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      Impact of CYP19A1 and ESR1 variants on early-onset side effects during combined endocrine therapy in the TEXT trial

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          Abstract

          Background

          Single nucleotide polymorphisms (SNPs) in the estrogen receptor 1 ( ESR1) and cytochrome P450 19A1 ( CYP19A1) genes have been associated with breast cancer risk, endocrine therapy response and side effects, mainly in postmenopausal women with early breast cancer. This analysis aimed to assess the association of selected germline CYP19A1 and ESR1 SNPs with early-onset hot flashes, sweating and musculoskeletal symptoms in premenopausal patients enrolled in the Tamoxifen and Exemestane Trial (TEXT).

          Methods

          Blood was collected from consenting premenopausal women with hormone-responsive early breast cancer, randomly assigned to 5-years of tamoxifen plus ovarian suppression (OFS) or exemestane plus OFS. DNA was extracted with QIAamp kits and genotyped for two CYP19A1 (rs4646 and rs10046) and three ESR1 (rs2077647, rs2234693 and rs9340799) SNPs by a real-time pyrosequencing technique. Adverse events (AEs) were recorded at baseline and 3-monthly during the first year. Associations of the genotype variants with grade ≥2 early-onset targeted AEs of hot flashes/sweating or musculoskeletal events were assessed using logistic regression models.

          Results

          There were 2660 premenopausal patients with breast cancer in the intention-to-treat population of TEXT, and 1967 (74 %) are included in this translational study. The CYP19A1 rs10046 variant T/T, represented in 23 % of women, was associated with a reduced incidence of grade ≥2 hot flashes/sweating (univariate odds ratio (OR) = 0.78; 95 % CI 0.63–0.97; P = 0.03), more strongly in patients assigned exemestane + OFS (TT vs CT/CC: OR = 0.65, 95 % CI = 0.48–0.89) than assigned tamoxifen + OFS (OR = 0.94, 95 % CI = 0.69–1.27, interaction P = 0.03). No association with any of the CYP19A1/ESR1 genotypes and musculoskeletal AEs was found.

          Conclusion

          The CYP19A1 rs10046 variant T/T favors lower incidence of hot flashes/sweating under exemestane + OFS treatment, suggesting endocrine-mediated effects. Based on findings from others, this SNP may potentially enhance treatment adherence and treatment efficacy. We plan to evaluate the clinical impact of this polymorphism during time, pending sufficient median follow up.

          Trial registration

          ClinicalTrials.gov NCT00066703, registered August 6, 2003.

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          Most cited references36

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          Reporting recommendations for tumor marker prognostic studies.

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            Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update.

            To update the ASCO clinical practice guideline on adjuvant endocrine therapy on the basis of emerging data on the optimal duration of treatment, particularly adjuvant tamoxifen. ASCO convened the Update Committee and conducted a systematic review of randomized clinical trials from January 2009 to June 2013 and analyzed three historical trials. Guideline recommendations were based on the Update Committee's review of the evidence. Outcomes of interest included survival, disease recurrence, and adverse events. This guideline update reflects emerging data on duration of tamoxifen treatment. There have been five studies of tamoxifen treatment beyond 5 years of therapy. The two largest studies with longest reported follow-up show a breast cancer survival advantage with 10-year durations of tamoxifen use. In addition to modest gains in survival, extended therapy with tamoxifen for 10 years compared with 5 years was associated with lower risks of breast cancer recurrence and contralateral breast cancer. Previous ASCO guidelines recommended treatment of women who have hormone receptor-positive breast cancer and are premenopausal with 5 years of tamoxifen, and those who are postmenopausal a minimum of 5 years of adjuvant therapy with an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor (in sequence). If women are pre- or perimenopausal and have received 5 years of adjuvant tamoxifen, they should be offered 10 years total duration of tamoxifen. If women are postmenopausal and have received 5 years of adjuvant tamoxifen, they should be offered the choice of continuing tamoxifen or switching to an aromatase inhibitor for 10 years total adjuvant endocrine therapy. © 2014 by American Society of Clinical Oncology.
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              Genome-wide association study identifies a novel breast cancer susceptibility locus at 6q25.1

              A genome-wide association study was conducted among Chinese women to identify risk variants for breast cancer. By analyzing 607,728 SNPs in 1505 cases and 1522 controls, we selected 29 promising SNPs for a fast-track replication in an independent set of 1554 cases and 1576 controls. Four replicated loci were further investigated in a third set of samples including 3472 cases and 900 controls. SNP rs2046210 at 6q25.1, located upstream of the estrogen receptor 1 gene (ESR1), exhibited strong and consistent association with breast cancer across all three stages. Adjusted odds ratio (95% CI) were 1.36 (1.24–1.49) and 1.59 (1.40–1.82), respectively, for genotypes A/G and A/A versus G/G (P for trend, 2.0×10−15) in the pooled analysis of samples from all three stages. A similar, although weaker, association was also found in an independent study including 1591 cases and 1466 controls of European ancestry (Ptrend, 0.01). These results provide strong evidence implicating 6q25.1 as a susceptibility locus for breast cancer.
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                Author and article information

                Contributors
                +390294372654 , harriet.johansson@ieo.it
                pkruan@jimmy.harvard.edu
                olivia.pagani@ibcsg.org
                mregan@jimmy.harvard.edu
                giuseppe.viale@ieo.it
                valentina.aristarco@ieo.it
                debora.macis@ieo.it
                antonellapuccio@tiscali.it
                Susanne.Roux@ibcsg.org
                rudolf.maibach@ibcsg.org
                marco.colleoni@ieo.it
                manuela.rabaglio@ibcsg.org
                +1-617-632-2459 , price@jimmy.harvard.edu
                alan.coates@ibcsg.org
                gelber@jimmy.harvard.edu
                aron.goldhirsch@ibcsg.org
                Rosita.Kammler@ibcsg.org
                bernardo.bonanni@ieo.it
                bwalley@ucalgary.ca
                Journal
                Breast Cancer Res
                Breast Cancer Res
                Breast Cancer Research : BCR
                BioMed Central (London )
                1465-5411
                1465-542X
                8 November 2016
                8 November 2016
                2016
                : 18
                : 110
                Affiliations
                [1 ]Division of Cancer Prevention and Genetics, European Institute of Oncology, Via Ripamonti 435, Milan, 20141 Italy
                [2 ]International Breast Cancer Study Group (IBCSG) Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard T. H. Chan School of Public Health, 450 Brookline Avenue, Boston, MA 02215 USA
                [3 ]Institute of Oncology of Southern Switzerland (IOSI), Bellinzona, Switzerland
                [4 ]International Breast Cancer Study Group, Bern, Switzerland
                [5 ]Swiss Group for Clinical Cancer Research SAKK, Lugano Viganello, Switzerland
                [6 ]IBCSG Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215 USA
                [7 ]Department of Pathology and Laboratory Medicine, IBCSG Central Pathology Laboratory, European Institute of Oncology, and University of Milan, Via Ripamonti 435, Milan, 20141 Italy
                [8 ]International Breast Cancer Study Group (IBCSG) Coordinating Center, Effingerstrasse 40, Bern, CH-3008 Switzerland
                [9 ]Division of Medical Senology, European Institute of Oncology, Via Ripamonti 435, Milan, 20141 Italy
                [10 ]IBCSG Statistical Center, Frontier Science and Technology Research Foundation, Boston, MA USA
                [11 ]IBCSG Statistical Center, Frontier Science and Technology Research Foundation, Boston, MA USA
                [12 ]International Breast Cancer Study Group and University of Sydney School of Public Health, Sydney, Australia
                [13 ]IBCSG Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Harvard Medical School, Frontier Science and Technology Research Foundation, 450 Brookline Avenue, Boston, MA 02215 USA
                [14 ]Program for Breast Health, European Institute of Oncology, Via Ripamonti 435, Milan, 20141 Italy
                [15 ]Translational Research Coordination and Central Pathology Office, IBCSG Coordinating Center, Effingerstrasse 40, Bern, CH-3008 Switzerland
                [16 ]Breast Unit of Southern Switzerland, Bellinzona, Switzerland
                [17 ]National Cancer Institute of Canada, Kingston, ON Canada
                [18 ]Dana-Farber Cancer Institute, Department of Biostatistics and Computatonal Biology, 450 Brookline Ave, Boston, MA 02215 USA
                Article
                771
                10.1186/s13058-016-0771-8
                5101790
                27825388
                0fe20a5b-94e3-4833-923f-0556b3ba9961
                © The Author(s). 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 21 July 2016
                : 17 October 2016
                Funding
                Funded by: FundRef http://dx.doi.org/http://dx.doi.org/10.13039/501100000925, National Health and Medical Research Council;
                Award ID: 351161, 510788, 1105058
                Funded by: FundRef http://dx.doi.org/http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: US NIH CA32102
                Funded by: FundRef http://dx.doi.org/http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: US NIH U10CA180821
                Funded by: FundRef http://dx.doi.org/http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: US NIH CA21115 and CA16116
                Funded by: FundRef http://dx.doi.org/http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: US NIH U10-CA-12027, U10-CA-69651, U10-CA-37377, U10-CA-69974
                Funded by: FundRef http://dx.doi.org/http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: US NIH CA077202
                Funded by: CCSRI
                Award ID: 015469 and 021039
                Funded by: FundRef http://dx.doi.org/10.13039/100005987, Susan G. Komen for the Cure, Komen Wyoming Affiliate;
                Award ID: KG080081
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2016

                Oncology & Radiotherapy
                side effects,aromatase inhibitors,tamoxifen,ovarian suppression,breast cancer,cyp19a1,esr1

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