Comprehensive genomic profiling of clinically advanced medullary thyroid carcinoma

Andreas M. Heilmann, Vivek Subbiah, Kai Wang, James X. Sun, Julia A. Elvin, Juliann Chmielecki, Steven I. Sherman, Ravi Murthy, Naifa L. Busaidy, Ishwaria Subbiah, Roman Yelensky, Chaitali Nangia, Jo Anne Vergilio, Saad A. Khan, Rachel L. Erlich, Doron Lipson, Jeffrey S. Ross, Vincent A. Miller, Manisha H. Shah, Siraj M. AliPhilip J. Stephens

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Objective: The aim of this study was to determine the genomic alterations of cancer-related genes in advanced medullary thyroid carcinoma during the course of clinical care. Methods: Hybrid-capture-based comprehensive genomic profiling was performed on 34 consecutive medullary thyroid carcinoma cases to identify all four classes of genomic alterations, and outcome for an index patient was collected. Results:RET was mutated in 88% (30/34) of cases, with RET M918T being responsible for 70% (21/30) of the RET alterations. The other RET alterations were RET E632-L633del, C634R, C620R, C618G/R/S, V804M, and RET amplification. Two of the four RET wild-type patients harbored mutations in KRAS or HRAS (1/34 each). The next most frequent genomic alterations were amplifications of CCND1, FGF3, and FGF19 and alterations in CDKN2A (3/34 each). One case with a RET M918T mutation developed acquired resistance to progressively dose-escalated vandetanib. When the mTOR inhibitor everolimus was added to continued vandetanib treatment, the patient achieved a second 25% reduction of tumor volume (RECIST 1.1) for 8 months. Conclusions: Comprehensive genomic profiling identified the full breadth of RET alterations in metastatic medullary thyroid carcinoma and possible cooperating oncogenic driver alterations. This approach may refine the use of targeted therapy for these patients.

Original languageEnglish (US)
Pages (from-to)339-346
Number of pages8
JournalOncology (Switzerland)
Volume90
Issue number6
DOIs
StatePublished - Jun 14 2016

Fingerprint

Mutation
Neoplasm Genes
Tumor Burden
Medullary Thyroid cancer
Therapeutics
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine
Everolimus
Response Evaluation Criteria in Solid Tumors

Keywords

  • Cabozantinib
  • Everolimus
  • Genomic profiling
  • Medullary thyroid carcinoma
  • Precision medicine
  • RET
  • Vandetanib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Heilmann, A. M., Subbiah, V., Wang, K., Sun, J. X., Elvin, J. A., Chmielecki, J., ... Stephens, P. J. (2016). Comprehensive genomic profiling of clinically advanced medullary thyroid carcinoma. Oncology (Switzerland), 90(6), 339-346. https://doi.org/10.1159/000445978

Comprehensive genomic profiling of clinically advanced medullary thyroid carcinoma. / Heilmann, Andreas M.; Subbiah, Vivek; Wang, Kai; Sun, James X.; Elvin, Julia A.; Chmielecki, Juliann; Sherman, Steven I.; Murthy, Ravi; Busaidy, Naifa L.; Subbiah, Ishwaria; Yelensky, Roman; Nangia, Chaitali; Vergilio, Jo Anne; Khan, Saad A.; Erlich, Rachel L.; Lipson, Doron; Ross, Jeffrey S.; Miller, Vincent A.; Shah, Manisha H.; Ali, Siraj M.; Stephens, Philip J.

In: Oncology (Switzerland), Vol. 90, No. 6, 14.06.2016, p. 339-346.

Research output: Contribution to journalArticle

Heilmann, AM, Subbiah, V, Wang, K, Sun, JX, Elvin, JA, Chmielecki, J, Sherman, SI, Murthy, R, Busaidy, NL, Subbiah, I, Yelensky, R, Nangia, C, Vergilio, JA, Khan, SA, Erlich, RL, Lipson, D, Ross, JS, Miller, VA, Shah, MH, Ali, SM & Stephens, PJ 2016, 'Comprehensive genomic profiling of clinically advanced medullary thyroid carcinoma', Oncology (Switzerland), vol. 90, no. 6, pp. 339-346. https://doi.org/10.1159/000445978
Heilmann AM, Subbiah V, Wang K, Sun JX, Elvin JA, Chmielecki J et al. Comprehensive genomic profiling of clinically advanced medullary thyroid carcinoma. Oncology (Switzerland). 2016 Jun 14;90(6):339-346. https://doi.org/10.1159/000445978
Heilmann, Andreas M. ; Subbiah, Vivek ; Wang, Kai ; Sun, James X. ; Elvin, Julia A. ; Chmielecki, Juliann ; Sherman, Steven I. ; Murthy, Ravi ; Busaidy, Naifa L. ; Subbiah, Ishwaria ; Yelensky, Roman ; Nangia, Chaitali ; Vergilio, Jo Anne ; Khan, Saad A. ; Erlich, Rachel L. ; Lipson, Doron ; Ross, Jeffrey S. ; Miller, Vincent A. ; Shah, Manisha H. ; Ali, Siraj M. ; Stephens, Philip J. / Comprehensive genomic profiling of clinically advanced medullary thyroid carcinoma. In: Oncology (Switzerland). 2016 ; Vol. 90, No. 6. pp. 339-346.
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AU - Wang, Kai

AU - Sun, James X.

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AU - Chmielecki, Juliann

AU - Sherman, Steven I.

AU - Murthy, Ravi

AU - Busaidy, Naifa L.

AU - Subbiah, Ishwaria

AU - Yelensky, Roman

AU - Nangia, Chaitali

AU - Vergilio, Jo Anne

AU - Khan, Saad A.

AU - Erlich, Rachel L.

AU - Lipson, Doron

AU - Ross, Jeffrey S.

AU - Miller, Vincent A.

AU - Shah, Manisha H.

AU - Ali, Siraj M.

AU - Stephens, Philip J.

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N2 - Objective: The aim of this study was to determine the genomic alterations of cancer-related genes in advanced medullary thyroid carcinoma during the course of clinical care. Methods: Hybrid-capture-based comprehensive genomic profiling was performed on 34 consecutive medullary thyroid carcinoma cases to identify all four classes of genomic alterations, and outcome for an index patient was collected. Results:RET was mutated in 88% (30/34) of cases, with RET M918T being responsible for 70% (21/30) of the RET alterations. The other RET alterations were RET E632-L633del, C634R, C620R, C618G/R/S, V804M, and RET amplification. Two of the four RET wild-type patients harbored mutations in KRAS or HRAS (1/34 each). The next most frequent genomic alterations were amplifications of CCND1, FGF3, and FGF19 and alterations in CDKN2A (3/34 each). One case with a RET M918T mutation developed acquired resistance to progressively dose-escalated vandetanib. When the mTOR inhibitor everolimus was added to continued vandetanib treatment, the patient achieved a second 25% reduction of tumor volume (RECIST 1.1) for 8 months. Conclusions: Comprehensive genomic profiling identified the full breadth of RET alterations in metastatic medullary thyroid carcinoma and possible cooperating oncogenic driver alterations. This approach may refine the use of targeted therapy for these patients.

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KW - Precision medicine

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