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Variation in the FGFR2 gene and the effects of postmenopausal hormone therapy on invasive breast cancer.

ABSTRACT: BACKGROUND:Breast cancer concern is a major reason for the recent marked reduction in use of postmenopausal hormone therapy, although equally effective means of controlling menopausal symptoms are lacking. Single nucleotide polymorphisms (SNP) in the fibroblast growth factor receptor 2 (FGFR2) gene are substantially associated with postmenopausal breast cancer risk and could influence hormone therapy effects. PARTICIPANTS AND METHODS:We interrogated eight SNPs in intron 2 of the FGFR2 gene for 2,166 invasive breast cancer cases from the Women's Health Initiative clinical trial and one-to-one matched controls to confirm an association with breast cancer risk. We used case-only analyses to examine the dependence of estrogen plus progestin and estrogen-alone odds ratios on SNP genotype. RESULTS:Seven FGFR2 SNPs, including six in a single linkage disequilibrium region, were found to associate strongly (P < 10(-7)) with breast cancer risk. SNP rs3750817 (minor allele T with frequency 0.39) had an estimated per-minor-allele odds ratio of 0.78, and was not in such strong linkage disequilibrium with the other SNPs. The genotype of this SNP related significantly (P < 0.05) to hormone therapy odds ratios. For estrogen plus progestin, the odds ratios (95% confidence intervals) at 0, 1, and 2 minor SNP alleles were 1.52 (1.14-2.02), 1.33 (1.01-1.75), and 0.69 (0.41-1.17), whereas the corresponding values for estrogen alone were 0.74 (0.51-1.09), 0.99 (0.68-1.44), and 0.34 (0.15-0.76). CONCLUSIONS:Postmenopausal women having TT genotype for SNP rs3750817 have a reduced breast cancer risk and seem to experience comparatively favorable effects of postmenopausal hormone therapy.

SUBMITTER: Prentice RL

PROVIDER: S-EPMC2783392 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Variation in the FGFR2 gene and the effects of postmenopausal hormone therapy on invasive breast cancer.

Prentice Ross L RL Huang Ying Y Hinds David A DA Peters Ulrike U Pettinger Mary M Cox David R DR Beilharz Erica E Chlebowski Rowan T RT Rossouw Jacques E JE Caan Bette B Ballinger Dennis G DG

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20091027 11

<h4>Background</h4>Breast cancer concern is a major reason for the recent marked reduction in use of postmenopausal hormone therapy, although equally effective means of controlling menopausal symptoms are lacking. Single nucleotide polymorphisms (SNP) in the fibroblast growth factor receptor 2 (FGFR2) gene are substantially associated with postmenopausal breast cancer risk and could influence hormone therapy effects.<h4>Participants and methods</h4>We interrogated eight SNPs in intron 2 of the F ...[more]

PMID: 19861516

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Project description:IntroductionParadoxically, a breast cancer risk reduction with conjugated equine estrogens (CEE) and a risk elevation with CEE plus medroxyprogesterone acetate (CEE + MPA) were observed in the Women's Health Initiative (WHI) randomized controlled trials. The effects of hormone therapy on serum sex hormone levels, and on the association between baseline sex hormones and disease risk, may help explain these divergent breast cancer findings.MethodsSerum sex hormone concentrations were measured for 348 breast cancer cases in the CEE + MPA trial and for 235 cases in the CEE trial along with corresponding pair-matched controls, nested within the WHI trials of healthy postmenopausal women. Association and mediation analyses, to examine the extent to which sex hormone levels and changes can explain the breast cancer findings, were conducted using logistic regression.ResultsFollowing CEE treatment, breast cancer risk was associated with higher concentrations of baseline serum estrogens, and with lower concentrations of sex hormone binding globulin. However, following CEE + MPA, there was no association of breast cancer risk with baseline sex hormone levels. The sex hormone changes from baseline to year 1 provided an explanation for much of the reduced breast cancer risk with CEE. Specifically, the treatment odds ratio (95% confidence interval) increased from 0.71 (0.43, 1.15) to 0.92 (0.41, 2.09) when the year 1 measures were included in the logistic regression analysis. In comparison, the CEE + MPA odds ratio was essentially unchanged when these year 1 measures were included.ConclusionsBreast cancer risk remains low following CEE use among women having favorable baseline sex hormone profiles, but CEE + MPA evidently produces a breast cancer risk for all women similar to that for women having an unfavorable baseline sex hormone profile. These patterns could reflect breast ductal epithelial cell stimulation by CEE + MPA that is substantially avoided with CEE, in conjunction with relatively more favorable effects of either regimen following a sustained period of estrogen deprivation. These findings may have implications for other hormone therapy formulations and routes of delivery.Trial registrationclinicaltrials.gov identifier: NCT00000611.

Project description:Risk assessment of future breast cancer risk through exposure to sex steroids currently relies on clinical scorings such as mammographic density. Knowledge about the gene expression patterns in existing breast cancer tumors may be used to identify risk factors in the breast tissue of women still free of cancer. The differential effects of estradiol, estradiol together with gestagens, or tibolone on breast cancer-related gene expression in normal breast tissue samples taken from postmenopausal women may be used to identify gene expression profiles associated with a higher breast cancer risk. Breast tissue samples were taken from 33 healthy postmenopausal women both before and after a six month treatment with either 2mg micronized estradiol [E2], 2mg micronized estradiol and 1mg norethisterone acetate [E2+NETA], 2.5mg tibolone [T] or [no HRT]. Except for [E2], which was only given to women after hysterectomy, the allocation to each of the three groups was randomized. The expression of 102 mRNAs and 46 microRNAs putatively involved in breast cancer was prospectively determined in the biopsies of 6 women receiving [no HRT], 5 women receiving [E2], 5 women receiving [E2+NETA], and 6 receiving [T]. Using epithelial and endothelial markers genes, non-representative biopsies from 11 women were eliminated. Treatment of postmenopausal women with [E2+NETA] resulted in the highest number of differentially (p<0.05) regulated genes (16.2%) compared to baseline, followed by [E2] (10.1%) and [T] (4.7%). Among genes that were significantly down-regulated by [E2+NETA] ranked estrogen-receptor-1 (ESR1, p=0.019) and androgen receptor (AR, p=0.019), whereas CYP1B1, a gene encoding an estrogen-metabolizing enzyme, was significantly up-regulated (p=0.016). Mammary cells triggered by [E2+NETA] and [E2] adjust for steroidogenic up-regulation through down-regulation of the estrogen-receptor pathway. In this prospective study, prolonged administration of [E2+NETA] and to a lesser extent of [E2] but not [T] were associated in otherwise healthy breast tissue with a change in the expression of genes putatively involved in breast cancer. Our data suggest that normal mammary cells triggered by [E2+NETA] adjust for steroidogenic up-regulation through down-regulation of the estrogen-receptor pathway. This feasibility study provides the basis for whole genome analyses to identify novel markers involved in increased breast cancer risk.

Project description:Resistance to endocrine therapy in breast cancer is associated with activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway. In early studies, the mTOR inhibitor everolimus added to endocrine therapy showed antitumor activity.In this phase 3, randomized trial, we compared everolimus and exemestane versus exemestane and placebo (randomly assigned in a 2:1 ratio) in 724 patients with hormone-receptor-positive advanced breast cancer who had recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor in the adjuvant setting or to treat advanced disease (or both). The primary end point was progression-free survival. Secondary end points included survival, response rate, and safety. A preplanned interim analysis was performed by an independent data and safety monitoring committee after 359 progression-free survival events were observed.Baseline characteristics were well balanced between the two study groups. The median age was 62 years, 56% had visceral involvement, and 84% had hormone-sensitive disease. Previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse events were stomatitis (8% in the everolimus-plus-exemestane group vs. 1% in the placebo-plus-exemestane group), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%). At the interim analysis, median progression-free survival was 6.9 months with everolimus plus exemestane and 2.8 months with placebo plus exemestane, according to assessments by local investigators (hazard ratio for progression or death, 0.43; 95% confidence interval [CI], 0.35 to 0.54; P<0.001). Median progression-free survival was 10.6 months and 4.1 months, respectively, according to central assessment (hazard ratio, 0.36; 95% CI, 0.27 to 0.47; P<0.001).Everolimus combined with an aromatase inhibitor improved progression-free survival in patients with hormone-receptor-positive advanced breast cancer previously treated with nonsteroidal aromatase inhibitors. (Funded by Novartis; BOLERO-2 ClinicalTrials.gov number, NCT00863655.).

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Variation in the FGFR2 gene and the effects of postmenopausal hormone therapy on invasive breast cancer.

Publications

Variation in the FGFR2 gene and the effects of postmenopausal hormone therapy on invasive breast cancer.

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