Predictors of Cancer in Patients With Endogenous Cushing’s Syndrome

Posted on July 21, 2025 by MaryO

We previously reported an increase in overall cancer risk in patients with endogenous Cushing’s syndrome (CS), mainly during the 10-year period following CS diagnosis.

To identify predictors of cancer in patients with CS, we conducted this retrospective nationwide cohort study of patients with CS, diagnosed between 2000 and 2023 in Israel. The cohort comprised 609 patients with CS (age at diagnosis, 48.1 ± 17.2 years; 65.0% women) and 3,018 age-, sex-, socioeconomic status-, and body mass index-matched controls (1:5 ratio).

Patients were grouped according to the occurrence of any malignancy within 10-years after the diagnosis of CS. Cox proportional hazards models, with death as a competing event, were used to identify predictors of cancer development. Independent predictors of cancer development in patients with CS included age ≥60 years (HR 1.75, 95% CI 1.01–2.68), male gender (HR 1.67, 95% CI 1.04–3.05), and adrenal-origin CS (HR 1.66, 95% CI 1.01–2.73). Baseline urinary-free cortisol levels were not associated with cancer development. Patients with ≥4 CS-associated comorbidities had a higher cancer risk (HR 1.76, 95% CI 1.03–3.02; age- and sex-adjusted). The overall 10-year risk of malignancy was twice as high in patients with CS compared to matched controls, with cancer developing, on average, 5 years earlier in patients with CS (62.3 ± 15.0 vs 67.2 ± 12.3 years). Cancer-related mortality at 10-years was twice as high in deceased patients with CS, compared to deceased controls. In conclusion, age ≥60 years at CS diagnosis, male gender, and adrenal-origin CS are independent predictors of cancer diagnosis within 10-years of initial confirmation of CS.

 

Introduction

Prolonged cortisol exposure may promote cancer development and growth (Mayayo-Peralta et al. 2021, Khadka et al. 2023). Epidemiological research showed that extended glucocorticoids use is associated with elevated overall cancer risk (Oh & Song 2020). Recently, several studies suggested that cortisol levels increase cancer risk in patients with endogenous Cushing’s syndrome (CS). A Danish study found higher rates of cancer at the time of CS diagnosis compared to controls (Dekkers et al. 2013). A Swedish study examined comorbidity rates in patients with CS and identified a nonsignificant trend of increased cancer rates in CS compared to the general population, but was probably underpowered for this relatively rare outcome (Papakokkinou et al. 2020). Our nationwide retrospective matched-cohort study, using the Clalit Health Services (CHS) database in Israel (including 609 patients with CS and 3,018 age-, sex-, socioeconomic status- and body mass index (BMI)-matched controls), observed higher rates of all cancer types in patients with CS, with a hazard ratio (HR) of 1.78 (95% CI 1.44–2.20) (Rudman et al. 2024). Elevated cancer incidence was evident in patients with Cushing’s disease (CD) and in patients with adrenal CS. The overall cancer risk remained elevated during the first 10 years that followed CS diagnosis (Rudman et al. 2024). Similarly, a nationwide cohort study from Taiwan investigated the association between endogenous CS and cancer incidence, and reported a standardized incidence ration of 2.08 (95% CI 1.54–2.75) for cancer in patients with endogenous CS (Wu et al. 2025).
Hypercortisolemia and CS-associated comorbidities could drive malignancy development in patients with CS (Rudman et al. 2024, Wu et al. 2025). While it is known that the incidence of diabetes, obesity and insulin resistance is higher in patients with CS than that of the general population (Pivonello et al. 2016, Fleseriu et al. 2021, Reincke & Fleseriu 2023) – all of which are linked to cancer development (Renehan et al. 2008, Ling et al. 2020) – it remains unclear whether these comorbidities specifically contribute to the risk of malignancy within the CS population.
Thus, the aims of the present study were to identify the baseline predictors of cancer development in CS and to test the hypothesis that cumulative cortisol exposure, measured by urinary-free cortisol (UFC), predicts cancer risk in patients with CS.

Methods

Study design and data collection

We conducted a retrospective matched-cohort study using the electronic health record database of Clalit Health Services (CHS), the largest health maintenance organization (HMO) in Israel with over 4.8 million members. The CHS database includes demographic and clinical data, hospital and outpatient clinic diagnoses, medication dispensation, and all laboratory test results conducted at the HMO’s laboratories. All diagnoses and respective dates were identified using the International Classification of Diseases, tenth revision (ICD-10) codes (Supplementary Table S1 (see section on Supplementary materials given at the end of the article)). Weight and height data, and smoking status, were recorded regularly during visits to primary care clinics and in some specialized clinics. 24 h UFC results were collected and the normal reference range for each kit used. As these tests were performed by several different laboratories and devices (in all cases the bioanalytical method used was an immunoassay test), the results were reported as multiples of the upper limit of normal (×ULN). Data were extracted using the CHS research data-sharing platform, powered by MDClone. Importantly, the diagnoses of chronic medical conditions, recorded at the time of CS diagnosis, were validated: any member of CHS who required chronic treatment for a medical condition (e.g., medication for hypertension or diabetes) could only receive his prescriptions if the primary physician has registered the diagnosis, coded according to the ICD-10, in the computerized system. Mortality data were collected from the hospital’s mortality database, which is updated from the Ministry of Interior’s population registry. Data on cancer-specific mortality were obtained from hospital discharge certificates at the time of the hospitalization that ultimately resulted in the patient’s death. The study protocol, including detailed data collection methods, has been previously published (Rudman et al. 2024).

Ethical approval

The study was approved by the institutional ethics review board of Rabin Medical Center. As data were collected anonymously and in a retrospective manner, a waiver of informed consent was granted.

Patients and outcome measures

The methods we used for patient selection and matched controls selection have been previously published (Rudman et al. 2024), as the current study is based on the same group of patients with CS and controls. After the initial screening, potential cases with ICD-10 diagnosis of CS had to fulfill at least one of the following criteria: i) 24 h UFC ≥4 ×ULN, ii) 24 h UFC ≥3 ×ULN and surgical intervention to remove a pituitary or adrenal adenoma, and iii) 24 h UFC ≥2 ×ULN and metyrapone, ketoconazole, osilodrostat, cabergoline, or pasireotide treatment. All patients with CS and non-suppressed adrenocorticotropic hormone (ACTH) levels who did not receive pituitary-directed therapy and were diagnosed with a malignancy possibly causative of ectopic CS, including small-cell lung carcinoma, bronchial and thymic carcinoids, medullary thyroid carcinoma, neuroendocrine tumors or pheochromocytoma, were suspected of ectopic CS and were excluded from this study (Rudman et al. 2024). Patients diagnosed with adrenocortical carcinoma before or within 5 years of CS diagnosis were excluded.
All identified cases were individually matched in a 1:5 ratio with age-, sex-, socioeconomic status-, and BMI-matched controls from the general population (CHS members who have never been tested for suspected hypercortisolism). The age of the individually matched controls matched the age of cases ±12 months.
The follow-up period began at the time of CS diagnosis for all cases (newly diagnosed patients with CS) and at the exact same day for each individually matched control. It continued until death, termination of CHS membership, or until the date of data collection (June 30, 2023).
The main outcome measure was the first diagnosis of any malignancy following CS diagnosis, excluding non-melanoma skin cancer. Recurrences of known malignancies were also excluded.

Statistical analysis

The statistical analysis was generated using the SAS Software, Version 9.4, SAS Institute Inc., Cary, NC, USA. Continuous variables were presented by the mean ± standard deviation or median (interquartile range (IQR)). Categorical variables were presented by (n, %). Normality of continuous variables was assessed using the Kolmogorov–Smirnov test. The t-test, Mann–Whitney test, and chi-square test were used for comparison of normally distributed, non-normal, and categorical variables, respectively. The Cox proportional hazard model, with death without malignancy treated as a competing risk, was used to calculate both univariate and multivariate HR; the Fine and Gray methodology for dealing with competing risks was used, both in the cumulative incidence plots and in HR calculations. Baseline variables found to be associated with malignancy in the univariate analysis (with a between-group P-value below 0.05) were incorporated into the multivariate model. The appropriateness of the proportional hazard assumption was assessed visually. Two-sided P-values less than 0.05 were considered statistically significant.

Results

Patient characteristics

From January 1, 2000, to June 30, 2023, a total of 609 patients with CS met the study inclusion criteria (65.0% women, mean age at CS diagnosis of 48.1 ± 17.2 years). All cases of CS were matched with up to five controls based on age, sex, socioeconomic status, and BMI, and amounted to a total of 3,018 controls. Baseline characteristics of all 609 patients and 3,018 controls, with subdivisions according to disease source, are shown in Table 1.

Table 1. Baseline characteristics (at diagnosis/time 0) of patients with Cushing’s syndrome (CS) and matched control of all patients with CS, Cushing’s disease (CD), and adrenal CS.

Baseline characteristics, all patients with CS CS (n = 609) Matched controls (n = 3,018) P value CD (n = 251) Matched controls (n = 1,246) P value Adrenal CS (n = 200) Matched controls (n = 991) P value
Age, years, mean (SD) 48.1 (17.2) 47.9 (17.2) 45.7 (17.8) 45.7 (17.8) 51.1 (16.6) 51.0 (16.6)
Sex, no. (%)
 Females 396 (65.0) 1,975 (65.4) 164 (65.3) 818 (65.6) 137 (68.5) 684 (69.0)
 Males 213 (35.0) 1,043 (34.6) 87 (34.7) 428 (34.4) 63 (31.5) 307 (31.0)
Socioeconomic status, no. (%)a
 Low 74 (12.8) 371 (13.0) 34 (14.2) 172 (14.5) 20 (10.5) 99 (10.4)
 Middle 349 (60.6) 1,719 (60.3) 145 (60.7) 713 (60.2) 119 (62.6) 594 (62.9)
 High 153 (26.6) 760 (26.7) 60 (25.1) 300 (25.3) 51 (26.9) 252 (26.7)
Body mass index, Kg/m2, mean (SD)b 30.9 (7.6) 30.0 (6.9) 30.2 (7.4) 29.6 (6.8) 30.8 (7.1) 30.3 (6.3)
Source of hypercortisolism, no. (%)
 Cushing’s disease 251 (41.2)
 Adrenal Cushing’s syndrome 200 (32.8)
 Indeterminatec 158 (25.9)
Smoking status, no. (%)d 0.35 0.77 0.18
 Non-smoker 198 (59.8) 910 (62.6) 87 (64.0) 387 (65.3) 61 (53.0) 327 (60.1)
 Smoker/former smoker 133 (40.2) 544 (37.4) 49 (36.0) 206 (34.7) 54 (47.0) 217 (39.9)
Comorbidities, no. (%)
 Diabetes mellitus 140 (23.0) 396 (13.1) <0.01 55 (21.9) 148 (11.9) <0.01 51 (25.5) 158 (15.9) <0.01
 Hypertension 343 (56.3) 957 (31.7) <0.01 129 (51.4) 338 (27.1) <0.01 129 (64.5) 387 (39.0) <0.01
 Dyslipidemia 258 (42.4) 874 (29.0) <0.01 97 (38.6) 305 (24.5) <0.01 97 (48.5) 339 (34.2) <0.01
 Ischemic heart disease 70 (11.5) 191 (6.3) <0.01 23 (9.2) 67 (5.4) 0.03 25 (12.5) 77 (7.8) 0.04
 Cerebrovascular disease 27 (4.4) 82 (2.7) 0.04 12 (4.8) 35 (2.8) 0.11 10 (5.0) 32 (3.2) 0.21
 Osteoporosis 75 (12.3) 187 (6.2) <0.01 26 (10.4) 57 (4.6) <0.01 28 (14.0) 82 (8.3) 0.02
 Malignancy before CS diagnosis 50 (8.2) 117 (3.9) <0.01 15 (6.0) 48 (3.9) 0.12 20 (10.0) 50 (5.0) 0.01
Cases and controls were individually matched for age, sex, socioeconomic status, and body mass index.
a
Cushing’s syndrome n = 576, controls n = 2,850; Cushing’s disease n = 239, controls n = 1,185; adrenal Cushing’s syndrome n = 190, controls n = 945.
b
Cushing’s syndrome n = 363, controls n = 1,549; Cushing’s disease n = 152, controls n = 644; adrenal Cushing’s syndrome n = 131, controls n = 570.
c
Ectopic ACTH secretion and adrenocortical carcinoma were excluded.
d
Cushing’s syndrome n = 331, controls n = 1,454; Cushing’s disease n = 136, controls n = 593; adrenal Cushing’s syndrome n = 115, controls n = 544.
At baseline, diabetes mellitus, hypertension, dyslipidemia, ischemic heart disease, and osteoporosis were more common among patients with CS (P < 0.01). Smoking rates were similar between the two groups (Table 1). A prior history of malignancy was more prevalent among patients with CS than controls (8.2 vs 3.9%, respectively; P < 0.01) (Table 1).

Predictors of new malignancy in patients with Cushing’s syndrome

Table 2 presents the baseline characteristics of 609 patients with CS, including demographic data, CS etiology, history of malignancy before CS diagnosis, maximal UFC at diagnosis, and CS-associated comorbidities. In a univariate time-to-event analysis of the 10-year cumulative cancer risk, accounting for death as a competing event, we found that age ≥60 years at CS diagnosis, male gender, adrenal-origin CS, hypertension, dyslipidemia, and ischemic heart disease at baseline were all associated with a higher cancer risk. The 10-year cumulative cancer risk, with death as a competing event, stratified by age, sex, and CS etiology is shown in Fig. 1. Prior malignancy, diabetes, and obesity were not associated with an increased risk of malignancy in patients with CS (Table 2). The cohort was divided into three groups based on baseline UFC level (below 5 ×ULN, 5–10 ×ULN, and above 10 ×ULN) with comparison of time to cancer occurrence. Higher UFC levels at the time of CS diagnosis were not associated with cancer development (Table 2 and Fig. 2). In a multivariable Cox regression model (multivariable model 1, Table 2), we found that age ≥60 years at CS diagnosis (HR 1.75, 95% CI 1.01–2.68), male gender (HR 1.67, 95% CI 1.04–3.05), and adrenal-origin CS (HR 1.66, 95% CI 1.01–2.73) were independent predictors of cancer development within 10 years after CS diagnosis. In an additional model (multivariable model 2, Table 2), we observed that patients with ≥4 CS-associated comorbidities at the time of CS diagnosis had a higher risk of cancer (HR 1.76, 95% CI 1.03–3.02), after adjustment for age and sex.

Table 2. Univariate analysis and multivariable regression models for the 10-year cumulative cancer risk in patients with Cushing’s syndrome, accounting for death as a competing event.

Baseline characteristics Patients (n = 609) Incident cases of cancer (n = 81) Deaths without cancer (n = 40) Univariate analysis Multivariable model 1* Multivariable model 2 (total no. of CS-associated comorbidities, with age and sex adjustment)
Age <60 years (ref) 444 44 10 – – –
Age ≥60 years 165 37 30 2.47 (1.60–3.82) 1.75 (1.01–2.68) 3.18 (2.09–4.86)
Female (ref) 396 42 23 – – –
Male 213 39 17 1.75 (1.13–2.70) 1.67 (1.04–3.05) 1.60 (1.11–2.29)
Low SESa 74 13 5 1.29 (0.65–2.56)
Medium SESa 349 42 21 0.87 (0.52–1.45)
High SES (ref)a 153 22 13 –
Cushing’s disease (ref)b 251 27 21 – –
Adrenal CSb 200 39 8 1.87 (1.14–3.05) 1.66 (1.01–2.73)
Non-smoker (ref)c 198 25 12 –
Smoker/former smokerc 133 21 12 1.25 (0.70–2.23)
Prior malignancy 50 6 14 0.91 (0.40–2.08)
No prior malignancy (ref) 559 75 26 –
Maximal urinary free cortisold
 <5 × ULN (ref) 231 38 18 –
 5–10 × ULN 135 18 7 0.86 (0.49–1.48)
 ≥10 × ULN 70 10 4 0.89 (0.45–1.78)
CS-associated comorbidities
 Obesitye 176 28 17 1.22 (0.71–2.11)
 No obesity (ref)e 187 24 12 –
 Diabetes mellitus 140 21 14 1.28 (0.78–2.10)
 No diabetes mellitus (ref) 469 60 26 –
 Hypertension 343 59 34 2.23 (1.36–3.65) 1.52 (0.83–2.81)
 No hypertension (ref) 266 22 6 – –
 Dyslipidemia 258 44 29 1.81 (1.17–2.81) 0.97 (0.55–1.72)
 No dyslipidemia (ref) 351 37 11 – –
 Ischemic heart disease 70 19 11 2.70 (1.62–4.51) 1.48 (0.81–2.71)
 No ischemic heart disease (ref) 539 62 29 –
 Stroke 27 3 2 1.07 (0.33–3.49)
 No stroke (ref) 582 78 38 –
 Osteoporosis 75 9 9 0.92 (0.46–1.84)
 No osteoporosis (ref) 534 72 31 –
Total no. of CS-associated comorbiditiesf
 0–1 (ref) 295 27 9 – –
 2–3 205 33 15 2.09 (1.36–3.22) 1.40 (0.87–2.26)
 ≥4 109 21 16 3.76 (2.37–5.97) 1.76 (1.03–3.02)
CS, Cushing’s syndrome; SES, socioeconomic status; ULN, upper limit of normal. Bold indicates statistical significance.
*
Included variables: age, sex, source of hypercortisolism, hypertension, dyslipidemia, and ischemic heart disease.
a
n = 576.
b
Ectopic ACTH secretion and adrenocortical carcinoma were excluded.
c
n = 331.
d
Maximal value of urinary-free cortisol divided by the upper limit of normal of the specific assay, n = 436.
e
n = 363.
f
CS-associated comorbidities include obesity, diabetes mellitus, hypertension, dyslipidemia, ischemic heart disease, and osteoporosis.
Figure 1

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Figure 1. The 10-year cumulative cancer risk, with death as a competing event, among patients with Cushing’s syndrome, according to age at diagnosis (A), sex (B), and Cushing’s syndrome etiology (C). CD, Cushing’s disease; CS, Cushing’s syndrome. A full colour version of this figure is available at https://doi.org/10.1530/ERC-25-0059.

Figure 2

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Figure 2. The 10-year cumulative cancer risk, with death as a competing event, among patients with Cushing’s syndrome, according to the maximal value of UFC divided by the upper limit of normal (ULN) of the specific assay used: UFC <5 × ULN (reference), 5–10 × ULN, and ≥10 × ULN. A full colour version of this figure is available at https://doi.org/10.1530/ERC-25-0059.

Univariate analysis and multivariable regression models for the 10-year cumulative cancer risk in patients with CD and adrenal CS are presented in Tables 3 and 4. In the univariate time-to-event analysis of 251 patients with CD, age ≥60 years at CS diagnosis and the presence of dyslipidemia and ischemic heart disease at baseline were associated with higher cancer risk. The multivariable Cox regression model did not identify any significant predicting factors in patients with CD. Tables 3 and 4 also present the univariate analysis for the 10-year cumulative cancer risk in 200 patients with adrenal CS, which showed that age ≥60 years, male gender, and ischemic heart disease were associated with cancer development. In the multivariable model, only age ≥60 years at CS diagnosis (HR 2.66, 95% CI 1.36–5.18) was found to be independently associated with cancer development in patients with adrenal CS (Table 4). UFC levels at the time of CS diagnosis were not associated with new cancer diagnosis in either patients with CD or with adrenal CS (Tables 3 and 4).

Table 3. Univariate analysis and multivariable regression models for the 10-year cumulative cancer risk in patients with Cushing’s disease, accounting for death as a competing event.

Cushing’s disease baseline characteristics Patients (n = 251) Incident cases of cancer (n = 27) Deaths without cancer (n = 21) Univariable Multivariable model 1 Multivariable model 2 (total no. of CS-associated comorbidities, with age and sex adjustment)
Age <60 years (ref) 196 16 8 – – –
Age ≥60 years 55 11 13 2.72 (1.27–5.81) 1.83 (0.65–5.18) 3.54 (1.81–6.92)
Female (ref) 164 14 14 – – –
Male 87 13 7 1.79 (0.85–3.80) 1.61 (0.73–3.56) 1.22 (0.68–2.18)
Low SESa 34 5 5 1.29 (0.42–3.99)
Medium SESa 145 13 12 0.81 (0.32–2.00)
High SES (ref)a 60 7 4 –
Non-smoker (ref)b 87 6 6 –
Smoker/former smokerb 49 8 8 2.59 (0.91–7.39)
Prior malignancy 15 26 15 0.66 (0.09–5.13)
No prior malignancy (ref) 236 1 6 –
Maximal urinary-free cortisolc
 <5 × ULN (ref) 133 15 14 –
 5–10 × ULN 70 6 3 0.78 (0.31–2.00)
 ≥10 × ULN 40 6 4 1.48 (0.57–3.79)
CS-associated comorbidities
 Obesityd 69 7 10 0.80 (0.31–2.09)
 No obesity (ref)d 83 10 6 –
 Diabetes mellitus 55 5 6 0.89 (0.34–2.35)
 No diabetes mellitus (ref) 196 22 15 –
 Hypertension 129 17 17 1.67 (0.76–3.64)
 No hypertension (ref) 122 10 4 –
 Dyslipidemia 97 15 13 2.31 (1.08–4.96) 1.64 (0.58–4.61)
 No dyslipidemia (ref) 154 12 8 – –
 Ischemic heart disease 23 5 4 2.71 (1.03–7.08) 1.29 (0.43–3.86)
 No ischemic heart disease (ref) 228 22 17 – –
 Stroke 12 2 1 2.34 (0.53–10.30)
 No stroke (ref) 239 25 20 –
 Osteoporosis 26 24 15 1.14 (0.35–3.66)
 No osteoporosis (ref) 225 3 6 –
Total no. of CS-associated comorbiditiese
 0–1 (ref) 136 11 6 – –
 2–3 74 10 8 2.19 (1.13–4.26) 1.48 (0.72–3.04)
 ≥4 41 6 7 3.69 (1.78–7.66) 1.72 (0.73–4.02)
CS, Cushing’s syndrome; SES, socioeconomic status; ULN, upper limit of normal. Bold indicates statistical significance.
a
n = 239.
b
n = 136.
c
Maximal value of urinary free cortisol divided by the upper limit of normal of the specific assay; n = 243.
d
Cushing’s disease, n = 152.
e
CS-associated comorbidities include obesity, diabetes mellitus, hypertension, dyslipidemia, ischemic heart disease, and osteoporosis.

Table 4. Univariate analysis and multivariable regression models for the 10-year cumulative cancer risk in patients with adrenal Cushing’s syndrome, accounting for death as a competing event.

Adrenal Cushing’s syndrome baseline characteristics Patients with CS at risk (n = 200) Incident cases of cancer (n = 39) Deaths without cancer (n = 8) Univariable Multivariable model 1 Multivariable model 2 (total no. of CS-associated comorbidities, with age and sex adjustment)
Age <60 years (ref) 134 20 1 – – –
Age ≥60 years 66 19 7 2.12 (1.13–3.96) 2.66 (1.36–5.18) 2.70 (1.35–5.42)
Female (ref) 137 17 3 – – –
Male 63 22 5 2.97 (1.58–5.58) 1.81 (0.94–3.51) 3.11 (1.73–5.57)
Low SESa 20 3 0 0.62 (0.17–2.28)
Medium SESa 119 22 3 0.73 (0.36–1.44)
High SES (ref)a 51 13 5 –
Non-smoker (ref)b 61 12 3 –
Smoker/former smokerb 54 10 2 0.86 (0.38–1.99)
Prior malignancy 20 4 2 1.03 (0.38–2.81)
No prior malignancy (ref) 180 35 6 –
Maximal urinary free cortisolc
 <5 × ULN (ref) 98 23 4 –
 5–10 × ULN 65 12 4 0.84 (0.42–1.69)
 ≥10 × ULN 30 4 0 0.53 (0.18–1.52)
CS-associated comorbidities
 Obesityd 64 15 4 1.68 (0.75–3.74)
 No obesity (ref)d 67 10 3 –
 Diabetes mellitus 51 12 3 1.47 (0.75–2.89)
 No diabetes mellitus (ref) 149 27 5 –
 Hypertension 129 29 7 1.73 (0.84–3.58)
 No hypertension (ref) 71 10 1 –
 Dyslipidemia 97 20 7 1.20 (0.65–2.25)
 No dyslipidemia (ref) 103 19 1 –
 Ischemic heart disease 25 10 4 2.65 (1.31–5.34) 1.51 (0.68–3.32)
 No ischemic heart disease (ref) 175 29 4 – –
 Stroke 10 1 1 0.58 (0.08–4.35)
 No stroke (ref) 190 38 7 –
 Osteoporosis 28 2 2 0.32 (0.08–1.33)
 No osteoporosis (ref) 172 37 6 –
Total no. of CS-associated comorbiditiese
 0–1 (ref) 82 14 1 – –
 2–3 76 15 2 1.24 (0.62–2.48) 0.95 (0.44–2.02)
 ≥4 42 10 5 2.46 (1.20–5.05) 1.21 (0.51–2.85)
CS, Cushing’s syndrome; SES, socioeconomic status; ULN, upper limit of normal. Bold indicates statistical significance.
a
n = 190.
b
n = 115.
c
Maximal value of urinary-free cortisol divided by the upper limit of normal of the specific assay; n = 193.
d
n = 131.
e
CS-associated comorbidities include obesity, diabetes mellitus, hypertension, dyslipidemia, ischemic heart disease, and osteoporosis.

The 10-year cancer risk in patients with Cushing’s syndrome vs controls

In the 10 years following CS diagnosis, 81 (13.3%) patients with CS were diagnosed with cancer and 40 (6.6%) died without malignancy, compared with 206 (6.8%) and 152 (5.0%) controls, respectively. Similar to the previously reported risk for the entire follow-up period (Rudman et al. 2024), the overall 10-year risk of malignancy, calculated with death as a competing event, was twice as high in patients with CS than in matched controls (HR 2.01; 95% CI, 1.55–2.60) (Supplementary Fig. S1).
The mean age of cancer development in patients with CS was 62.3 ± 15.0 years, compared with 67.2 ± 12.3 years in controls (P < 0.01). The risk of cancer across different subgroups (patients with CS vs controls) is shown in Fig. 3 and Table 5. The number of cases for each type of cancer in patients with CS and controls is shown in Supplementary Table S2.
Figure 3

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Figure 3. The 10-year cancer risk in subgroups of the entire cohort (cases vs matched controls). Cases and controls were individually matched for age, sex, socioeconomic status, and body mass index.

Table 5. The 10-year cancer risk in subgroups of the entire cohort (cases vs matched controls).

Subgroup Cushing’s syndrome Individually matched controls HR 95% CI
Patients Incident cases of cancer Deaths Patients Incident cases of cancer Deaths
Age
 <60 444 44 10 2,200 84 30 2.67 1.85–3.85
 ≥60 165 37 30 818 122 122 1.55 1.08–2.24
Sex
 Females 396 42 23 1,975 117 89 1.83 1.29–2.61
 Males 213 39 17 1,043 89 63 2.25 1.54–3.28
Socioeconomic status
 Low 74 13 5 371 14 17 5.03 2.37–10.68
 Middle 349 42 21 1,719 116 90 1.83 1.28–2.60
 High 153 22 13 760 73 36 1.52 0.94–2.45
Smoking status
 Smoker/former smoker 133 21 12 544 46 34 1.84 1.09–3.10
 Non-smoker 198 25 12 910 66 48 1.79 1.13–2.83
Comorbidities
 Obesity 176 28 17 698 45 62 2.52 1.57–4.04
 No obesity 187 24 12 851 70 46 1.58 0.99–2.51
 Diabetes mellitus 140 21 14 396 45 75 1.35 0.80–2.25
 No diabetes mellitus 469 60 26 2,622 161 77 2.13 1.58–2.86
 Hypertension 343 59 34 957 106 126 1.59 1.16–2.19
 No hypertension 266 22 6 2,061 100 26 1.71 1.07–2.72
 Dyslipidemia 258 44 29 874 100 100 1.53 1.07–2.17
 No dyslipidemia 351 37 11 2,144 106 52 2.15 1.47–3.13
 Ischemic heart disease 70 19 11 191 30 49 1.89 1.06–3.35
 No ischemic heart disease 539 62 29 2,827 176 103 1.88 1.41–2.52
 Stroke 27 3 2 82 7 17 1.50 0.39–5.74
 No stroke 582 78 38 2,936 199 135 2.02 1.56–2.63
 Osteoporosis 75 9 9 187 23 32 0.98 0.45–2.10
 No osteoporosis 534 72 31 2,831 183 120 2.15 1.64–2.83
Cases and controls were individually matched for age, sex, socioeconomic status, and body mass index.
Among 487 cases and 2,411 controls with an attainable follow-up period of at least 10 years, 52 patients with CS and 184 controls died (from any cause) during the 10 years that followed CS diagnosis. Eight (15.4%) patients with CS died due to malignancy, compared with 12 (6.5%) patients in the control group (P = 0.04).
During the 10-year follow-up after CS diagnosis, 27 out of 251 patients with CD (10.8%) were diagnosed with malignancy, compared to 71 (5.7%) controls. Among 200 patients with adrenal CS, 39 (19.5%) were diagnosed with cancer, compared to 79 (8.0%) controls. The 10-year risk of overall malignancy was higher in patients with CD (HR 1.92, 95% CI 1.23–3.00) and in patients with adrenal CS (HR 2.63, 95% CI 1.79–3.87), compared to controls (Supplementary Fig. S1). The number of cases for each specific cancer type in patients with CD and adrenal CS and their individually matched controls is elaborated in Supplementary Table S2.

Sensitivity analyses

Due to possible bias in individuals with a genetic predisposition to cancer, and in patients at increased risk due to prior cancer treatment, we excluded all patients with prior history of cancer (50 cases and 117 controls). Following this exclusion, patients with CS still exhibited a higher 10-year cancer risk (HR 2.12, 95% CI 1.62–2.77).
Patients with adrenal cancer diagnosed before or within 5 years of CS diagnosis were excluded from the study. However, as it is possible that adrenal cancer was either not recorded properly or unrecognized at the time of CS diagnosis, we performed an analysis of the risk of malignancy excluding all adrenal cancer cases and found no change in the 10-year risk of overall cancer (HR 1.92, 95% CI 1.48–2.50).
The diagnosis of CS patients in the study included an ICD-10 coding of the diagnosis and laboratory evidence of hypercortisolism (and test date) in all cases. However, because in many cases the diagnostic and treatment process are lengthy, there is a possibility of information bias caused by patients included in the database who were diagnosed before the time period included in the study. Therefore, we performed a sensitivity analysis excluding the first year of the study, without any change in the 10-year risk of malignancy among CS patients (HR 1.98, 95% CI 1.51–2.58).

Discussion

Patients with CS have higher morbidity and mortality (Gadelha et al. 2023, Loughrey et al. 2024), and it has been recently established that CS is associated with an increased cancer risk (Rudman et al. 2024, Wu et al. 2025). However, predictors of a new cancer diagnosis have not been studied. In this nationwide retrospective study, the 10-year cancer risk in 609 patients with CS was twice as high as in 3,018 matched controls. Importantly, the 10-year risk was notably higher in patients with CD (HR 1.92, 95% CI 1.23–3.00) and in those with adrenal CS (HR 2.63, 95% CI 1.79–3.87), compared to controls. Furthermore, the risk of cancer was higher in patients with CS, regardless of age and sex. On average, cancer development in patients with CS occurred at an age that was 5 years younger than that of controls who developed cancer (62.3 ± 15.0 vs 67.2 ± 12.3 years, respectively).
Our study is the first to identify predictors of new cancer diagnosis in patients with CS. A multivariate regression model showed that age ≥60 years at CS diagnosis (HR 1.75, 95% CI 1.01–2.68), male gender (HR 1.67, 95% CI 1.04–3.05), and adrenal-origin CS (HR 1.66, 95% CI 1.01–2.73) were identified as independent predictors of cancer development within 10 years. In addition, we found that patients with ≥4 CS-associated comorbidities at the time of CS diagnosis had an increased risk of cancer (HR 1.76, 95% CI 1.03–3.02; adjusted for age and sex). Interestingly, diabetes and obesity were not associated with malignancy development in patients with CS. Importantly, we found no association between UFC levels at the time of CS diagnosis and cancer development rates.
CS most commonly affects young women, a population not inherently at high risk for malignancy, with the exception of breast cancer (National Cancer Institute, Surveillance, Epidemiology, and End Results (SEER) Program, December 2024. https://seer.cancer.gov/statfacts/html/aya.html). Our study demonstrates that young patients and female patients with CS are at an increased risk of cancer, as compared with matched controls from the general population. However, within the group of patients with CS, we found age and sex disparities in malignancy risk: men and elderly patients (over 60 years of age) showed a higher cancer risk (Table 2). Advanced age is a universal risk factor for cancer (Campisi 2013), and patients with CS are no exception. Previous studies found that male patients with CS are more susceptible to metabolic derangements than female patients (Liu et al. 2015, Broersen et al. 2019), a difference that likely results from gender disparity in response to glucocorticoid receptor activation (Bourke et al. 2012).
In addition, our study found that CS of adrenal origin is associated with a higher risk of malignancy, as compared with CD, after adjustment for age, sex, and significant CS-related comorbidities. Notably, patients with a history of adrenal cancer or ectopic CS were excluded. This finding is difficult to explain, since most studies have found that patients with CD present with higher UFC levels (Berr et al. 2015, Rubinstein et al. 2019, Schernthaner-Reiter et al. 2019) and a longer delay in diagnosis (Rubinstein et al. 2019, Schernthaner-Reiter et al. 2019) compared to those with adrenal CS. One potential explanation for this observation is that adrenal adenomas may be linked to a higher incidence of malignancy, as studies have shown that cancer mortality is increased with autonomic cortisol secretion, with malignancy being the most common cause of death in patients with mild autonomous cortisol secretion (Patrova et al. 2017, Deutschbein et al. 2022). Another conceivable explanation stems from previous research that reported higher rates of non-adrenal malignancies in patients with bilateral adrenal tumors and autonomous cortisol secretion (Kawate et al. 2014), suggesting a possible genetic predisposition in patients with adrenal adenoma that may contribute to the development of overall cancer.
Interestingly, in our study, patients with adrenal CS had a history of malignancy at a higher rate than their individually matched controls at the time of CS diagnosis (Table 1). In contrast, no difference in the rate of malignancy was found between patients with CD and controls. Although it is possible that a prior history of malignancy contributed to the higher risk of cancer observed in patients with adrenal CS, we did not find that a prior malignancy predicted subsequent cancer risk in this population when we analyzed our cohort of patients with adrenal CS (Table 4).
In this study, we found no association between the cumulative exposure to excess glucocorticoids (measured as UFC levels) and the development of malignancy (Fig. 2), but we did identify an association between the total number of CS-related comorbidities and cancer risk (adjusted for age and sex) (Table 2). Previous studies have similarly shown no correlation between the degree of hypercortisolism and the presence of CS-related comorbidities in patients with CS (Schernthaner-Reiter et al. 2019), including diabetes and obesity (Giordano et al. 2014, Bavaresco et al. 2024). Those findings support the hypothesis that individual sensitivity to glucocorticoids varies across tissues, such that UFC levels do not always correlate with symptom burden or comorbidities. Patients who are more sensitive to excess cortisol may experience a broader range of CS-associated comorbidities. Several genetic mutations and alterations have already been identified as causes of variation in cortisol sensitivity, including the genes encoding the human glucocorticoid receptor (NR3C1) (Chrousos et al. 1982, Riebold et al. 2015, Laulhé et al. 2024), the chaperone protein that regulates proper folding of the glucocorticoid receptor (HSP90) (Riebold et al. 2015), and the nuclear protein that modulates glucocorticoid receptor actions (NR2C2) (Zhang et al. 2016). In addition, mutations in glucocorticoid response elements (Vandevyver et al. 2013), variations in RNA-binding to the glucocorticoid receptor (Lammer et al. 2023), and epigenetic changes (Paes et al. 2024) may also play a role in inter-individual differences in response to cortisol excess.
In the univariate model we have performed, the total number of CS-related comorbidities was associated with cancer development, and the risk of malignancy increased with the number of comorbidities. However, after adjustment for age and sex, the HR was significantly moderated (mainly due to a strong correlation between age and comorbidity) but remained graded. We find this observation to support the concept that cancer is a CS-associated comorbidity, and suggest that patients with CS (especially older men with adrenal CS) suffering from multiple disease-related comorbidities require closer follow-up and a rigorous age-adjusted cancer screening, in accordance with guidelines for the general population.
We have previously reported an increased risk of genitourinary, thyroid, and gynecological cancers in patients with CS (Rudman et al. 2024). A Taiwanese national cohort study reported that liver (27.7%), kidney (16.7%), and lung (13.0%) cancers were the most common cancers among patients with CS (Wu et al. 2025). Despite the small absolute number of cases in each cancer type in this study, we found that the incidence in patients with CS was higher across all cancer groups, except for malignant melanoma. One might think that patients with CS underwent more imaging and laboratory tests, and therefore more cases of low-risk cancers (e.g., clinically insignificant prostate or thyroid cancer) were diagnosed in patients with CS than in controls. However, as we have shown, the overall 10-year malignancy-associated mortality was twice as high in patients with CS compared to controls, indicating that malignancies in this group were clinically significant.
Surgery for CS, especially for CD, improves some but not all comorbidities (Dekkers et al. 2013, Terzolo et al. 2014, Papakokkinou et al. 2020, Puglisi et al. 2024). Improvement of comorbidities with medical therapy have been noted in several clinical trials (Fleseriu et al. 2012, 2022, Petersenn et al. 2017); however, there are no prospectively collected data on the risk of cancer in these patients treated long-term. A retrospective study examining the course of several CS-related comorbidities showed that the risk of cancer in patients with CS who did not achieve remission was higher compared to the risk of cancer for patients in remission, yet these analyses did not reach statistical significance, partly due to the limited sample size (Papakokkinou et al. 2020).
In order to successfully identify predictors of cancer in patients with CS, this research of an uncommon outcome (malignancy) in patients with a rare disease (CS) required a long-term follow-up of a large, population-representative cohort, paired with well-matched control group. Matching for socioeconomic status is another strength of this study, as its impact on morbidity has recently been demonstrated in several studies (Ebbehoj et al. 2022, Claudel & Verma 2024).
However, this study has limitations. Missing data prevented us from determining the specific CS etiology in some patients. Correct classification of all cases with an indeterminate diagnosis (as either CD or adrenal CS) would have allowed us to improve the power of subgroup analysis of patients with CD and adrenal CS; however, we had very strict criteria for determining the etiology of CS. Not all data regarding socioeconomic status, BMI, and smoking status were available. In addition, the impact of hypopituitarism and overreplacement of glucocorticoids in patients with CD could not be assessed.
Since the control group was drawn from the general population, ascertainment bias cannot be ruled out, as it is likely that patients with CS underwent more physician-initiated imaging and laboratory tests, and therefore more cases of cancer could have been diagnosed in patients with CS than in controls. However, we consider this bias to be unlikely for most cases of aggressive cancer, especially given our long follow-up period.
While this nationwide study includes a relatively large sample size, we acknowledge that it is likely that our current sample size was not sufficiently powered to detect risk predictors that are only modestly associated with malignancy risk. The small sample size of subgroups and the low frequency of the outcome in these subgroups meant we were unable to predict malignancy in patients with CD or adrenal CS, nor could we estimate the risk of specific malignancies. Moreover, we could not account for certain factors that may influence the risk of malignancy, such as family history of malignancy, duration of exposure to elevated cortisol levels, and the presence of genetic syndromes that predispose individuals to both CS and certain malignancies (e.g., multiple endocrine neoplasia type 1) (Hernández-Ramírez & Stratakis 2018). Finally, the lack of systematic prospective assessment of comorbidities is an important limitation and should raise the standards for future clinical care of these patients and collecting data in new registries. While patients receiving treatment for a particular comorbidity were successfully identified, those without treatment were not systemically recorded, which may have led to underreporting. Such is the case with osteoporosis: only patients who received treatment or whose treating physician decided to send them for a bone density scan were diagnosed, while others without such evaluations were assumed to be free of osteoporosis.
In conclusion, this large nationwide retrospective matched-cohort study found that the risk of cancer was consistently higher in patients with CS, regardless of age or sex, and on average, cancer development occurred 5 years earlier in patients with CS than in controls. The multivariate regression model we developed identified age ≥60 years at CS diagnosis, male gender, and CS of adrenal-origin as independent predictors of malignancy during the 10 years following CS diagnosis. Importantly, we found no association between UFC levels at CS diagnosis and cancer development rates. However, patients with ≥4 CS-associated comorbidities at CS diagnosis were more likely to develop cancer, after adjusting for age and sex. Given previous studies that identified overall cancer as a CS-related comorbidity and as one of the leading causes of death in this population, the results of the current study will help identify patients at high risk of malignancy, emphasize the importance of timely screening tests, in accordance with guidelines for the general population, and highlight the need for larger international cohorts to establish specific cancer screening recommendations for patients with CS.

Supplementary materials

This is linked to the online version of the paper at https://doi.org/10.1530/ERC-25-0059.

Declaration of interest

Yaron Rudman, Genady Drozdinsky, Hiba Masr-Iraqi, Tzippy Shochat, and Shiri Kushnir do not have any financial or personal relationships with other people or organizations to disclose. Maria Fleseriu has been a PI with research funding to the university from Crinetics and Sparrow and has received occasional scientific fees for scientific consulting and advisory boards from Crinetics, Recordati, Sparrow and Xeris. Ilan Shimon has been an investigator for Xeris Biopharma and has received occasional scientific fees for scientific consulting and advisory boards from Medison, CTS pharma, and Neopharm. Amit Akirov has received occasional scientific fees for scientific consulting and advisory boards from Medison, CTS pharma, and Neopharm.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Data availability

The data that support the findings of this study are available from Clalit Health Services. Restrictions apply to the availability of these data, which were used under license for this study. Deidentified individual participant-level data sharing will be considered by the corresponding author of this study, with the permission of Clalit Health Services. All applicants will be asked to sign a data access agreement. All requests will be assessed as to whether data sharing is appropriate, based on the scientific rigor of the proposal.

References

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Once-Daily Treatment for Cushing Syndrome May Safely Restore Cortisol Rhythms

Posted on June 13, 2025 by MaryO

Once-daily evening osilodrostat improved cortisol rhythms, sleep, and quality of life in Cushing syndrome without compromising disease control or safety.

 

Once-daily osilodrostat administered in the evening is safe, effective, and restores circadian cortisol rhythms in patients with biochemically controlled Cushing syndrome (CS), according to results published in the Journal of Clinical Endocrinology & Metabolism.

“By achieving lower evening cortisol exposures, this regimen improves sleep quality and overall quality of life. Over the long term, these changes may translate into potential cardiovascular benefits,” wrote corresponding author Andrea M. Isidori, MD, PhD, and colleagues.

A loss of circadian cortisol rhythm is a hallmark of CS and contributes to systemic adverse effects, the authors explained. The prospective pilot study assessed chronotherapy with once-daily osilodrostat and its effect on circadian cortisol profiles in 16 patients with well-controlled CS who transitioned from twice-daily osilodrostat therapy.

Researchers used ultra-high performance liquid chromatography–tandem mass spectrometry on saliva, serum, and urine samples to analyze circadian steroid hormones at baseline, when patients were taking twice-daily osilodrostat, and 60 to 90 days after they switched to a single equivalent daily dose at 19:00 ±1 hour. Investigators also assessed cardiometabolic markers, quality of life, sleep function, and safety outcomes.

At baseline, most patients had mild CS; the mean osilodrostat dose was 4.2 ±1.3 mg.

“Compared to the standard twice-daily regimen, once-daily dosing resulted in significantly reduced late afternoon to early morning cortisol exposure…without altering morning peak levels, reflecting an improved alignment with the natural circadian rhythm of glucocorticoids,” the researchers reported.

With the transition to dosing at 19:00 ±1 hour, salivary cortisol exposure decreased 6.1 ng/mL/h during the afternoon to early morning period, according to the study. Additionally, scores on the CushingQoL questionnaire increased 4.2 points, while scores on the Pittsburgh Sleep Quality Index decreased 1.7 points. The serum steroid precursors 11-deoxycorticosterone and 11-deoxycortisol also decreased.

“Eight patients advancing dosing to 16:00 ±1 hour showed comparable reductions,” the authors wrote, “with phase shifts in acrophase and nadir.”

No patients experienced adrenal insufficiency, liver toxicity, electrocardiogram abnormalities, or loss of disease control with the transition. Moreover, blood pressure, lipid profile, and glucose metabolism trended toward improvement.

“These results lay the groundwork for future large-scale, long-term studies to fully explore the potential of chronotherapy approach in the management of CS,” the researchers wrote.

https://www.physiciansweekly.com/once-daily-treatment-for-cushing-syndrome-may-safely-restore-cortisol-rhythms/

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Osilodrostat Treatment of Cushing Syndrome in Real-World Clinical Practice

Posted on May 23, 2025 by MaryO
Abstract
Context
In clinical trials, osilodrostat (11β-hydroxylase inhibitor) effectively reduced cortisol levels in patients with endogenous Cushing syndrome (CS).
Objectives
A real-world study (ILLUSTRATE) was conducted evaluating osilodrostat use in patients with various etiologies of CS in the United States.
Methods
A retrospective chart-review study was conducted of adults with CS treated with osilodrostat between May 1, 2020, and October 29, 2021.
Results
A total of 42 patients (Cushing disease, n = 34; CS due to adrenal adenoma, n = 5; ectopic adrenocorticotropin syndrome [EAS], n = 3) were included. Starting doses were 2 mg twice daily in 27/42 patients (64.3%), maintenance doses were 2 mg twice daily in 6 of 9 patients (66.7%) attaining them. During osilodrostat treatment, urinary free cortisol (UFC) decreased below the upper limit of normal (ULN) in 14 of 20 patients (70.0%) with pretreatment UFC greater than the ULN. Osilodrostat response was observed across a range of doses (2-20 mg/day). In Cushing disease, median UFC and late-night salivary cortisol decreased from 3.03 and 2.39 × ULN, respectively, to 0.71 and 1.13 × ULN at last assessment in those with available data (n = 17 and 8, respectively). UFC decreased in all patients with adrenal CS or EAS with available data (n = 2 each). There were no unexpected safety signals; the most common adverse events (incidence ≥20%) were fatigue, nausea, and lower-extremity edema. Glucocorticoid withdrawal syndrome and/or adrenal insufficiency were reported in 12 of 42 patients (28.6%) after osilodrostat initiation, resulting in treatment discontinuation in 4.
Conclusion
In routine practice with dosing individualized according to clinical condition, response, and tolerability, osilodrostat was effective and well tolerated regardless of CS etiology and severity.
Cushing disease, ectopic adrenocorticotropin syndrome, adrenal Cushing syndrome, osilodrostat, retrospective, real world
Subject Pituitary and Neuroendocrinology
Issue Section: Clinical Research Article
Endogenous neoplastic Cushing syndrome (CS) is a serious endocrine condition characterized by excessive endogenous cortisol secretion [1, 2]. Untreated, hypercortisolism has serious cardiovascular, metabolic, neuropsychiatric, and infectious consequences, which negatively affect patients’ quality of life [2-4]. The risk of mortality is higher in patients with CS than in the general population, mainly because of greater mortality from cardiovascular and infectious diseases [2-5]. More recently, it has been shown that cancer risk is increased in population cohorts with CS [6, 7].
Most cases of CS are caused by excess secretion of adrenocorticotropin (ACTH) from a pituitary adenoma (Cushing disease), which results in excess cortisol release from the adrenal glands [2, 4]. However, some patients may present with ectopic ACTH syndrome (EAS; also referred synonymously as ectopic CS) or ACTH-independent cortisol excess from adrenal adenomas, adrenocortical cancers, or bilateral nodular adrenal hyperplasia (adrenal CS) [2, 4].
Osilodrostat is a potent oral inhibitor of 11β-hydroxylase, the enzyme that catalyzes the final step of cortisol synthesis in the adrenal cortex [8]. In phase 3 trials in patients with Cushing disease, osilodrostat was associated with a rapid and sustained reduction in cortisol levels, as well as improvements in cardiovascular and metabolic parameters, the physical manifestations of Cushing disease, and patients’ quality of life [9-13]. The clinical development program for osilodrostat also included a phase 2 study in patients with EAS or adrenal CS, which demonstrated that osilodrostat can lower cortisol regardless of the etiology of CS [14]. Based on these data, osilodrostat was licensed for use in adults with Cushing disease for whom pituitary surgery is not an option or has not been curative (United States) [15] and in adults/patients with endogenous CS (Europe [16]/Japan [17]).
Although prospective clinical trials are essential for demonstrating the efficacy and safety of drug therapies, they entail enrollment of selected patient populations and a tightly controlled research setting [18]. Real-world observational studies, in which the drug is used according to physicians’ clinical practice, provide complementary and helpful information in this context. Previous real-world studies conducted in patients with CS in Europe have shown that osilodrostat reduces cortisol levels and improves comorbidities, with no unexpected safety signals [19-22]. The present study, osIlodrostat reaL-worLd Utilization Study To Retrospectively Assess paTient Experience (ILLUSTRATE), was conducted in multiple clinical practices in the United States to evaluate the dosing, effectiveness, and safety of osilodrostat in patients with CS, irrespective of its etiology.
Materials and Methods
ILLUSTRATE was a retrospective chart-review study of patients in the United States treated with osilodrostat between May 1, 2020, and October 29, 2021. The index date for each patient was defined as the date of the first osilodrostat prescription (between May 1, 2020, and October 29, 2021). Preprescription data were collected from the 12 months before each patient’s index date to provide baseline data for that patient.
Patients were eligible for inclusion if aged 18 years or older, with a diagnosis of endogenous neoplastic CS (due to a pituitary adenoma, adrenal adenoma, or ectopic tumor) and a documented prescription for osilodrostat on or after May 1, 2020. As osilodrostat was approved for Cushing disease in the United States earlier the same year (March 6, 2020) [23], the start date for ILLUSTRATE was selected to avoid inclusion of patients treated with osilodrostat in clinical trials. The study was approved by a central independent review board (Western Institutional Review Board). As the study employed secondary data collection of anonymized patient data, a waiver of consent was granted under the privacy rule of HIPPA (the Health Insurance Portability and Accountability Act).
If available, the following data were extracted from patients’ medical records into an electronic case report form (eCRF): demographic details (age, sex, race, ethnicity); clinical history (date of CS diagnosis, signs and symptoms, prior surgery and/or radiotherapy); duration of disease prior to osilodrostat prescription; other therapies (cortisol-lowering medications, concomitant steroid use or replacement, antihypertensive and antidiabetic medications); laboratory data (urinary free cortisol [UFC], late-night salivary cortisol [LNSC], morning serum cortisol, serum potassium, testosterone [female patients only]); osilodrostat use (starting dose, uptitration, downtitration, duration of treatment); and adverse events (AEs). AEs were selected from a dropdown list that included the following: hypotension, hyperkalemia, hypokalemia, prolonged QT interval on electrocardiogram, lower-extremity edema, dizziness, rash, constipation, fatigue, alopecia, headache, nausea, vomiting, pituitary tumor size, hypertension, hirsutism, acne, irregular menstruation, brain fog or other cognitive changes, insomnia, striae, muscle weakness, depression, anxiety, other emotional changes, arthralgia/myalgia, and sleep changes.
The following variables were derived from the information recorded in the eCRF: time to maintenance dose (maintenance dose was defined as the first dose that was not modified between two consecutive visits, which could include the baseline visit); titration interval (time between osilodrostat dose changes; if patients had multiple dose changes, the average was reported); and proportion of patients on osilodrostat 6 months after the index prescription. In patients who had dose changes after reaching the maintenance dose, the time between these dose changes was included in the calculation of average titration interval.
Investigator-reported events of glucocorticoid withdrawal syndrome (GWS) and adrenal insufficiency (AI) were evaluated by two of the authors (J.L.S.-S. and K.C.D.) and adjudicated according to symptoms and the level of morning serum cortisol, where available. If the symptoms were consistent with GWS and serum cortisol at the time of the event was greater than 10 µg/dL (>276 nmol/L), these cases were classified as GWS. If the symptoms were more severe or cortisol levels were less than or equal to 10 µg/dL (≤276 nmol/L), AI could not be ruled out, and these cases were classified as such. If the investigator recorded GWS and AI in the same patient at the same visit, they were classified as a single event.
Descriptive statistics were used for all variables based on the number of patients with data available for each variable. Laboratory measures were reported as n times the upper limit of normal (ULN). Independent quality assessments were conducted to check content, inconsistencies, and missing fields in the eCRF.
Results
Overall, 42 patients were included in the study: 34 patients with Cushing disease, 5 patients with adrenal CS as a result of adrenal adenoma, and 3 patients with EAS. Two patients with Cushing disease had only a single clinical encounter and were included in the baseline results only. Four patients (9.5%), all with Cushing disease, discontinued osilodrostat during follow-up; in all cases, this was because of GWS or AI.
Baseline Characteristics
Baseline demographics and clinical characteristics are summarized in Table 1. Mean age was 43.7 years, and most patients (76.2%) were female. Mean disease duration before osilodrostat prescription was 57.3 months, and most patients had previously undergone surgery (81.0%) and/or received one or more medical therapies (61.9%). In the subgroup of patients with adrenal CS (n = 5), 2 patients had undergone surgery and 2 patients had expressed a preference not to undergo surgery; in the final patient, information on previous surgery was not recorded in the eCRF. In the overall study population, median UFC, LNSC, and morning serum cortisol levels were 2.54, 2.39, and 1.16 × ULN, respectively. Twelve and 5 patients, respectively, had morning serum cortisol levels and UFC less than the ULN at baseline; of these, 6 (50.0%) and 3 (60.0%), respectively, had received previous medical therapy.
Table 1.Open in new tabBaseline demographic and clinical characteristics (overall and by etiology)
  All patients
(n = 42) Cushing disease (n = 34) Adrenal CS (n = 5)a EAS
(n = 3)b
Mean age (SD), y 43.7 (15.0) 40.8 (13.9) 49.2 (14.0) 66.7 (3.5)
Sex, n (%)
 Female 32 (76.2) 27 (79.4) 2 (40.0) 3 (100)
 Male 10 (23.8) 7 (20.6) 3 (60.0) 0
Race, n (%)
 White 22 (52.4) 17 (50.0) 4 (80.0) 1 (33.3)
 Black or African American 10 (23.8) 8 (23.5) 1 (20.0) 1 (33.3)
 Asian 2 (4.8) 1 (2.9) 0 1 (33.3)
 Multiracial 1 (2.4) 1 (2.9) 0 0
 Unknown 7 (16.7) 7 (20.6) 0 0
Ethnicity, n (%)
 Hispanic, Latino, or Spanish origin
  Yes 8 (19.0) 8 (23.5) 0 0
  No 28 (66.7) 20 (58.8) 5 (100) 3 (100)
 Unknown 6 (14.3) 6 (17.6) 0 0
Mean age at CS diagnosis (SD), y 37.7 (14.8) 34.9 (12.7) 40.0 (14.8) 66.3 (3.1)
Mean duration of disease prior to osilodrostat prescription (SD), mo 57.3 (82.0) 64.8 (86.7) 30.4 (26.6) 1.2 (0.3)
Previous pituitary or adrenal surgery for CS, n (%) 34 (81.0) 32 (94.1) 2 (40.0) 0
Radiotherapy for CS in last 5 y, n (%) 10 (23.8) 10 (29.4) 0 0
Previous medical therapy for CS,c n (%) 26 (61.9) 21 (61.8) 3 (60.0) 2 (66.7)
 Pasireotide 3 (7.1) 3 (8.8) 0 0
 Cabergoline 7 (16.7) 7 (20.6) 0 0
 Ketoconazole 10 (23.8) 8 (23.5) 0 2 (66.7)
 Metyrapone 2 (4.8) 1 (2.9) 1 (20.0) 0
 Mitotane 1 (2.4) 0 1 (20.0) 0
 Mifepristone 6 (14.3) 5 (14.7) 1 (20.0) 0
UFC,d × ULN n = 32 n = 25 n = 4 n = 3
 Mean (SD) 7.67 (14.84) 3.14 (2.98) 13.93 (15.25) 37.03 (36.46)
 Median (min-max) 2.54
(0.09-75.20) 2.28
(0.09-11.17) 13.77
(0.42-27.76) 33.33
(2.57-75.20)
LNSC,d × ULN n = 18 n = 16 n = 1 n = 1
 Mean (SD) 4.80 (8.18) 5.25 (8.59) 0.55 1.82
 Median (min-max) 2.39
(0.44-36.33) 2.78
(0.44-36.33) 0.55 1.82
Morning serum cortisol,d × ULN n = 32 n = 24 n = 5 n = 3
 Mean (SD) 1.23 (0.77) 1.13 (0.42) 1.08 (0.97) 2.33 (1.78)
 Median (min-max) 1.16
(0.19-4.38) 1.18
(0.19-1.88) 0.83
(0.39-2.76) 1.43
(1.17-4.38)
Potassium levels,d mmol/L n = 41 n = 33 n = 5 n = 3
 Mean (SD) 4.1 (0.6) 4.3 (0.5) 3.7 (0.5) 3.6 (0.9)
 Median (min-max) 4.0
(2.6-5.6) 4.2
(3.6-5.6) 3.4
(3.3-4.5) 3.7
(2.6-4.4)
Potassium levels <LLN,e n (%) n = 37
5 (13.5) n = 30
1 (3.3) n = 5
3 (60.0) n = 2
1 (50.0)
Testosterone levels,f × ULN n = 11 n = 9 n = 1 n = 1
 Mean (SD) 1.00 (1.48) 0.96 (1.56) 0.07 2.29
 Median (min-max) 0.36
(0.03-5.02) 0.36
(0.03-5.02) 0.07 2.29
ULNs varied between study centers, ranging from 32 to 64 µg/24 hours (88.3-176.6 nmol/L) for UFC, 0.01 to 0.112 µg/dL (0.28-3.09 nmol/L) for LNSC, 18.4 to 25 µg/dL (507.8-690.0 nmol/L) for morning serum cortisol, and 41 to 100 ng/dL (1.42-3.47 nmol/L) for testosterone (female patients).
Abbreviations: CS, Cushing syndrome; EAS, ectopic adrenocorticotropin syndrome; LLN, lower limit of normal; max, maximum; min, minimum; ULN, upper limit of normal.
aAll patients had adrenal adenoma.
bIn 1 patient, the primary tumor could not be located; in the other 2 patients, the location of the ectopic tumor was not recorded.
cReasons for stopping these therapies and switching to osilodrostat were not collected as part of this study.
dNot all patients had values recorded at baseline (see n numbers in each column).
eLLN was not available for all patients with available potassium data.
fFemale patients only.
Osilodrostat Dosing
Information on osilodrostat dosing is summarized in Table 2. The most common starting dose of osilodrostat was 4 mg/day in 28 of 47 patients (66.7%; Fig. 1A), comprising 2 mg twice daily in 27 patients and 4 mg once daily in 1 patient. Some patients with Cushing disease and adrenal CS were initiated on lower doses (1 mg once daily [n = 2] or twice daily [n = 10], or 2 mg once daily [n = 1]).
A, Total osilodrostat daily starting dose* in all patients (n = 42) and B, dose changes postinitiation (by etiology) in patients with at least one clinical encounter after initiating osilodrostat (n = 40). *Osilodrostat starting doses were given twice daily in all except 3 patients with Cushing disease (initiated on 1 mg once daily, 2 mg once daily, and 4 mg once daily) and 1 patient with adrenal CS (initiated on 1 mg once daily).
Figure 1.A, Total osilodrostat daily starting dose* in all patients (n = 42) and B, dose changes postinitiation (by etiology) in patients with at least one clinical encounter after initiating osilodrostat (n = 40). *Osilodrostat starting doses were given twice daily in all except 3 patients with Cushing disease (initiated on 1 mg once daily, 2 mg once daily, and 4 mg once daily) and 1 patient with adrenal CS (initiated on 1 mg once daily).
Open in new tabDownload slide
Abbreviations: CS, Cushing syndrome; EAS, ectopic adrenocorticotropin syndrome.
Table 2.Open in new tabOsilodrostat treatment (overall and by etiology)
  All patients
(n = 42) Cushing disease (n = 34) Adrenal CS (n = 5) EAS
(n = 3)
No. of patients with initial dose information 42 34 5 3
Starting total daily dose, mg
 Mean (SD) 3.4 (1.1) 3.4 (1.1) 3.0 (1.4) 4.0 (0.0)
 Median (min-max) 4 (1-6) 4 (1-6) 4 (1-4) 4 (4-4)
Starting dose schedule, n (%)
 Twice daily 38 (90.5) 31 (91.2) 4 (80.0) 3 (100)
 Once daily 4 (9.5) 3 (8.8) 1 (20.0) 0
Starting dose and schedule, n (%)
 1 mg once daily 2 (4.8) 1 (2.9) 1 (20.0) 0
 1 mg twice daily 10 (23.8) 9 (26.5) 1 (20.0) 0
 2 mg once daily 1 (2.4) 1 (2.9) 0 0
 2 mg twice daily 27 (64.3) 21 (61.8) 3 (60.0) 3 (100)
 3 mg twice daily 1 (2.4) 1 (2.9) 0 0
 4 mg once daily 1 (2.4) 1 (2.9) 0 0
No. of patients with postinitiation clinical encounters 40 32 5 3
Patients who reached maintenance dose by last interaction, n (%) 9 (22.5) 7 (21.9) 1 (20.0) 1 (33.3)
Time to maintenance dose or end of follow-up, wk
 Mean (SD) 34.7 (18.0) 36.7 (19.1) 23.0 (11.7) 33.6 (3.3)
 Median (min-max) 33 (0.7-78.1) 37 (0.7-78.1) 17 (13.0-37.6) 32 (31.3-37.4)
Maintenance dose,a n (%)
 2 mg twice daily 6 (66.7) 4 (57.1) 1 (100) 1 (100)
 4 mg twice daily 2 (22.2) 2 (28.6) 0 0
 10 mg twice daily 1 (11.1) 1 (14.3) 0 0
Patients with dose change, n (%) 25 (62.5) 21 (65.6) 2 (40.0) 2 (66.7)
Titration period in patients with dose change, wk
 Mean (SD) 13.8 (12.4) 14.8 (13.2) 4.9 (3.2) 13.0 (0.0)
 Median (min-max) 11 (2.6-57.0) 11 (4.6-57.0) 5 (2.6-7.1) 13 (13.0-13.0)
Osilodrostat treatment interruption,b n (%) 9 (22.5) 7 (21.9) 1 (20.0) 1 (33.3)
Duration of exposure up to treatment interruption or study end, wk
 Mean (SD) 35.2 (22.0) 36.5 (22.5) 26.8 (26.3) 35.8 (4.5)
 Median (min-max) 35 (0.7-78.1) 38 (0.7-78.1) 14 (4.0-69.7) 37 (30.7-39.3)
Duration of treatment up to study end,c wk
 Mean (SD) 37.0 (20.9) 38.2 (21.5) 29.4 (24.0) 36.0 (4.2)
 Median (min-max) 37 (0.7-78.1) 40 (0.7-78.1) 17 (13.0-69.7) 37 (31.3-39.3)
Patients on osilodrostat for ≥6 mo prior to study end,c,d n (%) 28 (96.6) 23 (95.8) 2 (100) 3 (100)
Duration of therapy prior to study endc in patients with ≥6 mo persistence, wk
 Mean (SD) 47.3 (15.2) 48.5 (15.3) 51.6 (25.6) 36.0 (4.2)
 Median (min-max) 44.9 (28.1-78.1) 45.7 (28.1-78.1) 51.7 (33.6-69.7) 37.4 (31.3-39.3)
Abbreviations: CS, Cushing syndrome; EAS, ectopic adrenocorticotropin syndrome.
aIn those who reached a maintenance dose (defined as a dose that was not modified between 2 consecutive visits) by last interaction.
bDefined as a break in osilodrostat treatment for 30 days or longer.
cOr treatment discontinuation (n = 4).
dIn 29 patients with 6 months’ follow-up (n = 24, 2, and 3 for Cushing disease, adrenal CS, and EAS, respectively).
Mean titration interval was 13.8 weeks for all patients (4.9 weeks in patients with adrenal CS, 13.0 weeks in patients with EAS, and 14.8 weeks in patients with Cushing disease). Nine patients (22.5%; 7 patients with Cushing disease and 1 patient each with adrenal CS and EAS) achieved a maintenance dose of osilodrostat (defined as no dose modification between 2 consecutive visits) after a mean (SD) of 34.7 (18.0) weeks. The most common maintenance dose was 2 mg twice daily (see Table 2).
Overall, 25 of 40 patients (62.5%) had their osilodrostat dose adjusted during the study. In most of these cases (n = 20), the dose was increased; 2 patients had a dose decrease and 3 patients had doses both increased and decreased (Fig. 1B). In those who had an osilodrostat dose increase only, most (14/20; 70.0%) had only a single dose increase; in the remaining patients, 4 (20.0%) had 2 dose increases and 2 (10.0%) had 4 dose increases. In those who had dose adjustments, there was no observable pattern between starting and final osilodrostat doses (Table 3). Overall, 9 of 40 patients (22.5%) had osilodrostat treatment temporarily interrupted, which occurred in the first 3 months of treatment in 5 patients, between treatment months 3 and 6 in 2 patients, and after 6 months in 2 patients. Reasons for temporary interruption were hypocortisolism-related AEs, patient undergoing surgery, lack of availability of osilodrostat in the hospital setting, and insurance noncoverage.
Table 3.Open in new tabShift table showing starting and final doses for those patients who had dose adjustments during the study period (n = 26)
Starting dosea Final dose, No. of patients
  1 mg/d 2 mg/d 4 mg/d 5 mg/d 6 mg/d 8 mg/d 10 mg/d 14 mg/d 20 mg/d
Cushing diseaseb
1 mg/d (n = 1)1
2 mg/d (n = 10)811
4 mg/d (n = 11) 1 1 1 4 2 2
Adrenal CS
1 mg/d (n = 1)1
4 mg/d (n = 1)1
EAS
4 mg/d (n = 2)11
Some patients had the same starting and final doses as their doses were increased then decreased during the study.
Abbreviations: CS, Cushing syndrome; EAS, ectopic adrenocorticotropin syndrome.
aOsilodrostat starting doses were given twice daily in all except 3 patients with Cushing disease (initiated on 1 mg once daily, 2 mg once daily, and 4 mg once daily) and 1 patient with adrenal CS (initiated on 1 mg once daily).
bOne patient had only their osilodrostat starting dose reported.
Mean (SD) duration of follow-up was 37.1 (20.5) weeks, and mean (SD) duration of osilodrostat treatment was 37.0 (20.9) weeks; almost all patients with postinitiation clinical encounters (96.6%) received treatment for 6 months or longer (see Table 2).
Changes in Cortisol Levels During Osilodrostat Treatment
In patients with available assessments, median values for all cortisol parameters decreased during osilodrostat treatment, regardless of CS etiology (Table 4). In the subgroup of patients with Cushing disease, median UFC and morning serum cortisol levels were less than the ULN at the last assessment (0.71 and 0.68 × ULN, respectively), while median LNSC levels were slightly higher than the ULN (1.13 × ULN). In patients with UFC, LNSC, and morning serum cortisol levels greater than the ULN at baseline, 12 of 16, 3 of 8, and 8 of 15, respectively, had levels less than the ULN during osilodrostat treatment (Fig. 2); the final osilodrostat doses in these patients ranged from 1 to 20 mg/day. Neither of the patients who had a final dose of 20 mg/day were receiving concomitant glucocorticoids (ie, they were not being treated with a “block-and-replace” approach). In those with UFC and morning serum cortisol less than the ULN at baseline, levels remained less than the ULN in 1 of 1 and 7 of 8 patients, respectively.
Changes in A, UFC; B, LNSC; and C, morning serum cortisol in individual patients. *In patient 23, the first and last doses recorded were both 2 mg twice daily; during the follow-up period, 2 changes in dose were recorded the same day on 2 separate occasions.
Figure 2.Changes in A, UFC; B, LNSC; and C, morning serum cortisol in individual patients. *In patient 23, the first and last doses recorded were both 2 mg twice daily; during the follow-up period, 2 changes in dose were recorded the same day on 2 separate occasions.
Open in new tabDownload slide
Abbreviations: CS, Cushing syndrome; EAS, ectopic adrenocorticotropin syndrome; LNSC, late-night salivary cortisol; NA, not available; UFC, urinary free cortisol; ULN, upper limit of normal.
Table 4.Open in new tabMedian (minimum-maximum) urinary free cortisol, late-night salivary cortisol, and morning serum cortisol levels (overall and by etiology)
  All patients Cushing disease Adrenal CS EAS
UFC, × ULN n = 21 n = 17 n = 2 n = 2
 Baseline 3.73 (0.09-75.20) 3.03 (0.09-11.17) 14.40 (1.03-27.76) 54.27 (33.33-75.20)
 Last assessment 0.71 (0.02-11.82) 0.71 (0.07-4.19) 6.18 (0.53-11.82) 1.44 (0.02-2.86)
LNSC, × ULN n = 8 n = 8 n = 0 n = 0
 Baseline2.39 (1.44-5.89)2.39 (1.44-5.89)
 Last assessment1.13 (0.44-4.44)1.13 (0.44-4.44)
Morning serum cortisol, × ULN n = 30 n = 23 n = 5 n = 2
 Baseline 1.15 (0.19-4.38) 1.16 (0.19-1.88) 0.83 (0.39-2.76) 2.91 (1.43-4.38)
 Last assessment 0.67 (0.02-2.76) 0.68 (0.19-1.87) 0.61 (0.05-2.76) 0.47 (0.02-0.93)
Results are based on patients with both baseline and postosilodrostat prescription data available.
Abbreviations: CS, Cushing syndrome; EAS, ectopic adrenocorticotropin syndrome; LNSC, late-night salivary cortisol; UFC, urinary free cortisol; ULN, upper limit of normal.
The effect of osilodrostat on UFC and morning serum cortisol levels in individual patients with adrenal CS or EAS and available data are shown in Fig. 2A and 2C, respectively. In patients with adrenal CS, UFC levels were reduced in the 2 patients with data available, and morning serum cortisol levels were reduced in 2 of 5 patients with data available. In patients with EAS, there were substantial reductions both in UFC and morning serum cortisol (n = 2).
The time course of cortisol changes and corresponding osilodrostat doses in 2 patients with Cushing disease and 2 patients with EAS are illustrated in Fig. 3.
Individual osilodrostat dosing, UFC, and serum cortisol levels during the study period in illustrative patients. ULN for UFC was 50 μg/24 hours for patients 11, 4, and 1 and 42 μg/24 hours for patient 2. *ULN for serum cortisol was not provided for this patient, so it was estimated to be approximately 18 µg/dL.
Figure 3.Individual osilodrostat dosing, UFC, and serum cortisol levels during the study period in illustrative patients. ULN for UFC was 50 μg/24 hours for patients 11, 4, and 1 and 42 μg/24 hours for patient 2. *ULN for serum cortisol was not provided for this patient, so it was estimated to be approximately 18 µg/dL.
Open in new tabDownload slide
Abbreviations: BID, twice daily; EAS, ectopic adrenocorticotropin syndrome; UFC, urinary free cortisol; ULN, upper limit of normal.
Safety and Tolerability
Overall, 29 patients (69.0%) had an AE reported. The most common AEs (incidence ≥20%) were fatigue, nausea, and lower-extremity edema (Table 5).
Table 5.Open in new tabAdverse events reported during osilodrostat treatment (overall patient population)a
AE, n (%) n = 42a
Any AE 29 (69.0)
Fatigue 23 (54.8)
Nausea 12 (28.6)
Lower-extremity edema 11 (26.2)
Headache 6 (14.3)
Dizziness 6 (14.3)
Hypokalemia 6 (14.3)
Alopecia 4 (9.5)
Vomiting 3 (7.1)
Hypotension 2 (4.8)
Hyperkalemia 1 (2.4)
Prolonged QT interval on electrocardiogram 1 (2.4)
Abbreviation: AE, adverse event.
aIncludes 2 patients who had no postinitiation interaction before study end.
According to the events reported by the investigators, 13 patients had GWS (n = 3), AI (n = 3), or both (n = 7). Of these, osilodrostat treatment was interrupted in 3 patients, the dose was decreased in 2 patients, and there was no change in dose in 4 patients; in the remaining 4 patients, osilodrostat treatment was discontinued. Glucocorticoid use was reported in 4 patients overall; this included 2 patients in whom AI and/or GWS were reported. The first patient reported to have AI and GWS by the investigator was prescribed hydrocortisone 5 mg twice daily for 2 weeks. The second patient (AI) was also prescribed hydrocortisone at a dose of 20 mg/day (duration not specified).
On author adjudication, using the criteria outlined in “Materials and Methods,” 1 case of AI was reclassified as GWS and 5 cases reported to be both GWS and AI by the investigator were reclassified as AI only. Another case of AI was excluded as the symptoms of AI had started before initiation of osilodrostat; this patient had been treated with pasireotide in the 5 months before starting osilodrostat. Thus, the number of author-adjudicated cases during osilodrostat treatment was 12: 4 for GWS, 6 for AI, and 2 for both (ie, patients experiencing ≥1 distinct episode of GWS and AI).
To illustrate different presentations and management practices of AI and GWS, we describe details regarding individual cases. In 1 patient with GWS, symptoms were dizziness, nausea, and fatigue, with serum cortisol levels remaining above 10 µg/dL (276 nmol/L). The symptoms occurred early in the course of treatment and were managed by reducing the osilodrostat dose. In another patient with GWS, symptoms occurred after prolonged treatment, and osilodrostat was discontinued. In 2 patients with AI, symptoms were also dizziness, nausea, and fatigue, but serum cortisol levels were less than or equal to 10 µg/dL (≤276 nmol/L). In the first patient, osilodrostat was maintained at the same dose; symptoms resolved and cortisol levels increased slightly, to above 10 µg/dL (276 nmol/L). Treatment was interrupted in the second patient, but further information on the symptoms and cortisol levels were unavailable.
In patients with available data at baseline and last assessment (n = 38), median (minimum-maximum) serum potassium levels were 4.0 (2.6-5.6) and 4.3 (3.7-5.5) mmol/L, respectively. In those who were normokalemic at baseline (n = 30), 2 patients had potassium levels less than the lower limit of normal during osilodrostat treatment; in those who were hypokalemic at baseline (n = 4), 3 patients had potassium levels reverting to normal during treatment. In female patients with available data at baseline and last assessment (n = 4), mean testosterone levels were 1.48 × ULN at baseline and 1.52 × ULN at the last posttreatment assessment.
Discussion
This study evaluated the real-world use of osilodrostat in patients in the United States with CS during the period shortly after osilodrostat was approved by the US Food and Drug Administration for the treatment of adults with Cushing disease for whom pituitary surgery is not an option or has not been curative. The results highlight the importance of selecting a starting dose and titration regimen according to each patient’s circumstances, clinical response, and tolerability, as the dose required to normalize cortisol levels varies between patients and does not appear to depend on baseline levels. Most of the patients in the study (n = 34/42 [81.0%]) had Cushing disease, as expected. In this subgroup, most patients (n = 21/34 [61.8%]) were initiated on the approved starting dose of osilodrostat (2 mg twice daily), but many (n = 11/34 [32.4%]) were started on lower doses. All patients with Cushing disease who were initiated on doses lower than 2 mg twice daily required a dose increase during the study. A dose of 2 mg twice daily was also the most common maintenance dose in those with Cushing disease who reached a maintenance dose: a total of 57.1% remained on 2 mg twice daily, while 28.6% and 14.3% were uptitrated to 4 mg twice daily and 10 mg twice daily, respectively. In phase 3 clinical trials of osilodrostat in patients with Cushing disease (LINC 3 and LINC 4), median (interquartile range) average doses at the end of the extension periods were 7.4 (3.5-13.6) mg/day in LINC 3 and 4.6 (3.7-9.2) mg/day in LINC 4 [9, 11]. In the present study, most patients whose dose was uptitrated required only one dose increase. Mean duration of the titration period in patients with Cushing disease, defined as the period between any osilodrostat dose changes, was 14.8 weeks. In LINC 3 and LINC 4, doses were increased according to UFC levels in the first 12 weeks, after which dose adjustments were permitted during the remainder of the 48-week core period based on efficacy and tolerability [10, 12]. In both trials, starting and final osilodrostat doses were lower in Asian patients with Cushing disease than in non-Asian patients, regardless of body mass index, likely because of differences in bioavailability [24].
In the subgroup of patients with Cushing disease, most of those with UFC and morning serum cortisol levels greater than the ULN at baseline had their levels reduced to normal during treatment (12/16 and 8/15, respectively). Some patients had UFC and morning serum cortisol levels less than the ULN when osilodrostat was initiated, presumably reflecting a switch to osilodrostat from another medical therapy (eg, because of tolerability issues). More than 60% of patients had received one or more medical therapies before starting osilodrostat, but the reasons for stopping these therapies were not collected as part of the study. In patients with normal levels at study baseline, levels remained less than the ULN in 1 of 1 patient for UFC and 6 of 8 patients for morning serum cortisol. Median levels of UFC and morning serum cortisol in the subgroup of patients with Cushing disease decreased to within the normal range during osilodrostat treatment. These real-world results are consistent with those from the 48-week core phases of LINC 3 and LINC 4 [10, 12, 13].
The present study also included a small number of patients with adrenal CS (n = 5) and EAS (n = 3). The starting dose was 2 mg twice daily in all patients with EAS; in patients with adrenal CS, the starting dose was 2 mg twice daily (n = 3), 1 mg twice daily (n = 1), and 1 mg once daily (n = 1). Baseline median UFC, which was higher in the adrenal CS and EAS subgroups than in patients with Cushing disease, decreased during osilodrostat treatment but remained above the ULN. Median morning serum cortisol levels decreased from above to within the normal range in patients with EAS and remained within the normal range in patients with adrenal CS. Notably, baseline levels of morning serum cortisol, mean UFC, or LNSC did not necessarily predict the osilodrostat dose needed for biochemical normalization. Again, these results emphasize the need to individualize the starting dose and titration regimen based on each patient’s clinical circumstances and response to treatment. Differences in the pathophysiology of CS subtypes may also influence decisions about osilodrostat titration; for example, unlike in Cushing disease, ACTH rarely rises during inhibition of cortisol synthesis in EAS, and the rise in ACTH is delayed after cortisol normalization in adrenal CS. The results for the adrenal CS and EAS subgroups in the present study should be interpreted with caution given the small number of patients, and data from individual patients are perhaps more illustrative in this context. Individual UFC and morning serum cortisol levels were reduced in all patients with adrenal CS or EAS except for 2 patients (both with adrenal CS), whose morning serum cortisol levels did not change; in one of these patients, morning serum cortisol was within the normal range at baseline. Data on LNSC levels should also be interpreted with caution given the small number of patients with data available for this parameter.
The safety profile of osilodrostat was similar to that observed in clinical trials [10, 12, 14], with no unexpected safety signals. GWS and AI are recognized as potential side effects of osilodrostat based on its mechanism of action, but they can be difficult to differentiate as many of their symptoms overlap [25]. In the present study, there were 12 cases of GWS and/or AI after initiation of osilodrostat (28.6% of patients); this rate is lower than in the LINC 3 clinical trial (54.0% of patients with hypocortisolism-related AEs) [9] and similar to that seen in LINC 4 (27.4%) [11]. In LINC 3 and LINC 4, most hypocortisolism-related AEs were classified by the investigator as AI [11], but further evaluation to differentiate between this and GWS was not possible. For the present study, we were able to evaluate the symptoms and biochemical changes associated with these AEs, and we confirmed that it was often not possible for clinicians to accurately distinguish GWS and AI based on symptoms alone. As GWS and AI may require different management approaches, measurement of serum cortisol levels is essential to help guide the management strategy in these cases. In the present study, most cases of GWS and AI were managed by reducing the dose or temporarily interrupting treatment, which is consistent with the results from LINC 3 and LINC 4 [9-12]; only 4 patients (9.5%) with AI or GWS in the present study had discontinued treatment as a result. Treatment with glucocorticoids was recorded in 2 patients; the timing of treatment indicates that glucocorticoids were used to treat the symptoms of AI/GWS rather than as part of a “block-and-replace” strategy, in which glucocorticoids are administered concomitantly with osilodrostat [21, 26]. Slower dose escalation may reduce the risk of hypocortisolism-related AEs; the longer titration interval in LINC 4 (every 3 weeks) than in LINC 3 (every 2 weeks) may explain the lower incidence of hypocortisolism-related AEs during LINC 4 [10, 12]. Regardless, and as with all steroidogenesis inhibitors, all patients treated with osilodrostat should be monitored regularly and educated on the signs and symptoms of GWS and AI. Case reports have described rare episodes of delayed cortisol reduction during chronic osilodrostat therapy and prolonged AI after its discontinuation, which emphasizes the importance of lifelong, close monitoring of symptoms and serum cortisol levels [27-29].
The results of the present study are consistent with those of previous studies demonstrating the efficacy and safety of osilodrostat in patients with EAS or adrenal CS. In a prospective phase 2 study conducted in Japan, mean UFC levels decreased in all patients and normalized in most following 12 weeks of treatment [14]. In LINC 7, a retrospective study conducted in France, 103 patients with adrenal CS or EAS were followed up retrospectively for up to 36 months; at last assessment, mean UFC was normalized in most patients [30]. Compared with LINC 7, the starting and maintenance doses of osilodrostat were lower in the present study, once again emphasizing the importance of individualizing osilodrostat dosing. In a second real-world study in France, which was conducted in 30 patients with EAS, median UFC decreased significantly following osilodrostat monotherapy (when used both first and second line) and combination therapy with other cortisol-lowering drugs [21]. There were also substantial improvements in hypertension, hyperglycemia, and hypokalemia, allowing the discontinuation or dose reduction of concomitant treatments. Several other case series and case reports have documented effective control of cortisol levels and good tolerability in patients with adrenal CS or EAS [26, 31-38], adding to the body of evidence supporting the use of osilodrostat in patients with CS irrespective of severity and etiology.
Limitations of the present study include the small patient numbers, particularly in the groups with adrenal CS and EAS. As the study was conducted shortly after osilodrostat was approved in the United States for patients with Cushing disease for whom pituitary surgery is not an option or has not been curative, the predominance of patients with Cushing disease was expected, albeit slightly higher (81%) than the overall prevalence of Cushing disease (up to 70%), vs other causes of CS in a clinical setting [2]. Another limitation is that data were extracted retrospectively from patients’ medical records rather than recorded prospectively according to a study protocol; this resulted in many missing data points, especially for laboratory data. Despite these limitations, the results provide invaluable information on the real-world use of osilodrostat in the United States, for which data are currently lacking. The design of the study also allowed adjudication of AI vs GWS events by the authors in some patients as morning cortisol levels were available. In addition, ILLUSTRATE is the only completed multicenter study in the United States to date that evaluates the effect of osilodrostat not only in Cushing disease, but also in adrenal CS and EAS, providing data on the cortisol-lowering effectiveness of osilodrostat across the spectrum of hypercortisolism etiologies.
Conclusions
Results of this real-world study are consistent with those from clinical trials and other real-world studies, showing that osilodrostat was effective and well tolerated in patients with varying etiologies and severities of CS when used by physicians in routine clinical practice. The results also highlight the importance of individualizing the osilodrostat dose and titration regimen according to each patient’s clinical condition, response, and tolerability.
Acknowledgments
We thank all clinicians and patients who participated in the study.
Funding
This work was supported by Recordati Rare Diseases Inc, Bridgewater, New Jersey, United States. AMICULUM provided medical editorial assistance, funded by Recordati Rare Diseases Inc.
Disclosures
M.F. reports grants to her university from Crinetics and Sparrow and occasional scientific consulting fees from Crinetics, Recordati Rare Diseases, Sparrow, and Xeris Pharmaceuticals; she served as a member of the LINC 3 steering committee. R.J.A. reports grants and personal fees from Xeris Pharmaceuticals, Spruce Biosciences, Neurocrine Biosciences, Corcept Therapeutics, Diurnal Ltd, Sparrow Pharmaceuticals, Crinetics Pharmaceuticals, and Recordati Rare Diseases and personal fees from Adrenas Therapeutics, Quest Diagnostics, H Lundbeck A/S, Novo Nordisk, and Besins Pharmaceuticals. W.H. reports grants to his institution from CinCor, Corcept, Crinetics, Spruce, and Ascendis and honoraria from Novo Nordisk, Recordati Rare Diseases, Chiesi, Crinetics, Neurocrine, Camurus, and Spruce. J.L.S.-S. reports research grants from Recordati Rare Diseases and scientific consulting fees from Crinetics, Recordati Rare Diseases, and Corcept. K.C.J.Y. reports grants to his institution from Corcept, Sparrow, Chiesi, and Ascendis and honoraria from Novo Nordisk, Ascendis, Chiesi, Recordati Rare Diseases, Xeris, Crinetics, Camurus, and Neurocrine. K.C.D. and J.P. are employees of Recordati Rare Diseases Inc. E.K.B. was an employee of Recordati Rare Diseases Inc at the time the study was conducted (current affiliation: Inizio Engage, Yardley, Pennsylvania, USA). A.K.D., C.C., and M.S.B. are employees of PHAR, which received funding from Recordati Rare Diseases Inc to conduct the analysis. A.G.I. reports grants to her university from Recordati Rare Disease, Xeris Pharmaceuticals, and Chiesi and occasional consulting fees from Xeris Pharmaceuticals, Crinetics, Camurus, and Chiesi.
Data Availability
Some data sets generated and/or analyzed during the present study are not publicly available but are available from the corresponding author on reasonable request.
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Abbreviations
ACTH
adrenocorticotropin
AE
adverse event
AI
adrenal insufficiency
CS
Cushing syndrome
EAS
ectopic adrenocorticotropin syndrome
eCRF
electronic case report form
GWS
glucocorticoid withdrawal syndrome
ILLUSTRATE
osIlodrostat reaL-worLd Utilization Study To Retrospectively Assess paTient Experience
LLN
lower limit of normal
LNSC
late-night salivary cortisol
UFC
urinary free cortisol
ULN
upper limit of normal
© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. See the journal About page for additional terms.

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Osilodrostat Treatment for Adrenal and Ectopic Cushing Syndrome

Posted on May 9, 2025 by MaryO

Integration of Clinical Studies With Case Presentations

Maria Fleseriu, Richard J Auchus, Irina Bancos, Beverly MK Biller
Journal of the Endocrine Society, Volume 9, Issue 4, April 2025, bvaf027
https://doi.org/10.1210/jendso/bvaf027

Abstract

Although most cases of endogenous Cushing syndrome are caused by a pituitary adenoma (Cushing disease), approximately one-third of patients present with ectopic or adrenal causes.

Surgery is the first-line treatment for most patients with Cushing syndrome; however, medical therapy is an important management option for those who are not eligible for, refuse, or do not respond to surgery.

Clinical experience demonstrating that osilodrostat, an oral 11β-hydroxylase inhibitor, is effective and well tolerated comes predominantly from phase III trials in patients with Cushing disease. Nonetheless, reports of its use in patients with ectopic or adrenal Cushing syndrome are increasing. These data highlight the importance of selecting the most appropriate starting dose and titration frequency while monitoring for adverse events, including those related to hypocortisolism and prolongation of the QT interval, to optimize treatment outcomes. Here we use illustrative case studies to discuss practical considerations for the management of patients with ectopic or adrenal Cushing syndrome and review published data on the use of osilodrostat in these patients.

The case studies show that to achieve the goal of reducing cortisol levels in all etiologies of Cushing syndrome, management should be individualized according to each patient’s disease severity, comorbidities, performance status, and response to treatment. This approach to osilodrostat treatment maximizes the benefits of effective cortisol control, leads to improvements in comorbid conditions, and may ameliorate quality of life for patients across all types and severities of Cushing syndrome.

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From https://www.endocrine.org/journals/journal-of-the-endocrine-society/osilodrostat-treatment-for-adrenal-and-ectopic-cushing-syndrome

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Thymic Neuroendocrine Tumor With Metastasis to the Breast Causing Ectopic Cushing’s Syndrome

Posted on April 9, 2025 by MaryO

Ectopic adrenocorticotropic hormone secretion (EAS) is responsible for approximately 10%–18% of Cushing’s syndrome cases. Thymic neuroendocrine tumors (NETs) comprise 5%–16% of EAS; therefore, they are very rare and the data about this particular tumors is scarce.

We present a case of a 34-year-old woman with a rapid onset of severe hypercortisolism in April 2016. After initial treatment with a steroid inhibitor (ketoconazole) and diagnostics including 68Ga DOTA-TATE PET/CT, it was shown to be caused by a small thymic NET.

After a successful surgery and the resolution of all symptoms, there was a recurrence after 5 years of observation caused by a metastasis to the breast, shown in the 68Ga DOTA-TATE PET/CT result and confirmed with a breast biopsy.

Treatment with a steroid inhibitor (metyrapone) and tumor resection were again curative. The last disease relapse appeared 7 years after the initial treatment, with severe hypercortisolism treated with osilodrostat. There was a local recurrence in the mediastinum, and a thoracoscopic surgery was performed with good clinical and biochemical effect.

The patient remains under careful follow-up. Our case stays in accordance with recent literature data, showing that patients with thymic NETs are younger than previously considered and that the severity of hypercortisolism does not correlate with the tumor size. The symptoms of EAS associated with thymic NET may develop rapidly and may be severe as in our case. Nuclear medicine improves the effectiveness of the tumor search, which is crucial in successful EAS therapy. Our case also underlines the need for lifelong monitoring of patients with thymic NETs and EAS.

1 Introduction

Ectopic adrenocorticotropic hormone secretion (EAS) represents between 9% and 18% of adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome (CS) cases (1–3). The tumors secreting ACTH may occur in many locations and present with different histopathological differentiation, resulting in various clinical outcomes. In the past, most of the EAS cases were associated with small cell lung cancer, characterized by rapid tumor progression and unfavorable prognosis. Recently, well-differentiated neuroendocrine tumors (NETs) from the foregut prevail in the clinical series of EAS, with most common locations in the lungs, thymus, and pancreas (1).

EAS is often associated with severe hypercortisolism. Typical Cushing’s appearance may not be present due to the rapid onset of the disease. Patients with this type of hypercortisolism need urgent treatment because they have the highest mortality of all forms of CS (4). A retrospective review of 43 patients with EAS reported deaths in 27 patients (62.8%) and a median overall survival of 32.2 months. The leading causes of mortality were the progression of primary malignancies and systemic infections; two patients died from pulmonary embolism (5).

Prompt surgical removal of the tumor secreting ACTH is the mainstay of the therapy. However, finding the tumor causing EAS can be challenging due to its small size and variety of locations. Most authors recommend a combination of computed tomography (CT) scanning of the chest, abdomen, and pelvis, with additional magnetic resonance imaging (MRI) of the pituitary, as the first-line examinations (1, 6, 7). However, the sensitivity of standard imaging modalities is suboptimal (8). In the analysis of 231 patients with EAS, cross-sectional imaging revealed the source of ACTH in 52.4% of them at initial evaluation, and another 29% was found during follow-up or due to nuclear medicine functional imaging, while 18.6% remained occult (9). Nuclear medicine improves the sensitivity of conventional radiology in the case of EAS, with the use of 18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT (18F-FDG PET/CT) expected to be useful in identifying EAS tumors with high proliferative activity and 68gallium-labeled somatostatin analogues (68Ga DOTA-TATE) PET/CT with the potential to detect NETs. In the head-to-head comparison, the detection rate of the source of EAS was 75% for 68Ga DOTA-TATE and 60% for 18F-FDG PET/CT, while the highest sensitivity (90%) was achieved when both methods were combined (10).

Thymic NETs comprise 2%–5% of all thymic neoplasms and may cause some paraneoplastic syndromes, with the most frequent being myasthenia gravis, syndrome of inappropriate antidiuretic hormone secretion, and hypercortisolism (11). EAS associated with thymic NETs are rare, representing between 5% and 16% of EAS in published case series (1). Because of the rarity and heterogeneity of the disease, no evidence-based guidelines are available.

We present a case of a patient with thymic NET causing EAS, with metastasis to the breast after 5 years of post-surgical remission and another local recurrence 7 years after the first operation.

Our case is unique because thymic NETs causing EAS are known as an aggressive disease with a median recurrence time of 24 months after thymectomy (12). There are only a few cases described of metastases to the breast from thymic NETs causing EAS (13–16). Moreover, 68Ga-SSTR PET/CT was very helpful in detecting both primary and metastatic ectopic ACTH-secreting tumor, which underlines its role in the diagnostic workout of EAS.

2 Case description

A 32-year-old woman with no relevant medical history was admitted to the endocrinology department in April 2016 due to the rapid onset of symptoms: weight gain, hypertension, skin changes, and oligomenorrhoea.

The measurements at initial physical examination were as follows: body mass index (BMI)—29 kg/m2, blood pressure—180/90 mmHg, and heart rate—88/min. She had plethora, acne, moon face, buffalo hump, central obesity, many red striae in the abdominal area, and mild hirsutism. The baseline laboratory findings are presented in Table 1, with hypokalemia, diabetes, leukocytosis, high levels of serum cortisol, ACTH, and chromogranin A, and increased urine-free cortisol (UFC) secretion. There was no suppression of serum cortisol or UFC after a high-dose dexamethasone test. ACTH-dependent CS was diagnosed, and EAS was suspected. The patient’s family history was negative for endocrine diseases or genetic disorders.

Table 1

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Table 1. Laboratory results at diagnosis (April 2016).

The first-line cross-sectional imaging studies (chest, abdomen, and pelvis CT and MRI of the pituitary gland) did not reveal the source of ACTH. Only a symmetrical enlargement of adrenals was observed. 68Ga DOTA-TATE PET/CT revealed an oval lesion in the anterior mediastinum (1.9 × 1.3 cm) with a subtle overexpression of somatostatin receptors (SUV max. 2.8, Figures 1A, B). The chest MRI confirmed a mass 1.5 × 2.0 × 2.5 cm, with high T2-weighted signal and high contrast enhancement, suggestive of NET. The patient was given ketoconazole (600 mg daily), spironolactone, potassium supplementation, antihypertensive drugs, and thromboembolic prophylaxis. In June 2016, thoracoscopic removal of the mediastinal tumor was performed. In the histopathological examination, the tumor was encapsulated, without evidence of invasion, and no lymph node metastases were described. The immunophenotype of the tumor was as follows: CgA (+), Syn (+), CKAE1+E3 (+) “dot-like”, S100 (-), calcitonin (-), EMA (+/-), Ki67 3% to 4% in hot spots, no necrosis, mitotic index 0/10HPF with conclusion: thymic NET—typical carcinoid (low-grade). The presence of paraganglioma was also taken into consideration, as such cases were described (17). However, the significant reaction with cytokeratin and lack of S100 protein expression made this diagnosis less probable.

Figure 1

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Figure 1. 68Ga-DOTATATE PET/CT scans. (A, B) Before the first surgery (April 2016). (C, D) Before the second surgery (May 2021). (E, F) Before the third surgery (January 2023).

The postoperative morning serum cortisol concentration was below 5 µg/dL, indicating biochemical remission. The patient received hydrocortisone substitution for a month. The clinical signs of CS disappeared, and there was a normalization of UFC.

During 5 years of follow-up, the patient got pregnant and delivered a healthy child. Genetic counseling was performed, and no germline mutation of MEN1 gene was identified. Other clinical manifestations of MEN1 (like primary hyperparathyroidism and pituitary secreting tumors) were excluded.

In May 2021, the patient experienced a sudden recurrence of CS symptoms. The laboratory findings confirmed severe hypercortisolism (Table 2); therefore, treatment with steroid inhibitor metyrapone was administered. The patient tolerated only 750 mg daily; there were side effects (skin rash and tachycardia) with higher doses. The chest MRI revealed no recurrence in the location of the primary tumor, only a lesion in the right breast (1.2 × 1.0 × 1.1 cm) with atypical contrast enhancement. The 68Ga-DOTA-TATE PET/CT result showed a subtle overexpression of the tracer (SUV max 1.9) in the right breast (Figures 1C, D). Breast ultrasonography confirmed a hypoechogenic, hypervascular mass in the right breast, BIRADS 3/4, diagnosed as NET in the breast biopsy. The tumor was removed in July 2021 without complications. The histopathological samples were compared with the primary lesion, confirming the metastasis from thymic NET to the breast—tumor size 0.7 × 1.5 cm, clear surgical margins (8 mm) with Ki67 3% (NET G2), and no lymph node metastases. After the breast surgery, the cortisol levels normalized in blood and urine and the CS symptoms disappeared. 18F-FDG PET/CT and 68Ga-DOTA-TATE PET/CT were performed, showing no pathological increase of radiotracer uptake in post-operative locations or mediastinal lymph nodes. The patient consulted with the oncology team, and no adjuvant therapy was recommended.

Table 2

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Table 2. Laboratory results during 7 years of observation.

The next recurrence of the disease occurred in February 2023, with the symptoms developing suddenly during a very short period (1 to 2 weeks), additionally with significant mental deterioration (concentration disorders, anxiety, severe mood swing). The laboratory findings confirmed excessive hypercortisolism (Table 2). The patient was given osilodrostat (the initial dose was 20 mg daily but later reduced to 10 mg daily for 2 weeks until surgery) and symptomatic treatment with good clinical and biochemical effect. The 68Ga-DOTA-TATE PET/CT result showed a slightly increased uptake of the tracer in the left mediastinum, between cervical vessels, 0.9 × 1.2 cm (Figures 1E, F)—probably a local recurrence. Thoracotomy was performed in February 2023, with subsequent clinical and biochemical improvement (Table 2). In the histopathological examination, mediastinal NET G1 was diagnosed, without necrosis, mitotic activity 0/2 mm2, immunophenotype CgA (+), CD56 (+), Ki 67 1%, CK AE1/AE3 (+), CD117 (+), p40 (-), TdT (-), PAX8 (-), and the presence of tumor cell embolism in the vessels. One metastatic lesion was found in the pericardium (the maximal dimension of the tissue was 13 mm, resected radically). Two metastatic lesions in the fat tissue were found (one tissue fragment from the mediastinum, max. 16 mm diameter, and the second tissue fragment was surrounding the jugular vein, max. diameter up to 40 mm, both resected radically). Two of the 10 resected lymph nodes had metastatic lesions: one from the area of the jugular vein, diameter 11 mm, with capsular invasion, and the second lymph node N2R with capsular invasion, both resected radically. The symptoms of hypercortisolism disappeared, and the cortisol values were normalized after the operation. The patient is currently under careful monitoring, without signs of clinical or biochemical recurrence. 68Ga-DOTA-TATE PET/CT is performed every 6 months.

3 Discussion

Our case is representative for thymic NETs causing EAS presented in literature, but it also shows some distinct features, giving new insight into this rare condition.

In recent series, ACTH-secreting thymic NETs occurred often in young adults, like our patient. The typical age of presentation is 21–35 years in the largest case series, and 7.4% were children under 15 years (12, 13). In contrast, the former series of thymic NETs showed a peak incidence in the sixth decade of life (11).

ACTH-secreting thymic NETs show a slight male preponderance (58.6%); however, the patient’s gender does not seem to relate with the disease outcome (12). There was only an association between male sex and larger tumor size preoperatively as found in one case series (13).

Thymic NETs causing EAS are very rarely associated with MEN1; we have also excluded it in our patient. On the contrary, 30% of thymic NETs not associated with CS are found in patients with MEN1, mostly male smokers (18). It is not clear why thymic NETs with EAS are less likely caused by MEN1 gene mutation, but the possibility of this genetic predisposition should always be taken into consideration.

Thymic NETs associated with EAS are generally considered aggressive, presenting significant cellular atypia in the histopathological examination (19). However, the biology of the tumors is variable. In the histopathological examination of 92 thymic NETs secreting ACTH, the most common subtype was atypical NET (46.7%), while 30.4% of the cases were typical NETs and 21.7% were carcinomas, with the median Ki-67 10%, ranging from 1% to 40%. The median tumor size among 112 patients was 4.7 cm, ranging from 1 to 20 cm, and 55.7% of patients had metastases at presentation (12). It proves the significant heterogeneity of the disease.

Our patient had typical NET with small dimensions and localized disease at the time of diagnosis. Despite this, we observed aggressive Cushing’s syndrome with a short duration of symptoms and life-threatening hypokalemia. It has been observed that there is no correlation between tumor size and hormone levels (12). Thymic NETs associated with EAS are often large, which simplifies the diagnosis and localization. However, in the case of incidental sellar mass or small thymic tumor, the differential diagnosis might be difficult. The highest sensitivity in distinguishing thymic EAS from Cushing’s disease was documented in inferior petrosal sinus sampling and corticotropin-releasing hormone (CRH) stimulation test (12, 20).

In severe cases, when small ACTH-secreting NET needs to be found urgently, PET/CT is a very helpful diagnostic tool. In a prospective study comprising 20 patients with histologically proven EAS, the 68Ga-DOTATATE PET/CT result correctly identified the tumor in 75%, with SUV max. ranging from 1.4 to 20.7, while the 18F-FDG PET/CT findings had a slightly worse result (identified 60% tumors), with SUV max. ranging from 1.8 to 10.0. Those methods are believed to be complementary in case of localization and discrimination of EAS. The 68Ga-DOTATATE PET/CT result revealed tumor in six cases with a negative 18F-FDG PET/CT result, while the 18F-FDG PET/CT procedure was diagnostic in three cases with a negative 68Ga-DOTATATE uptake; the combined sensitivity of both methods was 90% (10). The typical first-line diagnostic modalities’ (CT and MRI) sensitivities range from 52% to 66% (9). Our case remains in accordance with those results, showing difficulties in localizing the ACTH source in first-line radiological methods and with 68Ga-DOTATATE PET/CT being the most useful diagnostic tool. It should also be noted that the 68Ga-DOTATATE uptake was only mildly elevated both in primary tumor and its recurrences despite excessive hormonal activity. We did not perform 18F-FDG PET/CT until second operation, as it was believed to be rather helpful in poorly differentiated tumors and 68Ga-DOTATATE PET/CT was diagnostic. Later, we performed it in search for other metastatic tumors, but the examination showed no tumor spread.

The recommended treatment of thymic NETs regarded radically resectable is thymectomy by median sternotomy or thoracotomy and lymph node dissection (11, 21, 22). According to the last version of the ESMO Guidelines, available literature suggests no benefit from adjuvant therapy in ThCs. The majority of the authors of the Guidelines panel suggest individually discussing eventual postoperative therapies, including RT and/or systemic therapies, balancing the pros and cons only in selected patients with advanced stage R0 or R1-2 resection (22). Data on systemic therapies in thymic NETs are scarce; therefore, they should be discussed in a multidisciplinary expert team in case of morphologically progressive tumors, high tumor burden, or refractory hormonal syndromes. Somatostatin analogs are recommended as the first-line systemic therapy in typical carcinoids (22). We considered the adjuvant therapy with somatostatin analogs; however, due to the low uptake in PET examination and complete resolution of symptoms as well as the radical type of surgical removal, we did not decide to initiate such therapy. Other systemic treatment options include everolimus (second line in typical carcinoids or first line in atypical carcinoids), chemotherapy, peptide receptor radionuclide therapy (PRRT), and interferon-α (22, 23). There is also data on the benefits of combining long-acting lanreotide with temozolomide in progressive thymic NETs (24).

Due to the variable availability of steroid inhibitors during the course of the disease, our patient received three different preparations at each disease relapse. Both ketoconazole and osilodrostat were well tolerated and reduced the hypercortisolism within a few days, but metyrapone caused significant side effects (see below—”Patient’s perspective”), and it was not possible to normalize the cortisol values with this steroid inhibitor. It is worth noting that when using the most recent steroid inhibitor—osilodrostat—we initiated the therapy with a high dose without a previous dose titration. This strategy might be used in the case of severe hypercortisolism and proved effective and safe in our patient (25).

Most commonly, metastases from thymic NET producing ACTH are localized in lymph nodes, bone, lung, pleura, and, less commonly, liver and parotid gland (13). There are very few cases of EAS-related thymic NETs with breast metastases described in the literature, with some histopathological variability (one case related to atypical carcinoid, another to combined large-cell neuroendocrine carcinoma and atypical carcinoid, and third case of neuroendocrine carcinoma). All of them were female patients between 24 and 36 years of age, with mediastinal lymph nodes metastases at the time of presentation; one also had distant metastases to the bones (13–15). Contrary to the reported cases, our patient had typical carcinoid (confirmed by three independent pathologists from different centers) but similarly presented with severe hypercortisolism. It suggests that there is no connection between tumor differentiation and the severity of hypercortisolism. Interestingly, in a review of 661 patients with metastatic NETs from Sweden, there were 20 patients with NETs and breast metastases, and among them only one case of thymic NET (Ki 67 12%), but without EAS. A total of 11 patients with breast metastases had a primary tumor in the small intestine and eight in the lung (16).

Our case underlines the necessity of long-term follow-up in EAS, as the recurrences occurred 5 and 7 years after the initial successful treatment. According to guidelines, follow-up after treatment of thymic NETs should be life-long (22).

The strength of our report is the presentation of a thymic NET with metastasis to the breast, diagnosed and treated with many currently available tools and with a long period of follow-up. The limitation is the low number of other similar cases to compare, which is a consequence of the rarity of this disease.

In conclusion, our case proves that thymic NETs with EAS might present in young patients with well-differentiated character in histopathological examination and severe, life-threatening hypercortisolism despite the small size of the primary lesion. 68Ga-DOTATATE PET/CT is a very helpful tool to localize the tumor. Finally, life-long follow-up should be performed despite complete remission after surgery.

4 Patient’s perspective

The first symptoms that I observed were face edema and mood changes. I rapidly lost muscle mass (approximately 6 kg in 2 weeks), and I was not able to climb stairs, especially with my child’s pram. The most difficult to accept were changes in my appearances—hirsutism, losing hair, changes of my facial features. My sense of pain (for example, during medical procedures) was diminished. Other disruptive symptoms were intensive sweating, increased appetite, thirst, brain fog, and digestive problems. At every relapse, the disease manifestations were fluctuating, all of them intensifying at the same time, which was very difficult for me. Also stress evoked disease symptoms. I experienced a strange feeling of warm during cortisol outbursts.

As for the treatment, I did not tolerate metyrapone well. I had skin rash, anxiety attacks with heart palpitations, and a metallic taste in my mouth. Other drugs (ketoconazole, osilodrostat) were better for me.

After operations of the relapses, the symptoms diminished very quickly, especially the most difficult ones. My blood pressure and glycemia normalized within a few days. Other manifestations, like loss of hair or skin changes, persisted up to 3 months.

Data availability statement

The datasets presented in this article are not readily available because the data are potentially identifiable. Requests to access the datasets should be directed to Aleksandra Zdrojowy-Wełna, aleksandra.zdrojowy-welna@umw.edu.pl.

Ethics statement

This study was exempt from ethical approval procedures being a case report of a single patient who has voluntarily provided oral and written consent to participate in the study and to have her case published for the sake of helping us better understand the clinical picture and the course of thymic neuroendocrine tumors with EAS and share it with the medical community for awareness about it. Written informed consent was obtained from the participant/patient(s) for the publication of this case report.

Author contributions

AZ-W: Conceptualization, Data curation, Investigation, Methodology, Software, Writing – original draft. MB: Conceptualization, Supervision, Writing – review & editing. JS: Data curation, Investigation, Methodology, Writing – review & editing. AJ-P: Data curation, Investigation, Writing – review & editing. JK-P: Conceptualization, Data curation, Investigation, Methodology, Supervision, Writing – original draft.

Funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Acknowledgments

We would like to thank Prof. Barbara Górnicka and Prof. Michał Jeleń for their collaboration throughout the patient’s treatment.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The handling editor AJ declared a past co-authorship with the author MB.

The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

 

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2025.1492187/full#supplementary-material

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Keywords: ectopic Cushing`s syndrome, thymic neuroendocrine tumor, thymic NET, ectopic ACTH secretion, case report

Citation: Zdrojowy-Wełna A, Bolanowski M, Syrycka J, Jawiarczyk-Przybyłowska A and Kuliczkowska-Płaksej J (2025) Case Report: Thymic neuroendocrine tumor with metastasis to the breast causing ectopic Cushing’s syndrome. Front. Oncol. 15:1492187. doi: 10.3389/fonc.2025.1492187

Received: 11 September 2024; Accepted: 31 January 2025;
Published: 25 February 2025.

Edited by:

Aleksandra Gilis-Januszewska, Jagiellonian University Medical College, Poland

Reviewed by:

Piero Ferolla, Umbria Regional Cancer Network, Italy
Lukasz Dzialach, Warsaw Medical University, Poland

Copyright © 2025 Zdrojowy-Wełna, Bolanowski, Syrycka, Jawiarczyk-Przybyłowska and Kuliczkowska-Płaksej. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Aleksandra Zdrojowy-Wełna, aleksandra.zdrojowy-welna@umw.edu.pl

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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