Advanced Adrenocortical Carcinoma Research Articles

Venous thromboembolism in adrenocortical carcinoma: a retrospective analysis.

Venous thromboembolism (VTE) is a leading cause of death in patientswith cancer. Limited data exist about VTE in patients with adrenocortical carcinoma (ACC). The primary objective of this study was to identify the prevalence of VTE in a cohort of patients with ACC. Secondary objectives were to determine the impact of VTE events on overall survival (OS) and to describe the characteristics of VTE in patients with ACC. We retrospectively reviewed data from 289 patients with ACC cared for at a major referral center from February 2010 to June 2022. VTE prevalence was 18.7% (54 events). Thirty patients (55.6%) had pulmonary embolism (PE); 12 patients (22.2%) had deep vein thrombosis (DVT); and 12 patients (22.2%) had both PE and DVT. VTE occurred after ACC diagnosis in 50 patients (92.6%) including 44 patients (88%) with stage 3 or 4 ACC. VTEs were CTCAE grade ≤2 in 32 cases (59.3%), grade 3 in 17 (31.5%), and grade 4 in 2 (3.7%). Thirteen patients (24%) died within 6 months after VTE diagnosis, although there was no statistically significant association between VTE and overall survival. Despite the potential to underestimate the prevalence of VTEs, we found a high frequency of VTE events in patients with ACC. A majority of VTEs occurred in the context of advanced ACC and we observed high short-term mortality. Further studies are needed to validate our findings and investigate mechanisms associated with VTE in ACC.

CRISPR/Cas9-mediated glucocorticoid receptor knockout effectively enhances antitumor efficacy of ROR1 specific CAR-T cells in advanced adrenocortical carcinoma

CRISPR/Cas9-mediated glucocorticoid receptor knockout effectively enhances antitumor efficacy of ROR1 specific CAR-T cells in advanced adrenocortical carcinoma

Dual targeting Boolean logic gate CAR-T cells for selective tumor antigen encounter exert potent antitumor efficacy in advanced adrenocortical carcinoma

Dual targeting Boolean logic gate CAR-T cells for selective tumor antigen encounter exert potent antitumor efficacy in advanced adrenocortical carcinoma

Cabozantinib monotherapy for advanced adrenocortical carcinoma: a single-arm, phase 2 trial

Adrenocortical carcinoma is a rare malignancy with poor response to systemic chemotherapy. Mitotane is the only approved therapy for adrenocortical carcinoma. Cabozantinib is a multikinase inhibitor approved in multiple malignancies. This is the first prospective trial to explore the anti-tumour activity, safety, and pharmacokinetic profile of cabozantinib in patients with advanced adrenocortical carcinoma. This investigator-initiated, single-arm, phase 2 trial in adult patients (aged ≥18 years) with advanced adrenocortical carcinoma was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible patients had histologically confirmed adrenocortical carcinoma, were not candidates for surgery with curative intent, had measurable disease, had an estimated life expectancy of at least 3 months, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 with adequate organ function. Patients who had used mitotane within 6 months of study participation were required to have a serum mitotane level of less than 2 mg/L. Patients were given oral cabozantinib 60 mg daily with the option of dose reduction to manage adverse events. The primary endpoint was progression-free survival at 4 months, assessed in all patients who received at least one dose of study drug per protocol. This study is registered with ClinicalTrials.gov, NCT03370718, and is now complete. Between March 1, 2018, and May 31, 2021, we enrolled 18 patients (ten males and eight females), all of whom received at least one dose of study treatment. Of the 18 patients, eight (44%) had an ECOG performance status of 0, nine (50%) patients had a performance status of 1, and one (6%) patient had a performance status of 2. Median follow-up was 36·8 months (IQR 30·2-50·3). At 4 months, 13 (72·2%; 95% CI 46·5-90·3) of 18 patients had progression-free survival and median progression-free survival was 6 months (95% CI 4·3 to not reached). One patient remains on treatment. Treatment-related adverse events of grade 3 or worse occurred in 11 (61%) of 18 patients. The most common grade 3 adverse events were lipase elevation (three [17%] of 18 patients), elevated γ-glutamyl transferase concentrations (two [11%] patients), elevated alanine aminotransferase concentrations (two [11%] patients), hypophosphatemia (two [11%] patients), and hypertension (two [11%] patients). One (6%) of 18 patients had grade 4 hypertension. No treatment related deaths occurred on study. Cabozantinib in advanced adrenocortical carcinoma showed promising efficacy with a manageable and anticipated safety profile. Further prospective studies with cabozantinib alone and in combination with immune checkpoint therapy are ongoing. Exelixis.

"Expression and prognostic relevance of PD-1, PD-L1 and CTLA-4 immune checkpoints in adrenocortical carcinoma".

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with poor prognosis in advanced stages. While therapies targeting the checkpoint molecules programmed cell death 1 (PD-1), its ligand PD-L1 and the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have revolutionized treatment in many cancers, the results in ACC were heterogeneous. Their expression in ACC has not been systematically studied and might explain the variable response to checkpoint inhibitors. The expression of PD-1, PD-L1 and CTLA-4 was examined in 162 tumor samples from 122 ACC patients by immunohistochemistry (threshold of >1%) and correlated with tumoral T lymphocyte infiltration and clinical endpoints. Finally, uni- and multivariate analyses of progression-free and overall survival were performed. PD-1 and PD-L1 were expressed in 26.5% and 24.7% of samples, respectively, with low expression in most tumor samples (median positive cells: 2.1% and 21.7%. In contrast, CTLA-4 expression was observed in 52.5% of ACC with a median of 38.4% positive cells. Positive PD-1 expression was associated with longer progression-free survival (HR: 0.50, 95% CI 0.25-0.98, p=0.04) even after considering prognostic factors. In contrast, PD-L1 and CTLA-4 did not correlate with clinical outcome. Additionally, PD-1 and PD-L1 expression correlated significantly with the amount of CD3+, CD4+, FoxP3+ and CD8+ T cells. The heterogeneous expression of PD1, PD-L1, and CTLA-4 in this large series of well-annotated ACC samples might explain the heterogeneous results of the immunotherapies in advanced ACC. In addition, PD-1 expression is a strong prognostic biomarker that can easily be applied in routine clinical care and histopathological assessment.

The Efficacy and Safety of Immune Checkpoint Inhibitors in Adrenocortical Carcinoma: A Systematic Review and Meta-Analysis.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of different malignancies. However, their efficacy in advanced adrenocortical carcinoma (ACC) remains uncertain. Thus, we conducted a systematic review and meta-analysis to summarize the efficacy and tolerability of ICIs in patients with advanced ACC. We searched PubMed, Scopus, and CENTRAL for studies that used ICIs in ACC. Studies with more than five patients were included in the meta-analysis of the objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and grade 3/4 adverse events. Twenty studies with 23 treatment arms and 250 patients were included. Single-agent anti-PD1 or anti-PD-L1 treatment was utilized in 13 treatment arms, whereas an anti-PD1 or anti-PD-L1 and anti-CTLA4 combination was used in 4 treatment arms. Other anti-PD1- or anti-PD-L1-based combinations were used in five treatment arms. The ORR was 14% (95% CI = 10-19%, I2 = 0%), and the DCR was 43% (95% CI = 37-50%, I2 = 13%). The combination anti-PD1- or anti-PD-L1-based treatment strategies did not correlate with higher responses compared with monotherapy. The median OS was 13.9 months (95% CI = 7.85-23.05), and the median PFS was 2.8 months (95% CI = 1.8-5.4). ICIs have a modest efficacy in advanced ACC but a good OS. Further studies are needed to investigate predictive biomarkers for ICI response and to compare ICI-based strategies with the current standard of care.

Current Status and Future Direction in the Treatment of Advanced Adrenocortical Carcinoma.

To provide a comprehensive overview of the current understanding and developments in the treatment options for adrenocortical carcinoma (ACC), focusing on the strategies utilized for advanced disease. Research has delved into the genomic landscape of ACC, revealing potential targets for therapy. Despite the failure of inhibitors aimed at the insulin like growth factor 1(IGF-1) receptor, other approaches, including vascular endothelial growth factor receptor (VEFGR) tyrosine kinase inhibitors and immune checkpoint inhibitors, are being investigated. There are also ongoing trials of combination treatments such as lenvatinib with pembrolizumab and cabozantinib with atezolizumab. ACC remains a challenging malignancy with limited effective treatment options. Although EDP-M stands as the frontline treatment, the search for effective second-line therapies is ongoing. Targeted therapies and immunotherapies, especially in combination regimens, are demonstrating potential and are the subject of continued research. The evolving genomic landscape emphasizes the significance of targeted therapies and the need for further in-depth studies to solidify effective treatment regimens for ACC.

Exploring Theranostic Avenues in Adrenocortical Carcinoma Using Chemokine Receptor and Prostate-Specific Membrane Antigen-Directed PET/CT.

We report on an adrenocortical carcinoma (ACC) patient, which has exhausted previous treatment options and was scheduled for prostate-specific membrane antigen (PSMA)- and C-X-C motif chemokine receptor 4 (CXCR4)-targeted PET/CT. We identified PSMA-avid pulmonary metastases exhibiting modest radiotracer accumulation, while chemokine receptor PET/CT provided intense uptake. This dual-tracer molecular imaging approach revealed that chemokine receptor PET appears to be more suitable in patients with advanced ACC, indicating that CXCR4-directed radioligand therapy may be considered in such patients suffering from end-stage disease. Given its dismal prognosis, chemokine receptor-directed theranostics may therefore extend the therapeutic armamentarium as last-line option in advanced ACC.

The Value of Local Therapies in Advanced Adrenocortical Carcinoma.

International guidelines recommend local therapies (LTs) such as local thermal ablation (LTA; radiofrequency, microwave, cryoablation), transarterial (chemo)embolisation (TA(C)E), and transarterial radioembolisation (TARE) as therapeutic options for advanced adrenocortical carcinoma (ACC). However, the evidence for these recommendations is scarce. We retrospectively analysed patients receiving LTs for advanced ACC. Time to progression of the treated lesion (tTTP) was the primary endpoint. The secondary endpoints were best objective response, overall progression-free survival, overall survival, adverse events, and the establishment of predictive factors by multivariate Cox analyses. A total of 132 tumoural lesions in 66 patients were treated with LTA (n = 84), TA(C)E (n = 40), and TARE (n = 8). Complete response was achieved in 27 lesions (20.5%; all of them achieved by LTA), partial response in 27 (20.5%), and stable disease in 38 (28.8%). For the LTA group, the median tTTP was not reached, whereas it was reached 8.3 months after TA(C)E and 8.2 months after TARE (p < 0.001). The median time interval from primary diagnosis to LT was >47 months. Fewer than four prior therapies and mitotane plasma levels of >14 mg/L positively influenced the tTTP. In summary, this is one of the largest studies on LTs in advanced ACC, and it demonstrates a very high local disease control rate. Thus, it clearly supports the guideline recommendations for LTs in these patients.

Wnt/β-catenin signaling pathway in the tumor progression of adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is an uncommon, aggressive endocrine malignancy with a high rate of recurrence, a poor prognosis, and a propensity for metastasis. Currently, only mitotane has received certification from both the US Food and Drug Administration (FDA) and the European Medicines Agency for the therapy of advanced ACC. However, treatment in the advanced periods of the disorders is ineffective and has serious adverse consequences. Completely surgical excision is the only cure but has failed to effectively improve the survival of advanced patients. The aberrantly activated Wnt/β-catenin pathway is one of the catalysts for adrenocortical carcinogenesis. Research has concentrated on identifying methods that can prevent the stimulation of the Wnt/β-catenin pathway and are safe and advantageous for patients in view of the absence of effective treatments and the frequent alteration of the Wnt/β-catenin pathway in ACC. Comprehending the complex connection between the development of ACC and Wnt/β-catenin signaling is essential for accurate pharmacological targets. In this review, we summarize the potential targets between adrenocortical carcinoma and the Wnt/β-catenin signaling pathway. We analyze the relevant targets of drugs or inhibitors that act on the Wnt pathway. Finally, we provide new insights into how drugs or inhibitors may improve the treatment of ACC.

FRI199 Severe Hypertriglyceridemia And Acute Pancreatitis In A Patient With Adrenocortical Carcinoma (ACC) Taking Mitotane

Abstract Disclosure: B.N. Cortez: None. D.G. Varghese: None. A. Naimian: None. R. Mallorson: None. T. Magee: None. S. Kelley: None. N. Roper: None. A.T. Fojo: None. J. Del Rivero: None. Background: Adrenocortical carcinoma (ACC) is a rare tumor with an incidence of 0.7-2 per million people per year, and a poor prognosis with a five-year survival &amp;lt;35%. Many patients present with steroid hormone excess (glucocorticoids, mineralocorticoids, androgens). Treatment of choice for a localized primary or recurrence is radical surgical resection, which offers the best chance for prolonged recurrence-free survival. However, patients with recurrent or metastatic disease are infrequently curable by surgery alone. Chemotherapy options have limited benefit, though platinum-based therapies have response rates of 25-30%. Mitotane has been used for the treatment of advanced ACC since the 1960s and is generally recommended to reduce risk of future recurrence. Clinical case: A 36-year-old female of Ashkenazi Jewish ancestry presented with a prior history of well-differentiated, grade 1 pancreatic neuroendocrine tumor (NET) fully resected with no evidence of recurrence. On follow up MRI 7 months after resection, she was found to have a 3.8 x 2.5 x 3.3 cm bilobed left adrenal mass. Laparoscopic biopsy was initially reported as NET, however, a second opinion was reported as ACC. She subsequently had laparoscopic surgery with intraoperative tumor spillage and surgical pathology was consistent with high grade ACC, Ki67 of 15-25% with invasion through the adrenal capsule. Germline genetic testing showed no variants of concern. Post-adrenalectomy, the patient’s starting dose was 1g mitotane each day with replacement hydrocortisone. When on 2.5 grams daily, her symptoms were mild diarrhea, fatigue and occasional headaches. One month after starting mitotane, she developed extreme abdominal pain, nausea and vomiting and presented to the ED. Computed tomography at the time revealed no evidence of disease (5 months after resection). Laboratory results were significant for mild leukocytosis, as well as elevated lipase (510 U/L, 0-160), cholesterol (451 mg/dL, 125-200), triglycerides (&amp;gt;10,000 mg/dL, &amp;lt;150), and LDL (168 mg/dL, &amp;lt;100), with a lactic acid of 2.6 mmol/L (&amp;lt;2) consistent with acute pancreatitis likely due to hypertriglyceridemia. Microbiology positive for parainfluenza virus. Her condition worsened and she subsequently developed septic shock, acute renal failure, for which she received hemodialysis, and multiorgan failure. On her ninth day of admission, she succumbed to disease. Conclusion: While some studies show hypertriglyceridemia secondary to mitotane, others only show elevated cholesterol at 6 and 3 months, respectively. We describe an ACC patient with a history of fatty liver disease and mixed hyperlipidemia who developed severe hypertriglyceridemia and acute pancreatitis leading to multiorgan failure about one month after starting mitotane. This case highlights hypertriglyceridemia as a serious complication of mitotane in a patient with preexisting dyslipidemia. Presentation: Friday, June 16, 2023

THU617 Prolonged Exposure To Target Mitotane Concentrations Is Associated With Better Recurrence-free Survival In Patients With Adrenocortical Carcinoma On Adjuvant Treatment

Abstract Disclosure: S. Puglisi: None. A. Calabrese: None. V. Basile: None. O. Kimpel: Speaker; Self; HRA Pharmaceuticals. B. Altieri: None. A. Angelousi: None. G. Kaltsas: None. U. Ambroziak: None. M.L. Appetecchia: None. M. Arosio: None. A. Berruti: Advisory Board Member; Self; HRA Pharmaceuticals. D. Cosentini: None. L. Canu: None. F. Ceccato: None. G. Di Dalmazi: None. L. Bouys: None. R. Libè: None. K. Nowak: None. L. Papierska: None. J. Pittaway: None. T. Kienitz: None. M. Quinkler: None. Y. Elhassan: None. C. Ronchi: None. L. Saiegh: None. A. Stigliano: None. T. Dusek: None. D. Kastelan: None. M. Fassnacht: None. M. Terzolo: Advisory Board Member; Self; HRA Pharmaceuticals. Grant Recipient; Self; HRA Pharmaceuticals. Background: The management of adjuvant mitotane therapy in patients with adrenocortical carcinoma (ACC) is challenging. Plasma mitotane concentrations &amp;gt;14 mg/L have been associated with efficacy in the treatment of advanced ACC; however, data in the adjuvant setting are mixed. Moreover, there is no consensus on how to assess the optimal exposure to mitotane and all the proposed methods have inherent limitations. We have recently proposed a new method analogous to what is established for the anticoagulant warfarin, the time in target range (TTR). We aimed to evaluate whether the TTR is a factor influencing recurrence-free survival (RFS) in patients with ACC on adjuvant mitotane. Methods: This is an international, retrospective, cohort study undertaken in 18 centers in 8 countries, under the auspices of the European Network for the Study of Adrenal Tumors (ENSAT), including adult patients with ACC treated with adjuvant mitotane for at least 1 year following tumor resection, with the availability of at least 3 mitotane measurements per year. TTR was calculated with the Rosendaal method and expressed as the number of months with plasma mitotane concentration &amp;gt;14 mg/L. The following potential predictive factors for RFS have been investigated: patient sex and age, ENSAT stage, hormone secretion, resection status, Weiss score, Ki67 index, and TTR. Data are expressed as median and interquartile range. Results: From a total of 254 patients, 157 fulfilled inclusion criteria and were analyzed (F/M 94/63; age 49, 41-58 years), with a follow-up of 49 (33-92) months. The key baseline features were: 7.0% stage I, 69.4% II, 22.3% III, 1.3% IV; 51.6% secreting tumors; 87.2% R0, 2.6% R1, 10.2% RX; Weiss score 5 (4-7); Ki67 index 11 (5-20). All patients were treated with mitotane for 25 (22-36) months, with a TTR of 14 (6-21) months. At multivariate analysis, Ki67 index (HR 1.07, 95%CI, 1.02-1.12; p&amp;lt;0.01) and Weiss score (HR 1.7, 95%CI, 1.16-2.47; p&amp;lt;0.01) were associated with an increased risk of recurrence, while female sex (HR 0.14, 95%CI, 0.04-0.58; p&amp;lt;0.01) and TTR (HR 0.80, 95%CI, 0.70-0.90; p&amp;lt;0.001) were associated with a reduced risk. Conclusions The present findings show that the patients who are exposed to plasma mitotane &amp;gt;14 mg/L for longer periods have better RFS. These findings provide indirect evidence of the value of adjuvant therapy with mitotane and support the importance of drug monitoring to guide dose adjustment in clinical practice and improve patient outcome. Presentation: Thursday, June 15, 2023

Hypertriglyceridemia and its impact on mitotane monitoring in adrenocortical carcinoma.

Mitotane is used for treatment of advanced adrenocortical carcinoma. It is administered when the carcinoma is unresectable, metastasized, or at high-risk of recurrence after resection. In addition, mitotane is considered to have direct adrenolytic effects. Because of its narrow therapeutic-toxic range, therapeutic drug monitoring (TDM) is warranted. In 2020, a left-sided adrenal gland tumor was found (5.8 cm) in a 38-year-old man. Considering the size of this lesion and inability to exclude an adrenocortical carcinoma on imaging, a laparoscopic adrenalectomy was performed. Histopathologic examination determined presence of an adrenocortical carcinoma (pT2N0M0 ENSAT stadium II; ki67 10-15%). There was no evidence for residual or metastatic disease but given the high risk of recurrence, adjuvant therapy with mitotane was initiated. During TDM, a sudden and spuriously high level of mitotane was observed but without signs or symptoms of toxicity. After exploration, it was found that this high concentration was completely due to uncontrolled hypertriglyceridemia. After correction thereof, mitotane levels were again in the therapeutic range. This observation underscores the importance of TDM sampling in a fasting state with concurrent control of prevalent or incident dyslipidemia. TDM of mitotane is advocated to achieve therapeutic levels while avoiding toxicity. For correct TDM, sampling should be done at least 12 h after last intake of mitotane. Although sampling in fasting conditions in not explicitly mentioned in the guidelines, fasting state should be considered as elevated serum triglyceride levels might cause spuriously high mitotane levels. In patients undergoing treatment with mitotane and presenting with too high or unexplained fluctuating mitotane levels without signs or symptoms of toxicity, hypertriglyceridemia as a possible cause should be investigated. If dyslipidemia occurs in patients under mitotane treatment, other causes than mitotane (e.g. alcohol abuse and diabetes) should be considered and appropriate treatment should be initiated.

ROR-1 specific CAR-T cells with CRISPR/CAS9 mediated glucocorticoid receptor-knockout exert potent antitumor efficacy in advanced adrenocortical carcinoma

ROR-1 specific CAR-T cells with CRISPR/CAS9 mediated glucocorticoid receptor-knockout exert potent antitumor efficacy in advanced adrenocortical carcinoma

High-Dose Rate Brachytherapy Combined with PD-1 Blockade as a Treatment for Metastatic Adrenocortical Carcinoma - A Single Center Case Series.

The response rate of advanced adrenocortical carcinoma (ACC) to standard chemotherapy with mitotane and etoposide/doxorubicin/cisplatin (EDP-M) is unsatisfactory, and benefit is frequently short lived. Immune checkpoint inhibitors (CPI) have been examined in patient's refractory to EDP-M, but objective response rates are only approximately 15%. High-dose rate brachytherapy (HDR-BT) is a catheter-based internal radiotherapy and expected to favorably combine with immunotherapies. Here we describe three cases of patients with advanced ACC who were treated with HDR-BT and the CPI pembrolizumab. None of the tumors were positive for established response markers to CPI. All patients were female, had progressed on EDP-M and received external beam radiation therapy for metastatic ACC. Pembrolizumab was initiated 7 or 23 months after brachytherapy in two cases and prior to brachytherapy in one case. Best response of lesions treated with brachytherapy was complete (n=2) or partial response (n=1) that was ongoing at last follow up after 23, 45 and 4 months, respectively. Considering all sites of tumor, response was complete and partial remission in the two patients with brachytherapy prior to pembrolizumab. The third patient developed progressive disease with severe Cushing's syndrome and died due to COVID-19. Immune-related adverse events of colitis (grade 3), gastroduodenitis (grade 3), pneumonitis (grade 2) and thyroiditis (grade 1) occurred in the two patients with systemic response. HDR-BT controlled metastases locally. Sequential combination with CPI therapy may enhance an abscopal antitumoral effect in non-irradiated metastases in ACC. Systematic studies are required to confirm this preliminary experience and to understand underlying mechanisms.

Feasibility and Activity of Megestrol Acetate in Addition to Etoposide, Doxorubicin, Cisplatin, and Mitotane as First-Line Therapy in Patients with Metastatic/Unresectable Adrenocortical Carcinoma with Low Performance Status.

(1) Background: The standard first-line therapy for advanced adrenocortical carcinoma (ACC) is represented by EDP-M (etoposide, doxorubicin, cisplatin + mitotane). Progestins have shown cytotoxic activity both in vitro and in vivo on ACC; better EDP-M tolerability and efficacy have been hypnotized due to the association with progestins. (2) Methods: The feasibility and tolerability of EDP-M combined with oral megestrol acetate (EDP-MM) were tested in 24 patients (pts) affected by metastatic ACC with a low performance status (PS); the case group was compared with a 48 pts control group according to the propensity score. The secondary objectives were clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). (3) Results: Thirteen pts (54.2%) in the EDP-MM population experienced progestin-related toxicities; in particular, five pts experienced vaginal bleeding (20.8%); four pts experienced weight gain (16.7%); and thromboembolic events, worsening of hypertension, skin rashes, and hyperglycemia were registered in one patient each (4.2%). This led to the discontinuation of megestrol acetate in four pts (16.7%). EDP-M-related toxicities were similar in both groups. No differences in PFS and OS curves were observed; the CBR was 75.0% and 60.4%, respectively. (4) Conclusions: The association of EDP-M + megestrol acetate in ACC pts with a low PS is feasible and well tolerated; its efficacy appeared to be non-inferior to EDP-M administered to pts with a good PS.

Locally Advanced Adrenocortical Carcinoma in Children and Adolescents-Enigmatic and Challenging Cases.

Locally advanced tumors account for approximately 50% of children and adolescents with adrenocortical carcinoma (ACC), and of these, up to 50% relapse. We explored the five-item microscopic score and the pS-GRAS score for guiding management. Data from children and adolescents with COG stage II and III ACC registered in the MET studies were included. The five-item and pS-GRAS score were retrospectively calculated. By December 2021, 55 patients with stage II and III (stage II n = 18, stage III n = 37) had been reported. Median age was 4.3 years [0.1-17.8], median duration of follow-up 6.0 years [0-16.7]. 3-year event-free survival (EFS) rate was 76.5% and 49.8% (p = 0.088), respectively. In stage II tumors, neither the five-item score (p = 0.872) nor pS-GRAS grouping (p = 0.218) had any effect as prognostic factors. In stage III patients, EFS was impaired in tumors with unfavorable histology according to the five-item score (100% vs. 30.8%, p = 0.018). No difference was observed for pS-GRAS groups (p = 0.798). In patients with COG stage III, but not stage II, the five-item score affected EFS. Further studies are needed to identify patients at risk in COG stage II.

Outcome of Immunotherapy in Adrenocortical Carcinoma - A retrospective cohort study.

Clinical trials with immune checkpoint inhibitors (ICI) in adrenocortical carcinoma (ACC) have yielded contradictory results. We aimed to evaluate treatment response and safety of ICI in ACC in a real-life setting. Retrospective cohort study of 54 patients with advanced ACC receiving ICI as compassionate use at six German reference centres between 2016 and 2022. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and treatment-related adverse events (TRAE) were assessed. In 52 patients surviving at least 4 weeks after initiation of ICI, ORR was 13.5% (6-26) and DCR 24% (16-41). PFS was 3.0 months (95%CI 2.3-3.7). In all patients, median OS was 10.4 months (3.8-17). 17 TRAE occurred in 15 patients, which was associated with a longer PFS of 5.5 (1.9-9.2) vs. 2.5 (2.0- 3.0) months (HR 0.29, 95%CI 0.13-0.66, p=0.001) and OS of 28.2 (9.5-46.8) vs. 7.0 (4.1-10.2) months (HR 0.34, 95%CI 0.12-0.93). Positive tissue staining for programmed cell death ligand 1 (PD-L1) was associated with a longer PFS of 3.2 (2.6-3.8) vs. 2.3 (1.6-3.0, p<0.05) months. Adjusted for concomitant mitotane use, treatment with nivolumab was associated with lower risk of progression (HR 0.36, 0.15-0.90) and death (HR 0.20, 0.06-0.72) compared to pembrolizumab. In the real-life setting we observe a response comparable to other second-line therapies and an acceptable safety profile in ACC patients receiving different ICI. The relevance of PD-L1 as a marker of response and the potentially more favourable outcome in nivolumab treated patients require confirmation.

A-296 IMPACT OF EN BLOC EXTENDED R0 RESECTION ON ONCOLOGIC OUTCOME OF STAGE III ADRENOCORTICAL CARCINOMA

Abstract Background In locally advanced adrenocortical carcinoma (ACC) (ENSAT stage III – S-III) R0 surgery, involving en bloc extended resection, is the only potential curative treatment. We evaluated oncologic outcome and complications rate in S-III patients who underwent extended resection in comparison with stage I/II (S-I/II). Methods Among 931 adrenalectomies over 25 years (1997–2022) in a tertiary referral center, medical records of ACC patients were reviewed, excluding stage IV patients. Results Forty-one patients were identified: 6 S-I patients (14.6%), 30 S-II (73.2%) and 5 S-III (12.2%). The latter underwent extended en bloc resection (1 partial and 2 radical nephrectomies, 1 right hepatectomy and 1 renal vein thrombectomy). Minor complications (Clavien-Dindo ≤ 2) were observed in 11.5% of S-I/II patients and 20% of S-III (p=NS). Adjuvant treatments included: mitotane (all but 1 S-I patients), chemotherapy (2 S-II and 1 S-III) and radiotherapy (3 S-II). Four S-II patients (13.3%) developed locoregional recurrence (2 lodge, 1 paracaval nodes and 1 peritoneal) (median 21 months). Metastatic disease occurred in 13 (43.3%) S-II and 1 (20%) S-III patients. At a median follow-up of 108 months, all but 8 S-II patients were alive, with recurrent disease in 9 S-II (2 regional, 7 distant) and 1 S-III (lung). No difference was observed between S-I/II and S-III in terms of DFS and OS (p=NS). Conclusion OS and DFS of S-III ACC patients undergoing extended en bloc R0 resection were comparable to those of SII/III, without increasing postoperative morbidity. Multi-Institutional studies are necessary to validate these results.

WEE1 kinase inhibitor, adavosertib (AZD1775), as a novel potential therapeutic strategy in advanced adrenocortical carcinoma

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