at 10-year follow up [Cuzick et al. \u003Cem\u003ELancet Oncol\u003C\/em\u003E. 2010].\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EThe IMPACT trial [Dowsett M et al. \u003Cem\u003EClin Cancer Res.\u003C\/em\u003E 2005] was similar to the ATAC protocol but biopsy specimens were taken before and at 2 and 12 weeks after treatment initiation. The change in the cellular proliferation marker Ki67 was significantly greater with AI treatment vs tamoxifen (\u003Cem\u003EP\u003C\/em\u003E\u2009=\u2009.004 at 2 weeks and \u003Cem\u003EP\u003C\/em\u003E\u2009\u0026lt;\u2009.001 at 12 weeks) and suggested that Ki67 may correlate with patient outcomes. To further investigate whether the pretreatment or 2-week Ki67 levels predict recurrence-free survival, the POETIC trial [Dowsett M et al. \u003Cem\u003EJ Natl Cancer Inst Monogr\u003C\/em\u003E. 2011] has randomized nearly 4500 patients with early stage ER-positive BC. Two-thirds of the patients were randomized to AI therapy before surgery, while the other patients received standard hormone therapy. Biopsies and Ki67 measurements were conducted at diagnosis and 2 weeks later at surgery.\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EOther research has shown that plasma levels of estradiol are correlated with the expression of estrogen-regulated genes in postmenopausal ER-positive BC [Dunbier AK et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2010]. To date, 3300 core biopsy pre- and post treatment samples have been obtained in the POETIC study. Whole genome expression was suppressed in 926 and increased in 401. Dr Dowsett commented that this provided the opportunity to try to identify patient-specific mechanisms of resistance. To see if the menstrual cycle can be utilized as a test of hormone sensitivity in premenopausal women, the MenCER study was designed and has completed recruitment. Seventy paired biopsies from participants have been obtained and analysis is ongoing.\u003C\/p\u003E\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\/16.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"}