Clinicopathologic features of non- small-cell lung cancer harboring an NTRK gene fusion

Anna F. Farago, Martin S. Taylor, Robert C. Doebele, Viola W. Zhu, Shivaani Kummar, Alexander I. Spira, Theresa A. Boyle, Eric B. Haura, Maria E. Arcila, Ryma Benayed, Dara L. Aisner, Nora K. Horick, Jochen K. Lennerz, Long P. Le, A. John Iafrate, Sai Hong I. Ou, Alice T. Shaw, Mari Mino-Kenudson, Alexander Drilon

Research output: Contribution to journalArticle

Abstract

Purpose Gene rearrangements that involve NTRK1/2/3 can generate fusion oncoproteins that contain the kinase domains of TRKA/B/C, respectively. These fusions are rare in non-small-cell lung cancer (NSCLC), with frequency previously estimated to be < 1%. Inhibition of TRK signaling has led to dramatic responses across tumor types with NTRK fusions. Despite the potential benefit of identifying these fusions, the clinicopathologic features of NTRK fusion-positive NSCLCs are not well characterized. Methods We compiled a database of patients with NSCLCs that harbor NTRK fusions. We characterized clinical, molecular, and histologic features with central review of histology. Results We identified 11 patients with NSCLCs that harbor NTRK gene fusions verified by next-generation sequencing and with available clinical and pathologic data. Fusions involved NTRK1 (n = 7) and NTRK3 (n = 4), with five and two distinct fusion partners, respectively. Fifty-five percent of cohort patients were male with a median age at diagnosis of 47.6 years (range, 25.3 to 86.0 years) and a median smoking history of 0 pack-years (range, 0 to 58 pack-years). Seventy-three percent of patients had metastatic disease at diagnosis. No concurrent alterations in KRAS, EGFR, ALK, ROS1, or other known oncogenic drivers were identified. Nine patients had adenocarcinoma, including two with invasive mucinous adenocarcinoma and one with adenocarcinoma with neuroendocrine features; one had squamous cell carcinoma; and one had neuroendocrine carcinoma. By collating data on 4,872 consecutively screened, unique patients with NSCLC, we estimate a frequency of NTRK fusions in NSCLC of 0.23% (95% CI, 0.11% to 0.40%). Conclusion NTRK fusions occur in NSCLCs across sexes, ages, smoking histories, and histologies. Given the potent clinical activity of TRK inhibitors, we advocate that all NSCLCs be screened for NTRK fusions by using a multiplexed next-generation sequencing-based fusion assay.

Original languageEnglish (US)
JournalJCO Precision Oncology
Volume2
DOIs
StatePublished - Jan 1 2018

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Gene Fusion
Non-Small Cell Lung Carcinoma
Histology
Adenocarcinoma
Smoking
Neuroendocrine Carcinoma
Mucinous Adenocarcinoma
Gene Rearrangement
Oncogene Proteins
Squamous Cell Carcinoma
Phosphotransferases
Databases
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Clinicopathologic features of non- small-cell lung cancer harboring an NTRK gene fusion. / Farago, Anna F.; Taylor, Martin S.; Doebele, Robert C.; Zhu, Viola W.; Kummar, Shivaani; Spira, Alexander I.; Boyle, Theresa A.; Haura, Eric B.; Arcila, Maria E.; Benayed, Ryma; Aisner, Dara L.; Horick, Nora K.; Lennerz, Jochen K.; Le, Long P.; Iafrate, A. John; Ou, Sai Hong I.; Shaw, Alice T.; Mino-Kenudson, Mari; Drilon, Alexander.

In: JCO Precision Oncology, Vol. 2, 01.01.2018.

Research output: Contribution to journalArticle

Farago, AF, Taylor, MS, Doebele, RC, Zhu, VW, Kummar, S, Spira, AI, Boyle, TA, Haura, EB, Arcila, ME, Benayed, R, Aisner, DL, Horick, NK, Lennerz, JK, Le, LP, Iafrate, AJ, Ou, SHI, Shaw, AT, Mino-Kenudson, M & Drilon, A 2018, 'Clinicopathologic features of non- small-cell lung cancer harboring an NTRK gene fusion', JCO Precision Oncology, vol. 2. https://doi.org/10.1200/PO.18.00037
Farago, Anna F. ; Taylor, Martin S. ; Doebele, Robert C. ; Zhu, Viola W. ; Kummar, Shivaani ; Spira, Alexander I. ; Boyle, Theresa A. ; Haura, Eric B. ; Arcila, Maria E. ; Benayed, Ryma ; Aisner, Dara L. ; Horick, Nora K. ; Lennerz, Jochen K. ; Le, Long P. ; Iafrate, A. John ; Ou, Sai Hong I. ; Shaw, Alice T. ; Mino-Kenudson, Mari ; Drilon, Alexander. / Clinicopathologic features of non- small-cell lung cancer harboring an NTRK gene fusion. In: JCO Precision Oncology. 2018 ; Vol. 2.
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abstract = "Purpose Gene rearrangements that involve NTRK1/2/3 can generate fusion oncoproteins that contain the kinase domains of TRKA/B/C, respectively. These fusions are rare in non-small-cell lung cancer (NSCLC), with frequency previously estimated to be < 1{\%}. Inhibition of TRK signaling has led to dramatic responses across tumor types with NTRK fusions. Despite the potential benefit of identifying these fusions, the clinicopathologic features of NTRK fusion-positive NSCLCs are not well characterized. Methods We compiled a database of patients with NSCLCs that harbor NTRK fusions. We characterized clinical, molecular, and histologic features with central review of histology. Results We identified 11 patients with NSCLCs that harbor NTRK gene fusions verified by next-generation sequencing and with available clinical and pathologic data. Fusions involved NTRK1 (n = 7) and NTRK3 (n = 4), with five and two distinct fusion partners, respectively. Fifty-five percent of cohort patients were male with a median age at diagnosis of 47.6 years (range, 25.3 to 86.0 years) and a median smoking history of 0 pack-years (range, 0 to 58 pack-years). Seventy-three percent of patients had metastatic disease at diagnosis. No concurrent alterations in KRAS, EGFR, ALK, ROS1, or other known oncogenic drivers were identified. Nine patients had adenocarcinoma, including two with invasive mucinous adenocarcinoma and one with adenocarcinoma with neuroendocrine features; one had squamous cell carcinoma; and one had neuroendocrine carcinoma. By collating data on 4,872 consecutively screened, unique patients with NSCLC, we estimate a frequency of NTRK fusions in NSCLC of 0.23{\%} (95{\%} CI, 0.11{\%} to 0.40{\%}). Conclusion NTRK fusions occur in NSCLCs across sexes, ages, smoking histories, and histologies. Given the potent clinical activity of TRK inhibitors, we advocate that all NSCLCs be screened for NTRK fusions by using a multiplexed next-generation sequencing-based fusion assay.",
author = "Farago, {Anna F.} and Taylor, {Martin S.} and Doebele, {Robert C.} and Zhu, {Viola W.} and Shivaani Kummar and Spira, {Alexander I.} and Boyle, {Theresa A.} and Haura, {Eric B.} and Arcila, {Maria E.} and Ryma Benayed and Aisner, {Dara L.} and Horick, {Nora K.} and Lennerz, {Jochen K.} and Le, {Long P.} and Iafrate, {A. John} and Ou, {Sai Hong I.} and Shaw, {Alice T.} and Mari Mino-Kenudson and Alexander Drilon",
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T1 - Clinicopathologic features of non- small-cell lung cancer harboring an NTRK gene fusion

AU - Farago, Anna F.

AU - Taylor, Martin S.

AU - Doebele, Robert C.

AU - Zhu, Viola W.

AU - Kummar, Shivaani

AU - Spira, Alexander I.

AU - Boyle, Theresa A.

AU - Haura, Eric B.

AU - Arcila, Maria E.

AU - Benayed, Ryma

AU - Aisner, Dara L.

AU - Horick, Nora K.

AU - Lennerz, Jochen K.

AU - Le, Long P.

AU - Iafrate, A. John

AU - Ou, Sai Hong I.

AU - Shaw, Alice T.

AU - Mino-Kenudson, Mari

AU - Drilon, Alexander

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Purpose Gene rearrangements that involve NTRK1/2/3 can generate fusion oncoproteins that contain the kinase domains of TRKA/B/C, respectively. These fusions are rare in non-small-cell lung cancer (NSCLC), with frequency previously estimated to be < 1%. Inhibition of TRK signaling has led to dramatic responses across tumor types with NTRK fusions. Despite the potential benefit of identifying these fusions, the clinicopathologic features of NTRK fusion-positive NSCLCs are not well characterized. Methods We compiled a database of patients with NSCLCs that harbor NTRK fusions. We characterized clinical, molecular, and histologic features with central review of histology. Results We identified 11 patients with NSCLCs that harbor NTRK gene fusions verified by next-generation sequencing and with available clinical and pathologic data. Fusions involved NTRK1 (n = 7) and NTRK3 (n = 4), with five and two distinct fusion partners, respectively. Fifty-five percent of cohort patients were male with a median age at diagnosis of 47.6 years (range, 25.3 to 86.0 years) and a median smoking history of 0 pack-years (range, 0 to 58 pack-years). Seventy-three percent of patients had metastatic disease at diagnosis. No concurrent alterations in KRAS, EGFR, ALK, ROS1, or other known oncogenic drivers were identified. Nine patients had adenocarcinoma, including two with invasive mucinous adenocarcinoma and one with adenocarcinoma with neuroendocrine features; one had squamous cell carcinoma; and one had neuroendocrine carcinoma. By collating data on 4,872 consecutively screened, unique patients with NSCLC, we estimate a frequency of NTRK fusions in NSCLC of 0.23% (95% CI, 0.11% to 0.40%). Conclusion NTRK fusions occur in NSCLCs across sexes, ages, smoking histories, and histologies. Given the potent clinical activity of TRK inhibitors, we advocate that all NSCLCs be screened for NTRK fusions by using a multiplexed next-generation sequencing-based fusion assay.

AB - Purpose Gene rearrangements that involve NTRK1/2/3 can generate fusion oncoproteins that contain the kinase domains of TRKA/B/C, respectively. These fusions are rare in non-small-cell lung cancer (NSCLC), with frequency previously estimated to be < 1%. Inhibition of TRK signaling has led to dramatic responses across tumor types with NTRK fusions. Despite the potential benefit of identifying these fusions, the clinicopathologic features of NTRK fusion-positive NSCLCs are not well characterized. Methods We compiled a database of patients with NSCLCs that harbor NTRK fusions. We characterized clinical, molecular, and histologic features with central review of histology. Results We identified 11 patients with NSCLCs that harbor NTRK gene fusions verified by next-generation sequencing and with available clinical and pathologic data. Fusions involved NTRK1 (n = 7) and NTRK3 (n = 4), with five and two distinct fusion partners, respectively. Fifty-five percent of cohort patients were male with a median age at diagnosis of 47.6 years (range, 25.3 to 86.0 years) and a median smoking history of 0 pack-years (range, 0 to 58 pack-years). Seventy-three percent of patients had metastatic disease at diagnosis. No concurrent alterations in KRAS, EGFR, ALK, ROS1, or other known oncogenic drivers were identified. Nine patients had adenocarcinoma, including two with invasive mucinous adenocarcinoma and one with adenocarcinoma with neuroendocrine features; one had squamous cell carcinoma; and one had neuroendocrine carcinoma. By collating data on 4,872 consecutively screened, unique patients with NSCLC, we estimate a frequency of NTRK fusions in NSCLC of 0.23% (95% CI, 0.11% to 0.40%). Conclusion NTRK fusions occur in NSCLCs across sexes, ages, smoking histories, and histologies. Given the potent clinical activity of TRK inhibitors, we advocate that all NSCLCs be screened for NTRK fusions by using a multiplexed next-generation sequencing-based fusion assay.

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