ECE2018 Guided Posters Adrenal clinical (10 abstracts)
Germline CYP2W1*6 polymorphism is a new predictive marker of sensitivity to mitotane treatment in advanced adrenocortical carcinoma: a multicenter European study
Barbara Altieri 1, , Sabine Herterich 3 , Marco Volante 4 , Silviu Sbiera 1 , Silvia De Francia 5 , Silvia Della Casa 2 , Alfredo Pontecorvi 2 , Markus Quinkler 6 , Tina Kienitz 7 , Massimo Mannelli 8 , Letizia Canu 8 , Vasileios Chortis 9 , Gregory Kaltsas 10 , Matthias Kroiss 1 , Massimo Terzolo 5 , Martin Fassnacht 1 & Cristina L Ronchi 1,
1Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital of Wuerzburg, Wuerzburg, Germany; 2Division of Endocrinology and Metabolic Diseases, Catholic University of the Sacred Heart, Rome, Italy; 3Central Laboratory, University Hospital of Wuerzburg, Wuerzburg, Germany; 4Department of Oncology, University of Turin, San Luigi Hospital, Turin, Italy; 5Division of Internal Medicine I, University of Turin, San Luigi Hospital, Turin, Italy; 6Endocrinology in Charlottenburg, Berlin, Germany; 7Department of Endocrinology, Diabetes and Nutrition, Charité-Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; 8Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy; 9Institute of Metabolism and System Research, University of Birmingham, and Centre for Endocrinology, Diabetes and Metabolism (CEDAM), Birmingham Health Partners, Birmingham, UK; 101st Propaedeutic Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece.
The cytochrome P450 2W1 (CYP2W1) is an orphan enzyme able to activate anticancer pro-drugs and to metabolise endogenous substances as fatty acids and lysophospholipids. Aim of the study was to evaluate the frequency of CYP2W1 polymorphisms in patients with adrenocortical carcinoma (ACC) and correlate it with the sensitivity to mitotane, which represents the only approved drug for the treatment of advanced ACC.
Methods: A multicenter retrospective study including 182 Caucasian ACC patients (F/M=121/61) treated with mitotane monotherapy in adjuvant (n=103) or palliative (n=79) setting from six centers belonging to the European Network for the Study of Adrenocortical Tumors (ENSAT) was performed. DNA was extracted from whole-blood and three CYP2W1 polymorphisms were genotyped by PCR and sequencing: CYP2W1*2 (p.A181T), CYP2W1*5 (p.Q482H) and CYP2W1*6 (p.P448L). Clinico-pathological data and an accurate follow-up during mitotane monotherapy were annotated. The response to therapy was evaluated by time to progression (TTP) from the start of mitotane treatment.
Results: The frequencies for allele*2 and *6 were in Hardy-Weinberg equilibrium. CYP2W1*5, which is only reported in non-Caucasian population, was not found. We didn’t observe any correlation between the presence of CYP2W1*2 allele and clinical outcome. However, considering the incompletely resectable, metastasized or recurrent ACC, patients with CT/TT genotype at CYP2W1*6 showed a worse response to mitotane (median TTP 3 vs. 8 months, P=0.019, HR 1.77) and a higher rate of progressive disease (71% vs. 41%; P=0.018, chi-square=5.57) than the wild-type group. Looking at mitotane plasma levels, 76% of CT/TT patients did not reach the target therapeutic levels (14–20 mg/L) in comparison to 52% of wild-type group (P=0.052, chi-square=3.794). No relevant impact of CYP2W1*6 was observed in patients treated with mitotane in adjuvant setting.
Conclusion: We demonstrated that ACC patients with advanced disease and CT/TT genotype at CYP2W1*6 had a worse response to mitotane treatment. Thus, this study suggests a possible use of germline CYP2W1*6 polymorphism as a new predictor marker of response to mitotane treatment in advanced ACC, avoiding useless drug administration leading to toxicities for patients.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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