PMID- 27825388
OWN - NLM
STAT- MEDLINE
DCOM- 20170807
LR  - 20210816
IS  - 1465-542X (Electronic)
IS  - 1465-5411 (Print)
IS  - 1465-5411 (Linking)
VI  - 18
IP  - 1
DP  - 2016 Nov 8
TI  - Impact of CYP19A1 and ESR1 variants on early-onset side effects during combined 
      endocrine therapy in the TEXT trial.
PG  - 110
LID - 110
AB  - 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.
FAU - Johansson, Harriet
AU  - Johansson H
AD  - Division of Cancer Prevention and Genetics, European Institute of Oncology, Via 
      Ripamonti 435, Milan, 20141, Italy. harriet.johansson@ieo.it.
FAU - Gray, Kathryn P
AU  - Gray KP
AD  - 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.
FAU - Pagani, Olivia
AU  - Pagani O
AD  - Institute of Oncology of Southern Switzerland (IOSI), Bellinzona, Switzerland.
AD  - International Breast Cancer Study Group, Bern, Switzerland.
AD  - Swiss Group for Clinical Cancer Research SAKK, Lugano Viganello, Switzerland.
FAU - Regan, Meredith M
AU  - Regan MM
AD  - IBCSG Statistical Center, Department of Biostatistics and Computational Biology, 
      Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, 
      Boston, MA, 02215, USA.
FAU - Viale, Giuseppe
AU  - Viale G
AD  - Department of Pathology and Laboratory Medicine, IBCSG Central Pathology 
      Laboratory, European Institute of Oncology, and University of Milan, Via 
      Ripamonti 435, Milan, 20141, Italy.
FAU - Aristarco, Valentina
AU  - Aristarco V
AD  - Division of Cancer Prevention and Genetics, European Institute of Oncology, Via 
      Ripamonti 435, Milan, 20141, Italy.
FAU - Macis, Debora
AU  - Macis D
AD  - Division of Cancer Prevention and Genetics, European Institute of Oncology, Via 
      Ripamonti 435, Milan, 20141, Italy.
FAU - Puccio, Antonella
AU  - Puccio A
AD  - Division of Cancer Prevention and Genetics, European Institute of Oncology, Via 
      Ripamonti 435, Milan, 20141, Italy.
FAU - Roux, Susanne
AU  - Roux S
AD  - International Breast Cancer Study Group (IBCSG) Coordinating Center, 
      Effingerstrasse 40, Bern, CH-3008, Switzerland.
FAU - Maibach, Rudolf
AU  - Maibach R
AD  - International Breast Cancer Study Group (IBCSG) Coordinating Center, 
      Effingerstrasse 40, Bern, CH-3008, Switzerland.
FAU - Colleoni, Marco
AU  - Colleoni M
AD  - Division of Medical Senology, European Institute of Oncology, Via Ripamonti 435, 
      Milan, 20141, Italy.
FAU - Rabaglio, Manuela
AU  - Rabaglio M
AD  - IBCSG Statistical Center, Frontier Science and Technology Research Foundation, 
      Boston, MA, USA.
FAU - Price, Karen N
AU  - Price KN
AD  - IBCSG Statistical Center, Frontier Science and Technology Research Foundation, 
      Boston, MA, USA.
AD  - Dana-Farber Cancer Institute, Department of Biostatistics and Computatonal 
      Biology, 450 Brookline Ave, Boston, MA, 02215, USA.
FAU - Coates, Alan S
AU  - Coates AS
AD  - International Breast Cancer Study Group and University of Sydney School of Public 
      Health, Sydney, Australia.
FAU - Gelber, Richard D
AU  - Gelber RD
AD  - 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.
FAU - Goldhirsch, Aron
AU  - Goldhirsch A
AD  - Program for Breast Health, European Institute of Oncology, Via Ripamonti 435, 
      Milan, 20141, Italy.
FAU - Kammler, Roswitha
AU  - Kammler R
AD  - Translational Research Coordination and Central Pathology Office, IBCSG 
      Coordinating Center, Effingerstrasse 40, Bern, CH-3008, Switzerland.
FAU - Bonanni, Bernardo
AU  - Bonanni B
AD  - Division of Cancer Prevention and Genetics, European Institute of Oncology, Via 
      Ripamonti 435, Milan, 20141, Italy.
FAU - Walley, Barbara A
AU  - Walley BA
AD  - Breast Unit of Southern Switzerland, Bellinzona, Switzerland.
AD  - National Cancer Institute of Canada, Kingston, ON, Canada.
CN  - the TEXT principal investigators
LA  - eng
SI  - ClinicalTrials.gov/NCT00066703
GR  - N01 CA032102/CA/NCI NIH HHS/United States
GR  - U10 CA077202/CA/NCI NIH HHS/United States
GR  - U10 CA021115/CA/NCI NIH HHS/United States
GR  - U10 CA012027/CA/NCI NIH HHS/United States
GR  - U10 CA180821/CA/NCI NIH HHS/United States
GR  - U10 CA069651/CA/NCI NIH HHS/United States
GR  - U10 CA032102/CA/NCI NIH HHS/United States
GR  - U10 CA016116/CA/NCI NIH HHS/United States
GR  - U24 CA075362/CA/NCI NIH HHS/United States
GR  - U10 CA069974/CA/NCI NIH HHS/United States
GR  - U10 CA037377/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20161108
PL  - England
TA  - Breast Cancer Res
JT  - Breast cancer research : BCR
JID - 100927353
RN  - 0 (ESR1 protein, human)
RN  - 0 (Estrogen Receptor alpha)
RN  - EC 1.14.14.1 (Aromatase)
RN  - EC 1.14.14.1 (CYP19A1 protein, human)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antineoplastic Combined Chemotherapy Protocols/*adverse effects
MH  - Aromatase/*genetics
MH  - Breast Neoplasms/drug therapy/*genetics/mortality
MH  - Clinical Trials, Phase III as Topic
MH  - Drug-Related Side Effects and Adverse Reactions/*genetics
MH  - Estrogen Receptor alpha/*genetics
MH  - Female
MH  - *Genetic Variation
MH  - Hot Flashes/genetics
MH  - Humans
MH  - Middle Aged
MH  - Odds Ratio
MH  - *Pharmacogenomic Variants
MH  - Randomized Controlled Trials as Topic
MH  - Risk Factors
MH  - Sweating/genetics
PMC - PMC5101790
OTO - NOTNLM
OT  - Aromatase inhibitors
OT  - Breast cancer
OT  - CYP19A1
OT  - ESR1
OT  - Ovarian suppression
OT  - Side effects
OT  - Tamoxifen
EDAT- 2016/11/09 06:00
MHDA- 2017/08/08 06:00
PMCR- 2016/11/08
CRDT- 2016/11/10 06:00
PHST- 2016/07/21 00:00 [received]
PHST- 2016/10/17 00:00 [accepted]
PHST- 2016/11/10 06:00 [entrez]
PHST- 2016/11/09 06:00 [pubmed]
PHST- 2017/08/08 06:00 [medline]
PHST- 2016/11/08 00:00 [pmc-release]
AID - 10.1186/s13058-016-0771-8 [pii]
AID - 771 [pii]
AID - 10.1186/s13058-016-0771-8 [doi]
PST - epublish
SO  - Breast Cancer Res. 2016 Nov 8;18(1):110. doi: 10.1186/s13058-016-0771-8.