TY - JOUR
T1 - A Prospective Cohort Study to Define the Clinical Features and Outcome of Lung Cancers Harboring HER2 Aberration in Japan (HER2-CS STUDY)
AU - Ninomiya, Kiichiro
AU - Hata, Tae
AU - Yoshioka, Hiroshige
AU - Ohashi, Kadoaki
AU - Bessho, Akihiro
AU - Hosokawa, Shinobu
AU - Ishikawa, Nobuhisa
AU - Yamasaki, Masahiro
AU - Shibayama, T.
AU - Aoe, Keisuke
AU - Kozuki, Toshiyuki
AU - Harita, Shingo
AU - Ueda, Yutaka
AU - Murakami, T.
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, M.
AU - Fukamatsu, N.
AU - Ogata, Y.
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, H.
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, Akiko
AU - Ichihara, E.
AU - Kubo, Toshio
AU - Ninomiya, Takashi
AU - Hirata, T.
AU - Minami, Daisuke
AU - Kato, Yuka
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, M.
N1 - Funding Information:
Other contributions: The authors acknowledge and thank the investigators, coordinators, and all others involved who have contributed to this study. This study has been conducted with support from the LC-SCRUM group (S. Matsumoto and K. Goto) and the Center for Innovative Clinical Medicine, Okayama University Hospital (N. Kondoh, M. Fukata, S. Kuroda, S. Sugihara, N. Nakabayashi, N. Hiramatsu, S. Hinotsu, K. Zama, W. Ishii, Y. Ohe, C. Harada, M. Yoshida, K, Kamikawa, K. Shikata and J. Sakurai).
Funding Information:
Author contributions: The Steering Committee comprised K. H. K. O. K. N. S. T. and K. K.; and H. Yanai and M. T. were advisers to the HER2 aberration analysis. K. O. K. H. T. H. K. N. H. K. and K. K. also took part in the trial design and trial set-up; and K. O. K. H. K. N. and K. K. calculated the sample size. All authors contributed to the writing of the protocol. K. N. H. Yanai, and M. T. analyzed the data; T. H. H. Yoshioka, K. O. A. B. S. Hosokawa, N. I. M. Y. T. S. K. A. T. K. S. Harita, Y. U. T. M. and N. F. were responsible for acquisition of the data; S. T. and K. K. interpreted the results; and K. H. interpreted the results and drafted the manuscript. All authors critically reviewed the manuscript for important intellectual content. All authors have reviewed the version of the manuscript to be submitted and are in agreement with its content and submission. Financial/nonfinancial disclosures: The authors have reported to CHEST the following: K. N. has received honoraria outside the current work from Bristol-Myers Squibb and Merck Sharp & Dohme. K. O. has received research funding outside of the current work from Boehringer-Ingelheim and Novartis Pharmaceuticals Japan. K. H. has received honoraria outside the current work from AstraZeneca, Ono Pharmaceutical, Astellas, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Eli Lilly Japan, Daiichi-Sankyo Pharmaceutical, Boehringer-Ingelheim, Nihon Kayaku, Taiho Pharmaceutical, and Chugai Pharmaceutical. K. H. also has received research funding outside of the current work from AstraZeneca, Boehringer-Ingelheim, Ono Pharmaceutical, Astellas, Novartis, Bristol-Myers Squibb, Eli Lilly Japan, Merck Sharp & Dohme, and Chugai Pharmaceutical. K. K. has received honoraria outside the current work from Eli Lilly Japan, Nihon Kayaku, AstraZeneca, Daiichi-Sankyo Pharmaceutical, Chugai Pharmaceutical, Taiho Pharmaceutical, and Sanofi-Aventis. None declared (T. H. H. Yoshioka, K. O. A. B. S. Hosokawa, N. I. M. Y. T. S. K. A. T. K. S. Harita, Y. U. T. M. N. F. H. Yanai, S. T. M. T.). Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. HER2-CS Network Collaborators: This study has been conducted with dedicated contributions from the following: the HER2-CS Study group (K. Gemba, G. Ikeda, M. Yasugi, E. Kurimoto, K. Nakano [Chugoku Central Hospital], T. Moritaka, K. Inoue [Ehime Prefectural Central Hospital], S. Miyoshi, N. Hamaguchi, R. Ito, Y. Sano [Ehime University Hospital], I. Takata, A. Mitani [Fukuyama City Hospital], T. Nishisaka, H. Shoda, A. Nishida, S. Tamamoto [Hiroshima Prefectural Hospital], K. Fujitaka, T. Masuda, S. Miyamoto, N. Hattori [Hiroshima University Hospital], K. Sugimoto, S. Fujii, Y. Ueda [Japanese Red Cross Kobe Hospital], M. Sakugawa, N. Fukamatsu, Y. Ogata [Japanese Red Cross Okayama Hospital], S. Bandoh, N. Kanaji [Kagawa University Hospital], N. Takigawa, H. Yamane, N. Ochi, Y. Honda [Kawasaki Hospital], M. Oka, M. Kittaka [Kawasaki Medical School Hospital], T. Kubota, A. Yokoyama [Kochi Medical School Hospital], T. Yokoyama, E. Sato [Kurashiki Central Hospital], Y. Shiota, N. Horita [Kure Kyosai Hospital], T. Kanematsu [Matsuyama Red Cross Hospital], Y. Awaya, A. Nakamasu, Y. Sano [Miyoshi Central Hospital], I. Murakami [NHO Higashi-Hiroshima Medical Center], S. Kuyama, K. Kudo, T. Tamura, T. Umeno, D. Morichika [NHO Iwakuni Medical Center], K. Fujiwara, K. Sato [NHO Okayama Medical Center], D. Harada, N. Nogami [NHO Shikoku Cancer Center], K. Nishii [Okayama Health Foundation Hospital], Y. Fuchimoto, T. Kishimoto [Okayama Rosai Hospital], H. Kawai, K. Watanabe [Okayama Saiseikai General Hospital], K. Tokumo [Onomichi General Hospital], T. Isobe, Y. Tsubata [Shimane University School of Medicine], M. Inoue [Shimonoseki City Hospital], H. Ichikawa [Takamatsu Hospital], Y. Nishioka, M. Hanibuchi, H. Goto [Tokushima University Hospital], T. Sumikawa [Tottori Prefectural Central Hospital], M. Kodani, H. Suyama, H. Makino, Y. Ueda, N. Kinosita, E. Shimizu [Tottori University Hospital], H. Obata, H. Ikegami [Yamaguchi-ken Saiseikai Shimonoseki General Hospital], K. Chikamori, T. Maeda, T. Kishino, H. Kamei, H. Ueoka [NHO Yamaguchi-Ube Medical Center], Y. Kunihiro, T. Kobayashi, K. Ueda, M. Hayashi, M. Kamiya, J. Murakami [Yamaguchi University Hospital], A. Sato, E. Ichihara, T. Kubo, T. Ninomiya, T. Hirata, D. Minami, Y. Kato, H. Higo, G. Makimoto, Y. Toyota, N. Oda, M. Nakanishi, H. Kayatani, K. Nishii, S. Senoo, H. Kano, H. Watanabe, T. Ando, T. Nakasuka, N. Hara, J. Itano, H. Nakashima, and M. Tabata [Okayama University Hospital]). Other contributions: The authors acknowledge and thank the investigators, coordinators, and all others involved who have contributed to this study. This study has been conducted with support from the LC-SCRUM group (S. Matsumoto and K. Goto) and the Center for Innovative Clinical Medicine, Okayama University Hospital (N. Kondoh, M. Fukata, S. Kuroda, S. Sugihara, N. Nakabayashi, N. Hiramatsu, S. Hinotsu, K. Zama, W. Ishii, Y. Ohe, C. Harada, M. Yoshida, K, Kamikawa, K. Shikata and J. Sakurai). Additional information: The e-Appendix, e-Figures, and e-Tables can be found in the Supplemental Materials section of the online article. FUNDING/SUPPORT: This research was supported by a specific grant from the Japan Agency for Medical Research and Development, which is funded by the Japanese government.
Publisher Copyright:
© 2019 American College of Chest Physicians
PY - 2019/8
Y1 - 2019/8
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
UR - http://www.scopus.com/inward/record.url?scp=85065055094&partnerID=8YFLogxK
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
C2 - 31072612
AN - SCOPUS:85065055094
SN - 0012-3692
VL - 156
SP - 357
EP - 366
JO - Diseases of the chest
JF - Diseases of the chest
IS - 2
ER -
