Letrozole efficacy is related to human aromatase CYP19 single nucleotide polymorphisms (SNPs) in metastatic breast cancer

The efficacy of aromatase inhibitors varies widely among postmenopausal breast cancer patients, but it is not associated with aromatase gene expression. We evaluated whether polymorphisms of the aromatase gene CYP19 are related to the efficacy of the aromatase inhibitor letrozole.

PCR allelic discrimination was used to examine single nucleotide polymorphisms (SNPs) in DNA obtained from 67 breast carcinomas. Postmenopausal patients with hormone receptor positive metastatic breast cancer were treated with the aromatase inhibitor letrozole. All patients in the study had documented disease progression before receiving letrozole, and had been treated previously with tamoxifen or another selective estrogen receptor modulator (SERM). Sixty-five patients were evaluable for efficacy. Three regions of the aromatase CYP19 gene were examined: two were localized in the 3' untranslated region (UTR; rs10046 and rs4646) and one in the intronic region (rs727479). Presence of variant gene polymorphisms was correlated with the efficacy end-point of the study, which was time to treatment progression (TTP).

The median age of patients was 62 years, and the median number of metastatic sites was two. Median TTP was 12.1 months. Percentage of cases with allelic SNP variation of rs10046 was 69%, of rs4646 was 48%, and of rs727479 was 63%. TTP was significantly longer in patients with the rs4646 variant of CYP19 when compared with normal CYP19 (17.2 months versus 6.4 months; P = 0.02). A relationship of TTP with the rs10046 or rs727479 variant was not observed.

In hormone receptor positive metastatic breast cancer patients treated with the aromatase inhibitor letrozole, the presence of a SNP on the 3'-UTR of the CYP19 aromatase gene is associated with improved treatment efficacy, and may help in the future to select patients for antiaromatase therapy.