Editorial: Adrenocortical Carcinoma: Advancing treatment beyond surgery for a rare disease

Julie Hallanger Johnson ^*

• Mayo Clinic, Rochester, United States

Adrenal cancer itself is considered rare, since it is reported to have an incidence of approximately 1 person per million. Many patients are diagnosed late in their disease having Stage III and IV tumors without an immediate option for surgical cure due to the sinister nature of this particular cancer. This lead to searches for better systemic therapies since the rate of reponse to the standard of care therapy presently with mitotane plus etoposide, doxurubicin, and cisplatin was approximately 23% in the FIRM-ACT trial. 2 Unfortunately, thus far, in part due to the rarity of the disease, progress has been slow. We feel that any opportunity to push science and clinical care forward will be welcomed. Therefore, this grouping of articles was meant to help improve the current state and enhance understanding moving to a goal of improving outcomes for patients with advanced adrenocortical carcinoma.These articles span research on specific mutations to prognostic predictors in a single center review, to the neurological tolerance of mitotane and even the impact of radiation therapy. Starting with improving understanding the pathophysiology of the diease, Tai and Shang (insert link to Wnt/β-catenin signaling pathway in the tumor progression of adrenocortical carcinoma) provide an elegant discussion regarding Wnt/ β -catenin signaling and potential therapeutic targets in ACC. The understanding of this pathway in ACC will allow further exploration of these potential targets in the 30% of patients with ACC with Wnt/ β -catenin alterations . 3,4 Lalli (insert link to A reappraisal of transcriptional regulation by NR5A1 and beta-catenin in adrenocortical carcinoma) offered additional insight into the mechanism of NR5A1 and Wnt signaling in ACC, adding to the discussion on therapeutics.Situ et al (Systematic analysis of the BET family in adrenocortical carcinoma: The expression, prognosis, gene regulation network, and regulation targets) describe the bromodomain and extracellular terminal family (BET) role in ACC. The idea being that if the role is confirmed, some inhibitors could be used as targeted therapy. They found BRD4 expression upregulation in ACC and its expression correlated with disease staging. In addition, they explored other genes with expression levels correlating with the expression of BRD2, BRD3, and BRD4, furthering our depth of understanding of this disease.Several articles are included with clinical treatment highlights-from mitotane toxicities, radiation impact on outcomes, case report of immunotherapy success, to a review of single center experience treating ACC in Taiwan. Momando et al (insert Neurological adverse events of mitotane in adrenocortical carcinoma: results of a pilot study) describe measurements using neurological instruments such as EEG to measure neurotoxicity of elevated mitotane levels. This highlights one of the challenges of navigating the treatment of ACC with mitotane and the ongoing importance of monitoring levels and treating toxicities.Wu et al (insert link to Efficacy and safety of adjuvant radiation therapy in localized adrenocortical carcinoma) describe their single center experience with adjuvant radiation therapy in a retrospective analysis of 105 patients, 46 of whom received adjuvant radiation therapy. Interestingly, patients with early stage (ENSAT I/II) disease, adjuvant radiation therapy improved 3 year overall and disease-free survival. However, in further subgroup analyses, matched patients for Ki67 and stage did not suggest radiation was impactful on survival. They propose additional prospective studies to address this and other studies varied findings in the use of adjuvant radiation therapy for ACC.Pan et al (Prognostic predictors of adrenocortical carcinoma: A single-center thirty-year experience) describe their single center experience of caring for 67 patients with adrenocortical carcinoma. They confirm that ENSAT staging corresponded to overall survival. In addition, large vessel invasion was a predictor of poorer overall survival. Mitotane use improved outcomes in patients with Stage IV disease.Charles et al (Case Report: Response to ipilimumab and nivolumab in a patient with adrenocortical carcinoma) reports a successful case of neoadjuvant combination of cytotoxic T-lymphocyteassociated protein 4 (CTLA-4) inhibitor ipilimumab with programed-death 1 (PD-1) inhibitor therapy nivolumab. This was a case of mistaken initial diagnosis, but lead to a successful resection with no evidence of disease one year later. They raise the question of whether combination immunotherapy in the future would be more promising than previous studies suggest.These offer some glimpses of hope for this rare disease.