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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\u003EThe goal of precision medicine is to tailor medical treatments for patients based on their personal characteristics and responses to a specific treatment. Genome-wide association studies and pharmacogenomics are tools that may help clinicians determine how best to treat patients, such as those with breast cancer, based on genetic factors and phenotype.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Eprecision medicine\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Egenome-wide association study\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Epharmacogenomics\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Ebreast cancer\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Earomatase inhibitors\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Egenomics\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eendocrinology, diabetes \u0026amp; metabolism\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \n         \u003Cp id=\u0022p-2\u0022\u003EJames N. Ingle, MD, Mayo Clinic, Rochester, Minnesota, USA, presented the first of 2 Presidential Plenary sessions focused on the value of precision medicine in the endocrine treatment of breast cancer (BC).\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EDr Ingle began by reviewing the National Research Council\u2019s definition of precision medicine as \u201cthe tailoring of medical treatment to the individual characteristics of each patient\u201d and \u201cthe ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease or . . . in their response to a specific treatment\u201d [National Resource Council. \u003Cem\u003EToward Precision Medicine\u003C\/em\u003E. USA: National Academies Press; 2011: 125]. He then went on to discuss how pharmacogenomics\u2014the study of genetic variation across the entire genome in drug response\u2014influences precision medicine.\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EThe clinical goals of pharmacogenomics are 3-fold: (1) to select patients who are most likely to respond to a drug, (2) to maximize the efficacy of a drug, and (3) to mitigate adverse drug reactions. As well, pharmacogenomics provides researchers with a methodology to understand the mechanisms of a given drug on a specific population.\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EDr Ingle outlined an approach to achieve these goals, utilizing a genome-wide association study (GWAS; \u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E), which scans the complete genomes of many people to find variability related to a specific phenotype or disease. A GWAS typically focuses on the association between single-nucleotide polymorphisms (SNPs)\u2014changes in a single sequence of DNA\u2014and traits that are characteristic of major diseases. For example, GWAS has enabled scientists to map genome-wide differences in estrogen receptor (ER)-\u03b1 binding and to predict which women with ER\u003Cstrong\u003E-\u003C\/strong\u003Epositive BC are likely to have distinct clinical outcomes [Ross-Innes CS et al. \u003Cem\u003ENature\u003C\/em\u003E. 2012].\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\/15\/4\/2\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Flowchart of a GWAS StudyGWAS, genome-wide association study; SNP, single-nucleotide polymorphism.Reproduced with permission from JN Ingle, MD.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1754708303\u0022 data-figure-caption=\u0022Flowchart of a GWAS StudyGWAS, genome-wide association study; SNP, single-nucleotide polymorphism.Reproduced with permission from JN Ingle, MD.\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\/15\/4\/2\/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\/15\/4\/2\/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\/15\/4\/2\/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\/16528\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\u003EFlowchart of a GWAS Study\u003C\/p\u003E\n               \u003Cp id=\u0022p-7\u0022\u003EGWAS, genome-wide association study; SNP, single-nucleotide polymorphism.\u003C\/p\u003E\n               \u003Cp id=\u0022p-8\u0022\u003EReproduced with permission from JN Ingle, MD.\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\u003EDr Ingle described how GWAS studies have informed clinical research regarding the medical treatment of postmenopausal women with ER-positive BC [Liu M et al. \u003Cem\u003EMol Endocrinol\u003C\/em\u003E. 2013]. Using GWAS, researchers were able to observe a statistical association between SNPs in the \u003Cem\u003ETSYPL5\u003C\/em\u003E gene with fluctuating concentrations of estradiol and aromatase, an enzyme responsible for a key step in the synthesis of estrogen. According to Dr Ingle, these results represent a new mechanism for the control of aromatase and estrogens in postmenopausal women and may offer insights as to why some women can tolerate aromatase inhibitors (AIs) and others cannot.\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EDr Ingle then went on to discuss the fact that many women experience arthralgias and myalgias when undergoing BC treatment with AIs and that this is a common reason why women stop their treatment. An earlier GWAS had identified an SNP near the 3\u2032 end of the T-cell leukemia 1A (\u003Cem\u003ETCL1A\u003C\/em\u003E) gene that was associated with musculoskeletal pain in women who were taking AIs to treat their BC [Ingle JN et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E. 2010]. He then reviewed results from a GWAS that genotyped DNA from the cell lines of a total of 300 healthy European-American, African-American, and Han Chinese-American women [Liu M et al. \u003Cem\u003EBreast Cancer Res\u003C\/em\u003E. 2012]. The results suggested that increased expression of the \u003Cem\u003ETCL1A\u003C\/em\u003E gene upregulated expression of interleukin-17 receptor A, which is an indicator of inflammation often seen in patients with rheumatoid arthritis (RA). Results from another GWAS used 300 different lymphoblastoid cell lines cultured in increasing concentrations of estradiol [Ho M et al. \u003Cem\u003EClin Pharm Ther.\u003C\/em\u003E 2014]. These results showed that \u003Cem\u003ETCL1A\u003C\/em\u003E-mediated regulation of chemokine receptor 6 (CCR6)\u2014a cytokine associated with the development of RA\u2014was SNP dependent. According to Dr Ingle, this raises the possibility that postmenopausal women known to have a variant \u003Cem\u003ETCL1A\u003C\/em\u003E SNP might be more likely to develop arthralgias similar to those experienced by people with RA. If this could be pharmacologically manipulated perhaps the arthralgias could be minimized, which might allow patients to continue their treatment with AIs.\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EDr Ingle closed his talk by highlighting genetic research regarding the use of selective estrogen receptor modulators (SERMs) to prevent BC. To date, the two largest SERM BC prevention trials are the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial of tamoxifen [Fisher B et al. \u003Cem\u003EJ Natl Cancer Inst\u003C\/em\u003E. 1998] and the NSABP P-2 trial that compared raloxifene with tamoxifen [Vogel VG et al. \u003Cem\u003ECancer Prev Res (Phila).\u003C\/em\u003E 2010]. Combined, these studies involved \u0026gt;\u200532\u2005000 women and were the basis of the 2 drugs being approved by the US Food and Drug Administration to prevent BC [Ingle JN et al. \u003Cem\u003ECancer Discov.\u003C\/em\u003E 2013]. While these trials confirmed that 5 years of treatment with raloxifene and tamoxifen could reduce the recurrence of BC by one-half, the drugs are not routinely used for this indication. This is due in part to the high number of patients needed to treat to prevent one case of BC and because the SERMs can be associated with worrisome side effects.\u003C\/p\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EDr Ingle and his colleagues performed a GWAS that included 592 cases and 1171 controls from the NBASP P-1 and P-2 trials [Ingle JN et al. \u003Cem\u003ECancer Discov.\u003C\/em\u003E 2013]. A \u003Cem\u003EZNF423\u003C\/em\u003E SNP variant on chromosome 16 was associated with lower breast cancer risk (OR\u2005=\u20050.7), and these variant SNPs were found to be an estrogen-inducible \u003Cem\u003EBRCA1\u003C\/em\u003E transcription factor. A \u003Cem\u003ECTSO\u003C\/em\u003E SNP variant on chromosome 4 was associated with an increased risk of developing BC (OR\u2005=\u20051.42) and was found to disrupt the estrogen receptor element. The combined odds ratios for these 2 sets of SNPs suggest a broad range of relative odds ratios for the development of BC for women on SERM therapy for 5 years. Dr Ingle highlighted the fact that both the \u003Cem\u003ECTSO\u003C\/em\u003E and the \u003Cem\u003EZNF43\u003C\/em\u003E SNPs appear to be estrogen inducible and regulate estradiol-dependent induction of \u003Cem\u003EBRCA1\u003C\/em\u003E. He also emphasized that SERMS can reverse that SNP-dependent expression.\u003C\/p\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EIn summary, Dr Ingle emphasized that a GWAS is the starting point for a process that examines how an SNP works, how it relates to specific genes, and how these genes then influence the effect of the drug on a clinical phenotype. While pharmacogenomics studies have identified new biology and have substantial potential to provide clinical benefit, further work is needed to validate the clinical relevance and value of this approach.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2015 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\/15\/4\/2.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?nzlmo1\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?nzlmo1\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}