TY  - JOUR
A1  - Altieri, Barbara
A1  - Sbiera, Silviu
A1  - Herterich, Sabine
A1  - De Francia, Silvia
A1  - Della Casa, Silvia
A1  - Calabrese, Anna
A1  - Pontecorvi, Alfredo
A1  - Quinkler, Marcus
A1  - Kienitz, Tina
A1  - Mannelli, Massimo
A1  - Canu, Letizia
A1  - Angelousi, Anna
A1  - Chortis, Vasileios
A1  - Kroiss, Matthias
A1  - Terzolo, Massimo
A1  - Fassnacht, Martin
A1  - Ronchi, Cristina L.
T1  - Effects of Germline CYP2W1*6 and CYP2B6*6 Single Nucleotide Polymorphisms on Mitotane Treatment in Adrenocortical Carcinoma: A Multicenter ENSAT Study
JF  - Cancers
N2  - 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.
KW  - adrenocortical carcinoma
KW  - mitotane
KW  - CYP2W1
KW  - CYP2B6
KW  - SNP
KW  - biomarker
KW  - predictive marker
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200565
SN  - 2072-6694
VL  - 12
IS  - 2
ER  -