A Prospective Cohort Study to Define the Clinical Features and Outcome of Lung Cacers Harboring HER2 Aberration in Japan (HER2-CS STUDY)

Kiichiro Ninomiya, Tae Hata, Hiroshige Yoshioka, Kadoaki Oohashi, Akihiro Bessho, Shinobu Hosokawa, Nobuhisa Ishikawa, Masahiro Yamasaki, Takuo Shibayama, Keisuke Aoe, Toshiyuki Kozuki, Shingo Harita, Yutaka Ueda, Toshi Murakami, Nobukazu Fujimoto, Hiroyuki Yanai, Shinichi Toyooka, Minoru Takata, Katsuyuki Hotta, Katsuyuki Kiura & 108 others K. Gemba, G. Ikeda, M. Yasugi, E. Kurimoto, K. Nakano, T. Moritaka, K. Inoue, S. Miyoshi, N. Hamaguchi, R. Ito, Y. Sano, I. Takata, A. Mitani, T. Nishisaka, H. Shoda, A. Nishida, S. Tamamoto, K. Fujitaka, T. Masuda, S. Miyamoto, N. Hattori, K. Sugimoto, S. Fujii, Y. Ueda, Y. Sakugawa, N. Fukamatsu, K. Ogata, S. Bandoh, N. Kanaji, N. Takigawa, H. Yamane, N. Ochi, Y. Honda, M. Oka, M. Kittaka, T. Kubota, A. Yokoyama, T. Yokoyama, E. Sato, Y. Shiota, N. Horita, T. Kanematsu, Y. Awaya, A. Nakamasu, I. Murakami, S. Kuyama, K. Kudo, T. Tamura, T. Umeno, D. Morichika, K. Fujiwara, K. Sato, D. Harada, N. Nogami, K. Nishii, Y. Fuchimoto, T. Kishimoto, H. Kawai, K. Watanabe, K. Tokumo, T. Isobe, Y. Tsubata, M. Inoue, H. Ichikawa, Y. Nishioka, M. Hanibuchi, H. Goto, T. Sumikawa, M. Kodani, H. Suyama, Hirofumi Makino, N. Kinosita, E. Shimizu, H. Obata, H. Ikegami, K. Chikamori, T. Maeda, T. Kishino, H. Kamei, H. Ueoka, Y. Kunihiro, T. Kobayashi, K. Ueda, M. Hayashi, M. Kamiya, J. Murakami, A. Sato, Eiki Ichihara, Toshio Kubo, Takashi Ninomiya, T. Hirata, D. Minami, Y. Kato, H. Higo, G. Makimoto, Y. Toyota, N. Oda, M. Nakanishi, H. Kayatani, S. Senoo, H. Kano, H. Watanabe, T. Ando, T. Nakasuka, N. Hara, J. Itano, H. Nakashima, Masahiro Tabata

Research output: Contribution to journalArticle

Abstract

Background: Human epidermal growth factor 2 (HER2) is a potential driver oncogene. Although HER2-targeted precision therapy has been tested in non-small cell lung cancer (NSCLC), the demographic characteristics of HER2-positive NSCLC have not been systematically defined. Methods: Patients with pathologically confirmed stage IIIB/IV or recurrent NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, were prospectively registered. HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays were performed to screen patients. HER2 mutations were identified by using direct gene sequencing. The aim of this study was to clarify the frequency, characteristics, and outcome of HER2-positive NSCLC. HER2 was defined as positive if the tumor harbored IHC3+, IHC2+/FISH+, or exon 20 insertion mutations. Results: Of the 1,126 tumors screened, 34 (3.0%) were IHC3+, and 34 (3.0%) were IHC2+/FISH+. Among the 724 epidermal growth factor receptor wild-type tumors, 21 (2.9%) were HER2-mutant tumors, including A775-G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female patients had HER2-mutant tumors more frequently, whereas both IHC3+ and IHC2+/FISH+ tumors were detected more often in male subjects and smokers. Patients with an HER2-aberrant tumor had a significantly worse prognosis than those with epidermal growth factor receptor-positive and anaplastic lymphoma kinase-positive tumors, possibly due to the low proportion that received HER2-targeted therapies (n = 15 [26%]) and low response rates of 0% and 14% in patients with HER2-overexpressing and HER2-mutant tumors, respectively. Conclusions: This prospective large-scale cohort study is the first to show comprehensively the frequency and clinical demographic characteristics of those with HER2-positive advanced lung tumors in detail, providing critical historical data for future drug development against HER2-positive NSCLC. Future treatment strategies would be developed stratified according to the types of HER2 aberrations. Trial Registry: UMIN Registration No. 000017003; URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000019691

Original languageEnglish
JournalChest
DOIs
Publication statusPublished - Jan 1 2019

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Epidermal Growth Factor
Japan
Cohort Studies
Prospective Studies
Lung
Neoplasms
Non-Small Cell Lung Carcinoma
Fluorescence In Situ Hybridization
Epidermal Growth Factor Receptor
Demography
Insertional Mutagenesis
Human Development
Oncogenes
Registries
Exons
Therapeutics

Keywords

  • fluorescence in situ hybridization
  • human epidermal growth factor 2
  • immunohistochemistry
  • mutation
  • non-small cell lung cancer

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine
  • Cardiology and Cardiovascular Medicine

Cite this

A Prospective Cohort Study to Define the Clinical Features and Outcome of Lung Cacers Harboring HER2 Aberration in Japan (HER2-CS STUDY). / Ninomiya, Kiichiro; Hata, Tae; Yoshioka, Hiroshige; Oohashi, Kadoaki; Bessho, Akihiro; Hosokawa, Shinobu; Ishikawa, Nobuhisa; Yamasaki, Masahiro; Shibayama, Takuo; Aoe, Keisuke; Kozuki, Toshiyuki; Harita, Shingo; Ueda, Yutaka; Murakami, Toshi; Fujimoto, Nobukazu; Yanai, Hiroyuki; Toyooka, Shinichi; Takata, Minoru; Hotta, Katsuyuki; Kiura, Katsuyuki; Gemba, K.; Ikeda, G.; Yasugi, M.; Kurimoto, E.; Nakano, K.; Moritaka, T.; Inoue, K.; Miyoshi, S.; Hamaguchi, N.; Ito, R.; Sano, Y.; Takata, I.; Mitani, A.; Nishisaka, T.; Shoda, H.; Nishida, A.; Tamamoto, S.; Fujitaka, K.; Masuda, T.; Miyamoto, S.; Hattori, N.; Sugimoto, K.; Fujii, S.; Ueda, Y.; Sakugawa, Y.; Fukamatsu, N.; Ogata, K.; Bandoh, S.; Kanaji, N.; Takigawa, N.; Yamane, H.; Ochi, N.; Honda, Y.; Oka, M.; Kittaka, M.; Kubota, T.; Yokoyama, A.; Yokoyama, T.; Sato, E.; Shiota, Y.; Horita, N.; Kanematsu, T.; Awaya, Y.; Nakamasu, A.; Murakami, I.; Kuyama, S.; Kudo, K.; Tamura, T.; Umeno, T.; Morichika, D.; Fujiwara, K.; Sato, K.; Harada, D.; Nogami, N.; Nishii, K.; Fuchimoto, Y.; Kishimoto, T.; Kawai, H.; Watanabe, K.; Tokumo, K.; Isobe, T.; Tsubata, Y.; Inoue, M.; Ichikawa, H.; Nishioka, Y.; Hanibuchi, M.; Goto, H.; Sumikawa, T.; Kodani, M.; Suyama, H.; Makino, Hirofumi; Kinosita, N.; Shimizu, E.; Obata, H.; Ikegami, H.; Chikamori, K.; Maeda, T.; Kishino, T.; Kamei, H.; Ueoka, H.; Kunihiro, Y.; Kobayashi, T.; Ueda, K.; Hayashi, M.; Kamiya, M.; Murakami, J.; Sato, A.; Ichihara, Eiki; Kubo, Toshio; Ninomiya, Takashi; Hirata, T.; Minami, D.; Kato, Y.; Higo, H.; Makimoto, G.; Toyota, Y.; Oda, N.; Nakanishi, M.; Kayatani, H.; Senoo, S.; Kano, H.; Watanabe, H.; Ando, T.; Nakasuka, T.; Hara, N.; Itano, J.; Nakashima, H.; Tabata, Masahiro.

In: Chest, 01.01.2019.

Research output: Contribution to journalArticle

Ninomiya, K, Hata, T, Yoshioka, H, Oohashi, K, Bessho, A, Hosokawa, S, Ishikawa, N, Yamasaki, M, Shibayama, T, Aoe, K, Kozuki, T, Harita, S, Ueda, Y, Murakami, T, Fujimoto, N, Yanai, H, Toyooka, S, Takata, M, Hotta, K, Kiura, K, Gemba, K, Ikeda, G, Yasugi, M, Kurimoto, E, Nakano, K, Moritaka, T, Inoue, K, Miyoshi, S, Hamaguchi, N, Ito, R, Sano, Y, Takata, I, Mitani, A, Nishisaka, T, Shoda, H, Nishida, A, Tamamoto, S, Fujitaka, K, Masuda, T, Miyamoto, S, Hattori, N, Sugimoto, K, Fujii, S, Ueda, Y, Sakugawa, Y, Fukamatsu, N, Ogata, K, Bandoh, S, Kanaji, N, Takigawa, N, Yamane, H, Ochi, N, Honda, Y, Oka, M, Kittaka, M, Kubota, T, Yokoyama, A, Yokoyama, T, Sato, E, Shiota, Y, Horita, N, Kanematsu, T, Awaya, Y, Nakamasu, A, Murakami, I, Kuyama, S, Kudo, K, Tamura, T, Umeno, T, Morichika, D, Fujiwara, K, Sato, K, Harada, D, Nogami, N, Nishii, K, Fuchimoto, Y, Kishimoto, T, Kawai, H, Watanabe, K, Tokumo, K, Isobe, T, Tsubata, Y, Inoue, M, Ichikawa, H, Nishioka, Y, Hanibuchi, M, Goto, H, Sumikawa, T, Kodani, M, Suyama, H, Makino, H, Kinosita, N, Shimizu, E, Obata, H, Ikegami, H, Chikamori, K, Maeda, T, Kishino, T, Kamei, H, Ueoka, H, Kunihiro, Y, Kobayashi, T, Ueda, K, Hayashi, M, Kamiya, M, Murakami, J, Sato, A, Ichihara, E, Kubo, T, Ninomiya, T, Hirata, T, Minami, D, Kato, Y, Higo, H, Makimoto, G, Toyota, Y, Oda, N, Nakanishi, M, Kayatani, H, Senoo, S, Kano, H, Watanabe, H, Ando, T, Nakasuka, T, Hara, N, Itano, J, Nakashima, H & Tabata, M 2019, 'A Prospective Cohort Study to Define the Clinical Features and Outcome of Lung Cacers Harboring HER2 Aberration in Japan (HER2-CS STUDY)', Chest. https://doi.org/10.1016/j.chest.2019.01.011
Ninomiya, Kiichiro ; Hata, Tae ; Yoshioka, Hiroshige ; Oohashi, Kadoaki ; Bessho, Akihiro ; Hosokawa, Shinobu ; Ishikawa, Nobuhisa ; Yamasaki, Masahiro ; Shibayama, Takuo ; Aoe, Keisuke ; Kozuki, Toshiyuki ; Harita, Shingo ; Ueda, Yutaka ; Murakami, Toshi ; Fujimoto, Nobukazu ; Yanai, Hiroyuki ; Toyooka, Shinichi ; Takata, Minoru ; Hotta, Katsuyuki ; Kiura, Katsuyuki ; Gemba, K. ; Ikeda, G. ; Yasugi, M. ; Kurimoto, E. ; Nakano, K. ; Moritaka, T. ; Inoue, K. ; Miyoshi, S. ; Hamaguchi, N. ; Ito, R. ; Sano, Y. ; Takata, I. ; Mitani, A. ; Nishisaka, T. ; Shoda, H. ; Nishida, A. ; Tamamoto, S. ; Fujitaka, K. ; Masuda, T. ; Miyamoto, S. ; Hattori, N. ; Sugimoto, K. ; Fujii, S. ; Ueda, Y. ; Sakugawa, Y. ; Fukamatsu, N. ; Ogata, K. ; Bandoh, S. ; Kanaji, N. ; Takigawa, N. ; Yamane, H. ; Ochi, N. ; Honda, Y. ; Oka, M. ; Kittaka, M. ; Kubota, T. ; Yokoyama, A. ; Yokoyama, T. ; Sato, E. ; Shiota, Y. ; Horita, N. ; Kanematsu, T. ; Awaya, Y. ; Nakamasu, A. ; Murakami, I. ; Kuyama, S. ; Kudo, K. ; Tamura, T. ; Umeno, T. ; Morichika, D. ; Fujiwara, K. ; Sato, K. ; Harada, D. ; Nogami, N. ; Nishii, K. ; Fuchimoto, Y. ; Kishimoto, T. ; Kawai, H. ; Watanabe, K. ; Tokumo, K. ; Isobe, T. ; Tsubata, Y. ; Inoue, M. ; Ichikawa, H. ; Nishioka, Y. ; Hanibuchi, M. ; Goto, H. ; Sumikawa, T. ; Kodani, M. ; Suyama, H. ; Makino, Hirofumi ; Kinosita, N. ; Shimizu, E. ; Obata, H. ; Ikegami, H. ; Chikamori, K. ; Maeda, T. ; Kishino, T. ; Kamei, H. ; Ueoka, H. ; Kunihiro, Y. ; Kobayashi, T. ; Ueda, K. ; Hayashi, M. ; Kamiya, M. ; Murakami, J. ; Sato, A. ; Ichihara, Eiki ; Kubo, Toshio ; Ninomiya, Takashi ; Hirata, T. ; Minami, D. ; Kato, Y. ; Higo, H. ; Makimoto, G. ; Toyota, Y. ; Oda, N. ; Nakanishi, M. ; Kayatani, H. ; Senoo, S. ; Kano, H. ; Watanabe, H. ; Ando, T. ; Nakasuka, T. ; Hara, N. ; Itano, J. ; Nakashima, H. ; Tabata, Masahiro. / A Prospective Cohort Study to Define the Clinical Features and Outcome of Lung Cacers Harboring HER2 Aberration in Japan (HER2-CS STUDY). In: Chest. 2019.
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title = "A Prospective Cohort Study to Define the Clinical Features and Outcome of Lung Cacers Harboring HER2 Aberration in Japan (HER2-CS STUDY)",
abstract = "Background: Human epidermal growth factor 2 (HER2) is a potential driver oncogene. Although HER2-targeted precision therapy has been tested in non-small cell lung cancer (NSCLC), the demographic characteristics of HER2-positive NSCLC have not been systematically defined. Methods: Patients with pathologically confirmed stage IIIB/IV or recurrent NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, were prospectively registered. HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays were performed to screen patients. HER2 mutations were identified by using direct gene sequencing. The aim of this study was to clarify the frequency, characteristics, and outcome of HER2-positive NSCLC. HER2 was defined as positive if the tumor harbored IHC3+, IHC2+/FISH+, or exon 20 insertion mutations. Results: Of the 1,126 tumors screened, 34 (3.0{\%}) were IHC3+, and 34 (3.0{\%}) were IHC2+/FISH+. Among the 724 epidermal growth factor receptor wild-type tumors, 21 (2.9{\%}) were HER2-mutant tumors, including A775-G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female patients had HER2-mutant tumors more frequently, whereas both IHC3+ and IHC2+/FISH+ tumors were detected more often in male subjects and smokers. Patients with an HER2-aberrant tumor had a significantly worse prognosis than those with epidermal growth factor receptor-positive and anaplastic lymphoma kinase-positive tumors, possibly due to the low proportion that received HER2-targeted therapies (n = 15 [26{\%}]) and low response rates of 0{\%} and 14{\%} in patients with HER2-overexpressing and HER2-mutant tumors, respectively. Conclusions: This prospective large-scale cohort study is the first to show comprehensively the frequency and clinical demographic characteristics of those with HER2-positive advanced lung tumors in detail, providing critical historical data for future drug development against HER2-positive NSCLC. Future treatment strategies would be developed stratified according to the types of HER2 aberrations. Trial Registry: UMIN Registration No. 000017003; URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000019691",
keywords = "fluorescence in situ hybridization, human epidermal growth factor 2, immunohistochemistry, mutation, non-small cell lung cancer",
author = "Kiichiro Ninomiya and Tae Hata and Hiroshige Yoshioka and Kadoaki Oohashi and Akihiro Bessho and Shinobu Hosokawa and Nobuhisa Ishikawa and Masahiro Yamasaki and Takuo Shibayama and Keisuke Aoe and Toshiyuki Kozuki and Shingo Harita and Yutaka Ueda and Toshi Murakami and Nobukazu Fujimoto and Hiroyuki Yanai and Shinichi Toyooka and Minoru Takata and Katsuyuki Hotta and Katsuyuki Kiura and K. Gemba and G. Ikeda and M. Yasugi and E. Kurimoto and K. Nakano and T. Moritaka and K. Inoue and S. Miyoshi and N. Hamaguchi and R. Ito and Y. Sano and I. Takata and A. Mitani and T. Nishisaka and H. Shoda and A. Nishida and S. Tamamoto and K. Fujitaka and T. Masuda and S. Miyamoto and N. Hattori and K. Sugimoto and S. Fujii and Y. Ueda and Y. Sakugawa and N. Fukamatsu and K. Ogata and S. Bandoh and N. Kanaji and N. Takigawa and H. Yamane and N. Ochi and Y. Honda and M. Oka and M. Kittaka and T. Kubota and A. Yokoyama and T. Yokoyama and E. Sato and Y. Shiota and N. Horita and T. Kanematsu and Y. Awaya and A. Nakamasu and I. Murakami and S. Kuyama and K. Kudo and T. Tamura and T. Umeno and D. Morichika and K. Fujiwara and K. Sato and D. Harada and N. Nogami and K. Nishii and Y. Fuchimoto and T. Kishimoto and H. Kawai and K. Watanabe and K. Tokumo and T. Isobe and Y. Tsubata and M. Inoue and H. Ichikawa and Y. Nishioka and M. Hanibuchi and H. Goto and T. Sumikawa and M. Kodani and H. Suyama and Hirofumi Makino and N. Kinosita and E. Shimizu and H. Obata and H. Ikegami and K. Chikamori and T. Maeda and T. Kishino and H. Kamei and H. Ueoka and Y. Kunihiro and T. Kobayashi and K. Ueda and M. Hayashi and M. Kamiya and J. Murakami and A. Sato and Eiki Ichihara and Toshio Kubo and Takashi Ninomiya and T. Hirata and D. Minami and Y. Kato and H. Higo and G. Makimoto and Y. Toyota and N. Oda and M. Nakanishi and H. Kayatani and S. Senoo and H. Kano and H. Watanabe and T. Ando and T. Nakasuka and N. Hara and J. Itano and H. Nakashima and Masahiro Tabata",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.chest.2019.01.011",
language = "English",
journal = "Chest",
issn = "0012-3692",
publisher = "American College of Chest Physicians",

}

TY - JOUR

T1 - A Prospective Cohort Study to Define the Clinical Features and Outcome of Lung Cacers Harboring HER2 Aberration in Japan (HER2-CS STUDY)

AU - Ninomiya, Kiichiro

AU - Hata, Tae

AU - Yoshioka, Hiroshige

AU - Oohashi, Kadoaki

AU - Bessho, Akihiro

AU - Hosokawa, Shinobu

AU - Ishikawa, Nobuhisa

AU - Yamasaki, Masahiro

AU - Shibayama, Takuo

AU - Aoe, Keisuke

AU - Kozuki, Toshiyuki

AU - Harita, Shingo

AU - Ueda, Yutaka

AU - Murakami, Toshi

AU - Fujimoto, Nobukazu

AU - Yanai, Hiroyuki

AU - Toyooka, Shinichi

AU - Takata, Minoru

AU - Hotta, Katsuyuki

AU - Kiura, Katsuyuki

AU - Gemba, K.

AU - Ikeda, G.

AU - Yasugi, M.

AU - Kurimoto, E.

AU - Nakano, K.

AU - Moritaka, T.

AU - Inoue, K.

AU - Miyoshi, S.

AU - Hamaguchi, N.

AU - Ito, R.

AU - Sano, Y.

AU - Takata, I.

AU - Mitani, A.

AU - Nishisaka, T.

AU - Shoda, H.

AU - Nishida, A.

AU - Tamamoto, S.

AU - Fujitaka, K.

AU - Masuda, T.

AU - Miyamoto, S.

AU - Hattori, N.

AU - Sugimoto, K.

AU - Fujii, S.

AU - Ueda, Y.

AU - Sakugawa, Y.

AU - Fukamatsu, N.

AU - Ogata, K.

AU - Bandoh, S.

AU - Kanaji, N.

AU - Takigawa, N.

AU - Yamane, H.

AU - Ochi, N.

AU - Honda, Y.

AU - Oka, M.

AU - Kittaka, M.

AU - Kubota, T.

AU - Yokoyama, A.

AU - Yokoyama, T.

AU - Sato, E.

AU - Shiota, Y.

AU - Horita, N.

AU - Kanematsu, T.

AU - Awaya, Y.

AU - Nakamasu, A.

AU - Murakami, I.

AU - Kuyama, S.

AU - Kudo, K.

AU - Tamura, T.

AU - Umeno, T.

AU - Morichika, D.

AU - Fujiwara, K.

AU - Sato, K.

AU - Harada, D.

AU - Nogami, N.

AU - Nishii, K.

AU - Fuchimoto, Y.

AU - Kishimoto, T.

AU - Kawai, H.

AU - Watanabe, K.

AU - Tokumo, K.

AU - Isobe, T.

AU - Tsubata, Y.

AU - Inoue, M.

AU - Ichikawa, H.

AU - Nishioka, Y.

AU - Hanibuchi, M.

AU - Goto, H.

AU - Sumikawa, T.

AU - Kodani, M.

AU - Suyama, H.

AU - Makino, Hirofumi

AU - Kinosita, N.

AU - Shimizu, E.

AU - Obata, H.

AU - Ikegami, H.

AU - Chikamori, K.

AU - Maeda, T.

AU - Kishino, T.

AU - Kamei, H.

AU - Ueoka, H.

AU - Kunihiro, Y.

AU - Kobayashi, T.

AU - Ueda, K.

AU - Hayashi, M.

AU - Kamiya, M.

AU - Murakami, J.

AU - Sato, A.

AU - Ichihara, Eiki

AU - Kubo, Toshio

AU - Ninomiya, Takashi

AU - Hirata, T.

AU - Minami, D.

AU - Kato, Y.

AU - Higo, H.

AU - Makimoto, G.

AU - Toyota, Y.

AU - Oda, N.

AU - Nakanishi, M.

AU - Kayatani, H.

AU - Senoo, S.

AU - Kano, H.

AU - Watanabe, H.

AU - Ando, T.

AU - Nakasuka, T.

AU - Hara, N.

AU - Itano, J.

AU - Nakashima, H.

AU - Tabata, Masahiro

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Human epidermal growth factor 2 (HER2) is a potential driver oncogene. Although HER2-targeted precision therapy has been tested in non-small cell lung cancer (NSCLC), the demographic characteristics of HER2-positive NSCLC have not been systematically defined. Methods: Patients with pathologically confirmed stage IIIB/IV or recurrent NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, were prospectively registered. HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays were performed to screen patients. HER2 mutations were identified by using direct gene sequencing. The aim of this study was to clarify the frequency, characteristics, and outcome of HER2-positive NSCLC. HER2 was defined as positive if the tumor harbored IHC3+, IHC2+/FISH+, or exon 20 insertion mutations. Results: Of the 1,126 tumors screened, 34 (3.0%) were IHC3+, and 34 (3.0%) were IHC2+/FISH+. Among the 724 epidermal growth factor receptor wild-type tumors, 21 (2.9%) were HER2-mutant tumors, including A775-G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female patients had HER2-mutant tumors more frequently, whereas both IHC3+ and IHC2+/FISH+ tumors were detected more often in male subjects and smokers. Patients with an HER2-aberrant tumor had a significantly worse prognosis than those with epidermal growth factor receptor-positive and anaplastic lymphoma kinase-positive tumors, possibly due to the low proportion that received HER2-targeted therapies (n = 15 [26%]) and low response rates of 0% and 14% in patients with HER2-overexpressing and HER2-mutant tumors, respectively. Conclusions: This prospective large-scale cohort study is the first to show comprehensively the frequency and clinical demographic characteristics of those with HER2-positive advanced lung tumors in detail, providing critical historical data for future drug development against HER2-positive NSCLC. Future treatment strategies would be developed stratified according to the types of HER2 aberrations. Trial Registry: UMIN Registration No. 000017003; URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000019691

AB - Background: Human epidermal growth factor 2 (HER2) is a potential driver oncogene. Although HER2-targeted precision therapy has been tested in non-small cell lung cancer (NSCLC), the demographic characteristics of HER2-positive NSCLC have not been systematically defined. Methods: Patients with pathologically confirmed stage IIIB/IV or recurrent NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, were prospectively registered. HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays were performed to screen patients. HER2 mutations were identified by using direct gene sequencing. The aim of this study was to clarify the frequency, characteristics, and outcome of HER2-positive NSCLC. HER2 was defined as positive if the tumor harbored IHC3+, IHC2+/FISH+, or exon 20 insertion mutations. Results: Of the 1,126 tumors screened, 34 (3.0%) were IHC3+, and 34 (3.0%) were IHC2+/FISH+. Among the 724 epidermal growth factor receptor wild-type tumors, 21 (2.9%) were HER2-mutant tumors, including A775-G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female patients had HER2-mutant tumors more frequently, whereas both IHC3+ and IHC2+/FISH+ tumors were detected more often in male subjects and smokers. Patients with an HER2-aberrant tumor had a significantly worse prognosis than those with epidermal growth factor receptor-positive and anaplastic lymphoma kinase-positive tumors, possibly due to the low proportion that received HER2-targeted therapies (n = 15 [26%]) and low response rates of 0% and 14% in patients with HER2-overexpressing and HER2-mutant tumors, respectively. Conclusions: This prospective large-scale cohort study is the first to show comprehensively the frequency and clinical demographic characteristics of those with HER2-positive advanced lung tumors in detail, providing critical historical data for future drug development against HER2-positive NSCLC. Future treatment strategies would be developed stratified according to the types of HER2 aberrations. Trial Registry: UMIN Registration No. 000017003; URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000019691

KW - fluorescence in situ hybridization

KW - human epidermal growth factor 2

KW - immunohistochemistry

KW - mutation

KW - non-small cell lung cancer

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UR - http://www.scopus.com/inward/citedby.url?scp=85065055094&partnerID=8YFLogxK

U2 - 10.1016/j.chest.2019.01.011

DO - 10.1016/j.chest.2019.01.011

M3 - Article

JO - Chest

JF - Chest

SN - 0012-3692

ER -