Case Presentation: We report the case of a 45-year-old female with stage IA triple-negative breast cancer treated with neoadjuvant chemotherapy and pembrolizumab who developed secondary adrenal insufficiency due to adrenocorticotropic hormone (ACTH) deficiency six months after stopping the immune checkpoint inhibitor. She presented with persistent nausea, vomiting, weight loss, and altered mental status. Laboratory results on admission showed mild acute kidney injury and severe hypercalcemia, with a corrected calcium level of 15.8 mg/dL. Sodium levels were normal, and potassium was low. Parathyroid hormone (PTH) was suppressed, with normal 25-hydroxy and 1,25-dihydroxy vitamin D levels. A nuclear bone scan and CT of the chest, abdomen, and pelvis revealed no metastatic disease. The patient was treated with zoledronic acid and intravenous fluids; however, despite aggressive volume resuscitation, she developed shock. Suspecting an adrenal crisis, hydrocortisone was initiated. Endocrine evaluation revealed low morning cortisol (< 1 mcg/dL) and ACTH (< 5 pg/mL), with no response to ACTH stimulation testing.
Discussion: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that enhance antitumor activity by modulating the immune system.(1) Despite their success in improving outcomes for various cancers, ICIs can cause immune-related adverse effects (irAEs), which may emerge months after therapy discontinuation. (2) Adrenal insufficiency (AI) is a rare but potentially life-threatening immune-related adverse event (irAE), with a reported prevalence of less than 1% to approximately 5%. (1,3) Its symptoms are often nonspecific, potentially mimicking cancer progression or treatment-related effects, which can delay diagnosis. While hyponatremia and hyperkalemia are classic findings, they may be absent in patients with persistent vomiting or dehydration. Hypercalcemia in AI is thought to result from decreased renal excretion, increased bone resorption, and heightened intestinal calcium absorption due to elevated renal 1α-hydroxylase activity, leading to increased conversion of inactive vitamin D to its active form. (4)
Conclusions: In this case, the patient’s symptoms and hypercalcemia resolved promptly after initiating glucocorticoid replacement therapy. This underscores the critical importance of considering adrenal insufficiency in patients treated with ICIs who present with unexplained symptoms or electrolyte abnormalities, particularly hypercalcemia. Early recognition and timely treatment with glucocorticoids can be life-saving.