Influence of CYP19A1 polymorphisms on the treatment of breast cancer with aromatase inhibitors: a systematic review and meta-analysis

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Abstract

Background

Many clinical trials have shown the efficacy of aromatase inhibitors (AIs) in the management of breast cancer (BC). There is growing evidence that CYP19A1 single-nucleotide polymorphisms (SNPs) are associated with clinical response (CR) and adverse effects (AEs) among BC patients treated with AIs. The aim of this study was to analyze the association between CYP19A1 polymorphisms and AI treatment in BC patients.

Methods

A systematic review was performed in MEDLINE, EMBASE, and LILACS. A meta-analysis was conducted to compare the association between CYP19A1 variants and treatment response among BC patients.

Results

A total of 12 studies were included in the final analysis. There was significant variation among the populations studied and the SNPs and outcomes investigated. A meta-analysis was only possible for the evaluation of SNP rs4646 vs. the wild-type variant with respect to time to progression (TTP) among metastatic BC patients treated with AI. TTP was significantly increased in patients with the rs4646 variant compared with the wild-type gene (hazard ratio (HR) = 0.51 [95 % confidence interval (CI), 0.33–0.78], P = 0.002). Seven studies analyzed the association between AEs with different polymorphisms of CYP19A1. Although there was a statistically significant association with musculoskeletal adverse events (rs934635, rs60271534, rs700518rs, and haplotype M_3_5) and with vasomotor symptoms (rs934635, rs1694189, rs7176005, and haplotype M_5_3) in individual studies, similar associations were not observed in further studies. No statistically significant association between musculoskeletal AEs and SNPs rs4646, rs10046, rs727479, and rs1062033 was found.

Conclusions

These findings suggest that the presence of the rs4646 variant may be a predictive factor of the benefit of AI treatment for BC. The effects of CYP19A1 polymorphisms on clinical outcomes were most often detected in individual studies, suggesting that longer-term studies will better clarify these associations. Additional studies are needed to clarify the predictive value of other SNPs and whether CYP19A1 genotyping should be used to guide AI treatment.

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Most cited references 37

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Ammarin Thakkinstian, Patrick McElduff, Catherine d'Este … (2005)

Although population-based molecular association studies are becoming increasingly popular, methodology for the meta-analysis of these studies has been neglected, particularly with regard to two issues: testing Hardy-Weinberg equilibrium (HWE), and pooling results in a manner that reflects a biological model of gene effect. We propose a process for pooling results from population-based molecular association studies which consists of the following steps: (1) checking HWE using chi-square goodness of fit; we suggest performing sensitivity analysis with and without studies that are in HWE. (2) Heterogeneity is then checked, and if present, possible causes are explored. (3) If no heterogeneity is present, regression analysis is used to pool data and to determine the gene effect. (4) If there is a significant gene effect, pairwise group differences are analysed and these data are allowed to 'dictate' the best genetic model. (5) Data may then be pooled using this model. This method is easily performed using standard software, and has the advantage of not assuming an a priori genetic model. Copyright 2004 John Wiley & Sons, Ltd.

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Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis.

Eitan Amir, Saroj Niraula, Alberto Ocana … (2011)

Aromatase inhibitors are associated with consistent improvements in disease-free survival but not in overall survival. We conducted a literature-based meta-analysis of randomized trials to examine whether the relative toxicity of aromatase inhibitors compared with tamoxifen may explain this finding. We conducted a systematic review to identify randomized controlled trials that compared aromatase inhibitors and tamoxifen as primary adjuvant endocrine therapy in postmenopausal women by searching MEDLINE, EMBASE, and databases of the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium. Odds ratios (ORs), 95% confidence intervals (CIs), absolute risks, and the number needed to harm associated with one adverse event were computed for prespecified serious adverse events including cardiovascular disease, cerebrovascular disease, bone fractures, thromboembolic events, endometrial carcinoma and other second cancers not including new breast cancer. All statistical tests were two-sided. Seven trials enrolling 30,023 patients met the inclusion criteria. Longer duration of aromatase inhibitor use was associated with increased odds of developing cardiovascular disease (OR = 1.26, 95% CI = 1.10 to 1.43, P < .001; number needed to harm = 132) and bone fractures (OR = 1.47, 95% CI = 1.34 to 1.61, P < .001; number needed to harm = 46), but a decreased odds of venous thrombosis (OR = 0.55, 95% CI = 0.46 to 0.64, P < .001; number needed to harm = 79) and endometrial carcinoma (OR = 0.34, 95% CI = 0.22 to 0.53, P < .001; number needed to harm = 258). Five years of aromatase inhibitors was associated with a non-statistically significant increased odds of death without recurrence compared with 5 years of tamoxifen alone or tamoxifen for 2-3 years followed by an aromatase inhibitor for 2-3 years (OR = 1.11, 95% CI = 0.98 to 1.26, P = .09). The cumulative toxicity of aromatase inhibitors when used as up-front treatment may explain the lack of overall survival benefit despite improvements in disease-free survival. Switching from tamoxifen to aromatase inhibitors reduces this toxicity and is likely the best balance between efficacy and toxicity.

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Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98.

John F Forbes, István Láng, E Jakobsen … (2007)

Previous analyses of the Breast International Group (BIG) 1-98 four-arm study compared initial therapy with letrozole or tamoxifen including patients randomly assigned to sequential treatment whose information was censored at the time of therapy change. Because this presentation may unduly reflect early events, the present analysis is limited to patients randomly assigned to the continuous therapy arms and includes protocol-defined updated results. Four thousand nine hundred twenty-two of the 8,028 postmenopausal women with receptor-positive early breast cancer randomly assigned (double-blind) to the BIG 1-98 trial were assigned to 5 years of continuous adjuvant therapy with either letrozole or tamoxifen; the remainder of women were assigned to receive the agents in sequence. Disease-free survival (DFS) was the primary end point. At a median follow-up time of 51 months, we observed 352 DFS events among 2,463 women receiving letrozole and 418 events among 2,459 women receiving tamoxifen. This reflected an 18% reduction in the risk of an event (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .007). No predefined subsets showed differential benefit. Adverse events were similar to previous reports. Patients on tamoxifen experienced more thromboembolic events, endometrial pathology, hot flashes, night sweats, and vaginal bleeding. Patients on letrozole experienced more bone fractures, arthralgia, low-grade hypercholesterolemia, and cardiovascular events other than ischemia and cardiac failure. The present updated analysis, which was limited to patients on monotherapy arms in BIG 1-98, yields results similar to those from the previous primary analysis but more directly comparable with results from other trials of continuous therapy using a single endocrine agent.

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Author and article information

Contributors

Osvaldo Artigalás: artigalas@gmail.com

Tazio Vanni: taziovanni@gmail.com

Mara Helena Hutz: mara.hutz@ufrgs.br

Patricia Ashton-Prolla: pprolla@gmail.com

Ida Vanessa Schwartz: idadschwartz@gmail.com

Journal

Journal ID (nlm-ta): BMC Med

Journal ID (iso-abbrev): BMC Med

Title: BMC Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1741-7015

Publication date (Electronic): 11 June 2015

Publication date PMC-release: 11 June 2015

Publication date Collection: 2015

Volume: 13

Electronic Location Identifier: 139

Affiliations

[ ]Postgraduate Program in Genetics and Molecular Biology, Department of Genetics, UFRGS, Av. Bento Gonçalves, 9500 - Prédio 43323M CEP: 91501-970 - Caixa Postal 15053 Porto Alegre, Rio Grande do Sul Brazil

[ ]Genetics Unit, Children’s Hospital, Grupo Hospitalar Conceição, GHC, Av. Francisco Trein, 596, CEP 91350-200 Porto Alegre, RS Brazil

[ ]Coordenação Geral de Avaliação de Tecnologias em Saúde – CGATS, Department of Science and Technology, Ministry of Health, SCN Quadra 02 Projeção C Subsolo Sala T-004, CEP: 70712-902 Brasília, DF Brazil

[ ]Medical Genetics Service, Hospital de Clinicas de Porto Alegre, HCPA, Rua Ramiro Barcelos, 2350, CEP: 90035-903 Porto Alegre, RS Brazil

Article

Publisher ID: 373

DOI: 10.1186/s12916-015-0373-9

PMC ID: 4475294

PubMed ID: 26067721

SO-VID: 142c2952-5293-4ce2-a409-99455bc8842f

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 17 January 2015

Date accepted : 18 May 2015

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ScienceOpen disciplines: Medicine

Keywords: adverse effects,aromatase inhibitors,breast cancer,clinical outcomes,cyp19a1,meta-analysis,pharmacogenetics,systematic review

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ScienceOpen disciplines: Medicine

Keywords: adverse effects, aromatase inhibitors, breast cancer, clinical outcomes, cyp19a1, meta-analysis, pharmacogenetics, systematic review

Influence of CYP19A1 polymorphisms on the treatment of breast cancer with aromatase inhibitors: a systematic review and meta-analysis

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Karger: Oncology

Most cited references 37

A method for meta-analysis of molecular association studies.

Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis.

Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98.

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