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

BMC Cancer. 2010 Feb 9;10:36. doi: 10.1186/1471-2407-10-36.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions*
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / pharmacology
  • Aromatase / genetics*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics*
  • Disease Progression
  • Female
  • Humans
  • Immunohistochemistry / methods
  • Letrozole
  • Middle Aged
  • Neoadjuvant Therapy / methods*
  • Nitriles / pharmacology*
  • Polymorphism, Genetic*
  • Postmenopause
  • Treatment Outcome
  • Triazoles / pharmacology*

Substances

  • 3' Untranslated Regions
  • Antineoplastic Agents
  • Nitriles
  • Triazoles
  • Letrozole
  • Aromatase