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Anne Jouinot Department of Medical Oncology, Cochin Hospital, Paris Descartes University, CARPEM, AP-HP, Paris, France
Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

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Bernard Royer CHU Besançon, Clinical Pharmacology and Toxicology Dpt, Besançon cedex, France

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Etienne Chatelut Institut Claudius-Regaud, Université de Toulouse, INSERM, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France

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Sotheara Moeung Institut Claudius-Regaud, Université de Toulouse, INSERM, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France

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Guillaume Assié Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology, Center for Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France

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Audrey Thomas-Schoemann Department of Pharmacy, Cochin Hospital, Paris Descartes University, AP-HP, Paris, France
Pharmacokinetics and Pharmacochemistry Unit, Cochin Hospital, Paris Descartes University, AP-HP, Paris, France

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Jérôme Bertherat Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology, Center for Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France

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François Goldwasser Department of Medical Oncology, Cochin Hospital, Paris Descartes University, CARPEM, AP-HP, Paris, France

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Benoit Blanchet Pharmacokinetics and Pharmacochemistry Unit, Cochin Hospital, Paris Descartes University, AP-HP, Paris, France
UMR8638 CNRS, Pharmacy UFR, University of Paris Descartes, PRES sorbonne Paris Cité, Paris, France

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Background

The combination of mitotane and platinum-etoposide chemotherapy is a front-line treatment in metastatic adrenocortical carcinoma (ACC), although this regimen shows limited efficacy. Pharmacokinetic drug–drug interaction between mitotane, a strong CYP3A4 inducer, and etoposide, which is a substrate of CYP3A4, may contribute to chemoresistance. The aim of this pilot study was to assess the pharmacokinetic interaction between mitotane and etoposide in ACC patients.

Methods

Five consecutive ACC patients treated with platinum etoposide (120–150 mg/m2 day 1–2–3 at cycle 1), with or without concomitant mitotane, were included. In the absence of limiting toxicity, a dose escalation of etoposide was proposed since cycle 2. Plasma etoposide concentrations were measured using liquid chromatography at 0, 4 and 24 h after each infusion. Clearance and area under the curve (AUC) of etoposide were determined at each cycle.

Results

Patients received two to six chemotherapy cycles, in association with mitotane (N = 4) or after mitotane discontinuation (N = 1). Etoposide clearance was two-fold higher with concomitant mitotane (4.95 L/h) than after mitotane discontinuation (2.53 L/h, P = 0.014), and 2.5-fold higher than that in reference population not treated with mitotane (1.81 L/h). Etoposide dose escalation was performed in four patients under mitotane, resulting in two minor tumor responses and one severe toxicity (febrile aplasia) at dose of 300 mg/m2/day. Tumor response was associated with higher etoposide AUC (267.3 vs 188.8 mg.h/L, P = 0.04).

Conclusion

A drug–drug interaction between mitotane and etoposide may contribute to the low efficacy of platinum-etoposide chemotherapy. This pilot study suggests further a potential benefit of increasing etoposide dose in ACC patients receiving mitotane.

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Anne Jouinot Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

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Juliane Lippert Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, Wuerzburg, Germany

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Martin Fassnacht Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, Wuerzburg, Germany
Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany

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Bruno de La Villeon Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France

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Amandine Septier Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France

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Mario Neou Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France

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Karine Perlemoine Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France

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Silke Appenzeller Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, Wuerzburg, Germany

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Mathilde Sibony Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
Department of Pathology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

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Sébastien Gaujoux Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
Department of Digestive and Endocrine Surgery, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

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Bertrand Dousset Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
Department of Digestive and Endocrine Surgery, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

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Rossella Libe Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

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Lionel Groussin Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

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Cristina L Ronchi Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, Wuerzburg, Germany
Institute of Metabolism and System Research, University of Birmingham, Birmingham, UK
Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK

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Guillaume Assié Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

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Jérôme Bertherat Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

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Background:

The prognosis of adrenocortical carcinoma (ACC) is heterogeneous. Genomic studies have identified ACC subgroups characterized by specific molecular alterations, including features measured at DNA level (somatic mutations, chromosome alterations, DNA methylation), which are closely associated with outcome. The aim of this study was to evaluate intratumor heterogeneity of prognostic molecular markers at the DNA level.

Methods:

Two different tissue samples (primary tumor, local recurrence or metastasis) were analyzed in 26 patients who underwent surgery for primary or recurrent ACC. DNA-related biomarkers with prognostic role were investigated in frozen and paraffin-embedded samples. Somatic mutations of p53/Rb and Wnt/β-catenin pathways were assessed using next-generation sequencing (n = 26), chromosome alteration profiles were determined using SNP arrays (n = 14) and methylation profiles were determined using four-gene bisulfite pyrosequencing (n = 12).

Results:

Somatic mutations for ZNRF3, TP53, CTNN1B and CDKN2A were found in 7, 6, 6 and 4 patients, respectively, with intratumor heterogeneity in 8/26 patients (31%). Chromosome alteration profiles were ‘Noisy’ (numerous and anarchic alterations) in 8/14 and ‘Chromosomal’ (extended patterns of loss of heterozygosity) in 5/14 of the study samples. For these profiles, no intratumor heterogeneity was observed. Methylation profiles were hypermethylated in 5/12 and non-hypermethylated in 7/12 of the study samples. Intratumor heterogeneity of methylation profiles was observed in 2/12 patients (17%).

Conclusions:

Intratumor heterogeneity impacts DNA-related molecular markers. While somatic mutation can differ, prognostic DNA methylation and chromosome alteration profile seem rather stable and might be more robust for the prognostic assessment.

Open access
Fidéline Bonnet-Serrano Université Paris Cité, Paris, France
Inserm U1016-CNRS UMR8104, Paris, France
Hormonology Department, Cochin Hospital, Paris, France

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Maxime Barat Université Paris Cité, Paris, France
Inserm U1016-CNRS UMR8104, Paris, France
Radiology Department, Cochin Hospital, Paris, France

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Anna Vaczlavik Université Paris Cité, Paris, France
Inserm U1016-CNRS UMR8104, Paris, France
Reference Center for Rare Adrenal Diseases, Endocrinology Department, Cochin Hospital, Paris, France

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Anne Jouinot Inserm U1016-CNRS UMR8104, Paris, France

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Lucas Bouys Université Paris Cité, Paris, France
Inserm U1016-CNRS UMR8104, Paris, France
Reference Center for Rare Adrenal Diseases, Endocrinology Department, Cochin Hospital, Paris, France

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Christelle Laguillier-Morizot Université Paris Cité, Paris, France
Hormonology Department, Cochin Hospital, Paris, France
INSERM, Physiopathologie et Pharmacotoxicologie Placentaire Humaine : Microbiote Pré & Post natal, Paris, France

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Corinne Zientek Hormonology Department, Cochin Hospital, Paris, France

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Catherine Simonneau Hormonology Department, Cochin Hospital, Paris, France

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Etienne Larger Université Paris Cité, Paris, France
Inserm U1016-CNRS UMR8104, Paris, France
Diabetology Department, Cochin Hospital, Paris, France

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Laurence Guignat Reference Center for Rare Adrenal Diseases, Endocrinology Department, Cochin Hospital, Paris, France

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Lionel Groussin Université Paris Cité, Paris, France
Inserm U1016-CNRS UMR8104, Paris, France
Reference Center for Rare Adrenal Diseases, Endocrinology Department, Cochin Hospital, Paris, France

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Guillaume Assié Université Paris Cité, Paris, France
Inserm U1016-CNRS UMR8104, Paris, France
Reference Center for Rare Adrenal Diseases, Endocrinology Department, Cochin Hospital, Paris, France

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Jean Guibourdenche Université Paris Cité, Paris, France
Hormonology Department, Cochin Hospital, Paris, France
INSERM, Physiopathologie et Pharmacotoxicologie Placentaire Humaine : Microbiote Pré & Post natal, Paris, France

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Ioannis Nicolis Université Paris Cité, Paris, France
UR 7537 BioSTM, Paris, France

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Marie-Claude Menet Institut de Chimie Physique, Université Paris-Saclay-CNRS, UMR8000, Orsay, France

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Jérôme Bertherat Université Paris Cité, Paris, France
Inserm U1016-CNRS UMR8104, Paris, France
Reference Center for Rare Adrenal Diseases, Endocrinology Department, Cochin Hospital, Paris, France

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Objective

Large response of steroid precursors, including 17-hydroxyprogesterone, to adrenocorticotropic hormone (ACTH) has been described in adrenocortical tumors, suggesting the existence of intra-tumoral enzymatic deficiencies. This study aimed to compare steroidogenesis enzymes activity in unilateral and bilateral benign tumors using serum steroid profiling in liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) in the basal state and after ACTH 1-24 stimulation.

Design and methods

A serum profile of seven consecutive adrenal steroids was determined in LC-MS/MS in the basal state (T0) and after ACTH 1-24 stimulation (T60) in 35 patients with bilateral adrenocortical tumors (BL), 38 patients with unilateral tumors (UL) and 37 control subjects (CT). Response amplitude of each individual steroid was evaluated by T60/T0 ratio, whereas enzymatic activity was assessed by the downstream/upstream steroid ratio. Adrenal volume was quantified by a semi-automatic segmentation method.

Results

For the seven steroids assayed, the amplitude of response to ACTH was higher in BL than in UL and in CT. The difference between BL and UL persisted even after matching patients on adrenal volume. On glucocorticoids pathway, enzymatic activity of CYP11B1 was significantly decreased in BL (78.3 (43.1-199.4)) in comparison to both UL (122.7 (13.8-228.4), P = 0.0002) and CT (186.8 (42.1-1236.3), P < 0.0001). On mineralocorticoids and androgens pathways, the enzymatic activity of CYP11B2 and CYP17A1-17,20 lyase was also lower in BL than UL and CT.

Conclusions

Decreased activity of distal steroidogenesis enzymes CYP11B1, CYP11B2 and CYP17A1-17,20 lyase, responsible for an explosive response to ACTH of upstream precursors in bilateral tumors, limits the synthesis of bioactive steroids, in particular cortisol, despite the increase in adrenal mass.

Significance statement

Activity of distal steroidogenesis enzymes (CYP11B1, CYP11B2 and CYP17A1 on glucocorticoids, mineralocorticoids and androgens pathways, respectively) is decreased in adrenocortical benign tumors. This decrease is more pronounced in bilateral lesions and seems to depend more on the nature of the lesion than on the increase in adrenal volume. It is responsible for the explosive response to ACTH of steroid precursors located upstream of these enzymes. It probably allows bioactive steroids, particularly cortisol, to stay in the normal range for a long time despite the increase in adrenal mass.

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