Endocrine Abstracts (2018) 59 OC1.6 | DOI: 10.1530/endoabs.59.OC1.6

Germline CYP2W1*6 and CYP2B6*6 polymorphisms as predicting markers of sensitivity to mitotane treatment in advanced adrenocortical carcinoma: a multicentric ENSAT study

Barbara Altieri1,2, Sabine Herterich3, Silviu Sbiera1, Marco Volante4, Silvia De Francia5, Silvia Della Casa2, Alfredo Pontecorvi2, Marcus Quinkler6, Tina Kienitz7, Massimo Mannelli8, Letizia Canu8, Vasileios Chortis9, Gregory Kaltsas10, Matthias Kroiss1, Massimo Terzolo5, Martin Fassnacht1 & Cristina L Ronchi9

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.

Adrenocortical carcinoma (ACC) is a rare tumor with poor prognosis and the only approved drug for advanced disease is mitotane. The cytochromes P450 (CYP) 2W1 and 2B6 are proposed predicting markers of sensitivity to mitotane treatment. Aim of the study was to evaluate the relationship between CYP2W1 and/or CYP2B6 polymorphisms and response to mitotane in ACC.

Methods: We performed a multicentric retrospective study including 182 ACC patients (F/M=121/61) treated with mitotane monotherapy in adjuvant (n=103) or palliative (n=79) setting. CYP2W1*6 (p.P448L) and CYP2B6*6 (p.Q171H) were genotyped and sequenced in leukocyte DNA. Response to therapy was evaluated by time to progression (TTP) from the start of mitotane.

Results: Patients with advanced ACC and CYP2W1*6 CT/TT showed a worse response to mitotane compared to wild-type (wt) group (median TTP 3 vs 8 months, P=0.019, HR=2.10), also after adjustment for ENSAT stage (P=0.031, chi-square=4.67), and presented a higher rate of progression (71% vs 38%; P=0.01, chi-square=6.95). Moreover, 76% of CYP2W1*6 CT/TT patients did not achieve the mitotane target levels compared to 52% of wt (P=0.051, chi-square=3.79). Oppositely, a higher percentage of patients with CYP2B6*6 GT/TT achieved the target levels than wt (54% vs29%, P=0.027, chi-square=4.951), as well as had higher mitotane levels after 6 months of treatment (P=0.005). Combining these polymorphisms, 61% patients with GT/TT CYP2B6*6-CYP2W1*6 wt achieved target levels vs 21% with CT/TT CYP2W1*6–CYP2B6*6 wt and 32% with both CYPs wt (P=0.02 and P=0.037, respectively). No relevant results were observed in adjuvant setting.

Conclusion: We demonstrated that patients with advanced ACC and CYP2W1*6 CT/TT are less sensitive to mitotane and CYP2B6*6 correlates with mitotane levels after 6 month-treatment. We suggest that the association of CYP2W1*6 and CYP2B6*6 may predict the individual response to mitotane treatment, avoiding useless drug administration leading to toxicities.

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