Genomic Profiling of Parathyroid Carcinoma Reveals Genomic Alterations Suggesting Benefit from Therapy

Hyunseok Kang, Dean Pettinga, Adrian D. Schubert, Paul W. Ladenson, Douglas W. Ball, Jon H. Chung, Alexa B. Schrock, Russell Madison, Garrett M. Frampton, Phil J. Stephens, Jeffrey S. Ross, Vincent A. Miller, Siraj M. Ali

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Parathyroid carcinoma (PC) is a rare endocrine malignancy that can cause life-threatening hypercalcemia. We queried whether comprehensive genomic profiling (CGP) of PC might identify genomic alterations (GAs), which would suggest benefit from rationally matched therapeutics. Methods: We performed hybrid-capture-based CGP to identify GAs and tumor mutational burden (TMB) in tumors from patients with this malignancy. Results: There were 85 total GAs in 16 cases (5.3 GAs per case), and the median TMB was 1.7 mutations per megabase (m/Mb), with three cases having >20 m/Mb (18.7%). The genes most frequently harboring GA were CDC73 (38%), TP53 (38%), and MEN1 (31%). All MEN1-mutated cases also had loss of heterozygosity at that locus, but in contrast all CDC73-mutated cases retained heterozygosity. GAs suggesting potential benefit from matched targeted therapy were identified in 11 patients (69%) and most frequently found in PTEN (25%), NF1 (12.5%), KDR (12.5%), PIK3CA (12.5%), and TSC2 (12.5%). A patient whose tumor harbored KDR T668 K and who was treated with cabozantinib experienced a > 50% drop in parathyroid hormone level and radiographic partial response of 5.4 months with duration limited by toxicity. Conclusion: CGP identified GAs in PC that suggest benefit from targeted therapy, as supported by an index case of response to a matched tyrosine kinase inhibitor. Moreover, the unexpectedly high frequency of high TMB (>20 m/Mb) suggests a subset of PC may benefit from immune checkpoint inhibitors. Implications for Practice: Parathyroid carcinoma (PC) is a rare endocrine malignancy that can cause life-threatening hypercalcemia. However, its molecular characteristics remain unclear, with few systemic therapeutic options available for this tumor. Hybrid-capture-based comprehensive genomic profiling of 16 primary cancers demonstrated presence of potentially actionable genomic alterations, including PTEN, NF1, KDR, PIK3CA, and TSC2, and a subset of hypermutated cancers with more than 20 mutations per megabase, the latter of which could benefit from immune checkpoint inhibitor therapy. A case benefiting from rationally matched targeted therapy for activating KDR mutation is also presented. These findings should be further investigated for their therapeutic potential.

Original languageEnglish (US)
Pages (from-to)791-797
Number of pages7
JournalOncologist
Volume24
Issue number6
DOIs
StatePublished - Jun 2019

Keywords

  • Mutation
  • Parathyroid cancer
  • Profiling
  • Sequencing
  • Targeted therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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