Prognostic Significance of ESR1 Amplification and ESR1 PvuII, CYP2C19*2, UGT2B15*2 Polymorphisms in Breast Cancer Patients

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Abstract

Introduction

Amplification 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 Methods

Primary 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.

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Most cited references 27

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REporting recommendations for tumour MARKer prognostic studies (REMARK)

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Despite years of research and hundreds of reports on tumour markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons that multiple studies of the same marker lead to differing conclusions. A variety of methodological problems have been cited to explain these discrepancies. Unfortunately, many tumour marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalisability of the study results. The development of guidelines for the reporting of tumour marker studies was a major recommendation of the US National Cancer Institute and the European Organisation for Research and Treatment of Cancer (NCI-EORTC) First International Meeting on Cancer Diagnostics in 2000. Similar to the successful CONSORT initiative for randomised trials and the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, preplanned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines suggest helpful presentations of data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply.

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Biological determinants of endocrine resistance in breast cancer.

Elizabeth Musgrove, Robert Sutherland (2009)

Endocrine therapies targeting oestrogen action (anti-oestrogens, such as tamoxifen, and aromatase inhibitors) decrease mortality from breast cancer, but their efficacy is limited by intrinsic and acquired therapeutic resistance. Candidate molecular biomarkers and gene expression signatures of tamoxifen response emphasize the importance of deregulation of proliferation and survival signalling in endocrine resistance. However, definition of the specific genetic lesions and molecular processes that determine clinical endocrine resistance is incomplete. The development of large-scale computational and genetic approaches offers the promise of identifying the mediators of endocrine resistance that may be exploited as potential therapeutic targets and biomarkers of response in the clinic.

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Clinical significance of the cytochrome P450 2C19 genetic polymorphism.

X. Zhao, D Flockhart, Jae-Ho Shin … (2001)

Cytochrome P450 2C19 (CYP2C19) is the main (or partial) cause for large differences in the pharmacokinetics of a number of clinically important drugs. On the basis of their ability to metabolise (S)-mephenytoin or other CYP2C19 substrates, individuals can be classified as extensive metabolisers (EMs) or poor metabolisers (PMs). Eight variant alleles (CYP2C19*2 to CYP2C19*8) that predict PMs have been identified. The distribution of EM and PM genotypes and phenotypes shows wide interethnic differences. Nongenetic factors such as enzyme inhibition and induction, old age and liver cirrhosis can also modulate CYP2C19 activity. In EMs, approximately 80% of doses of the proton pump inhibitors (PPIs) omeprazole, lansoprazole and pantoprazole seem to be cleared by CYP2C19, whereas CYP3A is more important in PMs. Five-fold higher exposure to these drugs is observed in PMs than in EMs of CYP2C19, and further increases occur during inhibition of CYP3A-catalysed alternative metabolic pathways in PMs. As a result, PMs of CYP2C19 experience more effective acid suppression and better healing of duodenal and gastric ulcers during treatment with omeprazole and lansoprazole compared with EMs. The pharmacoeconomic value of CYP2C19 genotyping remains unclear. Our calculations suggest that genotyping for CYP2C19 could save approximately 5000 US dollars for every 100 Asians tested, but none for Caucasian patients. Nevertheless, genotyping for the common alleles of CYP2C19 before initiating PPIs for the treatment of reflux disease and H. pylori infection is a cost effective tool to determine appropriate duration of treatment and dosage regimens. Altered CYP2C19 activity does not seem to increase the risk for adverse drug reactions/interactions of PPIs. Phenytoin plasma concentrations and toxicity have been shown to increase in patients taking inhibitors of CYP2C19 or who have variant alleles and, because of its narrow therapeutic range, genotyping of CYP2C19 in addition to CYP2C9 may be needed to optimise the dosage of phenytoin. Increased risk of toxicity of tricyclic antidepressants is likely in patients whose CYP2C19 and/or CYP2D6 activities are diminished. CYP2C19 is a major enzyme in proguanil activation to cycloguanil, but there are no clinical data that suggest that PMs of CYP2C19 are at a greater risk for failure of malaria prophylaxis or treatment. Diazepam clearance is clearly diminished in PMs or when inhibitors of CYP2C19 are coprescribed, but the clinical consequences are generally minimal. Finally, many studies have attempted to identify relationships between CYP2C19 genotype and phenotype and susceptibility to xenobiotic-induced disease, but none of these are compelling.

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Author and article information

Contributors

Rui Medeiros: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 8 August 2013

Volume: 8

Issue: 8

Electronic Location Identifier: e72219

Affiliations

[1 ]Department of Medical Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland

[2 ]PostgraduateSchool of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland

[3 ]Department of Oncology and Radiotherapy, Medical University of Gdańsk, Gdańsk, Poland

[4 ]Bank of Frozen Tissues and Genetic Specimens, Department of Medical Laboratory Diagnostics, Medical University of Gdańsk, Gdańsk, Poland

[5 ]Department of Surgical Oncology, Medical University of Gdańsk, Gdańsk, Poland

[6 ]Department of Pathology, Medical University of Gdańsk, Gdańsk, Poland

IPO, Inst Port Oncology, Portugal

Author notes

* E-mail: azaczek@ 123456gumed.edu.pl

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: AM MWJ AJZ. Performed the experiments: AM J. Szade AJZ. Analyzed the data: AM AJZ J. Jassem. Contributed reagents/materials/analysis tools: AM MWJ J. Skokowski J. Jaskiewicz AJZ. Wrote the manuscript: AM AJZ. Drafted the article or revised it: AM MWJ J. Jaskiewicz J. Szade J. Skokowski J. Jassem AJZ. Final approval of the manuscript: AM MWJ J. Jaskiewicz J. Szade J. Skokowski J. Jassem AJZ.

Article

Publisher ID: PONE-D-13-09330

DOI: 10.1371/journal.pone.0072219

PMC ID: 3738574

PubMed ID: 23951298

SO-VID: 52b0627b-29e8-43e6-8823-bda94aee65bf

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 6 March 2013

Date accepted : 7 July 2013

Funding

This research was supported by a grant from the National Science Centre N N402 686240 and a grant from the University of Gdańsk 538-M000-1294-12. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Prognostic Significance of ESR1 Amplification and ESR1 PvuII, CYP2C192, UGT2B152 Polymorphisms in Breast Cancer Patients

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Abstract

Introduction

Materials and Methods

Results

Conclusions

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PLOS: COVID-19 pandemic

Most cited references 27

REporting recommendations for tumour MARKer prognostic studies (REMARK)

Biological determinants of endocrine resistance in breast cancer.

Clinical significance of the cytochrome P450 2C19 genetic polymorphism.

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