REVIEW   

Minerva Endocrinology 2022 June;47(2):203-14

DOI: 10.23736/S2724-6507.21.03601-0

Copyright © 2021 EDIZIONI MINERVA MEDICA

language: English

Mitotane treatment in adrenocortical carcinoma: mechanisms of action and predictive markers of response to therapy

Barbara ALTIERI ¹ ✉, Enzo LALLI ^{2, 3, 4}, Antongiulio FAGGIANO ⁵

¹ Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany; ² Institute of Molecular and Cellular Pharmacology CNRS UMR, Valbonne, France; ³ University of Côte d’Azur, Valbonne, France; ⁴ INSERM, Valbonne, France; ⁵ Unit of Endocrinology, Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, Sapienza University, Rome, Italy

Adrenocortical carcinoma (ACC) is a rare malignancy with a high risk of recurrence even in cases with complete surgical tumor resection. Mitotane represents the cornerstone of the adjuvant therapy as well as the first line of medical treatment in advanced cases. However, evidence on mitotane efficacy is mostly based on retrospective studies and the use of mitotane continues to represent a clinical challenge. Mitotane causes selective damage to adrenocortical cells, causing an increase of cell apoptosis through a disruption of mitochondria and the induction of the endoplasmic reticulum stress. Different clinical and molecular markers predicting response to mitotane have been proposed with uncertain results. Attainment of mitotane plasma levels within the target range of 14 to 20 mg/L represent the strongest predictor of mitotane effectiveness both in adjuvant and advanced tumor setting. The occurrence of late recurrence after primary ACC diagnosis and changes in metabolic activity on FDG-PET are only weakly associated with mitotane response. Among the proposed molecular markers associated with mitotane efficacy, the investigation of the CYP2W1*6 and CYP2B6*6 single nucleotide polymorphisms appears to be currently the most promising predictive molecular markers of mitotane therapy. However, none of the evaluated markers has been validated for clinical use. In the era of precision medicine, a better insight into mitotane molecular mechanisms as well as the potential use in the daily clinical practice of clinical parameters and molecular markers predicting the individual response to mitotane are urgently needed.

KEY WORDS: Adrenocortical carcinoma; Mitotane; CYP2W1 protein, human; CYP2B6 protein, human; Sterol O-acyltransferase 1