Adrenocortical carcinoma — towards genomics guided clinical care

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.Adrenocortical carcinoma (ACC) is a rare and aggressive neoplasm that arises in the adrenal gland cortex. This Review highlights how genomics can be used to stratify ACC and potentially improve clinical care, outcomes and patient quality of life.Key pointsAdrenocortical 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.