Citations

Abstract Objective Advanced adrenocortical carcinoma (ACC) is treated with mitotane alone or combined with cytotoxic chemotherapy, yet outcomes remain poor and prognostic models in this setting are lacking. This study aimed to evaluate the prognostic value of clinical parameters in a large cohort of patients with advanced ACC undergoing systemic therapy. Methods Multicenter, international cohort study investigating 418 patients with advanced ACC (61.5% = women, median age = 52 years) from 11 centers. Patients received mitotane monotherapy (n = 161), etoposide + doxorubicin + cisplatin ± mitotane (n = 178), or second-line regimens (gemcitabine + capecitabine ± mitotane or temozolomide + mitotane, n = 79). Variables included age, cortisol excess, performance status (ECOG-PS), tumor burden, and neutrophil-to-lymphocyte ratio (NLR) at start of therapy. Outcomes were overall survival (OS), time to progression (TTP), and best objective response. Results Tumor burden, cortisol excess, ECOG-PS, and NLR ≥5 independently predicted shorter OS (hazard ratio [HR] 1.55-2.68). We developed an integrated ENSAT Risk Score for Advanced ACC combining these variables: tumor burden (0-2), cortisol excess (0/1), ECOG-PS (0-2), and NLR (0/1). A score >2 (poor-risk) was significantly associated with worse OS and TTP across all treatment groups (HRs for OS: 3.05-3.96; TTP: 2.53-3.08). It also predicted poorer response to mitotane (P < .01) and second-line therapies (P = .04). Conclusions The ENSAT Risk Score for Advanced ACC is a practical, prognostic tool for patients with advanced ACC receiving systemic therapy. Based on accessible clinical and biochemical markers, it can support treatment decisions and facilitate informed discussions in routine care.

Abstract Disclosure: A. Prete: HRA Pharmaceuticals, Lundbeck, Diurnal. L. Adbi: None. J.T. Bain: None. F. Shaheen: None. O. Suntornlohanakul: None. E. Deflorenne: None. A. Blanchard: None. M. Nestola: None. C. Pamporaki: None. I. Tizianel: None. E. Nowak: None. J. Bertherat: None. D.A. Vassiliadi: None. I. Bancos: None. C.M. Dennedy: None. D. Kastelan: None. M. Fassnacht: None. P. Mulatero: None. U. Ambroziak: None. A. Tabarin: None. M. Quinkler: None. S. Puglisi: None. J. Deinum: None. G.Å. Ueland: None. L. Lenzini: None. F. Beuschlein: None. M. Reincke: None. F. Ceccato: None. G. Eisenhofer: None. S.M. Corsello: None. L. Amar: None. M. Zennaro: None. N. Karavitaki: None. A.E. Taylor: None. W. Arlt: None. Introduction: Twenty-four-hour urinary free cortisol is used to diagnose Cushing’s syndrome (CS); amongst its limitations is failure to differentiate ACTH-dependent CS (AD-CS) from ACTH-independent CS (AI-CS). We tested the performance of urine steroid metabolomics (USM), the computational analysis of 24-hour urine steroid metabolome data by machine learning, for the diagnosis and differential diagnosis of CS. Given the physiological diurnal rhythm of cortisol secretion and its loss in CS, we also hypothesised that the difference in glucocorticoid excretion between CS and controls should be higher during nighttime, thereby facilitating more sensitive detection of CS. Methods: 264 subjects completed a 24-hour urine collection (40 AD-CS, 103 AI-CS due to adrenocortical adenoma or hyperplasia, 121 healthy subjects). A subset of 52 individuals (13 CS, 39 healthy) provided a nighttime urine collection and a daytime urine collection. Mass spectrometry-based multi-steroid profiling was used to quantify the urinary excretion of 27 steroid metabolites. Data were analysed by generalised matrix learning vector quantisation (a prototype-based supervised machine learning approach), multiple linear regression adjusted for age, sex, and BMI, and multiple logistic regression adjusted for age, sex, and BMI. Results: Twenty-four-hour USM demonstrated very high accuracy in differentiating CS from healthy individuals (AUC-ROC 0.99, 95%CI 0.99-0.99), reflected by higher urinary excretion of glucocorticoid and glucocorticoid precursor metabolites in CS. USM yielded high accuracy in differentiating AD-CS from AI-CS (AUC-ROC 0.91, 95%CI 0.89-0.94), with androgen metabolites being the most discriminatory. We observed significant sex differences in steroid excretion in both healthy individuals and those with CS. Women exhibited markedly lower excretion of both glucocorticoids and mineralocorticoids compared to men: average glucocorticoid excretion was reduced by 43% in healthy women and 30% in CS women, while average mineralocorticoid excretion was 29% lower in healthy women and 51% lower in CS women (results adjusted for age and BMI). Timed steroid excretion in healthy individuals reflected the diurnal pattern of adrenal steroid secretion, with lower nighttime than daytime excretion of glucocorticoid metabolites. Nighttime glucocorticoid metabolite excretion (AUC-ROC 1.00, 95%CI 0.99-1.00) performed better than daytime (AUC-ROC 0.91, 95%CI 0.77-1.00) and 24-hour excretion (AUC-ROC 0.94, 95%CI 0.86-1.00) in separating CS cases from healthy individuals. Conclusions: USM is a non-invasive, one-step candidate test for the accurate diagnosis and differential diagnosis of CS. Timed nighttime urine collection leverages cortisol circadian rhythmicity and improves the diagnostic accuracy of the current reference standard 24-hour collection. Presentation: Sunday, July 13, 2025

Abstract Disclosure: B. Salama: None. M. Bassiony: None. J. Saini: None. P. Dogra: None. E. Atkinson: None. J. Larson: None. I. Vodanovic: None. D. Kastelan: None. D.A. Delivanis: None. J. Hubska: None. U. Ambroziak: None. I. Bancos: None. Background: Frailty is a clinical syndrome characterized by diminished physiological reserve and increased vulnerability to stressors. Patients with Mild Autonomous Cortisol Secretion (MACS) demonstrate a high prevalence of frailty, however, no data are available on the impact of management on frailty progression. Objectives: To determine the impact of conservative vs surgical management on and the progression of frailty in patients with MACS. Methods: We conducted a multicenter prospective cohort study of patients with (MACS), primary aldosteronism (PA), or non-functioning adrenal adenomas (NFA) between June 2020 and April 2025. Participants completed standardized frailty assessment (frailty index) at baseline and annually. Results: A total of 691 patients were included: 253 with MACS (median age 62 years, 73% women, 230 with NFA (median age 62 years, 67% women), and 208 with PA (median age 54 years, 50% women). At baseline, prevalence of frailty was highest patients with MACS (39%), followed by patients with PA (31%) and NFA (24%). Frailty was reassessed at 1 year post baseline in 189 patients with NFA (22% frail, median frailty index of 0.17) and 116 patients with MACS (27% frail, median frailty index of 0.16) managed conservatively, as well as in 108 patients with MACS treated with adrenalectomy (49% frail, median frailty score of 0.24). Conservatively treated patients with MACS and those treated with adrenalectomy had similar post-dexamethasone cortisol (median 2.9 mcg/dL vs 3.1 mcg/dL, p=0.396), but were older (median age 65 years vs 58 years, p=0.001) At one year follow up, patients with MACS treated with adrenalectomy demonstrated an improvement in frailty when compared to conservative management (delta frailty index: Est of −0.044, p = 0.004), after adjusting for age and sex. In contrast, when compared to conservatively managed patients with NFA, conservatively managed patients with MACS demonstrated worse frailty at 1 year follow up (delta frailty index: Est of 0.028, p = 0.013). Conclusion: In comparison to patients with NFA, conservatively managed patients with MACS demonstrated worse frailty at 1 year follow up. In contrast, adrenalectomy in patients with MACS led to improvement of frailty. Frailty index could be valuable to identify patients most likely to benefit from adrenalectomy. Patients with higher baseline frailty scores were more likely to undergo adrenalectomy, Presentation: Sunday, July 13, 2025

ABSTRACT Objective Data on bone health in patients with mild autonomous cortisol secretion (MACS) are limited and heterogenous. We sought to assess the prevalence of osteoporosis and symptomatic fragility fractures in patients with adrenal adenomas and hypercortisolism, and explore associations with the degree of cortisol excess and frailty. Design This multicenter cross ‐sectional study involved prospective enrollment of adults with nonfunctioning adrenal adenomas (NFA), MACS, Cushing syndrome (CS) and referent subjects without adrenal disorders during the study period (January 2019–September 2022). All participants completed a bone health questionnaire at enrollment and had dual‐energy X ‐ray absorptiometry bone mineral density assessment within 12‐months. Final analyses were adjusted for age, sex, body mass index, smoking status, alcohol use. Results Participants included 117 with NFA (median age 62 years, 80% women), 191 with MACS (median age 63 years, 74% women), 62 with CS (median age 50 years, 92% women), and 101 referent subjects (median age 59 years, 47% women). Both patients with CS (OR: 3.0, 95% CI: 1.1–8.3) and MACS (OR: 2.2, 95% CI: 1.9–4.9) had a higher prevalence of osteoporosis when compared to referents. Among patients with MACS, only those with post 1‐mg dexamethasone suppression test (post‐1mg‐DST) cortisol > 83 nmol/L had a higher prevalence of osteoporosis when compared to referents (OR: 3.2, 95% CI: 1.4–7.5) and NFA (OR: 2.2, 95% CI: 1.1–4.4). For clinical fragility fractures, only patients with CS showed an increased prevalence when compared to referents (OR: 6.1, 95% CI: 1.7–26.4) and NFA (OR: 3.8, 95% CI: 1.3–11.2). Prevalence of clinical fragility fractures was similar to referents in patients with MACS (OR: 1.8, 95% CI: 0.6–6.9) and NFA (OR: 1.5, 95% CI: 0.4–6.1), and was not associated with post‐1mg‐DST cortisol or frailty in the MACS and NFA groups. Conclusion Patients with CS, and those with MACS and post‐1mg‐DST cortisol > 83 nmol/L, exhibited a higher burden of osteoporosis. However, only CS was associated with an elevated risk of symptomatic fragility fractures.

Abstract Background Mitotane monotherapy is the standard adjuvant treatment for adrenocortical carcinoma (ACC), yet reliable predictors of treatment response remain lacking. Given the well-recognized interplay between inflammation and cancer progression, serum inflammation-based scores have shown prognostic significance in various malignancies, including ACC in palliative settings. However, their relevance during adjuvant mitotane therapy remains uncertain. This study aimed to assess the prognostic value of inflammation-scores in patients with ACC receiving adjuvant mitotane. Methods Multicenter ENSAT retrospective study including patients with ACC treated with adjuvant mitotane as first-line therapy. Clinical data including age, sex, ENSAT tumor stage, Ki67 index, resection status, and hormone secretion were collected at diagnosis. Inflammation-scores - neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), systemic immune inflammation index (SII), and pan-immune-inflammation value (PIV) - were calculated at diagnosis (pre-surgery) and at mitotane start. Median values of inflammation-scores at diagnosis defined low and high levels. Overall survival (OS) and time to progression (TTP) from mitotane start were the primary endpoints. Results The study included 395 patients (66% female; median age: 51 years). Median time to mitotane start was 54 days (IQR: 32–90). At diagnosis, patients with glucocorticoid excess (n=84) had significantly higher inflammation-scores than those without (n=104): NLR (3.61 vs 2.53), dNLR (2.31 vs 1.72), SII (864.1 vs 679.3), and PIV (531.6 vs 343.1); all p≤0.005. All scores significantly declined after surgery (p<0.05). Higher inflammatory scores at diagnosis were associated with worse OS (NLR: HR=3.85, 95%CI=1.95–7.59, p<0.001; dNLR: HR=3.19, 95%CI=1.67- 6.08, p<0.001; SII: HR=1.97, 95%CI = 1.07–3.61, p=0.03; PIV: HR=2.11, 95%CI=1.13-3.95, p=0.02). However, only the NLR and dNLR remained independently associated with OS at multivariate analysis adjusted for ENSAT stage, Ki67 index, and resection status (p<0.05). At mitotane start (n=372), high SII and PIV were associated with shorter TTP (SII: HR=1.36, 95%CI=1.02-1.82, p=0.03; PIV: HR=1.40, 95%CI=1.04-1-87, p=0.02), with only SII remaining significant at multivariate regression (p=0.04). Conclusions Inflammation-based scores are higher in patients with glucocorticoid excess and decrease postoperatively. NLR and dNLR at diagnosis, and SII at mitotane start, are associated with clinical outcomes in patients with ACC receiving mitotane adjuvant monotherapy. These readily available markers may help improve prognostic stratification in clinical practice.

Abstract Disclosure: M. Bassiony: None. P. Dogra: None. L. Šambula: None. J. Saini: None. U. Ambroziak: None. D. Kastelan: None. I. Bancos: None. Background: Frailty is characterized by a multi-system decline and increased vulnerability to adverse health outcomes. We have recently shown that patients with mild autonomous cortisol secretion (MACS) demonstrate a higher prevalence of frailty compared to patients with nonfunctioning adrenal adenomas (NFA). Objective: To determine the impact of adrenalectomy versus conservative management in patients with MACS, as compared to patients with NFA. Design: Multi-center, prospective cohort study (2019-2023). Methods: Adults with NFA and MACS were assessed for frailty at baseline and 1-year post-adrenalectomy, or conservative follow up. Frailty was assessed by frailty index (FI) that encompasses 47 health variables (comorbidities, symptoms, daily living activities). Patients with FI >0.25 were classified as frail. MACS was defined as post-dexamethasone cortisol>1.8 mcg/dL. Results: Paired frailty assessments were performed in 226 patients (MACS:117 and NFA:109). At baseline, patients’ median age was 63 years (interquartile range, IQR 55-78) and 113 (50%) were women, without differences between patients with MACS vs NFA. In conservatively treated patients with NFA (n=106) and MACS (n=61), baseline FI (median 0.15 vs 0.16, p=0.190) and frailty prevalence (18% vs 20%, p=0.846) were similar between groups. At follow up, patients with MACS demonstrated an increase in FI (mean of 0.013 vs -0.018 in patients with NFA, p=0.009). In conservatively treated patients, and after excluding outliers, post-dexamethasone cortisol positively correlated with a higher delta FI at follow up (estimate 0.015, p=0.01). Compared to conservatively treated, patients with MACS treated with adrenalectomy (n=56) were younger (median age of 58 vs 67 years, p=0.0002), had a similar post-dexamethasone cortisol (median 3.4 vs 2.8 mcg/dL, p=0.853), a higher FI (median 0.26 vs 0.15, p value <0.0001) and frailty prevalence (52% vs 20% P=0.0003) at baseline. At follow up, patients with MACS treated with adrenalectomy showed improved FI when compared to conservatively treated (mean delta FI of -0.025 vs 0.014, p=0.017). Conclusions: Patients with MACS treated conservatively demonstrate an accelerated frailty when compared to patients with NFA. In contrast, frailty improves in patients with MACS treated with adrenalectomy. Presentation: 6/2/2024

Abstract Objective Frailty, characterized by multi-system decline, increases vulnerability to adverse health outcomes and can be measured using Frailty Index (FI). We aimed to assess the prevalence of frailty in patients with adrenal disorders (based on hormonal sub-type) and examine association between FI and performance-based measures of physical function. Design Multi-centre, cross-sectional study (March 2019-August 2022). Methods Adult patients with adrenal disorders (non-functioning adrenal adenomas [NFA], mild autonomous cortisol secretion [MACS], Cushing syndrome [CS], primary aldosteronism [PA]) and referent subjects without adrenal disorders completed a questionnaire encompassing 47 health variables (comorbidities, symptoms, daily living activities). FI was calculated as the average score of all variables and frailty defined as FI ≥ 0.25. Physical function was assessed with hand grip, timed up-and-go test, chair rising test, 6-minute walk test, and gait speed. Results Compared to referent subjects (n = 89), patients with adrenal disorders (n = 520) showed increased age, sex, and body mass index-adjusted prevalence of frailty (CS [odds ratio—OR 19.2, 95% confidence interval—CI 6.7-70], MACS [OR 12.5, 95% CI 4.8-42.9], PA [OR 8.4, 95% CI 2.9-30.4], NFA [OR 4.5, 95% CI 1.7-15.9]). Prevalence of frailty was similar to referent subjects when post-dexamethasone cortisol was <28 nmol/L and was higher when post-dexamethasone cortisol was 28-50 nmol/L (OR 4.6, 95% CI 1.7-16.5). FI correlated with all measures of physical function (P < .001). Conclusions Whilst frailty prevalence was highest in patients with adrenocortical hormone excess, even patients with NFA demonstrated an increased prevalence compared to the referent population. Future longitudinal studies are needed to evaluate the impact of various management strategies on frailty.

Abstract Introduction Limited data suggest low bone density in patients with adrenal adenomas. However, most studies are retrospective, single-center, and none were conducted in the United States. We aimed to determine the impact of cortisol and aldosterone excess on bone density. Methods We conducted a preliminary analysis of data from our multicenter, prospective observational study of adult patients with adrenocortical hormone excess and referent subjects without adrenal disorders (January 2019 - March 2022). Patients were diagnosed with non-functioning adenomas (NFA), adenomas with mild autonomous cortisol secretion, MACS (defined as cortisol following an overnight 1-mg dexamethasone suppression test (DST)>1.8 mcg/dL), adrenal or pituitary Cushing syndrome (CS), primary aldosteronism (PA), and concomitant PA-MACS. Referent subjects were patients undergoing cross-sectional imaging for reasons other than adrenal disease. All participants were interviewed about their bone health, and had bone density measurements at the spine, hips, and/or radius. Bone disease was defined as osteopenia (T-score -1.1 to -2.4), or osteoporosis (T-score < -2.5). Results A total of 417 participants included 156 referent subjects (88, 56% women, median age 65, range 2-95 years) and 261 patients (190, 73% women, median age 59, range 21-88 years). Patients were diagnosed with NFA (51, 19%), PA (46, 17%), MACS (122, 47%), PA-MACS (12, 5%), and CS (30,12%). When compared to referent subjects, sex- and age-adjusted analysis demonstrated an increased prevalence of bone disease only in patients with CS (OR 4.8, 95%CI 1.7-13), but not in other adrenal disorders. After excluding patients with CS, those with post-DST cortisol >5 mcg/dL demonstrated a higher prevalence of bone disease when compared to patients with post-DST cortisol between 1.8-5 mcg/dL (OR 2.8, 95%CI 1.2-6.5) and those with post-DST cortisol <1.8 mcg/dL (OR 2.7, 95% CI 1.1-6.7). Patients with MACS and post-DST cortisol between 1.8-5 mcg/dL did not demonstrate increased sex and age-adjusted prevalence of bone disease compared to those with post-DST <1.8 mcg/dL or referent subjects. However, using post-DST cortisol as a continuous variable, we found that after adjusting for sex and age, the risk of bone disease in patients increased by 13% (OR 1.13, 95%CI 1.6-1.2) for every 1 mcg/dL increase in post-DST cortisol. Conclusions The prevalence of osteopenia and osteoporosis increases proportional to the increase in post-DST cortisol concentrations. Patients with CS, and those with MACS and post-DST cortisol > 5mcg/dL have the highest prevalence of bone disease. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

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.