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. Ali; Philip J. Stephens

doi:10.1159/000445978

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

Internal Medicine

Research output: Contribution to journal › Article › peer-review

44 Scopus citations

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 language	English (US)
Pages (from-to)	339-346
Number of pages	8
Journal	Oncology (Switzerland)
Volume	90
Issue number	6
DOIs	https://doi.org/10.1159/000445978
State	Published - Jun 14 2016

Keywords

Cabozantinib
Everolimus
Genomic profiling
Medullary thyroid carcinoma
Precision medicine
RET
Vandetanib

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1159/000445978

Cite this

Heilmann, A. M., Subbiah, V., Wang, K., Sun, J. X., Elvin, J. A., Chmielecki, J., Sherman, S. I., Murthy, R., Busaidy, N. L., Subbiah, I., Yelensky, R., Nangia, C., Vergilio, J. A., Khan, S. A., Erlich, R. L., Lipson, D., Ross, J. S., Miller, V. A., Shah, M. H., ... 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

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

@article{ff52fa9d1df24760b9fb28d5dc5c3b87,

title = "Comprehensive genomic profiling of clinically advanced medullary thyroid carcinoma",

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.",

keywords = "Cabozantinib, Everolimus, Genomic profiling, Medullary thyroid carcinoma, Precision medicine, RET, Vandetanib",

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

note = "Funding Information: We thank Dr. Jon Chung and Dr. Jennifer Spangle for helpful discussions. The University of Texas MD Anderson Cancer Center is supported by the National Institutes of Health through Cancer Center Support Grant CA016672. V.S. would like to thank the Dennis Lawrence and Joyce Lawrence research funds. Publisher Copyright: {\textcopyright} 2016 S. Karger AG, Basel.",

year = "2016",

month = jun,

day = "14",

doi = "10.1159/000445978",

language = "English (US)",

volume = "90",

pages = "339--346",

journal = "Oncology (Switzerland)",

issn = "0030-2414",

publisher = "UBM Medica Healthcare Publications",

number = "6",

}

TY - JOUR

T1 - Comprehensive genomic profiling of clinically advanced medullary thyroid carcinoma

AU - Heilmann, Andreas M.

AU - Subbiah, Vivek

AU - Wang, Kai

AU - Sun, James X.

AU - Elvin, Julia A.

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.

N1 - Funding Information: We thank Dr. Jon Chung and Dr. Jennifer Spangle for helpful discussions. The University of Texas MD Anderson Cancer Center is supported by the National Institutes of Health through Cancer Center Support Grant CA016672. V.S. would like to thank the Dennis Lawrence and Joyce Lawrence research funds. Publisher Copyright: © 2016 S. Karger AG, Basel.

PY - 2016/6/14

Y1 - 2016/6/14

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.

AB - 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.

KW - Cabozantinib

KW - Everolimus

KW - Genomic profiling

KW - Medullary thyroid carcinoma

KW - Precision medicine

KW - RET

KW - Vandetanib

UR - http://www.scopus.com/inward/record.url?scp=84975229391&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84975229391&partnerID=8YFLogxK

U2 - 10.1159/000445978

DO - 10.1159/000445978

M3 - Article

C2 - 27207748

AN - SCOPUS:84975229391

SN - 0030-2414

VL - 90

SP - 339

EP - 346

JO - Oncology (Switzerland)

JF - Oncology (Switzerland)

IS - 6

ER -

Comprehensive genomic profiling of clinically advanced medullary thyroid carcinoma

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this