Immunotherapy-induced isolated ACTH deficiency in cancer therapy

Central adrenal insufficiency (AI) due to isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) has been recently associated with immune checkpoint inhibitor (ICI) therapy. Our aim was to analyze the prevalence, clinical characteristics, and therapeutic outcomes in cancer patients with IAD induced by ICI therapy. A retrospective and multicenter study was performed. From a total of 4,447 cancer patients treated with ICI antibodies, 37 (0.8%) [23 men (62.2%), mean age 64.7 ± 8.3 years (range 46-79 yr)] were diagnosed with IAD. The tumor most frequently related to IAD was lung cancer (n=20, 54.1%), followed by melanoma (n=8, 21.6%). The most commonly ICI antibody inhibitor reported was nivolumab (n=18, 48.6%), pembrolizumab (n=16, 43.2%) and ipilimumab (n=8, 21.6%). About half of the patients (n=19, 51.4%) had other immune-related adverse events, mainly endocrine adverse effects (n=10, 27.0%). IAD was diagnosed at a median time of 7.0 months (IQR, 5-12) after starting immunotherapy. The main reported symptom at presentation was fatigue (97.3%), followed by anorexia (81.8%) and general malaise (81.1%). Mean follow-up time since IAD diagnosis was 15.2 ± 12.5 months (range 0.3-55 months). At last visit all patients continued with hormonal deficiency of ACTH. Median overall survival since IAD diagnosis was 6.0 months. In conclusion, IAD is a rare but a well-established complication associated with ICI therapy in cancer patients. It develops around 7 months after starting treatment, mainly anti-PD1 antibodies. Recovery of the corticotropic axis function should not be expected.

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MECHANISMS IN ENDOCRINOLOGY: Autoimmune hypopituitarism: novel mechanistic insights

Acta Endocrinologica ◽

10.1530/eje-19-1051 ◽

2020 ◽

Vol 182 (4) ◽

pp. R59-R66 ◽

Cited By ~ 3

Author(s):

Yutaka Takahashi

Keyword(s):

Vascular Injury ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Pituitary Tumors ◽

Underlying Mechanism ◽

Isolated Acth Deficiency ◽

Acth Deficiency ◽

Pathological Conditions ◽

Genetic Abnormalities

Hypopituitarism is caused by various insults to the pituitary, such as hypothalamic and pituitary tumors, inflammation, autoimmunity, vascular injury, genetic abnormalities, irradiation, and trauma. Recently, it has been found that autoimmunity to the pituitary involves many pathological conditions associated with specific or non-specific hormone deficiencies in the gland. This review discusses the recent findings on the underlying mechanism of autoimmune hypopituitarism particularly of lymphocytic hypophysitis, IgG4-related hypophysitis, immune checkpoint inhibitor-induced hypophysitis, anti-PIT-1 hypophysitis, and isolated ACTH deficiency.

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Follow-up of Cancer Patients Receiving Immune Checkpoint Inhibitor Therapy by Electronic Patient Reported Outcomes-tool

Case Medical Research ◽

10.31525/ct1-nct03928938 ◽

2019 ◽

Author(s):

Keyword(s):

Cancer Patients ◽

Immune Checkpoint ◽

Patient Reported Outcomes ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Inhibitor Therapy ◽

Patient Reported ◽

Checkpoint Inhibitor Therapy

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Identification of NOTCH4 mutation as a response biomarker for immune checkpoint inhibitor therapy

BMC Medicine ◽

10.1186/s12916-021-02031-3 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Junyu Long ◽

Dongxu Wang ◽

Xu Yang ◽

Anqiang Wang ◽

Yu Lin ◽

...

Keyword(s):

Lung Cancer ◽

Bladder Cancer ◽

Cancer Patients ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Small Cell ◽

Small Cell Lung ◽

Esophagogastric Cancer ◽

Clinical Benefits

Abstract Background Immune checkpoint inhibitor (ICI) therapy elicits durable antitumor responses in patients with many types of cancer. Genomic mutations may be used to predict the clinical benefits of ICI therapy. NOTCH homolog-4 (NOTCH4) is frequently mutated in several cancer types, but its role in immunotherapy is still unclear. Our study is the first to study the association between NOTCH4 mutation and the response to ICI therapy. Methods We tested the predictive value of NOTCH4 mutation in the discovery cohort, which included non-small cell lung cancer, melanoma, head and neck squamous cell carcinoma, esophagogastric cancer, and bladder cancer patients, and validated it in the validation cohort, which included non-small cell lung cancer, melanoma, renal cell carcinoma, colorectal cancer, esophagogastric cancer, glioma, bladder cancer, head and neck cancer, cancer of unknown primary, and breast cancer patients. Then, the relationships between NOTCH4 mutation and intrinsic and extrinsic immune response mechanisms were studied with multiomics data. Results We collected an ICI-treated cohort (n = 662) and found that patients with NOTCH4 mutation had better clinical benefits in terms of objective response rate (ORR: 42.9% vs 25.9%, P = 0.007), durable clinical benefit (DCB: 54.0% vs 38.1%, P = 0.021), progression-free survival (PFS, hazard ratio [HR] = 0.558, P < 0.001), and overall survival (OS, HR = 0.568, P = 0.006). In addition, we validated the prognostic value of NOTCH4 mutation in an independent ICI-treated cohort (n = 1423). Based on multiomics data, we found that NOTCH4 mutation is significantly associated with enhanced immunogenicity, including a high tumor mutational burden, the expression of costimulatory molecules, and activation of the antigen-processing machinery, and NOTCH4 mutation positively correlates activated antitumor immunity, including infiltration of diverse immune cells and various immune marker sets. Conclusions Our findings indicated that NOTCH4 mutation serves as a novel biomarker correlated with a better response to ICI therapy.

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Decelerated tumor growth due to hypothyroidism with prolongation of survival in a patient with lung adenocarcinoma: a case report

Journal of International Medical Research ◽

10.1177/0300060519885302 ◽

2019 ◽

Vol 48 (3) ◽

pp. 030006051988530

Author(s):

Jia Hou ◽

Shan-Shan Xiong ◽

Zhao-Qi Huang ◽

Xing-Dong Cai

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Tumor Therapy ◽

Stage Iv ◽

Small Cell Lung ◽

Anti Cancer ◽

Advanced Stages

Lung adenocarcinoma is a form of non-small-cell lung cancer with high mortality in the advanced stages, and is one of the most common histological subtypes of lung cancer in most countries. Prognosis of lung adenocarcinoma is generally poor, with a median survival of 4–13 months. We report a case of unusually prolonged survival of a patient with advanced lung adenocarcinoma complicated by hypothyroidism. A 71-year-old man with stage IV lung adenocarcinoma presented with hypothyroidism. Surprisingly, without any anti-tumor and anti-hypothyroidism therapy, he survived this lung cancer for longer than 2.5 years before his last follow-up visit. Patients with advanced lung adenocarcinoma rarely survive for longer than 2 years, even after therapy. We hypothesize that hypothyroidism is the cause for this discrepancy. Thyroid hormones can promote growth of carcinoma. Therefore, hypothyroidism appears to be beneficial to anti-cancer therapy. We believe that hypothyroidism, as an adverse event commonly occurring in anti-tumor therapy (e.g., an immune checkpoint inhibitor), might not be able to be completely eliminated.

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