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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">ESR1 and ESR2 polymorphisms in the BIG 1-98 trial comparing adjuvant letrozole versus tamoxifen or their sequence for early breast cancer</title>
<author><name sortKey="Leyland Jones, Brian" sort="Leyland Jones, Brian" uniqKey="Leyland Jones B" first="Brian" last="Leyland-Jones">Brian Leyland-Jones</name>
</author>
<author><name sortKey="Gray, Kathryn P" sort="Gray, Kathryn P" uniqKey="Gray K" first="Kathryn P." last="Gray">Kathryn P. Gray</name>
</author>
<author><name sortKey="Abramovitz, Mark" sort="Abramovitz, Mark" uniqKey="Abramovitz M" first="Mark" last="Abramovitz">Mark Abramovitz</name>
</author>
<author><name sortKey="Bouzyk, Mark" sort="Bouzyk, Mark" uniqKey="Bouzyk M" first="Mark" last="Bouzyk">Mark Bouzyk</name>
</author>
<author><name sortKey="Young, Brandon" sort="Young, Brandon" uniqKey="Young B" first="Brandon" last="Young">Brandon Young</name>
</author>
<author><name sortKey="Long, Bradley" sort="Long, Bradley" uniqKey="Long B" first="Bradley" last="Long">Bradley Long</name>
</author>
<author><name sortKey="Kammler, Roswitha" sort="Kammler, Roswitha" uniqKey="Kammler R" first="Roswitha" last="Kammler">Roswitha Kammler</name>
</author>
<author><name sortKey="Dell Rto, Patrizia" sort="Dell Rto, Patrizia" uniqKey="Dell Rto P" first="Patrizia" last="Dell Rto">Patrizia Dell Rto</name>
</author>
<author><name sortKey="Biasi, Maria Olivia" sort="Biasi, Maria Olivia" uniqKey="Biasi M" first="Maria Olivia" last="Biasi">Maria Olivia Biasi</name>
</author>
<author><name sortKey="Thurlimann, Beat" sort="Thurlimann, Beat" uniqKey="Thurlimann B" first="Beat" last="Thürlimann">Beat Thürlimann</name>
</author>
<author><name sortKey="Harvey, Vernon" sort="Harvey, Vernon" uniqKey="Harvey V" first="Vernon" last="Harvey">Vernon Harvey</name>
</author>
<author><name sortKey="Neven, Patrick" sort="Neven, Patrick" uniqKey="Neven P" first="Patrick" last="Neven">Patrick Neven</name>
</author>
<author><name sortKey="Arnould, Laurent" sort="Arnould, Laurent" uniqKey="Arnould L" first="Laurent" last="Arnould">Laurent Arnould</name>
</author>
<author><name sortKey="Maibach, Rudolf" sort="Maibach, Rudolf" uniqKey="Maibach R" first="Rudolf" last="Maibach">Rudolf Maibach</name>
</author>
<author><name sortKey="Price, Karen N" sort="Price, Karen N" uniqKey="Price K" first="Karen N." last="Price">Karen N. Price</name>
</author>
<author><name sortKey="Coates, Alan S" sort="Coates, Alan S" uniqKey="Coates A" first="Alan S." last="Coates">Alan S. Coates</name>
</author>
<author><name sortKey="Goldhirsch, Aron" sort="Goldhirsch, Aron" uniqKey="Goldhirsch A" first="Aron" last="Goldhirsch">Aron Goldhirsch</name>
</author>
<author><name sortKey="Gelber, Richard D" sort="Gelber, Richard D" uniqKey="Gelber R" first="Richard D." last="Gelber">Richard D. Gelber</name>
</author>
<author><name sortKey="Pagani, Olivia" sort="Pagani, Olivia" uniqKey="Pagani O" first="Olivia" last="Pagani">Olivia Pagani</name>
</author>
<author><name sortKey="Viale, Giuseppe" sort="Viale, Giuseppe" uniqKey="Viale G" first="Giuseppe" last="Viale">Giuseppe Viale</name>
</author>
<author><name sortKey="Rae, James M" sort="Rae, James M" uniqKey="Rae J" first="James M." last="Rae">James M. Rae</name>
</author>
<author><name sortKey="Regan, Meredith M" sort="Regan, Meredith M" uniqKey="Regan M" first="Meredith M." last="Regan">Meredith M. Regan</name>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">26590813</idno>
<idno type="pmc">4730949</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4730949</idno>
<idno type="RBID">PMC:4730949</idno>
<idno type="doi">10.1007/s10549-015-3634-6</idno>
<date when="2015">2015</date>
<idno type="wicri:Area/Pmc/Corpus">002012</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002012</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">ESR1 and ESR2 polymorphisms in the BIG 1-98 trial comparing adjuvant letrozole versus tamoxifen or their sequence for early breast cancer</title>
<author><name sortKey="Leyland Jones, Brian" sort="Leyland Jones, Brian" uniqKey="Leyland Jones B" first="Brian" last="Leyland-Jones">Brian Leyland-Jones</name>
</author>
<author><name sortKey="Gray, Kathryn P" sort="Gray, Kathryn P" uniqKey="Gray K" first="Kathryn P." last="Gray">Kathryn P. Gray</name>
</author>
<author><name sortKey="Abramovitz, Mark" sort="Abramovitz, Mark" uniqKey="Abramovitz M" first="Mark" last="Abramovitz">Mark Abramovitz</name>
</author>
<author><name sortKey="Bouzyk, Mark" sort="Bouzyk, Mark" uniqKey="Bouzyk M" first="Mark" last="Bouzyk">Mark Bouzyk</name>
</author>
<author><name sortKey="Young, Brandon" sort="Young, Brandon" uniqKey="Young B" first="Brandon" last="Young">Brandon Young</name>
</author>
<author><name sortKey="Long, Bradley" sort="Long, Bradley" uniqKey="Long B" first="Bradley" last="Long">Bradley Long</name>
</author>
<author><name sortKey="Kammler, Roswitha" sort="Kammler, Roswitha" uniqKey="Kammler R" first="Roswitha" last="Kammler">Roswitha Kammler</name>
</author>
<author><name sortKey="Dell Rto, Patrizia" sort="Dell Rto, Patrizia" uniqKey="Dell Rto P" first="Patrizia" last="Dell Rto">Patrizia Dell Rto</name>
</author>
<author><name sortKey="Biasi, Maria Olivia" sort="Biasi, Maria Olivia" uniqKey="Biasi M" first="Maria Olivia" last="Biasi">Maria Olivia Biasi</name>
</author>
<author><name sortKey="Thurlimann, Beat" sort="Thurlimann, Beat" uniqKey="Thurlimann B" first="Beat" last="Thürlimann">Beat Thürlimann</name>
</author>
<author><name sortKey="Harvey, Vernon" sort="Harvey, Vernon" uniqKey="Harvey V" first="Vernon" last="Harvey">Vernon Harvey</name>
</author>
<author><name sortKey="Neven, Patrick" sort="Neven, Patrick" uniqKey="Neven P" first="Patrick" last="Neven">Patrick Neven</name>
</author>
<author><name sortKey="Arnould, Laurent" sort="Arnould, Laurent" uniqKey="Arnould L" first="Laurent" last="Arnould">Laurent Arnould</name>
</author>
<author><name sortKey="Maibach, Rudolf" sort="Maibach, Rudolf" uniqKey="Maibach R" first="Rudolf" last="Maibach">Rudolf Maibach</name>
</author>
<author><name sortKey="Price, Karen N" sort="Price, Karen N" uniqKey="Price K" first="Karen N." last="Price">Karen N. Price</name>
</author>
<author><name sortKey="Coates, Alan S" sort="Coates, Alan S" uniqKey="Coates A" first="Alan S." last="Coates">Alan S. Coates</name>
</author>
<author><name sortKey="Goldhirsch, Aron" sort="Goldhirsch, Aron" uniqKey="Goldhirsch A" first="Aron" last="Goldhirsch">Aron Goldhirsch</name>
</author>
<author><name sortKey="Gelber, Richard D" sort="Gelber, Richard D" uniqKey="Gelber R" first="Richard D." last="Gelber">Richard D. Gelber</name>
</author>
<author><name sortKey="Pagani, Olivia" sort="Pagani, Olivia" uniqKey="Pagani O" first="Olivia" last="Pagani">Olivia Pagani</name>
</author>
<author><name sortKey="Viale, Giuseppe" sort="Viale, Giuseppe" uniqKey="Viale G" first="Giuseppe" last="Viale">Giuseppe Viale</name>
</author>
<author><name sortKey="Rae, James M" sort="Rae, James M" uniqKey="Rae J" first="James M." last="Rae">James M. Rae</name>
</author>
<author><name sortKey="Regan, Meredith M" sort="Regan, Meredith M" uniqKey="Regan M" first="Meredith M." last="Regan">Meredith M. Regan</name>
</author>
</analytic>
<series><title level="j">Breast cancer research and treatment</title>
<idno type="ISSN">0167-6806</idno>
<idno type="eISSN">1573-7217</idno>
<imprint><date when="2015">2015</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><sec id="S1"><title>Purpose</title>
<p id="P1">Estrogen receptor 1 (<italic>ESR1</italic>
) and <italic>ESR2</italic>
gene polymorphisms have been associated with endocrine-mediated physiological mechanisms, and inconsistently with breast cancer risk and outcomes, bone mineral density changes and hot flushes/night sweats (HF/NS).</p>
</sec>
<sec id="S2"><title>Methods</title>
<p id="P2">DNA was isolated and genotyped for six <italic>ESR1</italic>
and two <italic>ESR2</italic>
single nucleotide polymorphisms (SNPs) from tumor specimens from 3691 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG 1-98 trial to receive tamoxifen and/or letrozole for five years. Associations with recurrence and adverse events (AE) were assessed using Cox proportional hazards models.</p>
</sec>
<sec id="S3"><title>Results</title>
<p id="P3">3401 samples were successfully genotyped for five SNPs. <italic>ESR1</italic>
rs9340799(XbaI)(T>C) variants CC or TC were associated with reduced breast cancer risk (HR=0.82,95%CI=0.67–1.0), <italic>ESR1</italic>
rs2077647(T>C) variants CC or TC was associated with reduced distant recurrence risk (HR=0.69,95%CI=0.53–0.90), both regardless of the treatments. No differential treatment effects (letrozole vs. tamoxifen) were observed for the association of outcome with any of the SNPs. Letrozole-treated patients with rs2077647(T>C) variants CC,TC had a reduced risk of bone AE (HR=0.75,95%CI=0.58–0.98, P<sub>interaction</sub>
=0.08), whereas patients with rs4986938(G>A) genotype variants AA and AG had an increased risk of bone AE (HR=1.37,95%CI=1.01–1.84, P<sub>interaction</sub>
=0.07).</p>
</sec>
<sec id="S4"><title>Conclusions</title>
<p id="P4">We paradoxically observed 1) rare <italic>ESR1</italic>
homozygous polymorphisms were associated with lower recurrence, and 2) <italic>ESR1</italic>
and <italic>ESR2</italic>
SNPs were associated with bone AEs in letrozole-treated patients. Genes that are involved in estrogen signaling and synthesis have the potential to affect both breast cancer recurrence and side effects, suggesting that individual treatment strategies can incorporate not only oncogenic drivers but also SNPs related to estrogen activity.</p>
</sec>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">8111104</journal-id>
<journal-id journal-id-type="pubmed-jr-id">1254</journal-id>
<journal-id journal-id-type="nlm-ta">Breast Cancer Res Treat</journal-id>
<journal-id journal-id-type="iso-abbrev">Breast Cancer Res. Treat.</journal-id>
<journal-title-group><journal-title>Breast cancer research and treatment</journal-title>
</journal-title-group>
<issn pub-type="ppub">0167-6806</issn>
<issn pub-type="epub">1573-7217</issn>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">26590813</article-id>
<article-id pub-id-type="pmc">4730949</article-id>
<article-id pub-id-type="doi">10.1007/s10549-015-3634-6</article-id>
<article-id pub-id-type="manuscript">NIHMS740336</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>ESR1 and ESR2 polymorphisms in the BIG 1-98 trial comparing adjuvant letrozole versus tamoxifen or their sequence for early breast cancer</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Leyland-Jones</surname>
<given-names>Brian</given-names>
</name>
<degrees>MB BS PhD.</degrees>
<aff id="A1">Avera Cancer Institute, Sioux Falls, SD</aff>
<email>bleylandj@aol.com</email>
</contrib>
<contrib contrib-type="author"><name><surname>Gray</surname>
<given-names>Kathryn P.</given-names>
</name>
<degrees>PhD.</degrees>
<aff id="A2">International Breast Cancer Study Group Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard T. H. Chen School of Public Health, 450 Brookline Ave, Boston, MA 02215</aff>
<email>pkruan@jimmy.harvard.edu</email>
</contrib>
<contrib contrib-type="author"><name><surname>Abramovitz</surname>
<given-names>Mark</given-names>
</name>
<degrees>PhD.</degrees>
<aff id="A3">VM Institute of Research, 6100 Av Royalmount, Montréal H4P 2R2, QC</aff>
<email>mark.abramovitz@gmail.com</email>
</contrib>
<contrib contrib-type="author"><name><surname>Bouzyk</surname>
<given-names>Mark</given-names>
</name>
<degrees>PhD.</degrees>
<aff id="A4">AKESOgen, Inc., 3155 Northwoods Pl NW, Norcross, GA 30071</aff>
<email>mbouzyk@akesogen.com</email>
</contrib>
<contrib contrib-type="author"><name><surname>Young</surname>
<given-names>Brandon</given-names>
</name>
<degrees>BS.</degrees>
<aff id="A5">Avera Cancer Institute, Sioux Falls, SD 11099 North Torrey Pines, Suite 160, La Jolla, CA 92037 USA</aff>
<email>Brandon.Young@avera.org</email>
</contrib>
<contrib contrib-type="author"><name><surname>Long</surname>
<given-names>Bradley</given-names>
</name>
<degrees>MS.</degrees>
<aff id="A6">Genomic and Molecular Pathology, University of Chicago, 900 E 57th St. Room 1260D, Chicago, IL 60637</aff>
<email>Bradley.Long@uchospitals.edu</email>
</contrib>
<contrib contrib-type="author"><name><surname>Kammler</surname>
<given-names>Roswitha</given-names>
</name>
<degrees>BA.</degrees>
<aff id="A7">International Breast Cancer Study Group Coordinating Center and Central Pathology Office, Effingerstrasse 40 3008 Bern, Switzerland</aff>
<email>Rosita.Kammler@ibcsg.org</email>
</contrib>
<contrib contrib-type="author"><name><surname>Dell’Orto</surname>
<given-names>Patrizia</given-names>
</name>
<degrees>DSc.</degrees>
<aff id="A8">International Breast Cancer Study Group Central Pathology Office, Division of Pathology and Laboratory Medicine, European Institute of Oncology, Via Ripamonti 435, 20146 Milan, Italy</aff>
<email>patrizia.dellorto@ieo.it</email>
</contrib>
<contrib contrib-type="author"><name><surname>Biasi</surname>
<given-names>Maria Olivia</given-names>
</name>
<degrees>ScD.</degrees>
<aff id="A9">Division of Pathology and Laboratory Medicine, European Institute of Oncology, Via Ripamonti 435, 20146 Milan, Italy</aff>
<email>olivia.biasi@ieo.it</email>
</contrib>
<contrib contrib-type="author"><name><surname>Thürlimann</surname>
<given-names>Beat</given-names>
</name>
<degrees>MD.</degrees>
<aff id="A10">Breast Center, Kantonsspital St. Gallen, Rorschacher Strasse 95 CH- 9007 St. Gallen, Switzerland, Swiss Group for Clinical Cancer Research (SAKK) and International Breast Cancer Study Group Bern, Switzerland</aff>
<email>beat.thuerlimann@kssg.ch</email>
</contrib>
<contrib contrib-type="author"><name><surname>Harvey</surname>
<given-names>Vernon</given-names>
</name>
<degrees>MD.</degrees>
<aff id="A11">Auckland City Hospital, PO Box 26498, Epsom, Auckland 1344, New Zealand and Australia and New Zealand Clinical Trials Group, Newcastle, Australia and International Breast Cancer Study Group, Bern, Switzerland</aff>
<email>vernonh@adhb.govt.nz</email>
</contrib>
<contrib contrib-type="author"><name><surname>Neven</surname>
<given-names>Patrick</given-names>
</name>
<degrees>MD.</degrees>
<aff id="A12">KULeuven (University of Leuven), Department of Oncology, Multidisciplinary Breast Center, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium</aff>
<email>patrick.neven@uzleuven.be</email>
</contrib>
<contrib contrib-type="author"><name><surname>Arnould</surname>
<given-names>Laurent</given-names>
</name>
<degrees>MD.</degrees>
<aff id="A13">Institute Georges François Leclerc, 1 rue Professeur Marion BP 77 980 21079 Dijon cedex - France</aff>
<email>larnould@dijon.fnclcc.fr</email>
</contrib>
<contrib contrib-type="author"><name><surname>Maibach</surname>
<given-names>Rudolf</given-names>
</name>
<degrees>PhD.</degrees>
<aff id="A14">International Breast Cancer Study Group Coordinating Center, Effingerstrasse 40 3008 Bern, Switzerland</aff>
<email>rudolf.maibach@ibcsg.org</email>
</contrib>
<contrib contrib-type="author"><name><surname>Price</surname>
<given-names>Karen N.</given-names>
</name>
<degrees>BS.</degrees>
<aff id="A15">International Breast Cancer Study Group Statistical Center, Frontier Science and Technology Research Foundation, 450 Brookline Ave, Boston, MA 02215, USA</aff>
<email>price@jimmy.harvard.edu</email>
</contrib>
<contrib contrib-type="author"><name><surname>Coates</surname>
<given-names>Alan S.</given-names>
</name>
<degrees>MD.</degrees>
<aff id="A16">International Breast Cancer Study Group, Bern, Switzerland and University of Sydney, Sydney, Australia</aff>
<email>alan.coates@ibcsg.org</email>
</contrib>
<contrib contrib-type="author"><name><surname>Goldhirsch</surname>
<given-names>Aron</given-names>
</name>
<degrees>MD, PhD.</degrees>
<aff id="A17">Program for Breast Health (Senology), European Institute of Oncology, Via Ripamonti 435, 20146 Milan, Italy, International Breast Cancer Study Group, Bern, Switzerland</aff>
<email>aron.goldhirsch@ibcsg.org</email>
</contrib>
<contrib contrib-type="author"><name><surname>Gelber</surname>
<given-names>Richard D.</given-names>
</name>
<degrees>PhD.</degrees>
<aff id="A18">International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, Harvard T.H. Chan School of Public Health, Frontier Science and Technology Research Foundation, 450 Brookline Ave, Boston, MA 02215 USA</aff>
<email>gelber@jimmy.harvard.edu</email>
</contrib>
<contrib contrib-type="author"><name><surname>Pagani</surname>
<given-names>Olivia</given-names>
</name>
<degrees>MD.</degrees>
<aff id="A19">Institute of Oncology of Southern Switzerland (IOSI), Ospedale Italiano, Via Capelli, 6962 Viganello, Switzerland. Swiss Group for Clinical Cancer Research (SAKK) and International Breast Cancer Study Group, Bern, Switzerland</aff>
<email>olivia.pagani@ibcsg.org</email>
</contrib>
<contrib contrib-type="author"><name><surname>Viale</surname>
<given-names>Giuseppe</given-names>
</name>
<degrees>MD.</degrees>
<aff id="A20">International Breast Cancer Study Group Central Pathology Office, Division of Pathology and Laboratory Medicine, European Institute of Oncology, University of Milan, Via Ripamonti 435, 20146 Milan, Italy</aff>
<email>giuseppe.viale@ieo.it</email>
</contrib>
<contrib contrib-type="author"><name><surname>Rae</surname>
<given-names>James M.</given-names>
</name>
<degrees>PhD.</degrees>
<aff id="A21">Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, 1500 E Medical Cntr Drive/SPC 5946, Ann Arbor, MI 48109</aff>
<email>jimmyrae@med.umich.edu</email>
</contrib>
<contrib contrib-type="author"><name><surname>Regan</surname>
<given-names>Meredith M.</given-names>
</name>
<degrees>ScD.</degrees>
<aff id="A22">International Breast Cancer Study Group Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Harvard Medical School, 450 Brookline Ave, Boston, MA 02215, USA</aff>
<email>mregan@jimmy.harvard.edu</email>
</contrib>
<on-behalf-of>on behalf of the BIG 1-98 Collaborative Group</on-behalf-of>
</contrib-group>
<author-notes><corresp id="FN1">Co-Corresponding Authors: Brian Leyland-Jones, M.B. B.S., Ph.D. Vice President of Molecular and Experimental Medicine; Avera Cancer Institute; 1000 E 23<sup>rd</sup>
Street, Sioux Falls, SD 57105 Telephone: (605) 322-6900, Fax: (605) 322-6901, <email>bleylandj@aol.com</email>
. Karen N Price, International Breast Cancer Study Group Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston MA, 02215. Tel: 617-632-2459; Fax: 617-632-2444. <email>price@jimmy.harvard.edu</email>
</corresp>
<fn id="FN2"><p>Members of the BIG 1-98 Collaborative Group who submitted tumor blocks are listed in <xref rid="SD1" ref-type="supplementary-material">Supplementary Appendix</xref>
, available with the full text of this article at [journal website].</p>
</fn>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>26</day>
<month>12</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="epub"><day>21</day>
<month>11</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="ppub"><month>12</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>01</day>
<month>12</month>
<year>2016</year>
</pub-date>
<volume>154</volume>
<issue>3</issue>
<fpage>543</fpage>
<lpage>555</lpage>
<pmc-comment>elocation-id from pubmed: 10.1007/s10549-015-3634-6</pmc-comment>
<abstract><sec id="S1"><title>Purpose</title>
<p id="P1">Estrogen receptor 1 (<italic>ESR1</italic>
) and <italic>ESR2</italic>
gene polymorphisms have been associated with endocrine-mediated physiological mechanisms, and inconsistently with breast cancer risk and outcomes, bone mineral density changes and hot flushes/night sweats (HF/NS).</p>
</sec>
<sec id="S2"><title>Methods</title>
<p id="P2">DNA was isolated and genotyped for six <italic>ESR1</italic>
and two <italic>ESR2</italic>
single nucleotide polymorphisms (SNPs) from tumor specimens from 3691 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG 1-98 trial to receive tamoxifen and/or letrozole for five years. Associations with recurrence and adverse events (AE) were assessed using Cox proportional hazards models.</p>
</sec>
<sec id="S3"><title>Results</title>
<p id="P3">3401 samples were successfully genotyped for five SNPs. <italic>ESR1</italic>
rs9340799(XbaI)(T>C) variants CC or TC were associated with reduced breast cancer risk (HR=0.82,95%CI=0.67–1.0), <italic>ESR1</italic>
rs2077647(T>C) variants CC or TC was associated with reduced distant recurrence risk (HR=0.69,95%CI=0.53–0.90), both regardless of the treatments. No differential treatment effects (letrozole vs. tamoxifen) were observed for the association of outcome with any of the SNPs. Letrozole-treated patients with rs2077647(T>C) variants CC,TC had a reduced risk of bone AE (HR=0.75,95%CI=0.58–0.98, P<sub>interaction</sub>
=0.08), whereas patients with rs4986938(G>A) genotype variants AA and AG had an increased risk of bone AE (HR=1.37,95%CI=1.01–1.84, P<sub>interaction</sub>
=0.07).</p>
</sec>
<sec id="S4"><title>Conclusions</title>
<p id="P4">We paradoxically observed 1) rare <italic>ESR1</italic>
homozygous polymorphisms were associated with lower recurrence, and 2) <italic>ESR1</italic>
and <italic>ESR2</italic>
SNPs were associated with bone AEs in letrozole-treated patients. Genes that are involved in estrogen signaling and synthesis have the potential to affect both breast cancer recurrence and side effects, suggesting that individual treatment strategies can incorporate not only oncogenic drivers but also SNPs related to estrogen activity.</p>
</sec>
</abstract>
<kwd-group><kwd>ESR1</kwd>
<kwd>ESR2</kwd>
<kwd>letrozole</kwd>
<kwd>tamoxifen</kwd>
<kwd>polymorphism</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
</record>
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