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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 3  |  Page : 654-655

Adrenocortical carcinoma: Challenges and opportunities

1 University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Oklahoma City, Oklahoma, USA
2 Section of Hematology Oncology, Huntsman Cancer Institute (NCI.CCC), University of Utah, Salt Lake City, Utah, USA

Date of Submission15-Jul-2020
Date of Decision20-Jul-2020
Date of Acceptance22-Jul-2020
Date of Web Publication19-Sep-2020

Correspondence Address:
Neeraj Agarwal
Huntsman Cancer Institute, University of Utah (NCI-CCC), 2000 Circle of Hope Drive Suite 5726, Salt Lake City, Utah 84112
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_244_20

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How to cite this article:
Tripathi A, Agarwal N. Adrenocortical carcinoma: Challenges and opportunities. Cancer Res Stat Treat 2020;3:654-5

How to cite this URL:
Tripathi A, Agarwal N. Adrenocortical carcinoma: Challenges and opportunities. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Oct 25];3:654-5. Available from: https://www.crstonline.com/text.asp?2020/3/3/654/295498

Adrenal cortical carcinoma (ACC) is a rare but aggressive malignancy that has limited options for treatment. For patients with disease recurrence after the initial surgical resection, chemotherapy with etoposide, cisplatin, and doxorubicin in combination with mitotane has been the standard of care, based on the results from the First International Randomized Trial in Locally Adanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT).[1] However, the long-term survival continues to be poor with <25% of the patients surviving at 5 years.

Kapoor et al. recently reported their institutional experience focused predominantly on the patients with metastatic ACC who received systemic therapy.[2] The key findings of the study have been eloquently summarized in the accompanying editorial.[3] Although limited by the small sample size and missing data in many patients, the key highlights of the study include underutilization of mitotane, both in the adjuvant (2 out of 37 patients) and palliative settings (15 out of 52 patients), which was primarily driven by the lack of access to mitotane due to financial constraints. In patients treated with palliative chemotherapy who had evaluable outcome data, the median progression-free survival (PFS) and overall survival were 6 months (95% confidence interval [CI], 3.5–8.4) and 19 months (95% CI, 12.9–25.0), respectively. The results highlight the real-world practice patterns and existing barriers to improving outcomes in patients with this rare and challenging disease.

A better understanding of the genomic landscape of ACC has resulted in the identification of several novel therapeutic targets.[4],[5] For instance, CDK4 mutation or amplification is observed in around 13% of the patients with ACC, and the CDK4/6 inhibitor, palbociclib, has demonstrated encouraging results in preclinical models. ATRX or DAXX loss of function mutations is observed in 15% of the patients and can potentially sensitize tumors to ATR inhibitors. Alterations in the DNA damage repair genes such as ATM and BRCA1/2 and microsatellite instability (MSI) are observed in 4% of the patients and can be targeted with poly ADP ribose polymerase and programmed cell death-1 (PD-1) inhibitors, respectively. Interestingly, the anti-PD-1 antibody, pembrolizumab, has also demonstrated encouraging efficacy in biomarker unselected patients, regardless of their MSI status. In a phase II trial, treatment with pembrolizumab resulted in responses in 23% (n = 9) of the patients, of which only 2 were MSI-high.[6] The ongoing DART study (NCT02834013) is investigating dual checkpoint inhibition with the anti-PD-1 antibody, nivolumab, in combination with the cytotoxic T-lymphocyte-associated antigen-4 inhibitor, ipilimumab, in rare tumors including ACC. Although prior prospective studies with vascular endothelial growth factor-targeted agents, such as axitinib and sunitinib, have shown limited efficacy, the retrospective data suggest potential activity of cabozantinib (objective response rate: 18%, median PFS: 4 months), which is currently being investigated in ongoing trials (NCT03612232; NCT03370718).[7]

Novel therapeutics for the treatment of advanced ACC remain an area of unmet need. Although chemotherapy in combination with mitotane remains the cornerstone of therapy for most patients, therapies tailored to specific genomic alterations and those targeting the immune checkpoints have the potential to significantly change the treatment paradigm and outcomes of this disease. Given its rarity, collaborative multicenter clinical trials investigating these novel therapeutic strategies will be crucial for improving the outcomes for patients with ACC.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med 2012;366:2189-97.  Back to cited text no. 1
Kapoor A, Noronha V, Toshniwal A, Menon S, Joshi A, Patil VM, et al. Exploring the role of systemic therapy in adult adrenocortical carcinoma: A single-center experience. Cancer Res Stat Treat 2020;3:192-200.  Back to cited text no. 2
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Rajappa S. Treating advanced adrenal cortical carcinoma: The long, winding, and endless road. Cancer Res Stat Treat 2020;3:290-2.  Back to cited text no. 3
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Crona J, Beuschlein F. Adrenocortical carcinoma-Towards genomics guided clinical care. Nat Rev Endocrinol 2019;15:548-60.  Back to cited text no. 4
Zheng S, Cherniack AD, Dewal N, Moffitt RA, Danilova L, Murray BA, et al. Comprehensive pan-genomic characterization of adrenocortical carcinoma. Cancer Cell 2016;29:723-36.  Back to cited text no. 5
Raj N, Zheng Y, Kelly V, Katz SS, Chou J, Do RK, et al. PD-1 blockade in advanced adrenocortical carcinoma. J Clin Oncol 2020;38:71-80.  Back to cited text no. 6
Kroiss M, Megerle F, Kurlbaum M, Zimmermann S, Wendler J, Jimenez C, et al. Objective response and prolonged disease control of advanced adrenocortical carcinoma with cabozantinib. J Clin Endocrinol Metab 2020;105:dgz318.  Back to cited text no. 7


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