Abstract
IntroductionAmplification of the ESR1 gene, coding for estrogen receptor alpha, was shown to predict responsiveness to tamoxifen, however its prognostic impact in breast cancer patients has not been thoroughly investigated. Other factors that could contribute to responsiveness to tamoxifen treatment are polymorphisms in ESR1 gene and genes involved in tamoxifen metabolism.The aim of this study was to assess the prognostic role of ESR1 gene dosage in a consecutive group of breast cancer patients and to correlate this feature with clinico-pathological factors. Additionally, ESR1 PvuII, CYP2C19*2 and UGT2B15*2 polymorphisms were analyzed in the tamoxifen-treated subgroup of patients.Materials and MethodsPrimary tumor samples from 281 stage I-III consecutive breast cancer patients were analyzed for ESR1 gene dosage using real-time PCR with locked nucleic acids hydrolysis probes. In the tamoxifen-treated subgroup of patients, ESR1 PvuII, CYP2C19*2 and UGT2B15*2 polymorphism in leukocytes genomic DNA were analyzed. Results were correlated with clinico-pathological factors and with disease-free survival (DFS) and overall survival (OS).Results ESR1 amplification (with a cut-off level of 2.0) was found in 12% of the entire group of breast cancer patients, and in 18% of the ER-negative subgroup. This feature was associated with decreased DFS both in the entire group (P=0.007) and in the ER-negative subgroup (P=0.03), but not in the tamoxifen-treated patients.Patients with ESR1 PvuII wt/wt genotype and at least one UGT2B15 wt allele had a worse DFS (P=0.03) and showed a trend towards decreased Os (P=0.08) in comparison to patients with ESR1 PvuII wt/vt or vt/vt genotype and UGT2B15 *2/*2 genotype.Conclusions ESR1 amplification can occur in ER-negative tumors and may carry poor prognosis. In the tamoxifen-treated subgroup, poor prognosis was related to the combined presence of ESR1 PvuII wt/wt and UGT2B15wt/wt or wt/*2 genotype.
Highlights
Amplification of the ESR1 gene, coding for estrogen receptor alpha, was shown to predict responsiveness to tamoxifen, its prognostic impact in breast cancer patients has not been thoroughly investigated
Estrogen receptor (ER) facilitates normal development of mammary gland [1] but it is involved in stimulating the growth of ER-positive breast cancers [2]
ER-positivity indicates the dependence of the tumor on ER-related pathways for survival and sustained growth [4] and increased gene dosage of estrogen receptor alpha gene (ESR1), may influence the function of complex internal ER signaling pathways in breast cancer cells
Summary
Amplification of the ESR1 gene, coding for estrogen receptor alpha, was shown to predict responsiveness to tamoxifen, its prognostic impact in breast cancer patients has not been thoroughly investigated. The aim of this study was to assess the prognostic role of ESR1 gene dosage in a consecutive group of breast cancer patients and to correlate this feature with clinico-pathological factors. The frequency of ESR1 gene amplification varies largely from 1% [5] to 23% [6] depending on the method of ESR1 amplification analysis Clinical significance of this abnormality is unclear as it was found to predict both endocrine therapy responsiveness [6,7] and resistance [8]. Since most studies on ESR1 amplification included tamoxifen-treated groups [6,7,8,9], prognostic significance of ESR1 gene amplification in general population of breast cancer patients is unclear
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