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Polymorphism at 19q13.41 Predicts Breast Cancer Survival Specifically after Endocrine Therapy.

ABSTRACT: PURPOSE:Although most patients with estrogen receptor (ER)-positive breast cancer benefit from endocrine therapies, a significant proportion do not. Our aim was to identify inherited genetic variations that might predict survival among patients receiving adjuvant endocrine therapies. EXPERIMENTAL DESIGN:We performed a meta-analysis of two genome-wide studies; Helsinki Breast Cancer Study, 805 patients, with 240 receiving endocrine therapy and Prospective study of Outcomes in Sporadic versus Hereditary breast cancer, 536 patients, with 155 endocrine therapy patients, evaluating 486,478 single-nucleotide polymorphisms (SNP). The top four associations from the endocrine treatment subgroup were further investigated in two independent datasets totaling 5,011 patients, with 3,485 receiving endocrine therapy. RESULTS:A meta-analysis identified a common SNP rs8113308, mapped to 19q13.41, associating with reduced survival among endocrine-treated patients [hazard ratio (HR), 1.69; 95% confidence interval (CI), 1.37-2.07; P = 6.34 × 10(-7)] and improved survival among ER-negative patients, with a similar trend in ER-positive cases not receiving endocrine therapy. In a multivariate analysis adjusted for conventional prognostic factors, we found a significant interaction between the rs8113308 and endocrine treatment, indicating a predictive, treatment-specific effect of the SNP rs8113308 on breast cancer survival, with the per-allele HR for interaction 2.16 (95% CI, 1.30-3.60; Pinteraction = 0.003) and HR = 7.77 (95% CI, 0.93-64.71) for the homozygous genotype carriers. A biologic rationale is suggested by in silico functional analyses. CONCLUSIONS:Our findings suggest carrying the rs8113308 rare allele may identify patients who will not benefit from adjuvant endocrine treatment.

SUBMITTER: Khan S

PROVIDER: S-EPMC4574404 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Polymorphism at 19q13.41 Predicts Breast Cancer Survival Specifically after Endocrine Therapy.

Khan Sofia S Fagerholm Rainer R Rafiq Sajjad S Tapper William W Aittomäki Kristiina K Liu Jianjun J Blomqvist Carl C Eccles Diana D Nevanlinna Heli H

Clinical cancer research : an official journal of the American Association for Cancer Research 20150511 18

<h4>Purpose</h4>Although most patients with estrogen receptor (ER)-positive breast cancer benefit from endocrine therapies, a significant proportion do not. Our aim was to identify inherited genetic variations that might predict survival among patients receiving adjuvant endocrine therapies.<h4>Experimental design</h4>We performed a meta-analysis of two genome-wide studies; Helsinki Breast Cancer Study, 805 patients, with 240 receiving endocrine therapy and Prospective study of Outcomes in Spora ...[more]

PMID: 25964295

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Project description:We reviewed randomized phase II/III trials comparing first- or second-line endocrine therapy as monotherapy or in combination with targeted therapies for treatment of postmenopausal patients with hormone receptor-positive advanced breast cancer. First-line was defined as treatment for endocrine therapy-naïve advanced breast cancer or advanced disease treated with endocrine therapy in the adjuvant/neoadjuvant setting. Second-line was defined as endocrine therapy for advanced breast cancer following disease progression on endocrine therapy for advanced disease. Publications reporting progression-free survival (PFS)/time to progression (TTP) or overall survival (OS) for FDA-approved agents anastrozole, exemestane, fulvestrant 250 mg, fulvestrant 500 mg, letrozole (0.5 and 2.5 mg), megestrol acetate, and tamoxifen as monotherapy, or in combination with everolimus, palbociclib or ribociclib, were assessed. First-line monotherapy with anastrozole, fulvestrant 500 mg or letrozole 2.5 mg significantly improved PFS/TTP versus comparator endocrine therapy; however, only fulvestrant 500 mg improved OS. For endocrine therapy in combination with targeted therapies, palbociclib plus letrozole 2.5 mg, and ribociclib plus letrozole 2.5 mg significantly improved PFS versus letrozole 2.5 mg alone first-line. For second-line monotherapies, exemestane, fulvestrant 500 mg and letrozole 2.5 mg significantly improved PFS/TTP versus comparator endocrine therapy; only fulvestrant 500 mg and letrozole 2.5 mg improved OS. For second-line combination therapies, everolimus plus exemestane, and palbociclib plus fulvestrant 500 mg, improved PFS versus endocrine therapy alone. In both first- and second-line settings, aromatase inhibitors demonstrated PFS benefits versus comparator endocrine therapy; however, fulvestrant 500 mg was the only endocrine therapy included in our review to show both PFS and OS advantages compared with other endocrine therapies. Targeted agents in combination with endocrine therapy have demonstrated PFS improvements both first- and second-line; OS data are awaited.

Project description:BACKGROUND:In the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT), the 5-year rates of recurrence of breast cancer were significantly lower among premenopausal women who received the aromatase inhibitor exemestane plus ovarian suppression than among those who received tamoxifen plus ovarian suppression. The addition of ovarian suppression to tamoxifen did not result in significantly lower recurrence rates than those with tamoxifen alone. Here, we report the updated results from the two trials. METHODS:Premenopausal women were randomly assigned to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression in SOFT and to receive tamoxifen plus ovarian suppression or exemestane plus ovarian suppression in TEXT. Randomization was stratified according to the receipt of chemotherapy. RESULTS:In SOFT, the 8-year disease-free survival rate was 78.9% with tamoxifen alone, 83.2% with tamoxifen plus ovarian suppression, and 85.9% with exemestane plus ovarian suppression (P=0.009 for tamoxifen alone vs. tamoxifen plus ovarian suppression). The 8-year rate of overall survival was 91.5% with tamoxifen alone, 93.3% with tamoxifen plus ovarian suppression, and 92.1% with exemestane plus ovarian suppression (P=0.01 for tamoxifen alone vs. tamoxifen plus ovarian suppression); among the women who remained premenopausal after chemotherapy, the rates were 85.1%, 89.4%, and 87.2%, respectively. Among the women with cancers that were negative for HER2 who received chemotherapy, the 8-year rate of distant recurrence with exemestane plus ovarian suppression was lower than the rate with tamoxifen plus ovarian suppression (by 7.0 percentage points in SOFT and by 5.0 percentage points in TEXT). Grade 3 or higher adverse events were reported in 24.6% of the tamoxifen-alone group, 31.0% of the tamoxifen-ovarian suppression group, and 32.3% of the exemestane-ovarian suppression group. CONCLUSIONS:Among premenopausal women with breast cancer, the addition of ovarian suppression to tamoxifen resulted in significantly higher 8-year rates of both disease-free and overall survival than tamoxifen alone. The use of exemestane plus ovarian suppression resulted in even higher rates of freedom from recurrence. The frequency of adverse events was higher in the two groups that received ovarian suppression than in the tamoxifen-alone group. (Funded by Pfizer and others; SOFT and TEXT ClinicalTrials.gov numbers, NCT00066690 and NCT00066703 , respectively.).

Project description:Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor ? (ER?) are among the most effective systemic treatments for ER?-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ER? transcriptional regulatory plasticity. Herein we identify VAV3 as a critical component in this process.A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ER? was evaluated by molecular docking analyses, an agonist fluoligand assay and short hairpin (sh)RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot analysis of signaling and proliferation markers, and shRNA-mediated protein depletion in viability and clonogenic assays, were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine its association with therapeutic response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression.The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase), but instead was likely a result of binding to ER?. VAV3 was selectively reduced upon exposure to YC-1 or ER? depletion, and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with the response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value?=?8.4?×?10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy.This study proposes VAV3 as a biomarker and a rationale for its use as a signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.

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Polymorphism at 19q13.41 Predicts Breast Cancer Survival Specifically after Endocrine Therapy.

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Polymorphism at 19q13.41 Predicts Breast Cancer Survival Specifically after Endocrine Therapy.

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