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

Kang, Hyunseok; Pettinga, Dean; Schubert, Adrian; Ladenson, Paul W; Ball, Douglas W; Chung, Jon H; Schrock, Alexa B; Madison, Russell; Frampton, Garrett M; Stephens, Phil J; Ross, Jeffrey S; Miller, Vincent A; Ali, Siraj M (2019). Genomic Profiling of Parathyroid Carcinoma Reveals Genomic Alterations Suggesting Benefit from Therapy. The oncologist, 24(6), pp. 791-797. AlphaMed Press 10.1634/theoncologist.2018-0334

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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 (38%), (38%), and (31%). All -mutated cases also had loss of heterozygosity at that locus, but in contrast all -mutated cases retained heterozygosity. GAs suggesting potential benefit from matched targeted therapy were identified in 11 patients (69%) and most frequently found in (25%), (12.5%), (12.5%), (12.5%), and (12.5%). A patient whose tumor harbored 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 , , , , and 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 mutation is also presented. These findings should be further investigated for their therapeutic potential.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Ear, Nose and Throat Disorders (ENT)

UniBE Contributor:

Schubert, Adrian

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1549-490X

Publisher:

AlphaMed Press

Language:

English

Submitter:

Stefan Weder

Date Deposited:

23 Jan 2019 15:41

Last Modified:

06 Jan 2020 09:51

Publisher DOI:

10.1634/theoncologist.2018-0334

PubMed ID:

30373905

Uncontrolled Keywords:

Mutation Parathyroid cancer Profiling Sequencing Targeted therapy

URI:

https://boris.unibe.ch/id/eprint/123705

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