Advanced Adrenocortical Carcinoma: Current Perspectives on Medical Treatment

Abstract

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy. For stage I and II tumors, surgery is a curative option, but even in these cases recurrence is frequent. Practical guidelines advocate a combination of mitotane with etoposide, doxorubicin, and cisplatin as first-line therapy for metastatic adrenocortical carcinoma. However, this scheme presents limited efficacy and high toxicity. The use of Immune Checkpoint Inhibitors (ICI) and multi-Tyrosine Kinase Inhibitors (mTKI) has modified the approach of multiple malignancies. The expectation of their applicability on advanced adrenocortical carcinoma is high but the role of these new therapies persists unclear. This article provides a short summary of last years’ findings targeting outcomes, limitations, and adverse effects of these new therapeutic approaches. The results of recent trials and case series pointed pembrolizumab as the most promising drug among these new therapies. It is the most often used ICI and the one presenting the best results with less related adverse effects when in comparison to the standard treatment with mitotane. Hereafter, the identification of specific molecular biomarkers or immune profiles associated with ICI or mTKI good response will facilitate the selection of candidates for these therapies. So far, microsatellite instability and Lynch Syndrome related germline mutations are suggested as predictive biomarkers of good response. Contrarywise, cortisol secretion has been associated with more aggressive ACC tumors and potentially poor responses to immunotherapy.

Durable response to pembrolizumab in microsatellite instability‐high advanced adrenocortical carcinoma

“…This, as well as the pembrolizumab monotherapy discussed above, might be expected to provide a durable response. However, it was shown that patients receiving concomitant mitotane had a higher rate of grade 3 or higher AEs than those receiving pembrolizumab alone, particularly elevation in liver enzymes 14 . Although our patient had no severe AEs, it is necessary to make a careful decision concerning the use of concomitant mitotane.…”

“…However, it was shown that patients receiving concomitant mitotane had a higher rate of grade 3 or higher AEs than those receiving pembrolizumab alone, particularly elevation in liver enzymes. 14 Although our patient had no severe AEs, it is necessary to make a careful decision concerning the use of concomitant mitotane. Further research through clinical trials is necessary to assess the efficacy and safety of this combination therapy.…”

“…9 Grade 3 or higher AEs were observed in 20% of patients, which is lower than the rate of 58% in EDP-M therapy. 14 An objective response of SD or more was observed in 4 (67%) of 6 patients with MSI-H, compared with 11 (34%) of 32 patients without MSI-H, which suggests that MSI-H is a useful biomarker to determine the use of immune checkpoint inhibitors for ACC. 9 When switching EDP-M to pembrolizumab in the present case, we decided to continue mitotane, although the efficacy and safety of PEM-M remain unclear.…”

“… 9 Grade 3 or higher AEs were observed in 20% of patients, which is lower than the rate of 58% in EDP‐M therapy. 14 An objective response of SD or more was observed in 4 (67%) of 6 patients with MSI‐H, compared with 11 (34%) of 32 patients without MSI‐H, which suggests that MSI‐H is a useful biomarker to determine the use of immune checkpoint inhibitors for ACC. 9 …”

Prediction of Adrenocortical Carcinoma Relapse and Prognosis with a Set of Novel Multigene Panels

“…The estimated 5-year survival rate is less than 50% [ 8 ], with median survival around 3–4 years [ 9 ]. For patients with organ-confined disease, 5-year survival is 60–80%; for patients with locally advanced ACC or metastatic ACCs, 5-year survival is 35–50% and 0–28%, respectively [ 10 , 11 ]. A recent epidemiological study of 2014 ACC cases in the USA from 1973 to 2014 revealed the disease mortality is 52%, with a median survival time of less than 2 years [ 5 ].…”