ACC Patients Research Articles

Molecular Subtypes Defined by Cuproptosis-Associated Genes, Prognostic Model Development, and Tumor Immune Microenvironment Characterization in Adrenocortical Carcinoma.

This study aims to explore the role of cuproptosis-related genes in ACC, utilizing data from TCGA and GEO repositories, and to develop a predictive model for patient stratification. A cohort of 123 ACC patients with survival data was analyzed. RNA-seq data of 17 CRGs were examined, and univariate Cox regression identified prognostic CRGs. A cuproptosis-related network was constructed to show interactions between CRGs. Consensus clustering classified ACC into three subtypes, with transcriptional and survival differences assessed by PCA and survival analysis. Gene set variation analysis (GSVA) and ssGSEA evaluated functional and immune infiltration characteristics across subtypes. Differentially expressed genes (DEGs) were identified, and gene clusters were established. A risk score (CRG_score) was generated using LASSO and multivariate Cox regression, validated across datasets. Tumor microenvironment, stem cell index, mutation status, drug sensitivity, and hormone synthesis were examined in relation to the CRG_score. Protein expression of key genes was validated, and functional studies on ASF1B and NDRG4 were performed. Three ACC subtypes were identified with distinct survival outcomes. Subtype B showed the worst prognosis, while subtype C had the best. We identified 214 DEGs linked to cell proliferation and classified patients into three gene clusters, confirming their prognostic value. The CRG_score predicted patient outcomes, with high-risk patients demonstrating worse survival and possible resistance to immunotherapy. Drug sensitivity analysis suggested higher responsiveness to doxorubicin and etoposide in high-risk patients. This study suggests the potential prognostic value of CRGs in ACC. The CRG_score model provides a robust tool for risk stratification, with implications for treatment strategies.

Axitinib plus avelumab for recurrent/metastatic adenoid cystic carcinoma (R/M ACC): Biomarker analysis of the phase II trial.

6104 Background: In the phase II axitinib (VEGFR inhibitor) plus avelumab (PD-L1 inhibitor) trial in R/M ACC, response rate was 18% with a median progression-free survival (PFS) of 7.3 months, with subsequent inclusion of the combination in NCCN guidelines as a possible treatment for ACC (category 2B). We sought to identify potential biomarkers predictive of axitinib plus avelumab benefit in R/M ACC. Methods: The phase II trial included 28 R/M ACC patients (pts). Pre-treatment tumors were analyzed by whole exome sequencing (n=24), using Twist Human Core Exome V2 kit, and transcriptome profiling (n=26), using HTG Transcriptome Panel (19,616 probes). For 17 pts, imaging mass cytometry (IMC) was performed with 35 metal-tagged markers and analyzed with Visiopharm software. Microbiome composition was assessed in tumor (n=20), oral rinse (n=20) and fecal (n=19) samples via 16s rRNA gene sequencing. All results were assessed for association with PFS on therapy with a Cox proportional hazards model, maintaining ACC subtype (ACC-I vs. ACC-II) as a covariate. Results: Only 1 (6%) of 17 assessed tumors were PD-L1 positive. By WES, tumor mutational burden (TMB) was overall low (median 1.4 mut/Mb, range 0.7 – 18.7), but higher TMB was associated with worse PFS. Four mutational signatures significantly correlated with worse PFS, including SBS86, associated with previous chemotherapy exposure. Immune deconvolution of RNA-seq data revealed that a higher neutrophil-to-lymphocyte ratio and more T follicular helper cells associated with worse PFS, while presence of cytotoxic cells, T effector memory cells, and mast cells associated with longer PFS. Notably, a 167-gene predictive signature was developed and validated in the phase II ipilimumab plus nivolumab salivary gland cancer trial. This 167-gene signature was not prognostic in ACC pts who did not receive immunotherapy. IMC single-cell immune mapping revealed that pts with longer PFS had increased presence of CD8 T cells, CD73+ macrophages in tumor, a higher stromal CD8 T cell:Regulatory T cell ratio, increased stromal SIGLEC15 positive cells, and a higher tumor-to-stroma ratio of fibroblasts. Conversely, Ki67-positive T cells, cancer stem cells, and M2 macrophages were associated with worse PFS. Through microbiome analysis, 13 bacterial genera in tumor samples, 25 in stool, and 8 in oral rinse were significantly associated with therapy outcomes. Of note, in stool microbiome, presence of Akkermansia spp. and Bifidobacterium spp. were significantly correlated with improved PFS, with the latter association also seen in oral rinse. Conclusions: Correlative analysis of the phase II axitinib plus avelumab trial revealed potential biomarkers predictive of combination clinical benefit in ACC, including a gene-expression signature. These findings may guide patient stratification for combinatorial therapy.

Germline NGS targeted analysis in adult patients with sporadic adrenocortical carcinoma

BackgroundAdrenocortical carcinoma (ACC) is a rare cancer that arises sporadically or due to hereditary syndromes. Data on germline variants (GVs) in sporadic ACC are limited. Our aim was to characterize GVs of genes potentially related to adrenal diseases in 150 adult patients with sporadic ACC. MethodsThis was a retrospective analysis of stage I-IV ACC patients with sporadic ACC from two reference centers for ACC in Italy. Patients were included in the analysis if they had confirmed diagnosis of ACC, a frozen peripheral blood sample and complete clinical and follow-up data. Next generation sequencing technology was used to analyze the prevalence of GVs in a custom panel of 17 genes belonging to either cancer-predisposition genes or adrenocortical-differentiation genes categories. ResultsWe identified 18 GVs based on their frequency, enrichment and predicted functional characteristics. We found six pathogenic (P) or likely pathogenic (LP) variants in ARMC5, CTNNB1, MSH2, PDE11A and TP53 genes; and twelve variants lacking evidence of pathogenicity. New unique P/LP variants were identified in TP53 (p.G105D) and, for the first time, in ARMC5 (p.P731R). The presence of P/LP GVs was associated with reduced survival outcomes and had a significant and independent impact on both progression-free survival and overall survival. ConclusionsGVs were present in 6.7 % of patients with sporadic ACC, and we identified novel variants of ARMC5 and TP53. These findings may improve understanding of ACC pathogenesis and enable genetic counseling of patients and their families.

Adrenocortical Cancer in the Real World: A Comprehensive Analysis of Clinical Features and Management from the Turkish Oncology Group (TOG)

IntroductionAdrenocortical carcinoma (ACC) is a rare yet highly malignant tumor associated with significant morbidity and mortality. This study aims to delineate the clinical features, survival patterns, and treatment modalities of ACC, providing insights into the disease's prognosis. Materials and MethodsA retrospective analysis of 157 ACC patients was performed to assess treatment methodologies, demographic patterns, pathological and clinical attributes, and laboratory results. The data were extracted from the hospital's database. Survival analyses were conducted using the Kaplan–Meier method, with univariate and multivariate analyses being performed through the log-rank test and Cox regression analyses. ResultsThe median age was 45, and 89.4% had symptoms at the time of diagnosis. The median tumor size was 12 cm. A total of 117 (79.6%) patients underwent surgery. A positive surgical border was detected in 26 (24.1%) patients. Adjuvant therapy was administered to 44.4% of patients. The median overall survival for the entire cohort was 44.3 months. Median OS was found to be 87.3 months (95% confidence interval [CI] 74.4-100.2) in stage 2, 25.8 (95% CI 6.5-45.1) months in stage 3, and 13.3 (95% CI 7.0-19.6) months in stage 4 disease. Cox regression analysis identified age, Ki67 value, Eastern Cooperative Oncology Group performance status, and hormonal activity as significant factors associated with survival in patients with nonmetastatic disease. In metastatic disease, only patients who underwent surgery exhibited significantly improved overall survival in univariate analyses. ConclusionACC is an uncommon tumor with a generally poor prognosis. Understanding the defining prognostic factors in both localized and metastatic diseases is vital. This study underscores age, Ki67 value, Eastern Cooperative Oncology Group performance status, and hormonal activity as key prognostic determinants for localized disease, offering critical insights into the complexities of ACC management and potential avenues for targeted therapeutic interventions.

Anti-LGALS3BP antibody-drug conjugate treatment induces durable and potent antitumor response in a preclinical model of adenoid cystic carcinoma

ObjectivesAdenoid cystic carcinoma (ACC) is a rare type of cancer that typically arises from glandular tissues, most commonly in the salivary glands. Although relatively rare, it represents a serious clinical issue as the management of the disease is highly complex being the only therapeutic options represented by invasive surgery and/or radiotherapy. In the present study, we have explored the potential of galectin-3 binding protein (LGALS3BP) as a novel target for antibody-drug conjugate (ADC) therapy in ACC. Materials and methodsRNAseq was conducted on a panel of 10 ACC patient-derived xenografts (PDX)s tissues and 6 normal salivary glands to analyze LGALS3BP gene expression. Protein expression was assessed in ACC PDX and primary tumor tissues using immunohistochemistry. Anti-LGALS3BP ADC named 1959-sss/DM4, was tested in high LGALS3BP expressing ACC PDX model ST1502B. ResultsRNAseq analysis revealed that LGALS3BP expression was highly expressed in ACC PDX tissues compared to normal salivary gland tissues. As evaluated by immunohistochemical analysis, LGALS3BP protein was found to be heterogeneously expressed in 10 ACC PDX and in tumor tissues derived from a cohort of 37 ACC patients. Further, treatment with 1959-sss/DM4 ADC led to durable tumor growth inhibition (TGI) in 100% of animals without observed toxicity. ConclusionsOur study provides strong evidence that LGALS3BP is a promising therapeutic target for ACC, warranting further expedited preclinical and clinical investigation.

Incidence and Geographical Distribution of Adrenocortical Carcinoma: Retrospective Analysis of a State Cancer Registry

ObjectiveAdrenocortical carcinoma (ACC) is a rare malignancy without established association with environmental risk factors. ACC incidence is stable based on large surgical databases while referral centers data reported increasing number of cases seen. We studied ACC incidence and distribution at a county level to find potential ACC “hot spots” that could be linked to environmental exposures. MethodsA retrospective analysis of Texas Cancer Registry that included ACC patients diagnosed between 2000 and 2018. County-level heatmaps were created and compared with breast, prostate, and lung cancer. ResultsWe identified 448 ACC cases during the study period. Cases were registered in 110 of the 254 counties (43.3%) in Texas, representing 92.74% of the total population. The median incidence was 23 new cases/y (range 14-33). The mean population-adjusted ACC incidence rate was 0.104 per 100 000 per year (standard deviation 0.005; 95% CI, 0.092-0.116). Seven counties (6.3%) accounted for 215 (48.0%) cases, with more than 10 cases each and median standardized incidence ratio (SIR) of 0.1 (range, 0.0-0.9). One hundred three counties (93.7%) accounted for the remaining 233 cases (52%), with fewer than 10 cases per county. The highest standardized incidence ratios were found in counties with a median population of fewer than 14 000 residents and with only one reported case. ConclusionOur analysis is the first report to create ACC heatmap and could not detect any geographic clustering of ACC in Texas. The incidence of ACC remained stable and consistent with data from other large databases.

Therapeutic inhibition of Bmi-1 ablates chemoresistant cancer stem cells in adenoid cystic carcinoma

ObjectivesAdenoid Cystic Carcinomas (ACC) typically show modest responseto cytotoxic therapy. Cancer stem cells (CSC) have been implicated in chemoresistance and tumor relapse. However, their role in ACC remains unknown. The purpose of this work was to evaluate the impact of targeting ACC CSCs with Bmi-1 inhibitors on resistance to cytotoxic therapy and tumor relapse. Materials and methodsTherapeutic efficacy of a small molecule inhibitor of Bmi-1 (PTC596; Unesbulin) and/or Cisplatin on ACC stemness was evaluated in immunodeficient mice harboring PDX ACC tumors (UM-PDX-HACC-5) and in human ACC cell-lines (UM-HACC-2A,-14) or low passage primary human ACC cells (UM-HACC-6). The effect of therapy on stemness was examined by salisphere assays, flow cytometry for ALDH activity and CD44 expression, and Western blots for Bmi-1 (self-renewal marker) and Oct4 (embryonic stem cell marker) expression. ResultsPlatinum-based agents (Cisplatin, Carboplatin) induced Bmi-1 and Oct4 expression, increased salisphere formation and the CSC fraction in vitro and in vivo. In contrast, PTC596 inhibited expression of Bmi-1, Oct4 and pro-survival proteins Mcl-1 and Claspin; decreased the number of salispheres, and the fraction of ACC CSCs in vitro. Silencing Claspin decreased salisphere formation and CSC fraction. Both, single agent PTC596 and PTC596/Cisplatin combination decreased the CSC fraction in PDX ACC tumors. Notably, short-term combination therapy (2 weeks) with PTC596/Cisplatin prevented tumor relapse for 150 days in a preclinical trial in mice. ConclusionTherapeutic inhibition of Bmi-1 ablates chemoresistant CSCs and prevents ACC tumor relapse. Collectively, these results suggest that ACC patients might benefit from Bmi-1-targeted therapies.

The prognostic value and immunological role of SULF2 in adrenocortical carcinoma

BackgroundAdrenocortical carcinoma (ACC) represents the rare urological epithelial cancer of urinary tract, which has a large mass and is usually diagnosed at the advanced stage, thus inducing the poor prognosis. As a result, early detection and diagnosis are more important for the prognosis rather than the treatment of ACC. There is evidence supporting the association of Sulfatase2 (SULF2) with bladder cancer. However, the relationships of SULF2 with the clinical features and immune infiltration of ACC remain unclear. MethodsThis work comprehensively investigated the different expression levels of SULF2 within ACC and its prognostic significance through various databases including Gene Expression Profiling Interaction Analysis (GEPIA), Tumor Immune Estimation Resource (TIMER), The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Kaplan–Meier (KM) plotter and UALCAN. Besides, SULF2 levels within different tumor and paraneoplastic tissues were examined based on Human Protein Atlas (HPA) and TIMER. Afterwards, this study identified differentially expressed genes (DEGs) in high-compared with low-SULF2-expression groups. To predict the possible interaction between SULF2 and its targets, a protein-protein interaction (PPI) network was constructed based on relevant data collected in STRING database. Besides, the SULF2 functional annotation was carried out, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and GSEA. In addition, gene mutation analysis was also performed based on the cBioPortal database. The relation of SULF2 with immune infiltration was analyzed from various aspects by using the resources of various databases including TIMER, TISIDB, and GEPIA, which was first reported in this work. Finally, R package was utilized to plot the receiver operating characteristic (ROC) curves of diagnosis, time-dependent survival, and the association of SULF2 with cancer stage and the nomogram model. Finally, CellMiner dataset was adopted for SULF2 correlation as well as drug sensitivity analysis. ResultsRelative to healthy people, SULF2 level markedly elevated within ACC tissues. Besides, SULF2 up-regulation significantly predicted the dismal prognostic outcome, which may be an important prognostic factor. Afterwards, the PPI network was constructed, and the possible link of SULF2 with the corresponding targets was predicted. Besides, up-regulated SULF2 expression was tightly related to immune regulation and tumor-infiltration immune cell (TIICs), including CD8+, CD4+ and mast cells. Finally, SULF2 expression was speculated to help determine the sensitivity of certain drugs. ConclusionsSULF2 may offer a new therapeutic target for ACC patients and become an important potential prognostic biomarker.

High expression of GMNN predicts malignant progression and poor prognosis in ACC

BackgroundAdrenocortical carcinoma (ACC) is a rare endocrine neoplasm, which is characterized by poor prognosis and high recurrence rate. Novel and reliable prognostic and metastatic biomarkers are lacking for ACC patients. This study aims at screening potential prognostic biomarkers and therapeutic targets of ACC through bioinformatic methods and immunohistochemical (IHC) analysis.MethodsIn the present study, by using the Gene Expression Omnibus (GEO) database we identified differentially expressed genes (DEGs) in ACC and validated these DEGs in The Cancer Genome Atlas (TCGA) ACC cohort. A DEGs-based signature was additionally constructed and we assessed its prognosis and prescient worth for ACC by survival analysis and nomogram. Immunohistochemistry (IHC) was used to verify the relationship between hub gene–GMNN expressions and clinicopathologic outcomes in ACC patients.ResultsA total of 24 DEGs correlated with the prognosis of ACC were screened from the TCGA and GEO databases. Five DEGs were subsequently selected in a signature which was closely related to the survival rates of ACC patients and GMNN was identified as the core gene in this signature. Univariate and multivariate Cox regression showed that the GMNN was an independent prognostic factor for ACC patients (P < 0.05). Meanwhile, GMNN was closely related to the OS and PFI of ACC patients treated with mitotane (P < 0.001). IHC confirmed that GMNN protein was overexpressed in ACC tissues compared with normal adrenal tissues and significantly correlated with stage (P = 0.011), metastasis (P = 0.028) and Ki-67 index (P = 0.014).ConclusionsGMNN is a novel tumor marker for predicting the malignant progression, metastasis and prognosis of ACC, and may be a potential therapeutic target for ACC.

RPS3 Promotes the Metastasis and Cisplatin Resistance of Adenoid Cystic Carcinoma.

BackgroundAdenoid cystic carcinoma (ACC) is a malignant tumor in salivary gland tissue, that is characterized by strong invasiveness and lung metastasis, leading to poor survival rates. RPS3 is been reported to be associated with the biological functions of tumor cells. This study explored the regulatory effect of RPS3 in ACC to provide new therapeutic targets for ACC therapy.MethodsWe reviewed the clinical and pathologic data of 73 ACC patients. The expression of RPS3 was examined in ACC by immunohistochemistry. Transwell, wound healing, half-maximal inhibitory concentration (IC50) and other experiments were used to determine the regulatory effect of RPS3 on ACC functions. Coimmunoprecipitation and mass spectrometry analysis were used to detect the binding proteins of RPS3, mechanisms by which RPS3/STAT1/NF-kB signaling regulates ACC behavior were assessed using western blotting (WB), qPCR, etc. To explore the regulatory effect of RPS3 on ACC in vivo, we constructed nude mouse sciatic nerve infiltration model and a lung metastasis model for studies.ResultsHigh RPS3 expression was associated with metastasis and a poor prognosis in ACC patients. Inhibition of RPS3 expression reduced ACC migration, invasion and cisplatin resistance, and overexpression of RPS3 promoted ACC migration, invasion and cisplatin resistance. Further experiments revealed that RPS3 can activate the STAT1/NF-kB signaling pathway and regulate ACC behavior through binding to STAT1. The incidence of sciatic nerve infiltration and lung metastasis in nude mice after RPS3 knockdown was lower than that of the control group in vivo.ConclusionRPS3 is highly expressed and associated with the prognosis and survival of ACC patients. The RPS3/STAT1/NF-kB pathway may play an important regulatory role in ACC migration, invasion and chemoresistance. As a new therapeutic target of ACC, its clinical application value is worthy of attention and further exploration.

Loco-Regional Therapies in Oligometastatic Adrenocortical Carcinoma.

Simple SummaryThe treatment recommended for stage IVa Adrenocortical carcinoma (ACC) not amenable to radical resection is the mitotane plus loco-regional treatment (LR) strategy, which has not yet been validated. Moreover, prognosis factors for this strategy are not yet established. This study aimed to determine which stage IVa ACC patient population would benefit the most from this association. For this purpose, we reviewed all stage IVa patients (≤2 tumoral organs) treated with mitotane and LR from 2008 to 2021 in our institution. This study included 60 patients and 109 LR were performed. The primary endpoint was disease control (DC). We found that DC was associated with longer Time to second line Treatments (TTC). Moreover, DC rate was higher in patients that had ≤5 metastases or a maximum metastasis diameter below 3 cm. Based on those results we propose the first definition of oligometastatic ACC: stage IVa patients with ≤5 metastases or a maximum metastasis diameter below 3 cm. It is vitally important that scientists are able to describe their work simply and concisely to the public, especially in an open-access on-line journal.Objective: The recommended first-line treatment for low-tumor-burden ACC (stage IVa ACC) not amenable to radical resection is mitotane in association with loco-regional treatments (LRs). The aim of this study was to determine the patient population that would benefit the most from LR. Materials and methods: This retrospective monocentric expert center chart review study was performed from 2008 to 2021 and included stage IVa patients (≤2 tumoral organs) treated with LR (either radiotherapy, surgery, or interventional radiology). The primary endpoint was disease control (DC). Correlations between DC, time to systemic chemotherapy (TTC), overall survival (OS), and tumor characteristics were analyzed using Kaplan–Meier survival analysis and Cox’s proportional hazards regression model for multivariate analysis. Results: Thirty-four women (57%) and 26 men with a median age of 48.1 years (IQR: 38.3–59.8) were included. One hundred and nine LRs were performed, with a median of 2 (IQR: 1–3) per patient. DC was achieved in 40 out of 60 patients (66.7%). Patients with DC had a significantly longer TTC (HR: 0.27, p < 0.001) and OS (HR: 0.22, p < 0.001). Patients with less than or equal to 5 metastases (HR: 6.15 (95% CI: 1.88–20.0), p = 0.002) or a maximum metastasis diameter below 3 cm had higher rates of DC (HR: 3.78 (95% CI: 1.09–13.14), p = 0.035). Conclusion: stage IVa ACC patients with ≤5 metastases or a maximum metastasis diameter below 3 cm had favorable responses to LR. We propose the name oligometastatic ACC for this subgroup of patients.

P280 USE OF SYSTEMIC THROMBOLYSIS IN HEMODYNAMICALLY UNSTABLE PULMONARY EMBOLISM PATIENTS WITH AND WITHOUT CARDIAC ARREST: DATA FROM THE IPER REGISTRY

Abstract Background Systemic thrombolysis (ST) remains the treatment of choice in haemodynamically unstable patients with acute pulmonary embolism (PE). However, it remains frequently underused in clinical practice. The purpose of the study is to evaluate the use of ST in hemodynamically unstable PE patients with aand without acute cardiac arrest using the IPER registry. Materials and Methods IPER is a multicentre, national, prospective, web–based registry based on 47 Italian hospitals. In this study, the population was divided into two groups: patients with (ACC) and without (No ACC) cardio–circulatory arrest at admission. Results Of 1716 patients enrolled between September 2006 and August 2010, 201 (11.7%) [mean age 74 ± 14 years 127 females] were defined as high risk (i.e. haemodynamically unstable). Of these 59 (29.4%, mean age 76.4 ± 13.3 years, 40 females) were admitted with ACC while the remaining 142 (70.6, mean age 73.5 ± 13.7 years, 87 females) without. No differences were observed for venous thromboembolism risk factors, such as immobilization for more than three days, trauma, surgery within the previous 4 weeks, previous venous thromboembolism, history of heart failure, cancer and ischemic heart disease, among the two gropus. Mortality from all causes (62.7% vs 19.0, p &amp;lt; 0.001) and for acute PE (55.9% vs 9.9%, p &amp;lt; 0.001) was higher in ACC patients. Thrombolysis was administered in 82 (40.7%) of haemodynamically unstable patients and more frequently in ACC subjects (55.9% VSA 34.5%, p = 0.005) (Figure 1, panel A). The administration of systemic thrombolysis increased with aging in the No ACC group but showed a significant reduction in over–octogenarian patients (Figure 1, panel B). Major bleeding complications following reperfusive treatment were observed in 8 patients (3.9%); among these, intracranial hemorrhage was registered in 2.4% of cases. Conclusions Although systemic thrombolysis remains the first–line treatment in patients with hemodynamically unstable acute PE and is capable of improving both the mortality and morbidity, it continues to be underused in daily clinical practice, often for fear of major bleeding complications.

Tumor mutational burden presents limiting effects on predicting the efficacy of immune checkpoint inhibitors and prognostic assessment in adrenocortical carcinoma

BackgroundAdrenocortical carcinoma (ACC) is a highly malignant urologic cancer and tends to metastasize. Although immune checkpoint inhibitors (ICIs) bring a glimmer of light to conquer ACC, only a fraction of patients have benefit from ICIs treatment. It is well known that tumor mutational burden (TMB) is closely associated with the efficacy and response rate of immunotherapy. However, its roles in ACC were not investigated.MethodsUsing somatic mutations data of 92 ACC samples in TCGA database, we calculated their TMB values by the ‘maftools’ package in R software (Ver 3.6.3). To explore the roles of TMB in ICIs therapy, we have addressed this issue from three perspectives. First, the effects of TMB levels on tumor immune microenvironment (TIM) were analyzed through CIBERSORT algorithm, ssGSEA method and TIMER web server. Second, we investigated the expressive correlations between TMB level and five pivotal immune checkpoints based on Pearson coefficient. Third, the difference in TIDE score between high- and low-TMB groups was compared. The prognostic value of TMB was also evaluated. Besides, GSEA was performed to determine the changes in the activities of signaling pathways caused by TMB.ResultsTMB values in ACC samples were not high. The average of total mutation counts in each sample was only 21.5. High TMB could lead metabolic reprogramming and poor survival outcomes. However, it was unable to affect the infiltration levels of lymphocytes, and failed to facilitate the activities of immune-related pathways. Regarding immune checkpoints (ICs), only PD-L1 upregulation could result in a good prognosis, and TMB level did not correlate with the expressions of other ICs except for LAG3. There was no significant difference in TIDE score between high- and low-TMB groups. Combining the present results and previous study, we speculated that inadequate stimulation for neoantigens formation, intrinsic immune-resistance and special genomic alterations were three possible reasons for TMB limiting functions in TIM and ICIs. Besides, TMB was toughly applied in clinical practice due to its high cost of determination and non-universal definition of high TMB.ConclusionsTMB presents limiting effects on prediction for ICIs efficacy and prognostic assessment for ACC patients.

PD-0828 Risk factors for the development of maxillary osteoradionecrosis in ACC patients treated with CIRT

PD-0828 Risk factors for the development of maxillary osteoradionecrosis in ACC patients treated with CIRT

Phase II study of cabazitaxel as second-third line treatment in patients with metastatic adrenocortical carcinoma

BackgroundAdrenocortical carcinoma (ACC) is a rare and aggressive malignancy with a poor prognosis. No efficacious treatment options are currently available for patients with advanced metastatic disease with disease progression to standard etoposide, doxorubicin, cisplatin and mitotane (EDP-M) therapy. We assessed the activity and tolerability of cabazitaxel as a second/third-line approach in metastatic ACC.Patients and methodsPatients included in this single-center, phase II study (ClinicalTrials.gov identifier NCT03257891) had disease progression to a cisplatin-containing regimen (such as EDP) plus mitotane, plus/minus a further chemotherapy line. Cabazitaxel was administered intravenously at 25 mg/m2 on day 1 of a 21-day cycle, for a maximum of six cycles. The primary endpoint was a disease control rate after 4 months.ResultsFrom March 2018 to September 2019, 25 eligible patients were enrolled. A disease control rate after 4 months was obtained in six patients (24%). No patients attained a disease response according to RECIST 1.1, 9 patients (36%) had stable disease and 16 patients (64%) progressive disease. Median progression-free survival and overall survival were 1.5 months (range 0.3-7 months) and 6 months (range 1-22.2 months), respectively. Cabazitaxel therapy was well tolerated and only three (12%) patients developed grade 3 toxicity which were nausea in one patient (4%) and anemia in two patients (8%).ConclusionsCabazitaxel has a manageable toxicity profile but is poorly active as second/third-line treatment in advanced ACC patients. These results do not support further evaluation of cabazitaxel in this setting.

First randomized trial on adjuvant mitotane in adrenocortical carcinoma patients: The Adjuvo study.

1 Background: The ESE-ENSAT guidelines on ACC management suggest adjuvant mitotane for patients at high risk of recurrence. This indication has limited evidence base, lacking results from randomized controlled trials. No suggestion for or against adjuvant mitotane in low-risk patients was given, since studies did not stratify patients for prognosis. The randomized controlled study ADIUVO compared the efficacy of adjuvant mitotane treatment vs. observation in prolonging recurrence-free survival (RFS) in patients at low-intermediate risk of recurrence. Methods: The main inclusion criteria were: stage I-III ACC, R0 surgery, and Ki-67 ≤10%. Patients were randomly assigned 1:1 to adjuvant mitotane or observation. The primary endpoint of the study was RFS. Patients who refused randomization were eligible for the ADIUVO OBSERVATIONAL study. In this prospective, observational study, patients were managed as in ADIUVO except for randomization. A total of 91 patients were enrolled in ADIUVO, 45 in the mitotane and 46 in the observation arm. Baseline characteristics of patients were perfectly matched between the 2 arms: median age, 51 vs. 50.5 years; female, 73% vs. 67%; stage I, 20% vs. 26%; stage II, 67% vs. 63%, stage III, 13% vs. 11%; ACC secretion 44% vs. 36%; Weiss 5 vs. 5; respectively. In ADIUVO OBSERVATIONAL, 42 patients were treated with mitotane and 53 were untreated. Baseline characteristics of patients were matched between the 2 groups and with mitotane and observation groups in ADIUVO. Thus, the ADIUVO OBSERVATIONAL cohort was analyzed in parallel to deal with the lower than expected recruitment in ADIUVO. Results: In the ADIUVO study, recurrences were 8 in the MIT and 11 in the OBS arm, while deaths were 2 and 5, respectively. RFS and overall survival (OS) did not significantly differ between the 2 arms. In the OBS arm, the HR for recurrence was 1.321 (95%CI, 0.55-3.32, p = 0.54) and HR for death 2.171 (95%CI, 0.52-12.12, p = 0.29). The survival analysis in the ADIUVO OBSERVATIONAL study confirmed that of ADIUVO. Given the outcome of both studies, the NNT is 55. Conclusions: ACC patients at low-intermediate risk of recurrence after surgery are a minority; however, they show a far better prognosis than expected (5-yr RFS is 75%) and do not benefit significantly from adjuvant mitotane. The results of the ADIUVO study do not support routine use of adjuvant mitotane in this subset of patients, who may thus avoid a potentially toxic treatment. This is an important step toward personalization of ACC care. Clinical trial information: NCT00777244.

Treatment differences at high volume centers and low volume centers in non-metastatic and metastatic adrenocortical carcinoma

BackgroundAdrenocortical carcinoma (ACC) is rare with poor survival. Do treatment and outcomes vary by volume? MethodsNCDB (2004–2017) was searched for patients with ACC. High-volume centers (HVCs) were defined by ≥ 15 ACC and low-volume centers by ≤ 7 total cases. Multivariable Cox and logistic regression analysis were performed. ResultsACC patients at HVCs were significantly more likely to have surgery, chemotherapy, and had lower 90-day readmission. HVCs were significantly more likely than LVCs to administer chemotherapy to surgical NonMetastatic (NM)-ACC patients. There was no significant difference in overall survival (OS), 90-day mortality, length of stay, or radiation treatments between the two. Operative Metastatic (M)-ACC at HVC had significantly improved OS, more chemotherapy administered, and lower 90-day mortality. ConclusionNM-ACC and M-ACC treated at HVCs were more likely to have surgery and multimodality therapy. NM-ACC having surgery at HVCs and LVCs had similar OS. M-ACC at HVCs had improved OS and 90-day mortality.

A transcription factor signature predicts the survival of patients with adrenocortical carcinoma.

BackgroundAdrenocortical carcinoma (ACC) is a rare endocrine cancer that manifests as abdominal masses and excessive steroid hormone levels and is associated with poor clinical outcomes. Transcription factors (TFs) deregulation is found to be involved in adrenocortical tumorigenesis and cancer progression. This study aimed to construct a TF-based prognostic signature for the prediction of survival of ACC patients.MethodsThe gene expression profile and clinical information for ACC patients were downloaded from The Cancer Genome Atlas (TCGA, training set) and Gene Expression Omnibus (GEO, validation set) datasets after obtained 1,639 human TFs from a previously published study. The univariate Cox regression analysis was applied to identify the survival-related TFs and the LASSO Cox regression was conducted to construct the TF signature based on these survival-associated TFs candidates. Then, multivariate analysis was used to reveal the independent prognostic factors. Furthermore, Gene Set Enrichment Analysis (GSEA) was performed to analyze the significance of the TFs constituting the prognostic signature.ResultsLASSO Cox regression and multivariate Cox regression identified a 13-TF prognostic signature comprised of CREB3L3, NR0B1, CENPA, FOXM1, E2F2, MYBL2, HOXC11, ZIC2, ZNF282, DNMT1, TCF3, ELK4, and KLF6. The risk score based on the TF signature could classify patients into low- and high-risk groups. Kaplan-Meier analyses showed that patients in the high-risk group had significantly shorter overall survival (OS) compared to the low-risk patients. Receiver operating characteristic (ROC) curves showed that the prognostic signature predicted the OS of ACC patients with good sensitivity and specificity both in the training set (AUC > 0.9) and the validation set (AUC > 0.7). Furthermore, the TF-risk score was an independent prognostic factor.ConclusionsTaken together, we identified a 13-TF prognostic marker to predict OS in ACC patients.

S-GRAS score for prognostic classification of adrenocortical carcinoma: an international, multicenter ENSAT study

ObjectiveAdrenocortical carcinoma (ACC) has an aggressive but variable clinical course. Prognostic stratification based on the European Network for the Study of Adrenal Tumours stage and Ki67 index is limited. We aimed to demonstrate the prognostic role of a points-based score (S-GRAS) in a large cohort of patients with ACC.DesignThis is a multicentre, retrospective study on ACC patients who underwent adrenalectomy.MethodsThe S-GRAS score was calculated as a sum of the following points: tumour stage (1–2 = 0; 3 = 1; 4 = 2), grade (Ki67 index 0–9% = 0; 10–19% = 1; ≥20% = 2 points), resection status (R0 = 0; RX = 1; R1 = 2; R2 = 3), age (<50 years = 0; ≥50 years = 1), symptoms (no = 0; yes = 1), and categorised, generating four groups (0–1, 2–3, 4–5, and 6–9). Endpoints were progression-free survival (PFS) and disease-specific survival (DSS). The discriminative performance of S-GRAS and its components was tested by Harrell’s Concordance index (C-index) and Royston–Sauerbrei’s R2D statistic.ResultsWe included 942 ACC patients. The S-GRAS score showed superior prognostic performance for both PFS and DSS, with best discrimination obtained using the individual scores (0–9) (C-index = 0.73, R2D = 0.30, and C-index = 0.79, R2D = 0.45, respectively, all P < 0.01vs each component). The superiority of S-GRAS score remained when comparing patients treated or not with adjuvant mitotane (n = 481 vs 314). In particular, the risk of recurrence was significantly reduced as a result of adjuvant mitotane only in patients with S-GRAS 4–5.ConclusionThe prognostic performance of S-GRAS is superior to tumour stage and Ki67 in operated ACC patients, independently from adjuvant mitotane. S-GRAS score provides a new important guide for personalised management of ACC (i.e. radiological surveillance and adjuvant treatment).

Different management of adrenocortical carcinoma in children compared to adults: is it time to share guidelines?

Pediatric and adult adrenocortical carcinomas differ in many respects but treatment is often similar in both age groups. The Journal of Clinical Oncology recently published the results of a risk-stratified single-arm interventional trial conducted by the Children’s Oncology Group in which 77 patients were treated in three different interventional cohorts. In this Point of View paper we comment on the treatment strategies adopted within the ARAR0332 trial in terms of surgery approach, duration of adjuvant therapies, and palliative chemotherapy. We focus on the differences in the treatment of pediatric ACC patients compared to the ESE/ENSAT and ESMO guidelines released in 2018 for adult patients. For example, patients in stratum 3 and 4 received 8 (instead of 6) cycles of EDP chemotherapy but 8 months (instead of 24) of mitotane adjuvant therapy. Bearing clearly in the mind that pediatric and adult ACC patients represent different settings, we wonder whether there could be some areas of intervention overlapping to constitute a continuum of disease across ages. Thus, pediatric and adult cohoperative groups should be encouraged to collaborate in order to reach common guidelines for the treatment of such a rare disease.