Open Access Research article

A polymorphism at the 3'-UTR region of the aromatase gene defines a subgroup of postmenopausal breast cancer patients with poor response to neoadjuvant letrozole

Zaida Garcia-Casado1, Angel Guerrero-Zotano2, Antonio Llombart-Cussac3, Ana Calatrava4, Antonio Fernandez-Serra1, Amparo Ruiz-Simon2, Joaquin Gavila2, Miguel A Climent2, Sergio Almenar4, Jose Cervera-Deval6, Josefina Campos7, Carlos Vazquez Albaladejo7, Antonio Llombart-Bosch5, Vicente Guillem2 and Jose A Lopez-Guerrero1*

  • * Corresponding author: Jose A Lopez-Guerrero jalopez@fivo.org

  • † Equal contributors

Author Affiliations

1 Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, Valencia, Spain

2 Department of Medical Oncology, Fundación Instituto Valenciano de Oncología, Valencia, Spain

3 Department of Medical Oncology, Hospital Arnau de Villanova, Lleida, Spain

4 Department of Pathology, Fundación Instituto Valenciano de Oncología, Valencia, Spain

5 Department of Pathology, University of Valencia, Spain

6 Department of Radiology, Fundación Instituto Valenciano de Oncología, Valencia, Spain

7 Department of Surgery, Fundación Instituto Valenciano de Oncología, Valencia, Spain

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BMC Cancer 2010, 10:36  doi:10.1186/1471-2407-10-36

Published: 9 February 2010

Abstract

Background

Aromatase (CYP19A1) regulates estrogen biosynthesis. Polymorphisms in CYP19A1 have been related to the pathogenesis of breast cancer (BC). Inhibition of aromatase with letrozole constitutes the best option for treating estrogen-dependent BC in postmenopausal women. We evaluate a series of polymorphisms of CYP19A1 and their effect on response to neoadjuvant letrozole in early BC.

Methods

We analyzed 95 consecutive postmenopausal women with stage II-III ER/PgR [+] BC treated with neoadjuvant letrozole. Response to treatment was measured by radiology at 4th month by World Health Organization (WHO) criteria. Three polymorphisms of CYP19A1, one in exon 7 (rs700519) and two in the 3'-UTR region (rs10046 and rs4646) were evaluated on DNA obtained from peripheral blood.

Results

Thirty-five women (36.8%) achieved a radiological response to letrozole. The histopathological and immunohistochemical parameters, including hormonal receptor status, were not associated with the response to letrozole. Only the genetic variants (AC/AA) of the rs4646 polymorphism were associated with poor response to letrozole (p = 0.03). Eighteen patients (18.9%) reported a progression of the disease. Those patients carrying the genetic variants (AC/AA) of rs4646 presented a lower progression-free survival than the patients homozygous for the reference variant (p = 0.0686). This effect was especially significant in the group of elderly patients not operated after letrozole induction (p = 0.009).

Conclusions

Our study reveals that the rs4646 polymorphism identifies a subgroup of stage II-III ER/PgR [+] BC patients with poor response to neoadjuvant letrozole and poor prognosis. Testing for the rs4646 polymorphism could be a useful tool in order to orientate the treatment in elderly BC patients.