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.
Highlights
Adrenocortical carcinoma (ACC) is a rare tumor with an estimated incidence between 0.7 and2.0 per million per year, and characterized by a heterogeneous prognosis mainly depending on initial tumor stage according to the European Network for the Study of Adrenal Tumors (ENSAT)classification [1], resection status [2,3] and Ki67 proliferation index [4,5,6]
We previously showed that adrenocortical carcinoma (ACC) patients having high CYP2W1 immunostaining at tumor level present a better response to mitotane therapy in comparison to those with low CYP2W1 staining [15]
We evaluated single nucleotide polymorphisms (SNPs) of CYP2W1 and CYP2B6 as potential predictive markers of response to mitotane in a large cohort of patients treated with mitotane monotherapy as first pharmacological therapy either after radical resection or in not completely resectable, recurrent or advanced ACC
Summary
Adrenocortical carcinoma (ACC) is a rare tumor with an estimated incidence between 0.7 and2.0 per million per year, and characterized by a heterogeneous prognosis mainly depending on initial tumor stage according to the European Network for the Study of Adrenal Tumors (ENSAT)classification [1], resection status [2,3] and Ki67 proliferation index [4,5,6]. It has been recently shown that up to 20% of patients with advanced ACC can experience objective response after mitotane monotherapy, with a progression-free survival (PFS) and an overall survival (OS) of 4.1 and 18.5 months, respectively [11]. Both in adjuvant and palliative treatment, mitotane plasma levels greater than 14 mg/L have been associated with longer survival [11,12,13]. Mitotane is often associated with several adverse events, including adrenal insufficiency, gastrointestinal-, central nervous system (CNS)and other endocrine-related effects [8,9]
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