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01-11-2011 | Original Article

Single nucleotide polymorphisms of CYP19A1 predict clinical outcomes and adverse events associated with letrozole in patients with metastatic breast cancer

Authors: In Hae Park, Yeon-Su Lee, Keun Seok Lee, Sook-young Kim, Seung-Hyun Hong, Jaeheon Jeong, Hyewon Lee, Jungsil Ro, Byung-Ho Nam

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2011

Abstract

Purpose

The CYP19A1 gene encodes the aromatase enzyme involved in the peripheral conversion of androgen to estrogen. We evaluated the efficacy of the aromatase inhibitor letrozole in patients with metastatic breast cancer (MBC) as related to DNA polymorphisms of CYP19A1.

Patients and methods

One hundred and nine patients with hormone receptor–positive MBC were treated with letrozole alone or in combination with a GnRH agonist. DNA was isolated from peripheral blood and genotyped for 46 single nucleotide polymorphisms (SNPs) of CYP19A1.

Results

Among 46 SNPs examined, rs700518, rs10459592, and rs4775936 were significantly associated with higher clinical benefit rate (CBR, CR + PR + SD ≥ 6 months) (OR = 2.61 [95% CI; 1.13–6.03], P = 0.025; OR = 2.45 [95% CI; 1.06–5.65], P = 0.036; OR = 2.60 [95% CI; 1.12–6.02], P = 0.026, respectively). Median time to progression (TTP) was improved without statistical significance in patients having an over-dominant form of rs700518. In haplotype analysis, the specific haplotypes M_1_3 and M_2_1 showed a strong association with CBR (OR = 3.37 [95% CI 1.43–7.90], P = 0.005; OR = 5.33 [95% CI 1.63–17.45], P = 0.006, respectively). There was a statistically significant difference in TTP in patients with haplotype M_1_3 (5.61 months [95% CI 0.00–11.45] vs. 11.08 months [95% CI 6.75–15.42], P = 0.040) and M_2_1 (7.31 months [95% CI 4.63–9.99] vs. 12.95 months [95% CI 9.27–16.63], P = 0.038). Haplotypes M_3_5 (OR = 11.25 [95% CI 1.17–108.28], P = 0.01) and M_5_3 (OR = 4.12, [95% CI 1.09–15.61], P = 0.03) were associated with side effects of arthralgia and hot flash, respectively.

Conclusion

The genetic variations of CYP19A1 were significantly associated with clinical efficacy, suggesting potential predictive markers for letrozole treatment in patients with metastatic breast cancer.

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Title: Single nucleotide polymorphisms of CYP19A1 predict clinical outcomes and adverse events associated with letrozole in patients with metastatic breast cancer
Authors: In Hae Park
Yeon-Su Lee
Keun Seok Lee
Sook-young Kim
Seung-Hyun Hong
Jaeheon Jeong
Hyewon Lee
Jungsil Ro
Byung-Ho Nam
Publication date: 01-11-2011
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 5/2011
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-011-1615-y

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