Garcia-Casado et al. BMC Cancer 2010, 10:36 http://www.biomedcentral.com/1471-2407/10/36 R E S E A R C H A R T I C L E Open Access 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, Jose A Lopez-Guerrero1* 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. Background After cessation of ovarian activity at postmenopause, the aromatase [cytochrome P450 19 (CYP19); OMIM:107910] from bones, adipose tissue and muscle, becomes the key enzyme in estradiol and estrone bio- synthesis through the aromatization of testosterone and * Correspondence: jalopez@fivo.org † Contributed equally 1Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, Valencia, Spain androstenedione respectively [1]. Aromatase is encoded by CYP19A1 which maps at chromosome 15q21.1 and has a complex structure with a region that contains 10 tissue-specific non-coding upstream exons with separate promoters that regulate transcription in different cells and tissues [2]. Elevated levels of aromatase expression have been observed in breast tumors relative to normal breast tissue [3], and alterations in aromatase expression have been implicated in the pathogenesis of estrogen- dependent diseases, including breast cancer (BC) [4,5]. © 2010 Garcia-Casado et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.