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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  < 0.001). Using propensity score matching, the HR for RFS was 0.45 (0.29–0.89, 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.

In 2007, a retrospective case-control study provided evidence that adjuvant mitotane prolongs recurrence-free survival (RFS) in patients with radically resected adrenocortical carcinoma (ACC). We aimed to confirm the prognostic role of adjuvant mitotane in the same series after 9 additional years of follow-up. One hundred sixty-two ACC patients who did not recur or die after a landmark period of 3 months were considered. Forty-seven patients were enrolled in four Italian centers where adjuvant mitotane was routinely recommended (mitotane group), 45 patients in four Italian centers where no adjuvant strategy was undertaken (control group 1), and 70 German patients left untreated after surgery (control group 2). The primary aim was RFS, the secondary was overall survival. An increased risk of recurrence was found in both control cohorts [group 1: hazard ratio (HR) = 2.98; 95% confidence interval (CI), 1.75 to 5.09; P < 0.0001; group 2: HR = 2.61; 95% CI, 1.56 to 4.36; P < 0.0001] compared with the mitotane group. The risk of death was higher in control group 1 (HR = 2.03; 95% CI, 1.17 to 3.51; P = 0.011) but not in control group 2 (HR = 1.60; 95% CI, 0.94 to 2.74; P = 0.083), which had better prognostic factors and more aggressive treatment of recurrences than control group 1. The benefit of adjuvant mitotane on RFS was observed regardless of the hormone secretory status. Adjuvant mitotane is associated with prolonged RFS, without any apparent influence by the tumor secretory status. The retrospective nature of the study is a major limitation.

BackgroundAdrenocortical carcinoma (ACC) is a rare and aggressive malignancy with a poor prognosis, and its clinical management remains a significant challenge due to the high recurrence rates and limited treatment options. Despite advances in understanding the molecular mechanisms underlying ACC, no reliable biomarkers have been validated for routine clinical use.MethodsWe analyzed RNA sequencing data from The Cancer Genome Atlas (TCGA) database (n=79) and Genotype Tissue Expression (GTEx) database (n=128) to investigate the expression of VGF in ACC and normal adrenal tissues. Gene expression levels of VGF were quantified and correlated with clinicopathological features and survival outcomes. Statistical methods included Cox proportional hazards models and Kaplan-Meier analysis, while Gene Set Enrichment Analysis (GSEA) was utilized to identify relevant biological pathways associated with VGF expression. Clinical data from 7 ACC patients from YANTAI YUHUANGDING Hospital were also analyzed. The expression of VGF in ACC and normal adrenal gland tissue was further validated through IHC experiments.ResultsOur results demonstrate that VGF expression is elevated in ACC tissues compared to normal adrenal tissues and is significantly associated with advanced disease stages, lymph node involvement, metastasis and poor overall survival. VGF levels also correlate with immune cell infiltration, including Th2 cells, T helper cells, and Neutrophils. Importantly, our study establishes VGF as a potential prognostic biomarker for ACC and highlights its role in tumor progression and immune modulation. Additionally, GSEA analysis suggests that VGF is involved in cytokine receptor interaction and the P13K-Akt signaling pathway, possibly relating to tumor immunity.ConclusionsVGF could serve as a valuable marker for patient stratification, monitoring disease progression, and predicting responses to immunotherapies. Future studies should focus on investigating circulating VGF levels as a non-invasive biomarker for ACC to improve clinical management and treatment outcomes.

While immunotherapeutic targeting of cell surface proteins is an increasingly effective cancer therapy, identification of new surface proteins, particularly those with biological importance, is critical. Here, we uncover delta-like non-canonical Notch ligand 1 (DLK1) as a cell surface protein with limited normal tissue expression and high expression in multiple refractory adult metastatic cancers including small cell lung cancer (SCLC) and adrenocortical carcinoma (ACC), a rare cancer with few effective therapies. In ACC, ADCT-701, a DLK1 targeting antibody-drug conjugate (ADC), shows in vitro and in vivo activity but is overall limited due to high expression and activity of the drug efflux protein ABCB1 (MDR1, P-glycoprotein). In contrast, ADCT-701 induces complete responses in DLK1 + ACC and SCLC in vivo models with low or no ABCB1 expression. Genetic deletion of DLK1 in ACC dramatically downregulates ABCB1 and increases ADC payload and chemotherapy sensitivity through NOTCH1-mediated transdifferentiation. This work identifies DLK1 as an immunotherapeutic target that regulates tumor cell plasticity and chemoresistance in ACC and supports an active phase I clinical trial targeting DLK1 with an ADC in ACC and neuroendocrine neoplasms (NCT06041516). Adrenocortical carcinoma (ACC) has limited treatment options and few tumor-specific targets. Here the authors report that the Notch ligand DLK1 is highly expressed in ACC acting as a regulator of tumor cell plasticity and chemoresistance, and that DLK1 can be targeted with an antibody drug conjugate.

Adrenocortical carcinoma (ACC), with poor prognosis, is one of the most aggressive endocrine cancers. Surgery is the mainstay of treatment; nevertheless, chemotherapy is usually needed. Mitotane, the medication licenced for ACC, has had mixed results. Drug repositioning based on gene coexpression networks has proven to be an effective method of discovering potential cancer treatments. A total of 139 human specimens were examined, comprising 106 metastatic ACCs, 14 benign adrenocortical adenomas (ACAs), and 19 normal adrenal cortex tissues. Hub genes were identified using weighted correlation network analysis (WGCNA), and their differential expression was confirmed by microarrays and RNA sequencing. Hub genes were analyzed in more depth for enrichment, coexpression, and protein–protein interaction. Two phases of survival analysis were conducted considering sex. Hub gene expression was associated with TP53 mutations and cancer stage. Hub genes were evaluated using regression analysis. Hub genes were associated with immune cell infiltration. Network analysis identified transcription factors that regulate hub genes. Drug-gene interaction network analyses were performed to reposition existing drugs. WGCNA-PPI analysis revealed 31 hub genes, 11 of which were overexpressed by more than fourfold, as well as HMMR and UBE2T , which were novel genes. All hubs showed significant correlations with survival, tumor staging, and TP53 mutation status in ACC tissues. Women overexpressing CDK1 , UBE2C , PCLAF , and CCNB1 were more likely to suffer catastrophic deaths than men. In terms of ACC diagnostic capacity, all hub genes had AUCs greater than 0.90, with TOP2A , CDK1, and CCNB1 having the highest values. All hub genes, except for THYMS and RACGAP1 , were negatively correlated with M2 macrophages and CD8 + T cells infiltration. Hub genes were co-expressed and regulated by 21 DE-TFs expressed differently between ACC and normal tissues. Novel pharmaceuticals are represented by fifteen out of thirty-four medications directed at hub genes and DE-TFs. Paclitaxel and cisplatin were the central nodes within the drug-gene network. Multiple drugs target TYMS and TOP2A , making them both promising targets for ACC. Fluorouracil and epirubicin target HMMR novel hub gene. HMMR as a novel ACC hub gene targets by fluorouracil and epirubicin, but fluorouracil has advantageous. The reason for this is that M2 macrophages promote fluorouracil resistance, whereas tumors overexpressing the HMMR gene demonstrate a negative infiltration of macrophages. Hub genes, associated with ACC development and progression, have negative impacts on survival rates, particularly in women. Network analysis shows fluorouracil and epirubicin target the ACC novel hub gene, HMMR . Fluorouracil was more effective due to its impact on M2 macrophage infiltration.

The benefit of adjuvant radiation therapy (RT) in adrenocortical carcinoma (ACC) is not well characterized for those who undergo initial R0 surgical resection. Patients in the NCDB who underwent R0 resection were placed into two cohorts – those who underwent adjuvant RT and those who did not. 388 patients were identified with 51 receiving RT. No difference was observed between Kaplan-Meier survival estimates of the two cohorts (p ​= ​0.54). After adjusting for age, sex, co-morbidity index, race, receipt of chemotherapy, tumor size, grade, stage, and nodal stage, RT was not associated with improved OS. However, tumor size ≥6 ​cm (HR 1.54, [1.03–2.32], p ​= ​0.04), high tumor-grade (HR 3.46, [1.83–6.55], p ​< ​0.001), and N1-stage (HR 2.30, [1.06–4.94], p ​= ​0.03) were associated with worse OS, without benefit of RT on subgroup analysis of these factors. Treatment with adjuvant RT in patients with ACC who underwent R0 resection was not associated with an OS benefit. •A cohort of R0 resected ACCs from the NCDB were analyzed.•Adjuvant radiation is not associated with improved survival after R0 resection.•Large, high grade, or node positive tumors did not benefit on subanalysis.

Abstract Context 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 ACCs were heterogeneous. Objective Their expression in ACC has not been systematically studied and might explain the variable response to immune checkpoint inhibitors. Methods The expression of PD-1, PD-L1 and CTLA-4 was examined in 162 tumor samples from 122 patients with ACC by immunohistochemistry (threshold of >1%) and correlated with tumoral T lymphocyte infiltration and clinical endpoints. Finally, univariate and multivariate analyses of progression-free and overall survival were performed. Results 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 = .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. Conclusion 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.

Abstract Objective To test the ability of the 2015 modified version of the European Network for the Study of Adrenal Tumors staging system (mENSAT) in predicting cancer-specific mortality (CSM), as well as overall mortality (OM) in adrenocortical carcinoma (ACC) patients of all stages, in a large-scale, and contemporary United States cohort. Methods We relied on the Surveillance, Epidemiology, and End Results (SEER) database (2004–2020) to test the accuracy and calibration of the mENSAT and subsequently compared it to the 8th edition of the American Joint Committee on Cancer staging system (AJCC). Results In 858 ACC patients, mENSAT accuracy was 74.7% for 3-year CSM predictions and 73.8% for 3-year OM predictions. The maximum departures from ideal predictions in mENSAT were +17.2% for CSM and +11.8% for OM. Conversely, AJCC accuracy was 74.5% for 3-year CSM predictions and 73.5% for 3-year OM predictions. The maximum departures from ideal predictions in AJCC were −6.7% for CSM and −7.1% for OM. Conclusion The accuracy of mENSAT is virtually the same as that of AJCC in predicting CSM (74.7% vs 74.5%) and OM (73.7% vs 73.5%). However, calibration is lower for mENSAT than for AJCC. In consequence, no obvious benefit appears to be associated with the use of mENSAT relative to AJCC in US ACC patients.

Abstract Context Urine steroid metabolomics, combining mass spectrometry-based steroid profiling and machine learning, has been described as a novel diagnostic tool for detection of adrenocortical carcinoma (ACC). Objective, Design, Setting This proof-of-concept study evaluated the performance of urine steroid metabolomics as a tool for postoperative recurrence detection after microscopically complete (R0) resection of ACC. Patients and Methods 135 patients from 14 clinical centers provided postoperative urine samples, which were analyzed by gas chromatography–mass spectrometry. We assessed the utility of these urine steroid profiles in detecting ACC recurrence, either when interpreted by expert clinicians or when analyzed by random forest, a machine learning-based classifier. Radiological recurrence detection served as the reference standard. Results Imaging detected recurrent disease in 42 of 135 patients; 32 had provided pre- and post-recurrence urine samples. 39 patients remained disease-free for ≥3 years. The urine “steroid fingerprint” at recurrence resembled that observed before R0 resection in the majority of cases. Review of longitudinally collected urine steroid profiles by 3 blinded experts detected recurrence by the time of radiological diagnosis in 50% to 72% of cases, improving to 69% to 92%, if a preoperative urine steroid result was available. Recurrence detection by steroid profiling preceded detection by imaging by more than 2 months in 22% to 39% of patients. Specificities varied considerably, ranging from 61% to 97%. The computational classifier detected ACC recurrence with superior accuracy (sensitivity = specificity = 81%). Conclusion Urine steroid metabolomics is a promising tool for postoperative recurrence detection in ACC; availability of a preoperative urine considerably improves the ability to detect ACC recurrence.

Abstract Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy in the advanced setting with poor prognosis. This narrative review provides an overview of the epidemiology of ACC and its molecular pathogenesis with a summary of the main involved signaling pathways. We then provide an update on the clinical presentation, diagnosis, and current management strategies of both localized and metastatic disease from a multidisciplinary perspective. We highlight the debate around the use of mitotane in the adjuvant setting and review the use of combination chemotherapy with etoposide, doxorubicin, and cisplatin. The review also focuses on emerging data providing hope for the use of immune checkpoint inhibitors and targeted therapies in ACC with a summary of ongoing trials. This review reports on the epidemiology of adrenocortical carcinoma and its molecular pathogenesis. An update on clinical presentation, diagnosis, and current management strategies is provided, as well as emerging data on the use of immune checkpoint inhibitors and targeted therapies.