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.
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.
Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, Valencia, Spain.
Zaida
Z
Garcia-Casado
Angel
A
Guerrero-Zotano
Antonio
A
Llombart-Cussac
Ana
A
Calatrava
Antonio
A
Fernandez-Serra
Amparo
A
Ruiz-Simon
Joaquin
J
Gavila
Miguel A
MA
Climent
Sergio
S
Almenar
Jose
J
Cervera-Deval
Josefina
J
Campos
Carlos Vazquez
CV
Albaladejo
Antonio
A
Llombart-Bosch
Vicente
V
Guillem
Jose A
JA
Lopez-Guerrero
D020413:3' Untranslated Regions; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D001141:Aromatase / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D000077289:Letrozole; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D009570:Nitriles / Q000494:pharmacology*; D011110:Polymorphism, Genetic; D017698:Postmenopause; D016896:Treatment Outcome; D014230:Triazoles / Q000494:pharmacology*
D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole; D001141:Aromatase