Effects of germline CYP2W1*6 and CYP2B6*6 single nucleotide polymorphisms on mitotane treatment in adrenocortical carcinoma: a multicenter ENSAT study

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Authors

  • Barbara Altieri
  • Silviu Sbiera
  • Sabine Herterich
  • Silvia De Francia
  • Silvia Della Casa
  • Anna Calabrese
  • Alfredo Pontecorvi
  • Marcus Quinkler
  • Tina Kienitz
  • Massimo Mannelli
  • Letizia Canu
  • Anna Angelousi
  • Vasileios Chortis
  • Matthias Kroiss
  • Massimo Terzolo
  • Martin Fassnacht

Abstract

Mitotane is the only approved drug for advanced adrenocortical carcinoma (ACC) and no biomarkers are available to predict attainment of therapeutic plasma concentrations and clinical response. Aim of the study was to evaluate the suitability of cytochrome P450(CYP)2W1 and CYP2B6 single nucleotide polymorphisms (SNPs) as biomarkers. A multicenter cohort study including 182 ACC patients (F/M = 121/61) treated with mitotane monotherapy after radical resection (group A, n = 103) or in not completely resectable, recurrent or advanced disease (group B, n = 79) was performed. CYP2W1*2, CYP2W1*6, CYP2B6*6 and CYP2B6 rs4803419 were genotyped in germline DNA. Mitotane blood levels were measured regularly. Response to therapy was evaluated as time to progression (TTP) and disease control rate (DCR). Among investigated SNPs, CYP2W1*6 and CYP2B6*6 correlated with mitotane treatment only in group B. Patients with CYP2W1*6 (n = 21) achieved less frequently therapeutic mitotane levels (>14 mg/L) than those with wild type (WT) allele (76.2% vs 51.7%, p = 0.051) and experienced shorter TTP (HR = 2.10, p = 0.019) and lower DCR (chi-square = 6.948, p = 0.008). By contrast, 55% of patients with CYP2B6*6 vs. 28.2% WT (p = 0.016) achieved therapeutic range. Combined, a higher rate of patients with CYP2W1*6WT+CYP2B6*6 (60.6%) achieved mitotane therapeutic range (p = 0.034). In not completely resectable, recurrent or advanced ACC, CYP2W1*6 SNP was associated with a reduced probability to reach mitotane therapeutic range and lower response rates, whereas CYP2B6*6 correlated with higher mitotane levels. The association of these SNPs may predict individual response to mitotane.

Details

Original languageEnglish
Article number359
JournalCancers
Volume12
Issue number2
Publication statusPublished - 4 Feb 2020

Keywords

  • adrenocortical carcinoma, mitotane, CYP2W1, CYP2B6, SNP, biomarker, predictive marker