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Adrenocortical carcinoma (ACC) is a rare cancer with high recurrence rates and heterogeneous clinical behavior. The role of adjuvant therapy remains unclear because of the challenges in collecting high-quality data for a rare cancer. The current treatment recommendations and guidelines for adjuvant therapy are mostly derived retrospectively from national databases and the treatment outcomes of patients seen in referral centers. To better select patients for adjuvant therapy, multiple factors need to be considered including staging, markers of cellular proliferation (such as Ki67%), resection margins, hormonal function, and possibly genetic alterations of the tumor as well as patient-related factors such as age and performance status. Adjuvant mitotane remains the most commonly used adjuvant therapy in ACC based on clinical practice guidelines, though emerging data from ADIUVO trial (mitotane vs observation in low-risk ACC) suggest that mitotane use in low-risk patients may not be needed. An ongoing clinical trial (ADIUVO-2) is evaluating the role of mitotane vs mitotane combined with chemotherapy in high-risk ACC. The use of adjuvant therapy has been controversial but can be justified in select patients with positive resection margins or after the resection of localized recurrence. A prospective study is needed to study the role of adjuvant radiation in ACC as radiation is expected to help only with local control without impact on distant microscopic metastases. There are no recommendations or published data about using adjuvant immunotherapy in ACC, but this may be a future study after establishing the efficacy and safety profile of immunotherapy in metastatic ACC.

Supplementary Table Legend from Hepatocyte Growth Factor/cMET Pathway Activation Enhances Cancer Hallmarks in Adrenocortical Carcinoma

High MET expression in ACC patients (S1); High MET mRNA expression levels in ACC (S2); cMET signaling is activated in ACC (S3); Increased HGF/cMET signaling is associated with enhanced proliferation and reduced apoptosis in tumors from ACC patients (S4); HGF stimulates NCI-H295R ACC cell proliferation (S5); HGF/cMET signaling is important for ACC cell energy metabolism (S6).

Basic patients characteristics of the cohort used for serum HGF measurements ; Patients characteristics of second TMA ; Genes with significantly (P {less than or equal to} 0.05, absolute value of log ratio > 0.1) changed expression in tumors from ACC patients (dataset GSE10927) relative to expression in normal adrenocortical tissues ; Biological processes Significantly (P 0.1) changed in tumors from ACC patients with high MET expression compared to those with low MET expression (dataset GSE10927) ; Gene set enrichment analysis of ACC patients' cohort for genes related to cell proliferation (dataset GSE10927) ; Gene set enrichment analysis of ACC patients' cohort for genes related to the negative regulation of cell apoptosis (dataset GSE10927) ; Gene set enrichment analysis of ACC patients' cohort for genes related to cell proliferation (dataset GSEA49278) ; Gene set enrichment analysis of ACC patients' cohort for genes related to the negative regulation of cell apoptosis (dataset GSEA49278) ; Drug metabolism-related genes with significantly (P {less than or equal to} 0.05, absolute value of log ratio > 0.1) changed expression in tumors from ACC patients (dataset GSE10927) with high MET expression relative to those with low MET expression ; Gene set enrichment analysis detail of ACC patients' cohort for genes associated with resistance and metabolism of cisplatin, etoposide and doxorubicin (dataset GSEA10927) ; Gene set enrichment analysis detail of ACC patients' cohort for genes associated with resistance and metabolism of cisplatin, etoposide and doxorubicin (dataset GSEA49278) .

Context Reporting temporal trends in adrenocortical carcinoma (ACC) helps guide management strategies. Objective This work aimed to report the trends in disease burden and clinical outcomes over time that cannot be adequately captured from individual clinical trials. Methods A retrospective study was held of ACC patients seen at a referral cancer center between February 1998 and August 2019. Clinical outcomes were compared between an early cohort (February 1998-June 2007) and a late cohort (July 2007-August 2019). Results A total of 621 patients included with a median age at diagnosis of 49.3 years (range, 0.5-86.6 years). There were 285 (45.9%) patients with hormonal overproduction. More patients in the late cohort had stage IV disease compared to the early cohort (36.8% vs 23.1%; P Conclusion ACC clinical outcomes improved over the past 2 decades as more patients had complete resection or received more lines of systemic therapy.

Elevated glucocorticoid (GC) activity may limit tumor immune response and immune checkpoint inhibitor (ICI) efficacy. Adrenocortical carcinoma (ACC) provides a unique test case to assess correlates of GC activity, as approximately half of ACC patients exhibit excess GC production (GC+). ACC multi-omics were analyzed to identify molecular consequences of GC+ and assess the rationale for combining the glucocorticoid receptor (GR) antagonist relacorilant with an ICI. GC status, mRNA expression, and DNA mutation and methylation data from 71 adrenal tumors were accessed via The Cancer Genome Atlas. Expression of 858 genes differed significantly between GC− and GC+ ACC cases. KEGG pathway analysis showed higher gene expression of three pathways involved in steroid synthesis and secretion in GC+ cases. Fifteen pathways, most related to NK cells and other immune activity, showed lower expression. Hypomethylation was primarily observed in the steroid synthesis pathways. Tumor-infiltrating CD4+ memory (P = 0.003), CD8+ memory (P < 0.001), and NKT-cells (P = 0.014) were depleted in GC+ cases; tumor-associated neutrophils were enriched (P < 0.001). Given the pronounced differences between GC+ and GC− ACC, the effects of cortisol on NK cells were assessed in vitro (NK cells from human PBMCs stimulated with IL-2 or IL-12/15). Cortisol suppressed, and relacorilant restored, NK cell activation, proliferation, and direct tumor cell killing. Thus, GR antagonism may increase the abundance and function of NK and other immune cells in the tumor microenvironment, promoting immune response in GC+ ACC and other malignancies with GC+. This hypothesis will be tested in a phase 1 trial of relacorilant + ICI.

Context Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors. Metastases develop in 15% to 20%. The American Joint Committee on Cancer (AJCC) established inaugural guidelines for PPGL tumor-node-metastasis (TNM) staging. Objective The objective of this analysis is to investigate the associations between TNM staging and overall survival (OS). Methods We retrospectively applied the TNM staging at the time of diagnosis of the primary tumor. The primary outcome was OS. Unadjusted survival rates were estimated by the Kaplan–Meier method. Cox proportional hazards regression models were used to evaluate the associations between OS and covariates of interest. Results The study included 458 patients. Median OS was 18.0 (95% CI, 15.6-not reached) years. At diagnosis, 126 (27.5%) tumors were stage I, 213 (46.5%) were stage II, 47 (10.3%) were stage III, and 72 (15.7%) were stage IV. The 10-year OS probabilities were 0.844 (95% CI, 0.768-0.928) for patients with stage I tumors, 0.792 (95% CI, 0.726-0.865) for stage II, 0.595 (95% CI, 0.435-0.813) for stage III, and 0.221 (95% CI, 0.127-0.384) for stage IV. Compared with stage I, the hazard ratios (HR) for death were 1.50 (0.87-2.57) for stage II, 2.85 (1.45-5.63) for stage III, and 8.88 (5.16-15.29) for stage IV (P < 0.001). Compared with patients with no germline mutations, those with RET 634/918 had better OS (HR: 0.28; 95% CI, 0.12-0.69). Other germline mutations, including SDHB, did not exhibit worse OS than patients with metastasis and sporadic disease. Conclusion OS rates correlated with the recently developed AJCC TNM staging and were not worse in hereditary disease. Stage IV disease exhibited a significantly shorter OS compared with stages I-III. Future staging systems could be adjusted to better separate stages I and II.

Data on the diagnosis, natural course and management of immune checkpoint inhibitor (ICI)-related hypophysitis (irH) are limited. We propose this study to validate the diagnostic criteria, describe characteristics and hormonal recovery and investigate factors associated with the occurrence and recovery of irH. A retrospective study including patients with suspected irH at the University of Texas MD Anderson Cancer Center from 5/2003 to 8/2017 was conducted. IrH was defined as: (1) ACTH or TSH deficiency plus MRI changes or (2) ACTH and TSH deficiencies plus headache/fatigue in the absence of MRI findings. We found that of 83 patients followed for a median of 1.75 years (range 0.6–3), the proposed criteria used at initial evaluation accurately identified 61/62 (98%) irH cases. In the irH group (n = 62), the most common presentation was headache (60%), fatigue (66%), central hypothyroidism (94%), central adrenal insufficiency (69%) and MRI changes (77%). Compared with non-ipilimumab (ipi) regimens, ipi has a stronger association with irH occurrence (P = 0.004) and a shorter time to irH development (P < 0.01). Thyroid, gonadal and adrenal axis recovery occurred in 24, 58 and 0% patients, respectively. High-dose steroids (HDS) or ICI discontinuation was not associated with hormonal recovery. In the non-irH group (n = 19), one patient had isolated central hypothyroidism and six had isolated central adrenal insufficiency. All remained on hormone therapy at the last follow-up. We propose a strict definition of irH that identifies the vast majority of patients. HDS and ICI discontinuation is not always beneficial. Long-term follow-up to assess recovery is needed.

To evaluate the ability of radiomic feature extraction and a machine learning algorithm to differentiate between benign and malignant indeterminate adrenal lesions on contrast-enhanced computed tomography (CT) studies. Adrenal “incidentalomas” are adrenal lesions that are accidentally discovered during workup not related to the adrenal glands; they have an incidence as high as 5%. Small adrenal incidentalomas ( 10 HU) need further evaluation to calculate the absolute percentage of washout (APW). If the APW is 10 HU, and APW

Background Adrenocortical carcinoma (ACC) is a rare malignancy arising from the adrenal cortex. While ACC can be associated with adrenal hormone excess syndromes, classic paraneoplastic syndromes are rarely seen. Stauffer syndrome, a paraneoplastic phenomenon characterized by reversible cholestasis in the absence of liver metastases, has been described with renal carcinoma and other malignancies but has not been previously reported in ACC. Case Presentation A 38-year-old man presented with emesis, painless jaundice, pruritus, and weight loss. Laboratory evaluation demonstrated elevated total bilirubin of 8.7 mg/dL (N Conclusion This is the first report of a unique presentation of paraneoplastic-related hyperbilirubinemia in the setting of ACC. While extremely rare, Stauffer syndrome should still be considered in differential diagnosis in patients with ACC with liver dysfunction and jaundice without evidence of liver metastases.

Background In the face of the COVID‐19 pandemic, cancer care has had to adapt rapidly given the Centers for Disease Control and Prevention and the American College of Surgeons (ACS) issuing recommendations to postpone nonurgent surgeries. Methods An institutional multidisciplinary group of Head and Neck Surgical Oncology, Surgical Endocrinology, and Medical Endocrinology devised Surgical Triaging Guidelines for Endocrine Surgery during COVID‐19, aligned with phases of care published by the ACS. Results Phases of care with examples of corresponding endocrine cases are outlined. Most cases can be safely postponed with active surveillance, including most differentiated and medullary thyroid cancers. During the most acute phase, all endocrine surgeries are deferred, except thyroid tumors requiring acute airway management. Conclusions These guidelines provide context for endocrine surgery within the spectrum of surgical oncology, with the goal of optimal individualized multidisciplinary patient care and the expectation of significant resource diversion to care for patients with COVID‐19.

Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. Most tumors are either metastatic or locally invasive at the time of diagnosis. Differentiation between ACC and other adrenal masses depends on clinical, biochemical, and imaging factors. This review will discuss the genetics, pathological, and imaging feature of ACC.

Objectives Adrenal adenoma with myelolipomatous degeneration (AMD) is a rarely reported and often overlooked entity. The aim of this study is to improve understanding of these lesions by characterizing the imaging findings with pathologic and clinical correlation. Methods In the largest series to date, we report 11 nodules in 11 patients confirmed with a pathologic diagnosis of AMD. The available cross-sectional imaging and histopathologic features were reviewed by two radiologists and two pathologists, respectively. Clinical and laboratory data for each patient were obtained from the electronic medical records, when available. Results All 11 patients had a CT prior to resection or biopsy of the adrenal nodule, with five having received an adrenal mass protocol study. An MRI was available in three patients. The median size of the nodules on imaging was 4.5 cm (range 2.8–8.7) and all but one had macroscopic fat. The largest focus of macroscopic fat had a median size of 0.7 cm (range 0.2–1.6) and on average was 14.4% the size of the tumor, using greatest dimensions. Four (36.4%) patients had a diagnosis of Cushing syndrome prior to nodule resection. Conclusions Not all adrenal nodules with macroscopic fat on imaging are pure myelolipomas. An AMD should be considered, especially if the foci of fat are small and other features of an adenoma are present. Some may also be associated with Cushing syndrome. Advances in knowledge: Myelolipomatous degeneration within an adrenal adenoma has only rarely been previously reported with very few reports emphasizing the imaging features. There may be an association with cortisol hypersecretion and improved recognition of this entity could lead to changes in clinical management.

Oncocytic adrenocortical neoplasms (OANs) are rare endocrine tumors that present as a spectrum from benign to malignant. The outcomes after surgical resection of the oncocytic variant of adrenocortical carcinoma remain poorly understood. We sought to characterize the clinicopathologic features of OAN and compare oncocytic adrenocortical carcinoma (OAC) with conventional adrenocortical carcinoma (ACC).Adult patients who underwent adrenalectomy for OAN or ACC between January 1990 and September 2020 were identified. Demographics, clinicopathologic factors, American Joint Committee on Cancer stage, and cancer-related outcomes were reviewed. A matched cohort analysis of disease-free survival (DFS) and overall survival (OS) was performed between patients with OACs and those with ACCs.Forty-one patients with OAN and 214 patients with ACC were included. The OAN cohort median age was 45.2 years [interquartile ratio (IQR) 38.5-54.0 years], and 61.0% were female. OANs were benign (n = 11), of uncertain malignant potential (UMP, n = 9), or OAC (n = 21). Disease recurrence occurred in 12 (57.1%) patients with OAC compared with 1 (11.1%) and 0 patients with UMP or benign OAN, respectively (p0.001). Seven (33.3%) patients with OAC died during follow-up compared with 0 patients with UMP or benign OAN (p = 0.020). Kaplan-Meier survival analysis found no difference in DFS between ACC and OAC groups before (p = 0.218) and after 2:1 matching (p = 0.417). Overall survival was shorter for patients who had ACC compared with those who had OAC (p = 0.031), but the difference was not evident with matched analysis (p = 0.200).OAN presents as a spectrum from benign indolent tumors to aggressive carcinomas. OACs demonstrate similar clinicopathologic behavior and recurrence-free and overall survival when matched to conventional ACCs.

Adrenocortical carcinoma (ACC) is an aggressive cancer with a significant risk of recurrence and high mortality rates. ACC has limited response to currently used treatments and there is an unmet clinical need to identify new treatment options. Disease rarity coupled with absence of preclinical models of disease heterogeneity contributed to limited therapeutic progress in ACC. We previously established new in vitro and in vivo ACC models (CUACC1, CUACC2, CUACC9) with variable genomic alterations commonly seen in ACC tumors. Prior work demonstrated that maternal leucine embryonic kinase (MELK) is an oncogenic kinase in ACC, and that it can be targeted with the MELK inhibitor OTSSP167. To further evaluate the anti-tumor efficacy and mode of action of OTSSP167, this study used genetically diverse ACC cell lines (CUACC1, CUACC2, H295R), patient derived xenografts (PDX) (CUACC1 and CUACC9) and a cell line xenograft model (H295R) of ACC. ACC PDXs treated with 10 mg/kg OTSSP167 had significantly reduced MELK expression, tumor growth inhibition of more than 80%, reduced mitosis, and increased tumor tissue necrosis. Transcriptomic and phospho-proteomic analysis at multiple treatment timepoints in in vitro models revealed that OTSSP167 induced wide transcriptomic and proteomic changes involving effectors of signal transduction, cell cycle, protein translation, and epigenetic regulation to exert its anti-tumorigenic effects. Evaluation of OTSSP167's role in protein synthesis via a puromycin based SUnSET (surface sensing of translation) and kinase assay established that OTSSP167 inhibits de-novo protein synthesis, and targets RSK1 and its substrate rpS6 (S235/S236). Varying the degree of MELK silencing in H295R cell lines using a doxycycline inducible shRNA construct, inhibited RSK1 phosphorylation at T573 and S380 indicating a MELK-RSK1 axis in ACC. Additionally, OTSSP167's effect on the DNA damage pathway was validated, which activated the G2/M checkpoint protein Wee1, increased inhibitory phosphorylation of CDK1, causing an accumulation of cyclin B1 and G2/M arrest independent of TP53 status. Combination treatment with the Wee1 inhibitor AZD1775 and OTSSP167 enhanced OTSSP167 mediated cytotoxic effects in in-vitro models with an increase in mitotic entry and caspase mediated apoptosis. In summary, OTSSP167 exerted its anti-tumorigenic effects via inhibition of the protein translation machinery, DNA damage and cell cycle dysregulation causing drug sensitization. Results from these studies are a first demonstration of the anti-cancer effects of OTSSP167 in sensitization to Wee1 inhibition in ACC. These data suggest that OTSSP167 is a potential therapeutic option for patients with ACC and could be combined with Wee1 inhibitors in a clinical trial using a synthetic lethal approach. Presentation: Saturday, June 11, 2022 12:45 p.m. - 1:00 p.m.

Background After radical resection, patients with adrenocortical carcinoma (ACC) frequently experience recurrence and, therefore, effective adjuvant treatment is urgently needed. The aim of the study was to investigate the role of adjuvant platinum-based therapy. Methods In this retrospective multicentre cohort study, we identified patients treated with adjuvant platinum-based chemotherapy after radical resection and compared them with patients without adjuvant chemotherapy. Recurrence-free and overall survival (RFS/OS) were investigated in a matched group analysis and by applying a propensity score matching using the full control cohort (n = 268). For both approaches, we accounted for immortal time bias. Results Of the 31 patients in the platinum cohort (R0 n = 25, RX n = 4, R1 n = 2; ENSAT Stage II n = 11, III n = 16, IV n = 4, median Ki67 30%, mitotane n = 28), 14 experienced recurrence compared to 29 of 31 matched controls (median RFS after the landmark at 3 months 17.3 vs. 7.3 months; adjusted HR 0.19 (95% CI 0.09–0.42; P P = 0.021) and for OS 0.25 (0.09–0.69; P = 0.007). Conclusions Our study provides the first evidence that adjuvant platinum-based chemotherapy may be associated with prolonged recurrence-free and overall survival in patients with ACC and a very high risk for recurrence.

Context The role of cytoreduction of adrenocortical carcinoma (ACC) remains poorly understood. Objective To analyze the impact of cytoreductive surgery of the primary tumor in patients with metastatic ACC. Design and Setting We performed a multicentric, retrospective paired cohort study comparing the overall survival (OS) in patients with metastatic ACC who were treated either with cytoreductive surgery (CR group) or without cytoreductive surgery (no-CR group) of the primary tumor. Data were retrieved from 9 referral centers in the American-Australian-Asian Adrenal Alliance collaborative research group. Patients Patients aged ≥18 years with metastatic ACC at initial presentation who were treated between January 1, 1995, and May 31, 2019. Intervention Performance (or not) of cytoreductive surgery of the primary tumor. Main outcome and measures A propensity score match was done using age and the number of organs with metastasis (≤2 or >2). The main outcome was OS, determined from the date of diagnosis until death or until last follow-up for living patients. Results Of 339 patients pooled, 239 were paired and included: 128 in the CR group and 111 in the no-CR group. The mean follow-up was 67 months. Patients in the no-CR group had greater risk of death than did patients in the CR group (hazard ratio [HR] = 3.18; 95% CI, 2.34-4.32). Independent predictors of survival included age (HR = 1.02; 95% CI, 1.00-1.03), hormone excess (HR = 2.56; 95% CI, 1.66-3.92), and local metastasis therapy (HR = 0.41; 95% CI, 0.47-0.65). Conclusion Cytoreductive surgery of the primary tumor in patients with metastatic ACC is associated with prolonged survival.

Background Adrenocortical carcinoma (ACC) is a rare malignancy without good treatment options. There are limited data about the use of immunotherapy in ACC. We investigated the efficacy and safety of pembrolizumab in patients with metastatic ACC. Methods This is a pre-specified cohort of a single-center, investigator-initiated, phase II clinical trial using pembrolizumab monotherapy in patients with rare malignancies. Patients must have had prior treatment fail in the past 6 months before study enrollment. Patients were enrolled from August 2016 to October 2018. Follow-up data were updated as of March 26, 2019. Patients received 200 mg pembrolizumab intravenously every 3 weeks without concomitant oncologic therapy. The primary endpoint was non-progression rate (NPR) at 27 weeks. Other endpoints included adverse events, tumor responses measured independently by objective radiologic criteria, and select immunological markers. Results Sixteen patients with ACC (including eight women [50%]) were included in this cohort. Ten patients (63%) had evidence of hormonal overproduction (seven had cortisol-producing ACC). Non-progression rate at 27 weeks was evaluable in 14 patients, one patient was lost to follow-up, and one patient left the study because of an adverse event. Five of 14 patients were alive and progression-free at 27 weeks (non-progression rate at 27 weeks was 36, 95% confidence interval 13–65%). Of the 14 patients evaluable for imaging response by immune-related Response Evaluation Criteria in Solid Tumors, two had a partial response (including one with cortisol-producing ACC), seven had stable disease (including three with cortisol-producing ACC), and five had progressive disease, representing an objective response rate of 14% (95% confidence interval 2–43%). Of those who had stable disease, six had disease stabilization that lasted ≥4 months. Severe treatment-related adverse events (≥grade 3) were seen in 2 of 16 patients (13%) and resulted in one patient discontinuing study participation. All studied tumor specimens (14/14) were negative for programmed cell death ligand-1 expression. Thirteen of 14 tumor specimens (93%) were microsatellite-stable. Eight of 14 patients (57%) had a high tumor-infiltrating lymphocyte score on immunohistochemistry staining. Conclusions Single-agent pembrolizumab has modest efficacy as a salvage therapy in ACC regardless of the tumor’s hormonal function, microsatellite instability status, or programmed cell death ligand-1 status. Treatment was well tolerated in most study participants, with a low rate of severe adverse events. Trial registration ClinicalTrials.gov identifier: NCT02721732, Registered March 29, 2016.

Objectives Localization of ectopic ACTH-secreting tumours causing Cushing syndrome (ECS) is essential for clinical management, yet often difficult. [68 Ga]-DOTATATE PET/CT ([68 Ga]-DOTA-(Tyr3 )-octreotate)] is an FDA-approved high-resolution diagnostic tool for imaging neuroendocrine tumours. Data on the clinical utility of [68 Ga]-DOTATATE in patients with ECS, however, are scarce. The objectives of this study were to determine the efficacy for ECS localization and the clinical benefit of [68 Ga]-DOTATATE imaging. Method We conducted a retrospective review of all cases with ECS evaluated with [68 Ga]-DOTATATE from November 2016 through October 2018 at three referral centres. The clinical benefit of [68 Ga]-DOTATATE was based on detection of new tumours and resultant changes in management. Results Over the study period, 28 patients with ECS underwent [68 Ga]-DOTATATE: 17 for identification of the primary tumour and 11 during follow-up. [68 Ga]-DOTATATE identified the suspected primary ECS in 11/17 patients (65%). Of these, nine patients underwent surgery: eight with confirmed ECS (5 bronchial, 1 thymic, 1 pancreatic and 1 metastatic neuroendocrine tumour of unknown primary origin) and one patient with a false-positive scan (adrenal gland). Of the 11 patients with ECS who underwent [68 Ga]-DOTATATE evaluation during follow-up, the study led to changes in clinical management in 7/11 (64%) patients. Conclusions [68 Ga]-DOTATATE is sensitive in detecting primary and metastatic ECS, often identifies occult tumours after conventional imaging, and impacts clinical care in the majority of patients.

Introduction Adrenocortical carcinoma (ACC) is a rare cancer that commonly spreads to the liver, lungs and lymph nodes. Bone metastases are infrequent. Objective The aim of this report was to describe the clinical characteristics, survival perspective, prognostic factors and frequency of adverse skeletal-related events (SREs) in patients with ACC who developed bone metastasis. Methods This is a retrospective, observational, multicenter, multinational study of patients diagnosed with bone metastases from ACC who were treated and followed up in three European countries (France, Italy and The Netherlands) and one center in the United States. Results Data of 156 patients were captured. The median overall survival was 11 months. SREs occurred in 47% of patients: 17% bone fractures, 17% spinal cord compression, 1% hypercalcemia, 12% developed more than one SRE. In multivariate analysis, cortisol hypersecretion was the only prognostic factor significantly associated with a higher mortality risk (hazard ratio (HR) 2.24, 95% confidence interval (CI): 1.19–4.23, P = 0.013) and with the development of a SREs (of border line significance). The administration of antiresorptive therapies (bisphosphonates and denosumab) was associated with a lower risk of death, even if not significant, and their survival benefit appeared confined in patients attaining serum mitotane levels within the therapeutic range. Conclusion Bone metastases in ACC patients are associated with poor prognosis and high risk of SREs. Cortisol hypersecretion was the only prognostic factor suggesting a potential benefit from antisecretory medications. The therapeutic role of bisphosphonates and denosumab to improve patient outcome deserves to be tested in a prospective clinical trial.

Most adrenal incidentalomas are non-functioning adenomas that require no treatment. The presence of a myelolipomatous component of adrenal incidentalomas is a rare, but well-known occurrence in both hyperplastic and neoplastic lesions of the adrenal cortex. Although the improvements in abdominal imaging have increased identification of myelolipomatous adrenal cortical adenomas radiologically, due to the rarity of this lesion, the clinical pathological features of these lesions are unclear and can sometimes cause diagnostic difficulty. Eleven patients had surgeries at The University of Texas MD Anderson Cancer Center. Four additional cases were provided from an external collaborator. Of the 15 cases, there were 5 male and 10 female patients, with a median age of 52 years (mean 54 years, range 28-84 years). Clinical presentation included adrenal incidentaloma (n = 9), Cushing syndrome (n = 4, including 1 as a part of Carney complex), and subclinical Cushing syndrome (n = 2, including 1 with bilateral macronodular adrenal hyperplasia). In this study, we present the clinicopathologic features of fifteen myelolipomatous adrenal adenomas, the largest series published thus far.

IntroductionPheochromocytomas and sympathetic paragangliomas (PPGL) are neuroendocrine catecholamine-secreting tumors that are usually localized. Metastatic disease is rare and systemic treatment consists of conventional chemotherapy and high-specific-activity iodine-131-MIBG which was approved by the FDA in 2018. Although chemotherapy combinations still have value in specific settings, the debilitating side effects of treatment with only modest benefit have limited their use. With the introduction of a new generation of targeted therapy and immunotherapy patients with metastatic PPGL may have improved therapeutic options.Areas CoveredThe current paper presents a case of a patient with metastatic PPGL who received multiple lines of systemic treatment. Despite progression on previous single agent cabozantinib and single agent pembrolizumab on separate clinical trials, the patient has exhibited a major response to the combination of cabozantinib and nivolumab for the past 22 months. In addition, we will review the available therapies for metastatic PPGL and discuss novel agents under clinical development.ConclusionNewer targeted therapies and immunotherapy options are under clinical development with promising results for patients with PPGL.

Objective: The aim of this Disease State Clinical Review is to provide a practical approach to patients with newly diagnosed adrenocortical carcinoma, as well as to follow-up and management of patients with persistent or recurrent disease. Methods: This is a case-based clinical review. The provided recommendations are based on evidence available from randomized prospective clinical studies, cohort studies, cross-sectional and case-based studies, and expert opinions. Results: Adrenocortical carcinoma is a rare malignancy, often with poor outcomes. For any patient with an adrenal mass suspicious for adrenocortical carcinoma, the approach should include prompt evaluation with detailed history and physical exam, imaging, and biochemical adrenal hormone assessment. In addition to adrenal-focused imaging, patients should be evaluated with chest-abdomen-pelvis cross-sectional imaging to define the initial therapy plan. Patients with potentially resectable disease limited to the adrenal gland should undergo en bloc open surgery by an expert surgeon. For patients presenting with advanced or recurrent disease, a multidisciplinary approach considering curative repeat surgery, local control with surgery, radiation therapy or radiofrequency ablation, or systemic therapy with mitotane and/or cytotoxic chemotherapy is recommended. Conclusion: As most health care providers will rarely encounter a patient with adrenocortical carcinoma, we recommend that patients with suspected adrenocortical carcinoma be evaluated by an expert multidisciplinary team which includes clinicians with expertise in adrenal tumors, including endocrinologists, oncologists, surgeons, radiation oncologists, pathologists, geneticists, and radiologists. We recommend that patients in remote locations be followed by the local health care provider in collaboration with a multidisciplinary team at an expert adrenal tumor program. Abbreviations: ACC = adrenocortical carcinoma; ACTH = adrenocorticotropic hormone; BRACC = borderline resectable adrenocortical carcinoma; CT = computed tomography; DHEAS = dehydroepiandrosterone sulfate; EDP = etoposide, doxorubicin, cisplatin; FDG = 18F-fluorodeoxyglucose; FNA = fine-needle aspiration; HU = Hounsfield units; IVC = inferior vena cava; LFS = Li-Fraumeni syndrome; MEN1 = multiple endocrine neoplasia type 1; MRI = magnetic resonance imaging; OAC = oncocytic adrenocortical carcinoma; PC = palliative care; PET = positron emission tomography

BackgroundThere is no effective systemic therapy for metastatic adrenal cortical carcinoma (ACC) after failure of platinum-based chemotherapy. The efficacies of single-agent oral multikinase inhibitors (MKIs) or salvage immune checkpoint inhibitors (CPIs) have been very limited. It is unknown whether combining CPIs, such as pembrolizumab (PEM), with other therapies, such as MKIs, could yield higher response rates in ACC, yet this combination has shown promise in other cancers. Herein, we describe the first case series using PEM in combination with the MKI lenvatinib (LEN) in patients with progressive, metastatic ACC.MethodsA retrospective case series describing the use of LEN/PEM as salvage therapy in patients with progressive/metastatic ACC.ResultsEight patients were treated with the LEN/PEM combination therapy. Half were female, and the median age at time of diagnosis was 38 years (range 21–49). Three (37.5%) patients had hormonally active ACC. The median number of prior lines of systemic therapy was 4 (range 2–9). Six (75%) patients had had disease progression on prior CPIs and five (62.5%) patients had progressed on prior MKI therapy. The median progression-free survival was 5.5 months (95% CI 1.8–not reached) and median duration of therapy was 8.5 months (range 2–22). Two (25%) patients had a partial response, one (12.5%) patient had stable disease, and five (62.5%) patients had progressive disease. None of the eight patients stopped therapy because of adverse events.ConclusionsIn our small cohort of heavily pretreated patients with ACC, the combination of LEN/PEM was associated with objective responses in a subset of patients without significant toxicity. This combination should be formally investigated in phase II clinical trial with robust correlative studies to identify predictors for response.

BACKGROUND: Adrenocortical carcinoma (ACC) in an aggressive malignancy with suboptimal response to frontline chemotherapy and without established second line treatment. cMET activation is associated with ACC resistance to chemotherapy. Cabozantinib is a multi-kinase inhibitor that targets the VEGFR, c-MET, AXL, and RET receptors. We report interim data about using cabozantinib in ACC through a prospective phase II clinical trial. Methods: This is an investigator-initiated, open label clinical trial to evaluate the efficacy and safety of cabozantinib in patients with unresectable/metastatic ACC (ClinicalTrials.gov Identifier: NCT03370718). The primary objective is 4-month progression-free survival rate (PFS4). Participants are ≥ 18 years old with histologically confirmed ACC. Subjects who used mitotane within 6 months of consent must have mitotane serum level of < 2 mg/L. Cabozantinib starting dose is 60 mg daily with possible dose reductions. Subjects stopped treatment at time of disease progression, death, or occurrence of severe adverse events. Objective tumor responses were assessed per RECIST v.1.1 criteria. Adverse effects were graded per CTCAE v.4.03 Results: At time of data cut off (Oct 28, 2019), we screened 16 patients for enrollment. Ten patients (3 females) received cabozantinib out of whom 5 had history of mitotane use. Nine patients were eligible for response evaluation, defined as having at least one follow up imaging. One patient was taken off study after one week due to hypertensive crisis. Median age at time of diagnosis was 45 years (range 32 - 72). Five patients had hormonally active ACC. Median number of prior lines of systemic therapy was 2 (range 0 -5). Median duration of cabozantinib therapy was 6.6 months (range 0.7 -11.3). Eight patients (80%) were without evidence of progression at 4 months (achieved study endpoint). At time of data cut off, 1 patient had partial response (53% reduction over 8.8 months and ongoing), 3 patients had stable disease, and 5 patients had progressive disease. Nine patients were alive with disease and one patient died (not drug related). Grade 3/4 clinical adverse events included thromboembolic events (3 patients), severe hypertension (1 patient), intracranial hemorrhage secondary to hypertensive crisis (1 patient), weight loss (1 patient), and abdominal pain (1 patient). Grade 3/4 laboratory adverse events included increased AST (2 patient), increased ALT (1 patient), increased GGT, increased amylase (1 patient), increased lipase (1 patient) and hyponatremia (1 patient). Conclusions: In this interim analysis of phase II study, majority of subjects reached the study primary endpoint (PFS4). These data are in favor of continuing study accrual to assess magnitude of response to therapy and safety profile in ACC. Aggressive blood pressure management and close monitoring of liver enzymes are crucial to ensure the safety of study subjects.

Introduction: Most thyroid cancers (TC) are due to mutually exclusive somatic driver mutations. NTRK fusions are rare oncogenic drivers in papillary TC (PTC), poorly differentiated TC (PDTC) and anaplastic TC (ATC), estimated to be in 2.3% of all TC. However, the clinical presentation and behavior of TRK-fusion TC remains largely unknown. Methods / Case Presentation: Using institutional databases, we identified all TC patients (pts) with an NTRK fusion reported on somatic testing performed by a CLIA-certified laboratory. Data from the medical records were collected. The objective of this study was to investigate the clinical and pathological features of TC pts whose tumors harbored an NTRK fusion. Results / Discussion: We identified 36 TC pts with somatic NTRK fusions. Fusion testing was generally done in pts with advanced or radioactive iodine refractory (RAI-R) disease. Median age at diagnosis was 27.4 years (range 4–75 years), 21 (58%) were female and 16 (44%) were pediatric. 28/36 (78%) pts had PTC, 2/36 (5%) PDTC and 6/36 (17%) ATC. There were a total of 12 (33%) NTRK1, 24 (67%) NTRK3, and no NTRK2 fusions. In ATC and PDTC pts NTRK3 was the most common NTRK fusion 7/8 (87%). In PTC pts, 11 (39%) had NTRK1 and 17 (61%) had NTRK3. In the adult pts NTRK3 was more common 17/20 (85%) (Odds Ratio 7.2, P=0.013), however, in pediatric pts rate of NTRK1 and NTRK3 were similar. One pt had additional mutations along with the NTRK fusion, an ATC pt with multiple mutations including BRAF V600E. Of the 30 PTC/PDTC pts, 23 (77%) had distant metastases (mets). 14 (38%) pts had distant mets at diagnosis and 11 (69%) pediatric pts had distant mets. Lung 21 (70%) and bone 9 (30%) were the most common distant mets sites. In the PTC pts with distant mets, 9 (41%) had RAI-avid and 11 (50%) had RAI-R disease. In the entire cohort of 36 pts, 17 (53%) were on a systemic therapy of whom 11 pts were PTC. NTRK directed was the most common systemic therapy 16 (94%). All PTC pts were alive with a median time from diagnosis of 46 months (Interquartile 1–3: 25–118 months). Four ATC and one PDTC pts had died at the time of the analysis. Conclusions: In this study we confirmed that NTRK fusions occur primarily in PTC but also in less differentiated tumors. Most were young pts but NTRK fusions were identified in tumors from adults as old as 75 years. NTRK1 and NTRK3 were the most common NTRK fusions with NTRK3 being more common in adults. In thyrocyte-derived TC pts, NTRK fusions are mutually exclusive genetic events that occur in pts of all ages and varying histologies. Given the availability of NTRK targeted therapy, consideration should be given to testing for NTRK fusions in advanced thyroid cancer pts, especially those in whom prior genetic testing did not identify an oncogenic driver.

PURPOSE The aims of the study were to assess the typical and atypical radiologic features of pathologically proven adrenal adenomas and to determine the relationship between the radiologic and histopathologic classification. METHODS We retrospectively studied 156 pathologically proven adrenal adenomas in 154 patients from our institutional databases who have computed tomography (CT) and/or magnetic resonance imaging (MRI) examinations before intervention. We determined the histopathologic diagnosis (typical or atypical) using Weiss scoring and classified the adenomas radiologically into typical, atypical, or indeterminate based on lesion size, precontrast CT attenuation, absolute percentage washout, calcification, and necrosis. The κ statistic was used to assess the agreement between radiologists. The Fisher exact test was used to compare the radiologic and pathological classifications. RESULTS In consensus, there were 83 typical, 42 atypical, and 31 indeterminate adrenal lesions. Logistic regression model showed that radiologically atypical adenoma was significantly associated with larger size, lobulated shape, higher unenhanced CT attenuation, heterogeneous appearance, nonfunctioning status, absolute percentage washout of less than 60%, and a signal intensity index of less than 16.5%.Pathologically, 147 adenomas were pathologically typical (Weiss 0), and 9 adenomas were pathologically atypical (Weiss 1-2). Radiologically, there was substantial agreement between both readers, with Cohen κ at 0.71. Approximately 98% of radiologically typical adenomas were pathologically typical. Only 17% of radiologically atypical adenomas were pathologically atypical. All radiologically indeterminate adenomas were pathologically typical. However, some of the radiologically indeterminate and typical adenomas still had an atypical component on pathologic analysis, such as necrosis, nuclear atypia, or oncocytic features. CONCLUSIONS Radiologically atypical lesion was significantly associated with larger size and higher unenhanced CT attenuation. Approximately 27% of the cases demonstrated atypical features on imaging. Most radiologically atypical adrenal adenomas are pathologically typical.

The evaluation and management of adrenal disease is a complex endeavor that relies on an expert knowledge of human physiology and anatomy. Careful and proper patient assessment mandates a balanced approach which marries the disciplines of endocrinology, surgery, and radiology. Any of these three specialties may be on the front line in performing the initial workup when an adrenal neoplasm is discovered. With an ever-increasing volume of cross-sectional imaging, be it CT, MRI, or PET, large numbers of adrenal incidentalomas are being discovered. A close collaboration amongst specialties should strive to streamline the initial evaluation and minimize unnecessary testing and treatment.

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with high risk of recurrence despite macroscopically complete surgical resection. The main predictors of ACC recurrence include advanced disease stage, incomplete surgical resection, cortisol production, certain genetic alterations, and high proliferation rate (Ki-67 proliferation index). Mitotane has been the mainstay adjuvant therapy of ACC. However, the use of mitotane is based on retrospective and occasionally conflicting evidence. As mitotane levels can take a few months before reaching therapeutic levels, there is an emerging practice of combining platinum-based chemotherapy with mitotane in the adjuvant setting. Retrospective data indicate that radiotherapy is an option for select patients, particularly those with positive resection margins. There are multiple knowledge gaps in selecting patients for adjuvant therapy. It is of great importance to establish risk calculators to predict recurrence and to implement molecular profiling of ACC to guide adjuvant therapy. The role of immunotherapy in metastatic ACC is emerging and if deemed efficacious, then future studies will be needed to ascertain the role of adjuvant immunotherapy in ACC.

Adrenocortical carcinoma (ACC) is a rare but aggressive cancer, with complete surgical resection offering the best opportunity for cure. Despite complete surgical resection, most patients with ACC will experience recurrence, and the efficacy of systemic therapy is limited. This chapter will discuss the presentation, diagnostic evaluation, and therapeutic options for patients with adrenocortical carcinoma.

Adrenocortical cancer; Checkpoint inhibitors; Metastatic paraganglioma Cáncer adrenocortical; Inhibidores de puntos de control; Paraganglioma metastásico Càncer adrenocortical; Inhibidors de punts de control; Paraganglioma metastàtic Adrenocortical cancers and metastatic pheochromocytomas are the most common malignancies originating in the adrenal glands. Metastatic paragangliomas are extra-adrenal tumors that share similar genetic and molecular profiles with metastatic pheochromocytomas and, subsequently, these tumors are studied together. Adrenocortical cancers and metastatic pheochromocytomas and paragangliomas are orphan diseases with limited therapeutic options worldwide. As in any other cancers, adrenocortical cancers and metastatic pheochromocytomas and paragangliomas avoid the immune system. Hypoxia-pseudohypoxia, activation of the PD-1/PD-L1 pathway, and/or microsatellite instability suggest that immunotherapy with checkpoint inhibitors could be a therapeutic option for patients with these tumors. The results of clinical trials with checkpoint inhibitors for adrenocortical carcinoma or metastatic pheochromocytoma or paraganglioma demonstrate limited benefits; nevertheless, these results also suggest interesting mechanisms that might enhance clinical responses to checkpoint inhibitors. These mechanisms include the normalization of tumor vasculature, modification of the hormonal environment, and vaccination with specific tumor antigens. Combinations of checkpoint inhibitors with classical therapies, such as chemotherapy, tyrosine kinase inhibitors, radiopharmaceuticals, and/or novel therapies, such as vaccines, should be evaluated in clinical trials.

Background Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with very limited treatment options. Nevanimibe HCl (formerly ATR-101), a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, has been shown in nonclinical studies to decrease adrenal steroidogenesis at lower doses and to cause apoptosis of adrenocortical cells at higher doses. Methods This phase 1, multicenter, open-label study assessed the safety and pharmacokinetics (PK) of nevanimibe in adults with metastatic ACC (NCT01898715). A “3 + 3” dose-escalation design was used. Adverse events (AEs), PK, and tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were evaluated every 2 months. Results 63 patients with metastatic ACC, all of whom had previously failed systemic chemotherapy and only 2 of whom were mitotane-naive, were dosed with oral nevanimibe at doses ranging from 1.6 mg/kg/day to 158.5 mg/kg/day. Subjects who did not experience tumor progression or a dose-limiting toxicity (DLT) could continue to receive additional cycles. No patients experienced a complete or partial response; however, 13 of the 48 (27%) patients who underwent imaging at 2 months had stable disease (SD), and 4 of these had SD > 4 months. In addition, drug-related adrenal insufficiency, considered a pharmacologic effect of nevanimibe, was observed in two patients. The most common treatment-emergent AEs were gastrointestinal disorders (76%), including diarrhea (44%) and vomiting (35%). A maximum tolerated dose (MTD) could not be defined, as very few dose-limiting toxicities (DLTs) occurred. Because the large number of tablets required at the highest dose (i.e., ~24 tablets/day) resulted in low-grade gastrointestinal adverse effects, a maximum feasible dose of 128.2 mg/kg/day was established as a dose that could be taken on a long-term basis. Conclusions This study demonstrated the safety of nevanimibe at doses of up to ~6000 mg BID. As the total number of tablets required to achieve an MTD exceeded practical administration limits, a maximum feasible dose was defined. Given that the expected exposure levels necessary for an apoptotic effect could not be achieved, the current formulation of nevanimibe had limited efficacy in patients with advanced ACC.

BACKGROUND: Hypertension (HTN) is an established class effect of vascular endothelial growth factor receptor (VEGFR) inhibition. In the phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial, HTN was the most frequent adverse event of lenvatinib, an inhibitor of VEGFR1, VEGFR2, VEGFR3, fibroblast growth factor receptor 1 (FGFR1), FGFR2, FGFR3, FGFR4, platelet-derived growth factor receptor (PDGFR), ret proto-oncogene (RET), and stem cell factor receptor (KIT). This exploratory analysis examined treatment-emergent hypertension (TE-HTN) and its relation with lenvatinib efficacy and safety in SELECT. METHODS: In the multicenter, double-blind SELECT trial, 392 patients with progressive radioiodine-refractory differentiated thyroid cancer (RR-DTC) were randomized 2:1 to lenvatinib (24 mg/d on a 28-day cycle) or placebo. Survival endpoints were assessed with Kaplan-Meier estimates and log-rank tests. The influence of TE-HTN on progression-free survival (PFS) and overall survival (OS) was analyzed with univariate and multivariate Cox proportional hazards models. RESULTS: Overall, 73% of lenvatinib-treated patients and 15% of placebo-treated patients experienced TE-HTN. The median PFS for lenvatinib-treated patients with (n = 190) and without TE-HTN (n = 71) was 18.8 and 12.9 months, respectively (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.39-0.88; P = .0085). For lenvatinib-treated patients, the objective response rate was 69% with TE-HTN and 56% without TE-HTN (odds ratio, 1.72; 95% CI, 0.98-3.01). The median change in tumor size for patients with and without TE-HTN was -45% and -40%, respectively (P = .2). The median OS was not reached for patients with TE-HTN; for those without TE-HTN, it was 21.7 months (HR, 0.43; 95% CI, 0.27-0.69; P = .0003). CONCLUSIONS: Although HTN is a clinically significant adverse event that warrants monitoring and management, TE-HTN was significantly correlated with improved outcomes in patients with RR-DTC, indicating that HTN may be predictive for lenvatinib efficacy in this population. (C) 2018 American Cancer Society.

Adrenocortical carcinoma (ACC) has a poor prognosis and there is an unmet clinical need for biomarkers to improve both diagnostic and prognostic assessment. Pituitary-tumor transforming gene (PTTG1) has been shown to modulate cancer invasiveness and response to therapy. The potential role of PTTG1 protein levels in ACC has not been previously addressed. We assessed whether increased nuclear protein expression of PTTG1 distinguished ACCs from adrenocortical adenomas (ACAs). Patients with ACC or ACA were identified from prospective tissue banks at two independent institutions. Two tissue microarrays (TMAs) consisting of adrenal specimens from 131 patients were constructed and clinically annotated. Immunohistochemical analysis for PTTG1 and Ki-67 was performed on each TMA. TMA-1 (n = 80) contained 20 normal adrenals, 20 ACAs, and 40 ACCs, and the validation, TMA-2 (n = 51), consisted of 10 normal adrenals, 14 ACAs, and 27 ACCs. On TMA-1, nuclear staining of PTTG1 was detected in 12 (31%) ACC specimens, while all ACAs and normal adrenal glands were negative for PTTG1. On TMA-2, 20 (74%) of the ACC tumors demonstrated PTTG1 nuclear staining of PTTG1, and 13 (93%) ACA and 4 (44%) normal adrenal glands were negative for PTTG1. ACC tumors with increased PTTG1 protein staining had a significantly higher Ki-67 index (p

Adrenocortical carcinoma (ACC) is an aggressive cancer with poor response to chemotherapeutic and immunotherapeutic agents. About half of ACCs produce glucocorticoids (GC), and the presence of GC excess (hypercortisolism) is correlated with decreased survival in patients with ACC. The broad immunosuppressive effects of GC may contribute to the limited efficacy of immune checkpoint inhibitors, such as pembrolizumab, in these patients. Antagonism of the glucocorticoid receptor (GR) has the potential to increase immune-related transcripts, thus promoting tumor immune response in ACC with GC excess. To test this hypothesis, we introduce a phase 1b study evaluating the combined treatment of relacorilant (CORT125134, Corcept Therapeutics) with pembrolizumab in patients with advanced ACC and hypercortisolism (NCT04373265). Relacorilant is a selective (no activity at other steroid receptors), oral GR modulator in development for Cushing syndrome and, in combination with chemotherapy, for various solid tumors. In healthy subjects, prednisone causes rapid reductions in eosinophils, lymphocytes, and osteocalcin and rapid increases in neutrophils. Relacorilant ameliorates these effects. In a phase 2 study in patients with endogenous Cushing syndrome treated with relacorilant, improvements in the signs and symptoms of GC excess were seen. The primary objective of this study is to determine the safety and efficacy of the recommended regimen of relacorilant with pembrolizumab in patients with advanced ACC and hypercortisolism. Pembrolizumab infusion will occur on day 1 of each 21-day cycle, and relacorilant will be administered once daily, starting 3 days before the first pembrolizumab infusion. Relacorilant doses will be escalated in 100-mg increments (100 mg up to 400 mg, as tolerated). Patients will receive treatment until they experience disease progression or unacceptable toxicity. Approximately 20 adults with confirmed advanced, unresectable and/or metastatic ACC will be enrolled. GC excess must be documented by either ACTH 1.8 µg/dL after dexamethasone suppression testing (DST), or the presence of two of the following criteria: elevated urinary free cortisol; high late-night salivary cortisol; and DST cortisol >1.8 µg/dL. Assessments will include safety, tolerability, and efficacy. Secondary objectives include a determination of the non-progression rate at 27 weeks, evaluation of progression-free survival, overall survival, duration of response, and an assessment of the effect of the combination on clinical manifestations of hypercortisolism. This will be the first clinical study to evaluate whether GR antagonism promotes tumor response in patients with ACC and GC excess treated with checkpoint inhibitors.

Context Interpretation of calcitonin measurement to predict the prognosis of medullary thyroid carcinoma (MTC) requires multiple measurements over an extended time period, making it an imperfect biomarker for evaluating prognosis or disease behavior. Single circulating cell-free DNA (cfDNA) values have been shown to be a valuable prognostic marker for several solid tumors. Objective We tested the hypothesis that cfDNA containing the RET M918T mutation could be detected in the blood of patients with advanced MTC whose tumor harbored an M918T mutation and would be able to predict overall survival more reliably than calcitonin. Design The level of cfDNA containing RET M918T mutation was measured in the plasma of patients with MTC via droplet digital polymerase chain reaction. Patients Patients had a confirmed sporadic MTC diagnosis, a serum calcitonin measurement >100 pg/mL, and tumor tissue biopsy results providing RET M918T mutation status. There were 75 patients included in this study, 50 of whom harbored an RET M918T mutation by tissue biopsy. Results RET M918T cfDNA was detected in 16 of 50 patients (32%) with a positive tissue biopsy. The detection of RET M918T cfDNA strongly correlated with worse overall survival and more accurately predicted a worse outcome than calcitonin doubling time. Conclusions Liquid biopsy is able to detect RET M918T mutations in patient plasma with high specificity but low sensitivity. In patients with established somatic RET M918T mutations, the allelic fraction of circulating tumor DNA is prognostic for overall survival and may play a role in monitoring response to treatment.