Abstract P5-12-05: CYP3A4*22 polymorphism is associated with increased exemestane concentrations in postmenopausal breast cancer patients
Authors: Hertz DL , Kidwell KM , Seewald NJ , Gersch CL , Desta Z , Flockhart DA , Storniolo AM , Stearns V , Skaar TC , Hayes DF , Henry NL , Rae JM 
Published: May 2016

Background: Exemestane is a second generation steroidal aromatase inhibitor (AI) used for the treatment of estrogen receptor (ER) positive breast cancer in postmenopausal women. Variability in AI treatment efficacy and side effects seen across patients may be due, in part, to inter-patient differences in drug exposure. This exposure variability is likely caused by patient genetics factors, such as single nucleotide polymorphisms (SNPs) in drug metabolizing enzymes, or clinical factors such as patient body size, organ function, and comorbidities. The objective of this secondary correlative analysis was to identify genetic and clinical characteristics that affect steady state exemestane concentration, with a specific focus on the influence of inherited genetic variants and baseline hepatic function.

Methods: 500 patients were enrolled on the Exemestane and Letrozole Pharmacogenetics (ELPh) Study and randomized to either drug. Clinical data and DNA were collected at baseline and blood samples were collected after 1 or 3 months of treatment to measure steady-state exemestane concentration via HPLC/MS. Genotyping was performed on a custom Sequenom MassARRAY iPLEX that included the recently discovered low activity CYP3A4*22 (rs35599367) SNP and several other SNPs with putative functional consequence in enzymes thought to be involved in exemestane metabolism (CYP1A1/2, CYP1B1, CYP3A4, CYP4A11, AKR1C3/4, AKR7A2). Our primary hypothesis was that patients carrying CYP3A4*22 variants would have higher serum exemestane concentrations. Other SNPs and clinical characteristics (hepatic and renal function, age, body mass index (BMI), time of sample collection, prior chemotherapy) were assessed for independent association, and then adjusted for in a multivariable tobit regression model for CYP3A4*22 on log-transformed censored exemestane concentration.

Results: 246 (225 randomized to exemestane arm, 21 crossed-over from letrozole arm) patients had exemestane steady state levels and were evaluable in this analysis. As hypothesized, the CYP3A4*22 polymorphism (minor allele frequency=0.06) was associated with a 54% increase in exemestane concentration (95% CI: 14% - 109%, p&lt;0.01). Exemestane concentration was 44% greater in patients who had evidence of hepatic impairment (AST or ALT&gt;40) at baseline (95% CI: 2% - 104%, p=0.02), 1% lower per unit increase in BMI (95% CI: 0% - 3%, p=0.05), and 20% lower in patients who received prior chemotherapy (95% CI: 4% - 34%, p=0.03). Age, renal impairment, and other SNPs were not associated with exemestane concentration. After adjustment for significant clinical covariates the CYP3A4*22 SNP remained significant (p&lt;0.01).

Conclusions: Genetic and clinical predictors of exemestane concentration were discovered in a large cohort of prospectively enrolled estrogen responsive breast cancer patients. Ongoing analyses will determine whether the variability in exemestane concentration was associated with downstream effects on estrogen depletion or treatment-related toxicity. If so, these genetic and clinical characteristics could be useful for individualizing dosing of exemestane to ensure that all patients are receiving maximal benefit with minimal toxicity.

Citation Format: Hertz DL, Kidwell KM, Seewald NJ, Gersch CL, Desta Z, Flockhart DA, Storniolo AM, Stearns V, Skaar TC, Hayes DF, Henry NL, Rae JM. CYP3A4*22 polymorphism is associated with increased exemestane concentrations in postmenopausal breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-12-05.