ASingle-NucleotidePolymorphismintheAromataseGeneIs AssociatedwiththeEfficacyoftheAromataseInhibitor LetrozoleinAdvancedBreastCarcinoma RamonColomer, 1 Mariano Monzo, 3 IgnasiTusquets, 5 Juli Rifa, 9 Jose¤ M.Baena, 10 AgustiBarnadas, 4 LourdesCalvo, 11 FranciscoCarabantes, 12 CarmenCrespo, 2 MontserratMun ˜ oz, 6 AntonioLlombart, 14 ArratePlazaola, 15 RosaArtells, 3 MonstsrratGilabert, 7 BelenLloveras, 8 andEmilioAlba 13 Abstract 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 inthe3¶ 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 allelicSNPfrequencieswerers10046,71%;rs4646,46%;andrs727479,63%.Ofthe67patients, 65 were evaluable for efficacy. MedianTTP was 12.1months.We observed no relationship betweenTTP and the rs10046 or rs727479 variants. In contrast, we found thatTTP 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 withhormone receptor^positive metastatic breast cancer treated with thearomataseinhibitorletrozole,thepresenceofaSNPinthe3¶ untranslatedregionof theCYP19 aromatase gene is associated with improved treatment efficacy.Testing for the CYP19 rs4646 SNPasapredictivetoolforbreastcancerpatientsonantiaromatasetherapydeservesprospective evaluation. Aromatase inhibitors, when administered to postmenopausal women, prevent the conversion of androgens to estrogens via inhibition of the aromatase enzyme. The antiaromatase com- pounds have emerged as a family of potent target-directed agents in the hormonal treatment of breast cancer. Third-generation aromatase inhibitors are used in the treatment of metastatic breast carcinoma (1, 2) and in the adjuvant setting (3 – 5). Currently, the clinical indication for the use of aromatase inhibitors in breast cancer patients is guided by two criteria: a postmenopausal status and a positive hormone receptor status. Menopause is the critical criterion because functioning ovaries synthesize estrogen in an amount that would preclude aromatase inhibitors from being active. Positivity of estrogen or progester- one receptors in breast carcinomas has been related to the efficacy of tamoxifen as well as aromatase inhibitors. A recent review concluded that, when using anastrozole or letrozole as first-line treatment of patients with metastatic breast cancer, positive hormone receptor status is of prime importance in improving the time to disease progression (6). However, the clinical relevance of hormone receptors when using aromatase inhibitors is moderate because only f30% of the patients exhibit an objective clinical response (7 – 9) and, therefore, the power to discriminate potentially responding from nonrespond- ing patients is low. Additional biomarkers that could help in predicting the efficacy of aromatase inhibitors in the clinical setting are being avidly sought as guides in the use of these target- directed drugs (10). Approximately two thirds of human breast carcinomas express aromatase protein or show aromatase enzyme activity (11 – 14). However, to date, the levels of aromatase protein or biochemical activity measured in breast carcinomas have failed to show a clear clinical benefit following the administration of aromatase inhibitors (15 – 17). Cancer Therapy: Clinical Authors’Affiliations: 1 M.D.AndersonCancerCenterEspan ˜ a; 2 Hospital Ramony 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, Corun ˜ a, Spain; 12 Hospital Carlos Haya; 13 HospitalVirgen de laVictoria, Malaga, Spain; 14 Hospital Arnau deVilanova, Lleida, Spain; and 15 Instituto Oncolo¤ gico de Guipuzcoa, San Sebastian,Spain Received8/5/07;revised9/29/07;accepted11/5/07. Grantsupport: NovartisFarma,Spain. Thecostsofpublicationofthisarticleweredefrayedinpartbythepaymentofpage charges.This article must therefore be hereby marked advertisement in accordance with18U.S.C.Section1734solely toindicatethisfact. Note: PresentedinpartattheAmericanSocietyofClinicalOncology2004Annual Meeting, New Orleans, Louisiana. Requestsforreprints: Ramon Colomer, M. D. Anderson Cancer Center Espan ˜ a, 28033 Madrid, Spain. Phone: 34-91-768-0682; Fax: 34-91-787-8635; E-mail: rcolomer@mdanderson.es. F 2008AmericanAssociationforCancerResearch. doi:10.1158/1078-0432.CCR-07-1923 www.aacrjournals.org ClinCancerRes2008;14(3)February1,2008 811 Research. on April 25, 2020. © 2008 American Association for Cancer clincancerres.aacrjournals.org Downloaded from