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

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 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.Aromatase inhibitors, when administered to postmenopausal women, prevent the conversion of androgens to estrogens via inhibition of the aromatase enzyme. The antiaromatase compounds 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 progesterone 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 nonresponding patients is low. Additional biomarkers that could h...

Impact of Aromatase Genetic Variation on Hormone Levels and Global Outcome after Severe TBI

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Rs1008805 polymorphism of CYP19A1 gene is associated with the efficacy of hormone therapy in stage I‑II and operable stage III breast cancer

“…In addition, a study conducted by Garcia-Casado et al (18) estimated that the same variant was significantly associated with poorer progression-free survival (PFS) in patients with letrozole neoadjuvant therapy, and patients with genotypic variants of rs4646 were more frequently represented in the non-responder cohort (48 vs. 26%). However, Liu et al (19) suggested that A allele of rs4646 was significantly associated with longer time to progression (TTP) and OS when assessed in patients with metastatic breast cancer (MBC) receiving anastrozole treatment, consistent with the study of Colomer et al (20), which indicated that TTP was significantly prolonged in patients with the minor T allele of CYP19A1 rs4646 compared with those with homozygous common allele (GG) from a cohort of postmenopausal MBC with letrozole administration.…”

Short-Term Biomarker Modulation Prevention Study of Anastrozole in Women at Increased Risk for Second Primary Breast Cancer

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