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Original Investigation
July 11, 2019

Value of Molecular Classification for Prognostic Assessment of Adrenocortical Carcinoma

Author Affiliations
  • 1Institut Cochin, INSERM U1016, CNRS UMR8104, Paris Descartes University, Paris, France
  • 2Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
  • 3Medical Oncology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
  • 4Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany
  • 5Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany
  • 6Department of Oncogenetics, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
  • 7Department of Pathology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
  • 8Department of Pathology, Assistance Publique Hôpitaux de Paris, Hôpital Pitié Salpétrière, Paris, France
  • 9Department of Digestive and Endocrine Surgery, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
  • 10Institute of Metabolism and System Research, University of Birmingham, Birmingham, United Kingdom
  • 11Department of Pathology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
  • 12Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands
  • 13Department of Surgery, University Hospital Giessen and Marburg, Campus Marburg, Marburg, Germany
  • 14Endocrinology in Charlottenburg, Berlin, Germany
  • 15Department of Endocrinology, Diabetes and Metabolic Diseases, University Hospital of Bordeaux, Bordeaux, France
  • 16Department of Endocrinology, University Hospital of Grenoble, Grenoble, France
  • 17Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
  • 18Department of Nuclear Medicine and Endocrine Oncology, Institut Gustave Roussy, Villejuif, France
  • 19Hypertension Unit, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France
  • 20Biostatistics and Epidemiology Unit, Hôtel Dieu, Assistance Publique-Hôpitaux de Paris, Paris, France
  • 21Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany
  • 22Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Universitätsspital Zürich, Zurich, Switzerland
JAMA Oncol. Published online July 11, 2019. doi:10.1001/jamaoncol.2019.1558
Key Points

Question  Is the prognostic molecular classification of adrenocortical carcinoma (ACC) more accurate than other known prognostic factors?

Findings  In this prognostic study of 368 patients who had undergone surgical removal of ACC localized tumors, molecular classification was an independent prognostic factor in patients stage I to III disease after complete surgery, and the combination of tumor stage, tumor grade, and molecular class provided the best prognostic model of disease-free survival. The prognostic value of molecular classification was confirmed using targeted molecular measurements in a large independent cohort.

Meaning  The findings suggest that in patients with low-grade and stage I to III ACC, molecular classification can better discriminate poor outcome ACC, which may spare patients from unnecessary adjuvant treatment.

Abstract

Importance  The risk stratification of adrenocortical carcinoma (ACC) based on tumor proliferation index and stage is limited. Adjuvant therapy after surgery is recommended for most patients. Pan-genomic studies have identified distinct molecular groups closely associated with outcome.

Objective  To compare the molecular classification for prognostic assessment of ACC with other known prognostic factors.

Design, Setting, and Participants  In this retrospective biomarker analysis, ACC tumor samples from 368 patients who had undergone surgical tumor removal were collected from March 1, 2005, to September 30, 2015 (144 in the training cohort and 224 in the validation cohort) at 21 referral centers with a median follow-up of 35 months (interquartile range, 18-74 months). Data were analyzed from March 2016 to March 2018.

Exposures  Meta-analysis of pan-genomic studies (transcriptome, methylome, chromosome alteration, and mutational profiles) was performed on the training cohort. Targeted biomarker analysis, including targeted gene expression (BUB1B and PINK1), targeted methylation (PAX5, GSTP1, PYCARD, and PAX6), and targeted next-generation sequencing, was performed on the training and validation cohorts.

Main Outcomes and Measures  Disease-free survival. Cox proportional hazards regression and C indexes were used to assess the prognostic value of each model.

Results  Of the 368 patients (mean [SD] age, 49 [16] years), 144 were in the training cohort (100 [69.4%] female) and 224 were in the validation cohort (142 [63.4%] female). In the training cohort, pan-genomic measures classified ACC into 3 molecular groups (A1, A2, and A3-B), with 5-year survival of 9% for group A1, 45% for group A2, and 82% for group A3-B (log-rank P < .001). Molecular class was an independent prognostic factor of recurrence in stage I to III ACC after complete surgery (hazard ratio, 55.91; 95% CI, 8.55-365.40; P < .001). The combination of European Network for the Study of Adrenal Tumors (ENSAT) stage, tumor proliferation index, and molecular class provided the most discriminant prognostic model (C index, 0.88). In the validation cohort, the molecular classification, determined by targeted biomarker measures, was confirmed as an independent prognostic factor of recurrence (hazard ratio, 5.96 [95% CI, 1.81-19.58], P = .003 for the targeted classifier combining expression, methylation, and chromosome alterations; and 2.61 [95% CI, 1.31-5.19], P = .006 for the targeted classifier combining methylation, chromosome alterations, and mutational profile). The prognostic value of the molecular markers was limited for patients with stage IV ACC.

Conclusions and Relevance  The findings suggest that in localized ACC, targeted classifiers may be used as independent markers of recurrence. The determination of molecular class may improve individual prognostic assessment and thus may spare unnecessary adjuvant treatment.

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