Abstract P3-12-07: Pharmacogenetic determinants of aromatase inhibitors pharmacokinetics and side effects: 6-month results of the adjuvant breast cancer longitudinal PHACS study (NCT01127295)
Authors: Thomas F , Marquet P , Pinguet F , White-Koning M , Robert J , Tafzi N , Solassol I , Despax R , Levasseur N , Ellis S , Massoubre A , Mbatchi L , Le Morvan V , Roché H , Chatelut E , Evrard A 
Published: February 2018

Abstract
Supported by a PHRC grant (#09-18-005)
Background: Recent literature has suggested that germline genetic variants of drug-metabolizing enzymes or CYP19A1 (coding for aromatase) may be involved in the systemic aromatase inhibitors (AI) concentrations or the occurrence of side effects (Hertz et al. Pharmacogenomics 2017). A prospective multicentre 3-year follow-up study was carried out to investigate the relationships between pharmacogenetics (PG), pharmacokinetics (PK) and toxicity in breast cancer patients treated with adjuvant AI (n=1098) or tamoxifen (n=879). The clinical results and the tamoxifen PG/PK analyses are described elsewhere (abstracts #851544 and #850248).
Methods: SNP genotyping of 95 SNPs was performed on the Biomark (Fluidigm) with Taqman assays and was available for 373, 515 and 151 patients treated with anastrozole (ANA), letrozole (LETRO) and exemestane (EXE) respectively. CYP2A6 metaboliser status (MS) (poor, intermediate or normal) was determined based on alleles function (*1, *9, *2) and number of CYP2A6 copies. Trough plasma concentrations of each drug were determined 6 months after the start of the study by UPLC-MS/MS and were available for 342, 463 and 130 patients of the ANA, LETRO and EXE arms. Patients with AI concentrations below the limit of quantification were excluded for non-compliance (9 patients for ANA, 8 patients for LETRO and 7 patients for EXE). Toxicity was measured as a binary outcome (occurrence or worsening of hot flushes, fatigue, pain, arthralgia, vaginal dryness). All genetic associations were adjusted for multiple testing.
Results: ANA concentration was significantly higher in patients experiencing pain (p=0.025) and was associated with rs28365063 (UGT2B7 g.372A&gt;G).
LETRO concentrations were strongly associated with CYP2A6 metabolizer status (p=0.0001) but did not differ in patients with or without toxicity.
In the EXE arm, patients with hot flushes or arthralgia had a significantly lower level of exemestane (p= 0.0002 and p=0.023 respectively) but since the metabolism of EXE leads to active 17-hydroexemestane, we can hypothesize that the lower EXE concentration is an indirect reflection of the metabolite formation. A SNP (rs2307424) in NR1I3 gene (coding for the constitutive androstane receptor CAR) was associated with EXE concentrations. CAR has been shown to regulate CYP2B6, which is involved in the formation of 6-hydroxy-methyl-exemestane (inactive metabolite).
Regarding the relationships between PG and toxicity, in the ANA arm, 3 SNPs of CYP19A1 gene tended to be associated with hot flushes worsening (rs934635) and arthralgia (rs10046 and rs2304463) but did not remain significant after multiple tests correction. In the EXE arm, several SNPs in NR1I3 gene were associated with fatigue.
In the LETRO arm, patients with a poor CYP2A6 MS had a higher risk of experiencing depression.
Conclusions: Our study confirms the predominant role of CYP2A6 in LETRO PK. To our knowledge, this is the first study to report on the role of UGT2B7 rs28365063 in ANA and NR1I3 in EXE PK and side effects. These relationships need to be re-evaluated with the drug concentrations obtained during the 3-year follow-up.
Citation Format: Thomas F, Marquet P, Pinguet F, White-Koning M, Robert J, Tafzi N, Solassol I, Despax R, Levasseur N, Ellis S, Massoubre A, Mbatchi L, Le Morvan V, Roché H, Chatelut E, Evrard A. Pharmacogenetic determinants of aromatase inhibitors pharmacokinetics and side effects: 6-month results of the adjuvant breast cancer longitudinal PHACS study (NCT01127295) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-12-07.