Browsing by Author "Douglas, Julie A."

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    Genome-wide association study of aromatase inhibitor discontinuation due to musculoskeletal symptoms.
    (Springer, 2022-07-01) Hertz, Daniel L.; Douglas, Julie A.; Miller, Robert M.; Kidwell, Kelley M.; Gersch, Christina L.; Desta, Zeruesenay; Storniolo, Anna Maria; Stearns, Vered; Skaar, Todd C.; Hayes, Daniel F.; Henry, N. Lynn; Rae, James M.
    OBJECTIVE: Aromatase inhibitors (AIs) are commonly used to treat hormone receptor positive (HR +) breast cancer. AI-induced musculoskeletal syndrome (AIMSS) is a common toxicity that causes AI treatment discontinuation. The objective of this genome-wide association study (GWAS) was to identify genetic variants associated with discontinuation of AI therapy due to AIMSS and attempt to replicate previously reported associations. METHODS: In the Exemestane and Letrozole Pharmacogenetics (ELPh) study, postmenopausal patients with HR + non-metastatic breast cancer were randomized to letrozole or exemestane. Genome-wide genotyping of germline DNA was conducted followed by imputation. Each imputed variant was tested for association with time-to-treatment discontinuation due to AIMSS using a Cox proportional hazards model assuming additive genetic effects and adjusting for age, baseline pain score, prior taxane treatment, and AI arm. Secondary analyses were conducted within each AI arm and analyses of candidate variants previously reported to be associated with AIMSS risk. RESULTS: Four hundred ELPh participants were included in the combined analysis. Two variants surpassed the genome-wide significance level in the primary analysis (p value < 5 × 10(-8)), an intronic variant (rs79048288) within CCDC148 (HR = 4.42, 95% CI: 2.67-7.33) and an intergenic variant (rs912571) upstream of PPP1R14C (HR = 0.30, 95% CI: 0.20-0.47). In the secondary analysis, rs74418677, which is known to be associated with expression of SUPT20H, was significantly associated with discontinuation of letrozole therapy due to AIMSS (HR = 5.91, 95% CI: 3.16-11.06). We were able to replicate associations for candidate variants previously reported to be associated with AIMSS in this cohort, but were not able to replicate associations for any other variants previously reported in other patient cohorts. CONCLUSIONS: Our GWAS findings identify several candidate variants that may be associated with AIMSS risk from AI generally or letrozole specifically. Validation of these associations in independent cohorts is needed before translating these findings into clinical practice to improve treatment outcomes in patients with HR + breast cancer.
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    Genome-wide association study of letrozole plasma concentrations identifies non-exonic variants that may affect CYP2A6 metabolic activity.
    (Wolters Kluwer, 2021-07-01) Hertz, Daniel L.; Douglas, Julie A.; Kidwell, Kelley M.; Gersch, Christina L.; Desta, Zeruesenay; Storniolo, Ana-Maria; Stearns, Vered; Skaar, Todd C.; Hayes, Daniel F.; Henry, N. Lynn; Rae, James M.
    OBJECTIVES: Letrozole is a nonsteroidal aromatase inhibitor used to treat hormone-receptor-positive breast cancer. Variability in letrozole efficacy and toxicity may be partially attributable to variable systemic drug exposure, which may be influenced by germline variants in the enzymes responsible for letrozole metabolism, including cytochrome P450 2A6 (CYP2A6). The objective of this genome-wide association study (GWAS) was to identify polymorphisms associated with steady-state letrozole concentrations. METHODS: The Exemestane and Letrozole Pharmacogenetics (ELPh) Study randomized postmenopausal patients with hormone-receptor-positive nonmetastatic breast cancer to letrozole or exemestane treatment. Germline DNA was collected pretreatment and blood samples were collected after 1 or 3 months of treatment to measure steady-state letrozole (and exemestane) plasma concentrations via HPLC/MS. Genome-wide genotyping was conducted on the Infinium Global Screening Array (>650 000 variants) followed by imputation. The association of each germline variant with age- and BMI-adjusted letrozole concentrations was tested in self-reported white patients via linear regression assuming an additive genetic model. RESULTS: There were 228 patients who met the study-specific inclusion criteria and had both DNA and letrozole concentration data for this GWAS. The association for one genotyped polymorphism (rs7937) with letrozole concentration surpassed genome-wide significance (P = 5.26 × 10-10), explaining 13% of the variability in untransformed steady-state letrozole concentrations. Imputation around rs7937 and in silico analyses identified rs56113850, a variant in the CYP2A6 intron that may affect CYP2A6 expression and activity. rs7937 was associated with age- and BMI-adjusted letrozole levels even after adjusting for genotype-predicted CYP2A6 metabolic phenotype (P = 3.86 × 10-10). CONCLUSION: Our GWAS findings confirm that steady-state letrozole plasma concentrations are partially determined by germline polymorphisms that affect CYP2A6 activity, including variants near rs7937 such as the intronic rs56113850 variant. Further research is needed to confirm whether rs56113850 directly affects CYP2A6 activity and to integrate nonexonic variants into CYP2A6 phenotypic activity prediction systems.