Integrating Molecular Profiling of Adrenocortical Carcinoma Into Clinical Practice

Processes used to identify and understand genetic markers detailing the prognosis and responsiveness to therapy in adrenocortical carcinoma (ACC) face a number of implementation barriers, limiting the potential for individualized ACC management.

A review article in Clinical Endocrinology detailed the progress in identification and understanding of DNA, RNA, and epigenetic markers of prognosis and responsiveness to therapy in adrenocortical carcinoma (ACC).

According to the authors of the review, ACC, a rare malignancy of the adrenal cortex, has limited therapeutic options, low response rates to drug therapies, and “heterogeneous clinical behaviour,” and there is currently no effective treatment for advanced stages of the disease. Thus, they wrote, “an individualized management approach could be therefore extremely relevant for these patients.”

Although studies have identified associations between molecular markers and prognosis, which may help to distinguish less and more aggressive subtypes and better inform therapy decisions, these workflows have not yet been implemented in routine ACC treatment, the authors said.

Potential applicability of prognostic markers to clinical practice

In an exhaustive table outlining tumor molecular profiling studies in ACC, the authors listed copy number and sequence variants at the DNA level, DNA epigenetic modifications including methylation status of specific genes, changes in messenger RNA expression, and changes in microRNA (miRNA) expression that have been identified in ACC.

They illustrated how these molecular markers cluster according to good, intermediate, or bad prognosis. However, there are obstacles in implementing analysis of these markers into routine clinical practice, such as the quality of material needed and complexity of the laboratory work and data analysis. They wrote, “the methods used to generate this ‘omics’ data are still too expensive and analysis workflow too complex to be implemented in a routine workflow.”

DNA sequence variants and DNA epigenetic modifications are the most implementable markers, the authors noted, but liquid biopsy is a promising method for analyzing prognostic markers such as circulating miRNAs or cell-free DNA. Liquid biopsy, they wrote, is non-invasive and can examine molecular changes “that can be traced back to the tumour.” In contrast, tumor tissue from biopsy or resection cannot “fully capture the mutation spectrum.”

Also deemed promising by the authors was a combination analysis of sequence variants, affected signaling pathways, methylation patterns, and clinical histopathological parameters, which was developed by research cited in their review.

Predictors of therapy response and new drug targets

Associations between molecular markers and response to current therapies have been studied. However, the authors wrote, “few molecular predictors of response to cytotoxic chemotherapies

have been proposed in ACC,” and “there are no promising DNA‐ or RNA-related biomarkers associated with the response to standard chemotherapies in ACC.”

Because of the low response rates to standard therapies, the reviewers said, “there is an urgent need for alternative therapies for aggressive ACCs.” Initial studies on immune checkpoint inhibitors reviewed by the authors had limited sample size and heterogeneous results. There have been few clinical studies on signaling pathways known to be deregulated in ACC in recent years, according to the authors. These included inhibitors of receptor tyrosine kinases or the mammalian target of rapamycin or insulin-like growth factor (IGF) pathways. The reviewers explained that the IGF pathway is deregulated in more than 90% of ACC cases. However, clinical research on a drug targeting the pathway (linsitinib) did not demonstrate any effect on progression-free or overall survival.

The authors noted that several clinical studies have demonstrated “small proportions of ACC patients showing a response to certain targeted therapy,” suggesting that subgroups of patients might benefit from treatment tailored to their tumor molecular markers.

Finally, they discussed preclinical studies that suggested genes involved in cell cycle regulation and the Wnt/𝛃-catenin pathway are promising targets for future development of drug therapies for ACC. For epigenetically targeted drugs, they said further research is required, and therapeutic options utilizing miRNA strategies have been tested only in cell culture thus far.

The reviewers closed by saying that although there is still no routine molecular analysis in clinical care of ACC they, “are convinced that there are methods that hold the potential to be implemented in a clinical routine workflow in the near future.” In particular, the authors expect that analysis of a combination of molecular profiles from tumor material and clinical and histopathological characteristics “will guide clinicians (and patients) for treatment decisions in the near future,” and that “liquid biopsy‐related approaches might represent promising tools in the field of prognostication and surveillance for ACC patients.”

Reference

Lippert J, Fassnacht M, Ronchi CL. The role of molecular profiling in adrenocortical carcinoma. Clin Endocrinol. November 8, 2021. doi:10.1111/cen.14629.