SAT-297 - Parathyroid Carcinoma in A Patient with Germline BRCA2 Mutation: Expanding the BRCA2 Tumor Spectrum

Background: Parathyroid carcinoma (PC) is among the rarest endocrine malignancies, comprising fewer than 1% of primary hyperparathyroidism cases. Germline CDC73 mutations account for most hereditary cases. BRCA2 pathogenic variants predispose to breast, ovarian, pancreatic, and prostate cancers but have not been reported in PC.
Clinical

Case: A 24-year-old male presented with primary hyperparathyroidism (PTH 375 pg/mL, calcium 15 mg/dL). Parathyroidectomy revealed Ki-67 40%, vascular invasion, and absent parafibromin staining, consistent with PC. Over 12 years, he underwent seven surgeries including total thyroidectomy, central neck dissection, partial sternotomy, mediastinal metastasectomy, thymectomy, and manubriectomy, plus two courses of radiotherapy for locally advanced disease.
Tumor genomic profiling identified BRCA2 c.3751dup (p.Glu1251Asnfs*14) at 89% variant allele frequency. Germline testing confirmed this as a constitutional pathogenic variant. The tumor harbored two somatic CDC73 frameshift mutations, potentially arising from homologous recombination deficiency (HRD)-associated genomic instability. Somatic NOTCH1 c.1342C>T (p.Arg448*) was also detected. Germline CDC73, MEN1, RET, and CDKN1B testing was negative, with no family history of endocrine tumors.
Based on BRCA2 status, the patient received olaparib in a clinical trial. He achieved durable partial response with PTH reduction from 800 to 110 pg/mL over 22 months. Upon progression, repeat genomic profiling revealed acquired BRCA2 p.K1180_S1268>I, a secondary mutation restoring the reading frame, a recognized PARPi resistance mechanism. He currently receives axitinib for progressive disease.
Clinical Lessons: This first germline BRCA2-associated PC suggests parathyroid carcinoma may belong to the hereditary BRCA2 tumor spectrum. The olaparib response and acquired reversion mutation demonstrate that BRCA2-driven PC follows established PARPi sensitivity/resistance patterns, supporting consideration of PARP inhibitor therapy in molecularly selected cases.

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