Associations between polymorphisms and abnormal RPFNA cytomorphology in high-risk postmenopausal women taking HRT

Introduction: Hormone replacement therapy (HRT) is an effective treatment option for women experiencing symptoms of menopause but long-term use is associated with an increased risk of breast cancer. HRT-related breast cancer risk is dependent on many other factors including age at menopause, age at initiation of therapy, duration of use, dose and method of delivery. Differences in genetic factors, specifically single nucleotide polymorphisms (SNP) may identify those women whose breast tissue is likely or unlikely to be seriously affected by HRT. Methods: Post-menopausal women at increased risk for breast cancer underwent breast tissue sampling by random periareolar fine needle aspiration (RPFNA) and epithelial cells were characterized as to whether they exhibited cytologic evidence of hyperplasia with atypia. DNA was isolated from buccal cells for assessment of candidate genes involved in steroid metabolism, receptor function, cell cycle control, DNA repair and/or carcinogen metabolism. Associations between each SNP and RPFNA atypia were examined by unconditional logistic regression in three different genetic models: a log-additive, dominant, and co-dominant. Linear regression was used to assess the association between each SNP and worsening cytomorphology while taking systemic HRT for ≥ 6 months vs. off systemic HRT. The adjusted significance level, p<0.001 was used to account for multiple testing. Results: RAD54 Gln929Glu, TFR Gly142Ser, VEGF 3'UTR and ACE16 I/D were associated with RPFNA atypia in all women at p<0.05 and TFR Gly142Ser reached borderline significance (p=0.0025). Interestingly, the cohort of women with RPFNA cytomorphology both while taking HRT and off HRT showed the most significant results. RAD23B Ala249Val was significantly associated with worsening cytomorphology while on HRT vs. off HRT (p=0.0009) and ERCC1 3'UTR was borderline (p=0.0015). SNPs associated with worse cytomorphology showed similar effects when we defined the outcome variable as evidence of atypia while on systemic HRT with no atypia while off systemic HRT. Conclusion: Promising associations exist between polymorphisms involved in DNA repair and worse RPFNA cytomorphology as a consequence of HRT use. However, given the probability of chance finding due to multiple testing, these results will need to be validated in an independent cohort.