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 journalArticle

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)
JournalOncologist
DOIs
StateAccepted/In press - Jan 1 2018

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Parathyroid Neoplasms
Neoplasms
Mutation
Tumor Burden
Multiple Endocrine Neoplasia Type 1
Hypercalcemia
Therapeutics
Loss of Heterozygosity
Parathyroid Hormone
Protein-Tyrosine Kinases

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Genomic Profiling of Parathyroid Carcinoma Reveals Genomic Alterations Suggesting Benefit from Therapy. / Kang, Hyunseok; Pettinga, Dean; Schubert, Adrian D.; 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.

In: Oncologist, 01.01.2018.

Research output: Contribution to journalArticle

Kang, H, Pettinga, D, Schubert, AD, Ladenson, PW, Ball, DW, Chung, JH, Schrock, AB, Madison, R, Frampton, GM, Stephens, PJ, Ross, JS, Miller, VA & Ali, SM 2018, 'Genomic Profiling of Parathyroid Carcinoma Reveals Genomic Alterations Suggesting Benefit from Therapy', Oncologist. https://doi.org/10.1634/theoncologist.2018-0334
Kang, Hyunseok ; Pettinga, Dean ; Schubert, Adrian D. ; 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. / Genomic Profiling of Parathyroid Carcinoma Reveals Genomic Alterations Suggesting Benefit from Therapy. In: Oncologist. 2018.
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title = "Genomic Profiling of Parathyroid Carcinoma Reveals Genomic Alterations Suggesting Benefit from Therapy",
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.",
keywords = "Mutation, Parathyroid cancer, Profiling, Sequencing, Targeted therapy",
author = "Hyunseok Kang and Dean Pettinga and Schubert, {Adrian D.} and Ladenson, {Paul W} and Ball, {Douglas W} and Chung, {Jon H.} and Schrock, {Alexa B.} and Russell Madison and Frampton, {Garrett M.} and Stephens, {Phil J.} and Ross, {Jeffrey S.} and Miller, {Vincent A.} and Ali, {Siraj M.}",
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T1 - Genomic Profiling of Parathyroid Carcinoma Reveals Genomic Alterations Suggesting Benefit from Therapy

AU - Kang, Hyunseok

AU - Pettinga, Dean

AU - Schubert, Adrian D.

AU - Ladenson, Paul W

AU - Ball, Douglas W

AU - Chung, Jon H.

AU - Schrock, Alexa B.

AU - Madison, Russell

AU - Frampton, Garrett M.

AU - Stephens, Phil J.

AU - Ross, Jeffrey S.

AU - Miller, Vincent A.

AU - Ali, Siraj M.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

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KW - Parathyroid cancer

KW - Profiling

KW - Sequencing

KW - Targeted therapy

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