Mitotane is the only approved drug for the treatment of advanced adrenocortical carcinoma (ACC) and we recently demonstrated that a high expression of cytochrome P450 2W1 (CYP2W1) correlated with response to mitotane. The association between CYP2W1 alleles and a generally increased cancer risk is under debate. Aim of the study was to evaluate the frequency of CYP2W1 polymorphisms and its correlation with the response to mitotane treatment in ACC patients.
Methods: DNA was isolated from whole blood of 108 Caucasian ACC patients (F/M=68/40) treated with mitotane monotherapy in adjuvant (ns=66) or palliative (n=42) setting. Three CYP2W1 polymorphisms were genotyped by PCR and sequenced: CYP2W1*2 (p.A181T), CYP2W1*5 (p.Q482H) and CYP2W1*6 (p.P448L). The response to therapy was evaluated by time to progression (TTP).
Results: The allele frequencies for CYP2W1*2 and CYP2W1*6 were 8 and 18%, respectively, and are comparable to those found in the European population (1000 Genomes Project Phase 3 allele frequencies, ENSEMBLE, 5% for CYP2W1*2 and 17% for CYP2W1*6). For CYP2W1*6 there were slightly more homozygotes than expected (P=0.1). Both variant alleles were in the Hardy-Weinberg equilibrium. CYP2W1*5, which is only reported in non-Causasian population, was not found. We did not find any correlation between CYP2W1*2 allele and clinical outcomes. Whereas, we observed that patients with advanced disease who have CYP2W1*6 allele have a worse response to therapy (median TTP 3.0 vs 5.5 months, P=0.03, HR 1.83). Among these patients, 86% who have CYP2W1*6 allele did not reach the therapeutic range of mitotane plasma level (1420 mg/l) in comparison to 61% of those without CYP2W1*6 allele (P=0.09, chi-squared=2.7). No relevant impact of CYP2W1*6 was observed in patients treated with adjuvant mitotane.
Conclusion: This study further suggests that CYP2W1 might be involved on mitotane metabolism and that CYP2W1*6 allele might correlate with a worse sensitivity to mitotane palliative treatment.
20 - 23 May 2017
European Society of Endocrinology