MON-783 - An Astonishing Anomaly; Paraneoplastic Syndrome Co-Secretion of PTHrP and FGF-23

Paraneoplastic syndromes in breast cancer are rare, occurring in fewer than 1% of patients, yet they precipitate profound metabolic disruptions. We report a 48-year-old woman who presented with a right breast mass and progressive back pain, subsequently diagnosed via core needle biopsy as estrogen receptor-positive, progesterone receptor-positive, HER2-negative stage IV breast carcinoma. The disease was complicated by extensive metastases to the thoracic and lumbar spine, resulting in pathologic fractures of the T10 and L3 vertebrae that necessitated kyphoplasty. Initial laboratory evaluation revealed a severe, refractory electrolyte profile characterized by persistent hypercalcemia 11.0-13.0 mg/dL and marked hypophosphatemia 0.5-2.1 mg/dL. Management with intravenous fluids, denosumab, and aggressive phosphate supplementation provided only transient stabilization. Post-discharge, the patient’s condition deteriorated, requiring recurrent intravenous phosphorus infusions to counteract persistent renal phosphate wasting.
A comprehensive metabolic workup was initiated to identify the drivers of this refractory state, revealing a suppressed parathyroid hormone (PTH) level of < 6.0pg/mL, a 25-hydroxyvitamin D of 20 ng/mL, and a magnesium level of 2.2 mg/dl. The PTH-independent hypercalcemia was driven by a significantly elevated PTHrP 60-70 pg/mL and a paradoxically high 1,25-dihydroxyvitamin D level of 334 pg/mL. During this clinical course, the patient’s oncologic regimen was transitioned from cisplatin to fulvestrant and ribociclib with palliative radiation, and her antiresorptive therapy was switched from denosumab to zoledronic acid due to intolerance. Despite these interventions, the patient developed symptomatic, life-threatening hypophosphatemia < 1.0. A random urinary phosphorus measurement of 11mg/dL in the setting of profound hypophosphatemia confirmed inappropriate renal phosphate wasting. This prompted the measurement of FGF-23, which was markedly elevated at 215 RU/mL. PET imaging confirmed the progression of extensive osseous metastases, which served as the likely source of this dual-hormone secretion.
This case represents a rare "dual-hit" paraneoplastic mechanism where PTHrP and FGF-23 act synergistically on the proximal tubule to downregulate sodium-phosphate cotransporters, leading to compounded renal phosphate loss. FGF-23 typically acts to suppress 1-alpha hydroxylase and lower 1,25-dihydroxyvitamin D levels. However, in this instance, the stimulatory effect of PTHrP on 1-alpha- hydroxylase and perhaps autonomous production by the tumor itself completely overrode the inhibitory signals of FGF-23, resulting in high levels of 1,25-dihydroxyvitamin D that further exacerbated hypercalcemia through increased intestinal absorption.

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