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Adrenocortical carcinoma — towards genomics guided clinical care

Nature Reviews Endocrinology volume 15, pages 548–560 (2019)Cite this article

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Abstract

Adrenocortical carcinoma (ACC) is an aggressive and rare neoplasm that originates in the cortex of the adrenal gland. The disease is associated with heterogeneous but mostly poor outcomes and lacks effective pharmaceutical treatment options. Multi-omics studies have defined the landscape of molecular alterations in ACC. Specific molecular signatures can be detected in body fluids, potentially enabling improved diagnostic applications for patients with adrenal tumours. Importantly, pan-molecular data sets further reveal a spectrum within ACC, with three major subgroups that have different disease outcomes. These new subgroups have value as prognostic biomarkers. Research has revealed that the p53–RB and the WNT–β-catenin pathways are common disease drivers in ACC. However, these pathways remain difficult to target by therapeutic interventions. Instead, a unique characteristic of ACC is steroidogenic differentiation, which has emerged as a potential treatment target, with several agents undergoing preclinical or clinical investigations. Finally, a large proportion of ACC tumours have genetic profiles that are associated with promising therapeutic responsiveness in other cancers. All these opportunities now await translation from the laboratory into the clinical setting, thereby offering a real potential of improved survival outcomes and increased quality of life for patients with this serious condition.

Key points

  • Adrenocortical carcinoma (ACC) is an ultra-rare disease that is associated with poor outcomes; surgery, mitotane-based and platinum-based chemotherapy remain the only effective therapeutic strategies.

  • Ongoing clinical trials include two phase III trials (ADIUVO and ADIUVO-2) as well as multiple phase II studies.

  • Two large consortia have characterized the landscape of molecular alterations in ACC, which included high chromosomal aneuploidy, and the most common driver genes are TP53 and CTNNB1.

  • Three molecular subtypes of ACC have been defined that correlate with prognosis; related surrogate biomarkers that are adopted for clinical use have been described.

  • Up to 50% of metastatic ACCs might harbour genetic aberrations associated with treatment efficacy in other diseases; evaluating a precision oncology approach based on these features will require implementation of new clinical trial designs.

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Fig. 1: Timeline of ACC research.
Fig. 2: Biology of ACC from different perspectives.
Fig. 3: Molecular hallmarks and drug targets in ACC.
Fig. 4: A biomarker-driven umbrella trial for treatment of ACC.

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Acknowledgements

J.C. acknowledges the support of Akademiska Sjukhuset, Cancerfonden, Tore Nilsons Stiftelse and Wallenberg Stiftelsen. F.B. acknowledges the support of the Deutsche Forschungsgemeinschaft (DFG) within the CRC/Transregio 205/1 (‘The Adrenal: Central Relay in Health and Disease’).

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Nature Reviews Endocrinology thanks R. Ribeiro and other, anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Medical Sciences, Uppsala Universitet, Uppsala, Sweden

    Joakim Crona

  2. Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany

    Felix Beuschlein

  3. Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, UniversitätsSpital Zurich, Zurich, Switzerland

    Felix Beuschlein

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  1. Joakim Crona
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The authors contributed equally to all aspects of the article.

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Correspondence to Joakim Crona or Felix Beuschlein.

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Competing interests

J.C. received lecture honoraria from Novartis and honoraria for educational material from NET Connect (funded by Ipsen). F.B. has received funding from HRA Pharma and Ipsen.

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OncoKB Precision Oncology Knowledge Database: http://oncokb.org/

Glossary

R0 resection

Absence of cancer cells at the resection margin by microscopic analysis.

Neoadjuvant treatment

Ancillary therapy administered before main therapy.

Adjuvant therapy

Ancillary therapy administered after main therapy.

Adrenal adenomas

Benign tumour lesions of the adrenal cortex.

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Crona, J., Beuschlein, F. Adrenocortical carcinoma — towards genomics guided clinical care. Nat Rev Endocrinol 15, 548–560 (2019). https://doi.org/10.1038/s41574-019-0221-7

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