CYP2D6 Genotype and Tamoxifen Response in Postmenopausal Women with Endocrine-Responsive Breast Cancer: The Breast International Group 1-98 Trial
Identifieur interne : 005515 ( Main/Exploration ); précédent : 005514; suivant : 005516CYP2D6 Genotype and Tamoxifen Response in Postmenopausal Women with Endocrine-Responsive Breast Cancer: The Breast International Group 1-98 Trial
Auteurs : Meredith M. Regan ; Brian Leyland-Jones ; Mark Bouzyk ; Olivia Pagani ; Weining Tang ; Roswitha Kammler ; Patrizia Dell Rto ; Maria Olivia Biasi ; Beat Thürlimann ; Maria B. Lyng ; Henrik J. Ditzel ; Patrick Neven ; Marc Debled ; Rudolf Maibach ; Karen N. Price ; Richard D. Gelber ; Alan S. Coates ; Aron Goldhirsch ; James M. Rae ; Giuseppe VialeSource :
- JNCI Journal of the National Cancer Institute [ 0027-8874 ] ; 2012.
Abstract
Adjuvant tamoxifen therapy is effective for postmenopausal women with endocrine-responsive breast cancer. Cytochrome P450 2D6 (CYP2D6) enzyme metabolizes tamoxifen to clinically active metabolites, and
We obtained tumor tissues and isolated DNA from 4861 of 8010 postmenopausal women with hormone receptor–positive breast cancer who enrolled in the randomized, phase III double-blind Breast International Group (BIG) 1-98 trial between March 1998 and May 2003 and received tamoxifen and/or letrozole treatment. Extracted DNA was used for genotyping nine
No association between CYP2D6 metabolism phenotypes and breast cancer-free interval was observed among patients who received tamoxifen monotherapy without previous chemotherapy (
CYP2D6 phenotypes of reduced enzyme activity were not associated with worse disease control but were associated with increased hot flushes, contrary to the hypothesis. The results of this study do not support using the presence or absence of hot flushes or the pharmacogenetic testing of
Url:
DOI: 10.1093/jnci/djs125
PubMed: 22395644
PubMed Central: 3309132
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en"><italic>CYP2D6</italic> Genotype and Tamoxifen Response in Postmenopausal Women with Endocrine-Responsive Breast Cancer: The Breast International Group 1-98 Trial</title><author><name sortKey="Regan, Meredith M" sort="Regan, Meredith M" uniqKey="Regan M" first="Meredith M." last="Regan">Meredith M. Regan</name></author><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="Bouzyk, Mark" sort="Bouzyk, Mark" uniqKey="Bouzyk M" first="Mark" last="Bouzyk">Mark Bouzyk</name></author><author><name sortKey="Pagani, Olivia" sort="Pagani, Olivia" uniqKey="Pagani O" first="Olivia" last="Pagani">Olivia Pagani</name></author><author><name sortKey="Tang, Weining" sort="Tang, Weining" uniqKey="Tang W" first="Weining" last="Tang">Weining Tang</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="Lyng, Maria B" sort="Lyng, Maria B" uniqKey="Lyng M" first="Maria B." last="Lyng">Maria B. Lyng</name></author><author><name sortKey="Ditzel, Henrik J" sort="Ditzel, Henrik J" uniqKey="Ditzel H" first="Henrik J." last="Ditzel">Henrik J. Ditzel</name></author><author><name sortKey="Neven, Patrick" sort="Neven, Patrick" uniqKey="Neven P" first="Patrick" last="Neven">Patrick Neven</name></author><author><name sortKey="Debled, Marc" sort="Debled, Marc" uniqKey="Debled M" first="Marc" last="Debled">Marc Debled</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="Gelber, Richard D" sort="Gelber, Richard D" uniqKey="Gelber R" first="Richard D." last="Gelber">Richard D. Gelber</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="Rae, James M" sort="Rae, James M" uniqKey="Rae J" first="James M." last="Rae">James M. 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Regan</name></author><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="Bouzyk, Mark" sort="Bouzyk, Mark" uniqKey="Bouzyk M" first="Mark" last="Bouzyk">Mark Bouzyk</name></author><author><name sortKey="Pagani, Olivia" sort="Pagani, Olivia" uniqKey="Pagani O" first="Olivia" last="Pagani">Olivia Pagani</name></author><author><name sortKey="Tang, Weining" sort="Tang, Weining" uniqKey="Tang W" first="Weining" last="Tang">Weining Tang</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="Lyng, Maria B" sort="Lyng, Maria B" uniqKey="Lyng M" first="Maria B." last="Lyng">Maria B. Lyng</name></author><author><name sortKey="Ditzel, Henrik J" sort="Ditzel, Henrik J" uniqKey="Ditzel H" first="Henrik J." last="Ditzel">Henrik J. Ditzel</name></author><author><name sortKey="Neven, Patrick" sort="Neven, Patrick" uniqKey="Neven P" first="Patrick" last="Neven">Patrick Neven</name></author><author><name sortKey="Debled, Marc" sort="Debled, Marc" uniqKey="Debled M" first="Marc" last="Debled">Marc Debled</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="Gelber, Richard D" sort="Gelber, Richard D" uniqKey="Gelber R" first="Richard D." last="Gelber">Richard D. Gelber</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="Rae, James M" sort="Rae, James M" uniqKey="Rae J" first="James M." last="Rae">James M. Rae</name></author><author><name sortKey="Viale, Giuseppe" sort="Viale, Giuseppe" uniqKey="Viale G" first="Giuseppe" last="Viale">Giuseppe Viale</name></author></analytic><series><title level="j">JNCI Journal of the National Cancer Institute</title><idno type="ISSN">0027-8874</idno><idno type="eISSN">1460-2105</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Adjuvant tamoxifen therapy is effective for postmenopausal women with endocrine-responsive breast cancer. Cytochrome P450 2D6 (CYP2D6) enzyme metabolizes tamoxifen to clinically active metabolites, and <italic>CYP2D6</italic> polymorphisms may adversely affect tamoxifen efficacy. In this study, we investigated the clinical relevance of <italic>CYP2D6</italic> polymorphisms.</p></sec><sec><title>Methods</title><p>We obtained tumor tissues and isolated DNA from 4861 of 8010 postmenopausal women with hormone receptor–positive breast cancer who enrolled in the randomized, phase III double-blind Breast International Group (BIG) 1-98 trial between March 1998 and May 2003 and received tamoxifen and/or letrozole treatment. Extracted DNA was used for genotyping nine <italic>CYP2D6</italic> single-nucleotide polymorphisms using polymerase chain reaction–based methods. Genotype combinations were used to categorize CYP2D6 metabolism phenotypes as poor, intermediate, and extensive metabolizers (PM, IM, and EM, respectively; n = 4393 patients). Associations of CYP2D6 metabolism phenotypes with breast cancer-free interval (referred to as recurrence) and treatment-induced hot flushes according to randomized endocrine treatment and previous chemotherapy were assessed. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.</p></sec><sec><title>Results</title><p>No association between CYP2D6 metabolism phenotypes and breast cancer-free interval was observed among patients who received tamoxifen monotherapy without previous chemotherapy (<italic>P</italic> = .35). PM or IM phenotype had a non-statistically significantly reduced risk of breast cancer recurrence compared with EM phenotype (PM or IM vs EM, HR of recurrence = 0.86, 95% CI = 0.60 to 1.24). CYP2D6 metabolism phenotype was associated with tamoxifen-induced hot flushes (<italic>P</italic> = .020). Both PM and IM phenotypes had an increased risk of tamoxifen-induced hot flushes compared with EM phenotype (PM vs EM, HR of hot flushes = 1.24, 95% CI = 0.96 to 1.59; IM vs EM, HR of hot flushes = 1.23, 95% CI = 1.05 to 1.43).</p></sec><sec><title>Conclusions</title><p>CYP2D6 phenotypes of reduced enzyme activity were not associated with worse disease control but were associated with increased hot flushes, contrary to the hypothesis. The results of this study do not support using the presence or absence of hot flushes or the pharmacogenetic testing of <italic>CYP2D6</italic> to determine whether to treat postmenopausal breast cancer patients with tamoxifen.</p></sec></div></front></TEI><affiliations><list></list><tree><noCountry><name sortKey="Biasi, Maria Olivia" sort="Biasi, Maria Olivia" uniqKey="Biasi M" first="Maria Olivia" last="Biasi">Maria Olivia Biasi</name><name sortKey="Bouzyk, Mark" sort="Bouzyk, Mark" uniqKey="Bouzyk M" first="Mark" last="Bouzyk">Mark Bouzyk</name><name sortKey="Coates, Alan S" sort="Coates, Alan S" uniqKey="Coates A" first="Alan S." last="Coates">Alan S. Coates</name><name sortKey="Debled, Marc" sort="Debled, Marc" uniqKey="Debled M" first="Marc" last="Debled">Marc Debled</name><name sortKey="Dell Rto, Patrizia" sort="Dell Rto, Patrizia" uniqKey="Dell Rto P" first="Patrizia" last="Dell Rto">Patrizia Dell Rto</name><name sortKey="Ditzel, Henrik J" sort="Ditzel, Henrik J" uniqKey="Ditzel H" first="Henrik J." last="Ditzel">Henrik J. Ditzel</name><name sortKey="Gelber, Richard D" sort="Gelber, Richard D" uniqKey="Gelber R" first="Richard D." last="Gelber">Richard D. Gelber</name><name sortKey="Goldhirsch, Aron" sort="Goldhirsch, Aron" uniqKey="Goldhirsch A" first="Aron" last="Goldhirsch">Aron Goldhirsch</name><name sortKey="Kammler, Roswitha" sort="Kammler, Roswitha" uniqKey="Kammler R" first="Roswitha" last="Kammler">Roswitha Kammler</name><name sortKey="Leyland Jones, Brian" sort="Leyland Jones, Brian" uniqKey="Leyland Jones B" first="Brian" last="Leyland-Jones">Brian Leyland-Jones</name><name sortKey="Lyng, Maria B" sort="Lyng, Maria B" uniqKey="Lyng M" first="Maria B." last="Lyng">Maria B. Lyng</name><name sortKey="Maibach, Rudolf" sort="Maibach, Rudolf" uniqKey="Maibach R" first="Rudolf" last="Maibach">Rudolf Maibach</name><name sortKey="Neven, Patrick" sort="Neven, Patrick" uniqKey="Neven P" first="Patrick" last="Neven">Patrick Neven</name><name sortKey="Pagani, Olivia" sort="Pagani, Olivia" uniqKey="Pagani O" first="Olivia" last="Pagani">Olivia Pagani</name><name sortKey="Price, Karen N" sort="Price, Karen N" uniqKey="Price K" first="Karen N." last="Price">Karen N. Price</name><name sortKey="Rae, James M" sort="Rae, James M" uniqKey="Rae J" first="James M." last="Rae">James M. Rae</name><name sortKey="Regan, Meredith M" sort="Regan, Meredith M" uniqKey="Regan M" first="Meredith M." last="Regan">Meredith M. Regan</name><name sortKey="Tang, Weining" sort="Tang, Weining" uniqKey="Tang W" first="Weining" last="Tang">Weining Tang</name><name sortKey="Thurlimann, Beat" sort="Thurlimann, Beat" uniqKey="Thurlimann B" first="Beat" last="Thürlimann">Beat Thürlimann</name><name sortKey="Viale, Giuseppe" sort="Viale, Giuseppe" uniqKey="Viale G" first="Giuseppe" last="Viale">Giuseppe Viale</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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