Association of functional polymorphisms in CYP19A1 with aromatase inhibitor associated arthralgia in breast cancer survivors.
BACKGROUND
Aromatase inhibitor-associated arthralgia (AIAA) is a common and often debilitating symptom in breast cancer survivors. Since joint symptoms have been related to estrogen deprivation through the menopausal transition, we hypothesized that genetic polymorphisms in CYP19A1, the final enzyme in estrogen synthesis, may be associated with the occurrence of AIAA.


METHODS
We performed a cross-sectional study of postmenopausal women with stage 0 to III breast cancer receiving adjuvant aromatase inhibitor (AI) therapy. Patient-reported AIAA was the primary outcome. DNA was genotyped for candidate CYP19A1 polymorphisms. Serum estrogen levels were evaluated by radioimmunoassay. Multivariate analyses were performed to examine associations between AIAA and genetic variants controlling for possible confounders.


RESULTS
Among 390 Caucasian participants, 50.8% reported AIAA. Women carrying at least one 8-repeat allele had lower odds of AIAA (adjusted odds ratio (AOR) 0.41, 95% confidence interval (CI) 0.21 to 0.79, P = 0.008) after adjusting for demographic and clinical covariates. Estradiol and estrone were detectable in 47% and 86% of subjects on AIs, respectively. Although these post-AI levels were associated with multiple genotypes, they were not associated with AIAA. In multivariate analyses, women with more recent transition into menopause (less than five years) were significantly more likely to report AIAA than those greater than ten years post-menopause (AOR 3.31, 95% CI 1.72 to 6.39, P < 0.001).


CONCLUSIONS
Functional polymorphism in CYP19A1 and time since menopause are associated with patient-reported AIAA, supporting the hypothesis that the host hormonal environment contributes to the pathophysiology of AAIA. Prospective investigation is needed to further delineate relationships between host genetics, changing estrogen levels and AIAA.
Department of Family Medicine and Community Health, University of Pennsylvania School of Medicine, 3400 Spruce Street/2 Gates, Philadelphia, PA 19104, USA. maoj@uphs.upenn.edu
Jun J
JJ
Mao
H Irene
HI
Su
Rui
R
Feng
Michelle L
ML
Donelson
Richard
R
Aplenc
Timothy R
TR
Rebbeck
Frank
F
Stanczyk
Angela
A
DeMichele
D000368:Aged; D001141:Aromatase / Q000235:genetics*; D047072:Aromatase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D018771:Arthralgia / Q000139:chemically induced* / Q000235:genetics*; D001943:Breast Neoplasms / Q000150:complications* / Q000188:drug therapy; D003430:Cross-Sectional Studies; D004967:Estrogens / Q000097:blood; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017741:Survivors
D047072:Aromatase Inhibitors; D004967:Estrogens; D001141:Aromatase; C561410:CYP19A1 protein, human
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