Targeted genomic analysis of 364 adrenocortical carcinomas

Abstract

Despite recent advances in elucidating molecular pathways underlying adrenocortical carcinoma (ACC), this orphan malignancy is associated with poor survival. Identification of targetable genomic alterations is critical to improve outcomes. The objective of this study was to characterize the genomic profile of a large cohort of patient ACC samples to identify actionable genomic alterations. Three hundred sixty-four individual patient ACC tumors were analyzed. The median age of the cohort was 52 years and 60.9% (n = 222) were female. ACC samples had common alterations in epigenetic pathways with 38% of tumors carrying alterations in genes involved in histone modification, 21% in telomere lengthening, and 21% in SWI/SNF complex. Tumor suppressor genes and WNT signaling pathway were each mutated in 51% of tumors. Fifty (13.7%) ACC tumors had a genomic alteration in genes involved in the DNA mismatch repair (MMR) pathway with many tumors also displaying an unusually high number of mutations and a corresponding MMR mutation signature. In addition, genomic alterations in several genes not previously associated with ACC were observed, including IL7R, LRP1B, FRS2 mutated in 6, 8 and 4% of tumors, respectively. In total, 58.5% of ACC (n = 213) had at least one potentially actionable genomic alteration in 46 different genes. As more than half of ACC have one or more potentially actionable genomic alterations, this highlights the value of targeted sequencing for this orphan cancer with a poor prognosis. In addition, significant incidence of MMR gene alterations suggests that immunotherapy is a promising therapeutic for a considerable subset of ACC patients.

Overview of the 2022 WHO Classification of Adrenal Cortical Tumors

“…The application of MMR proteins (MLH1, MSH2, MSH6 and PMS2) has gained popularity not only for the purpose of screening for an extracolonic manifestation of Lynch syndrome [18,179,180] (Fig. 36), but also to provide additional guidance on the use of immunotherapy trials [4,181]. Similarly, the PDL1/ PD1 expression status of ACCs has been an area of interest.…”

Phase II study of cabazitaxel as second-third line treatment in patients with metastatic adrenocortical carcinoma

“…Although more than half of ACCs have one or more potentially actionable genomic alterations, results of nextgeneration sequencing or other methods to assess ACC for personalized approaches revealed that the vast majority of DNA alterations detected are not druggable by molecular target agents currently available in the treatment of solid tumors results. 35,36 In the current single-institution, nonrandomized phase II study, cabazitaxel showed a disease control rate after 4 months of 24%. Therefore, formally we could not conclude that this drug is not efficacious in the management of chemotherapy pretreated advanced ACC patients, according to the predefined limits that we have fixed to calculate the sample size of this trial.…”

“…Although more than half of ACCs have one or more potentially actionable genomic alterations, results of next-generation sequencing or other methods to assess ACC for personalized approaches revealed that the vast majority of DNA alterations detected are not druggable by molecular target agents currently available in the treatment of solid tumors results. 35 , 36 …”

Targeted Therapy for Adrenocortical Carcinoma: A Genomic-Based Search for Available and Emerging Options

“…CTNNB1 was altered in 14.8% of the TCGA samples and 28% of the foundation one tumors [ 14 ]. Interestingly, it was more frequently altered in metastatic ACC, as opposed to localized stages ( Figure 2 ), suggesting that CTNNB1 could be involved in the switch to metastasis.…”

“…Beta-catenin seems to play a major role in both localized and advanced or metastatic ACC, which additionally displays ERBB4, GPCR, RAR, and PDGFR as further possible targets [ 9 ]. However, in spite of a recent study suggesting that more than a half of 364 ACC tumors may show actionable mutations based on OncoKB [ 10 ], clinical studies testing drugs that target the vascular endothelial growth factor (VEGF) pathway [ 11 ], the epidermal growth factor receptor (EGFR) pathway [ 12 , 13 ], the insulin-like growth factor 1 receptor (IGF-IR) pathway [ 14 ] or the mammalian target of rapamycin (mTOR) pathway [ 15 , 16 ] were discouraging so far [ 17 , 18 , 19 , 20 ].…”