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Single nucleotide polymorphisms of CYP19A1 predict clinical outcomes and adverse events associated with letrozole in patients with metastatic breast cancer
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Single nucleotide polymorphisms of CYP19A1 predict clinical outcomes and adverse events associated with letrozole in patients with metastatic breast cancer
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Single nucleotide polymorphisms of CYP19A1 predict clinical outcomes and adverse events associated with letrozole in patients with metastatic breast cancer
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Journal Article
Single nucleotide polymorphisms of CYP19A1 predict clinical outcomes and adverse events associated with letrozole in patients with metastatic breast cancer
2011
Overview
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.
Publisher
Springer-Verlag,Springer,Springer Nature B.V
Subject
/ Aged
/ Antineoplastic Agents - adverse effects
/ Antineoplastic Agents - therapeutic use
/ Biological and medical sciences
/ Breast Neoplasms - drug therapy
/ Breast Neoplasms - pathology
/ Enzymes
/ Female
/ Gonadotropin-releasing hormone
/ Gynecology. Andrology. Obstetrics
/ Hormones
/ Humans
/ Medicine
/ Oncology
/ Pharmacology. Drug treatments
/ Polymorphism, Single Nucleotide
/ Single-nucleotide polymorphism
/ Tumors
