title: Single nucleotide polymorphisms of CYP19A1 predict clinical outcomes and adverse events associated with letrozole in patients with metastatic breast cancer.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  The genetic variations of CYP19A1 were significantly associated with clinical efficacy, suggesting potential predictive markers for letrozole treatment in patients with metastatic breast cancer.
authors: Center for Breast Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Korea.
authors: In Hae
authors: IH
authors: Park
authors: Yeon-Su
authors: YS
authors: Lee
authors: Keun Seok
authors: KS
authors: Lee
authors: Sook-young
authors: SY
authors: Kim
authors: Seung-Hyun
authors: SH
authors: Hong
authors: Jaeheon
authors: J
authors: Jeong
authors: Hyewon
authors: H
authors: Lee
authors: Jungsil
authors: J
authors: Ro
authors: Byung-Ho
authors: BH
authors: Nam
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001141:Aromatase / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009570:Nitriles / Q000009:adverse effects / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D014230:Triazoles / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole; D001141:Aromatase; C561410:CYP19A1 protein, human