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A Single-Nucleotide Polymorphism in the Aromatase Gene Is Associated with the Efficacy of the Aromatase Inhibitor Letrozole in Advanced Breast Carcinoma

Authors' Affiliations: ¹ M. D. Anderson Cancer Center España; ² Hospital Ramon y Cajal, Madrid, Spain; ³ Universitat de Barcelona; ⁴ Hospital Sant Pau; ⁵ Hospital del Mar; ⁶ Hospital Clinic; ⁷ Novartis Oncology; ⁸ Institut Catala d'Oncologia, L'Hospitalet, Barcelona, Spain; ⁹ Hospital Son Dureta, Palma de Mallorca, Spain; ¹⁰ Hospital Puerta del Mar, Cadiz, Spain; ¹¹ Hospital Juan Canalejo, Coruña, Spain; ¹² Hospital Carlos Haya; ¹³ Hospital Virgen de la Victoria, Malaga, Spain; ¹⁴ Hospital Arnau de Vilanova, Lleida, Spain; and ¹⁵ Instituto Oncológico de Guipuzcoa, San Sebastian, Spain

Requests for reprints: Ramon Colomer, M. D. Anderson Cancer Center España, 28033 Madrid, Spain. Phone: 34-91-768-0682; Fax: 34-91-787-8635; E-mail: rcolomer{at}mdanderson.es.

Purpose: To evaluate the efficacy of treatment with the aromatase inhibitor letrozole in breast cancer patients segregated with respect to DNA polymorphisms of the aromatase gene CYP19.

Patients and Methods: Postmenopausal patients (n = 67) with hormone receptor–positive metastatic breast cancer were treated with the aromatase inhibitor letrozole. PCR allelic discrimination was used to examine three single-nucleotide polymorphisms (SNP) in DNA obtained from breast carcinoma tissue. Two SNPs analyzed (rs10046 and rs4646) were located in the 3' untranslated region and one (rs727479) was in the intron of the aromatase CYP19 gene. The primary end point of treatment efficacy was time to progression (TTP).

Results: Median age was 62 years and median number of metastatic sites was 2. Observed allelic SNP frequencies were rs10046, 71%; rs4646, 46%; and rs727479, 63%. Of the 67 patients, 65 were evaluable for efficacy. Median TTP was 12.1 months. We observed no relationship between TTP and the rs10046 or rs727479 variants. In contrast, we found that TTP was significantly improved in patients with the rs4646 variant, compared with the wild-type gene (17.2 versus 6.4 months; P = 0.02).

Conclusion: In patients with hormone receptor–positive metastatic breast cancer treated with the aromatase inhibitor letrozole, the presence of a SNP in the 3' untranslated region of the CYP19 aromatase gene is associated with improved treatment efficacy. Testing for the CYP19 rs4646 SNP as a predictive tool for breast cancer patients on antiaromatase therapy deserves prospective evaluation.

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