Effects of Germline CYP2W1*6 and CYP2B6*6 Single Nucleotide Polymorphisms on Mitotane Treatment in Adrenocortical Carcinoma: A Multicenter ENSAT Study

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, <i>n</i> = 103) or in not completely resectable, recurrent or advanced disease (group B, <i>n</i> = 79) was performed. <i>CYP2W1*2</i>, <i>CYP2W1*6</i>, <i>CYP2B6*6</i> and <i>CYP2B6 rs4803419</i> 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, <i>CYP2W1*6</i> and <i>CYP2B6*6</i> correlated with mitotane treatment only in group B. Patients with <i>CYP2W1*6</i> (<i>n</i> = 21) achieved less frequently therapeutic mitotane levels (>14 mg/L) than those with wild type (WT) allele (76.2% vs 51.7%, <i>p</i> = 0.051) and experienced shorter TTP (HR = 2.10, <i>p</i> = 0.019) and lower DCR (chi-square = 6.948, <i>p</i> = 0.008). By contrast, 55% of patients with <i>CYP2B6*6</i> vs. 28.2% WT (<i>p</i> = 0.016) achieved therapeutic range. Combined, a higher rate of patients with <i>CYP2W1*6WT</i>+<i>CYP2B6*6</i> (60.6%) achieved mitotane therapeutic range (<i>p</i> = 0.034). In not completely resectable, recurrent or advanced ACC, <i>CYP2W1*6</i> SNP was associated with a reduced probability to reach mitotane therapeutic range and lower response rates, whereas <i>CYP2B6*6</i> correlated with higher mitotane levels. The association of these SNPs may predict individual response to mitotane.