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Article

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

by
Barbara Altieri
1,2,
Silviu Sbiera
1,
Sabine Herterich
3,
Silvia De Francia
4,
Silvia Della Casa
2,
Anna Calabrese
5,
Alfredo Pontecorvi
2,
Marcus Quinkler
6,
Tina Kienitz
6,7,
Massimo Mannelli
8,
Letizia Canu
8,
Anna Angelousi
9,
Vasileios Chortis
10,11,
Matthias Kroiss
1,12,
Massimo Terzolo
5,
Martin Fassnacht
1,3,12 and
Cristina L. Ronchi
1,10,11,*
1
Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg, 97080 Würzburg, Germany
2
Division of Endocrinology and Metabolic Diseases, Catholic University of the Sacred Heart, 00168 Rome, Italy
3
Central Laboratory, University Hospital of Würzburg, 97080 Würzburg, Germany
4
Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, 10043 Turin, Italy
5
Division of Internal Medicine I, University of Turin, San Luigi Gonzaga Hospital, Orbassano, 10043 Turin, Italy
6
Endocrinology in Charlottenburg, 10627 Berlin, Germany
7
Department of Endocrinology, Diabetes and Nutrition, Charité-Universitätsmedizin Berlin, Campus Mitte, 10117 Berlin, Germany
8
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50134 Florence, Italy
9
1st Propaedeutic Department of Internal Medicine, National and Kapodistrian University of Athens, Laiko Hospital, 11527 Goudi, Greece
10
Institute of Metabolism and System Research, University of Birmingham, Birmingham B152TT, UK
11
Centre for Endocrinology, Diabetes and Metabolism (CEDAM), Birmingham Health Partners, Birmingham B152TT, UK
12
Comprehensive Cancer Center Mainfranken, University of Würzburg, 97080 Würzburg, Germany
 
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*
Author to whom correspondence should be addressed.
Cancers 2020, 12(2), 359; https://doi.org/10.3390/cancers12020359
Submission received: 12 December 2019 / Revised: 19 January 2020 / Accepted: 31 January 2020 / Published: 4 February 2020
(This article belongs to the Special Issue Adrenocortical Carcinoma)
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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.
Keywords: adrenocortical carcinoma; mitotane; CYP2W1; CYP2B6; SNP; biomarker; predictive marker adrenocortical carcinoma; mitotane; CYP2W1; CYP2B6; SNP; biomarker; predictive marker

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MDPI and ACS Style

Altieri, B.; Sbiera, S.; Herterich, S.; De Francia, S.; Della Casa, S.; Calabrese, A.; Pontecorvi, A.; Quinkler, M.; Kienitz, T.; Mannelli, M.; et al. Effects of Germline CYP2W1*6 and CYP2B6*6 Single Nucleotide Polymorphisms on Mitotane Treatment in Adrenocortical Carcinoma: A Multicenter ENSAT Study. Cancers 2020, 12, 359. https://doi.org/10.3390/cancers12020359

AMA Style

Altieri B, Sbiera S, Herterich S, De Francia S, Della Casa S, Calabrese A, Pontecorvi A, Quinkler M, Kienitz T, Mannelli M, et al. Effects of Germline CYP2W1*6 and CYP2B6*6 Single Nucleotide Polymorphisms on Mitotane Treatment in Adrenocortical Carcinoma: A Multicenter ENSAT Study. Cancers. 2020; 12(2):359. https://doi.org/10.3390/cancers12020359

Chicago/Turabian Style

Altieri, Barbara, Silviu Sbiera, Sabine Herterich, Silvia De Francia, Silvia Della Casa, Anna Calabrese, Alfredo Pontecorvi, Marcus Quinkler, Tina Kienitz, Massimo Mannelli, and et al. 2020. "Effects of Germline CYP2W1*6 and CYP2B6*6 Single Nucleotide Polymorphisms on Mitotane Treatment in Adrenocortical Carcinoma: A Multicenter ENSAT Study" Cancers 12, no. 2: 359. https://doi.org/10.3390/cancers12020359

APA Style

Altieri, B., Sbiera, S., Herterich, S., De Francia, S., Della Casa, S., Calabrese, A., Pontecorvi, A., Quinkler, M., Kienitz, T., Mannelli, M., Canu, L., Angelousi, A., Chortis, V., Kroiss, M., Terzolo, M., Fassnacht, M., & Ronchi, C. L. (2020). Effects of Germline CYP2W1*6 and CYP2B6*6 Single Nucleotide Polymorphisms on Mitotane Treatment in Adrenocortical Carcinoma: A Multicenter ENSAT Study. Cancers, 12(2), 359. https://doi.org/10.3390/cancers12020359

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