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Preclinically, HER3 ligand heregulin induces resistance to EGFR-TKIs, whereas the pan-human EGFR family inhibitor afatinib remains effective. Here, we examined whether soluble heregulin levels have clinical implications for <jats:italic>EGFR<\/jats:italic>-mutant NSCLC treated with EGFR-TKIs. Soluble heregulin was immunologically measured in plasma from <jats:italic>EGFR<\/jats:italic>-mutant NSCLC patients. Cutoff values were determined by 1-year PFS ROC curve. The relationship between soluble heregulin and PFS following EGFR-TKI therapy was analyzed by Cox proportional hazards model. Seventy-three patients were enrolled: 44 were treated with 1<jats:sup>st<\/jats:sup>-generation and 29 with 2<jats:sup>nd<\/jats:sup>-generation EGFR-TKIs. Soluble heregulin levels varied (range: 274\u20137,138\u2009pg\/mL, median: 739\u2009pg\/mL). Among patients treated with 1<jats:sup>st<\/jats:sup>-generation EGFR-TKIs, those with high heregulin (n\u2009=\u200920, &gt;800\u2009pg\/mL) had a tendency for shorter PFS than those with low heregulin (n\u2009=\u200924, &lt;800\u2009pg\/mL), with median PFS of 322 and 671 days, respectively. Cox proportional hazards model also indicated a trend toward resistance against 1<jats:sup>st<\/jats:sup>-generation EGFR-TKIs (HR: 1.825, 95% CI: 0.865\u20134.318) but not against 2<jats:sup>nd<\/jats:sup>-generation EGFR-TKIs. Soluble heregulin potentially correlates with resistance to EGFR-TKIs but not 2<jats:sup>nd<\/jats:sup>-generation EGFR-TKIs in patients with <jats:italic>EGFR<\/jats:italic>-mutant NSCLC.<\/jats:p>","DOI":"10.1038\/s41598-019-55939-5","type":"journal-article","created":{"date-parts":[[2019,12,20]],"date-time":"2019-12-20T11:03:02Z","timestamp":1576839782000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Heregulin expression and its clinical implication for patients with EGFR-mutant non-small cell lung cancer treated with EGFR-tyrosine kinase inhibitors"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0816-5315","authenticated-orcid":false,"given":"Kimio","family":"Yonesaka","sequence":"first","affiliation":[]},{"given":"Eiji","family":"Iwama","sequence":"additional","affiliation":[]},{"given":"Hidetoshi","family":"Hayashi","sequence":"additional","affiliation":[]},{"given":"Shinichiro","family":"Suzuki","sequence":"additional","affiliation":[]},{"given":"Ryoji","family":"Kato","sequence":"additional","affiliation":[]},{"given":"Satomi","family":"Watanabe","sequence":"additional","affiliation":[]},{"given":"Takayuki","family":"Takahama","sequence":"additional","affiliation":[]},{"given":"Junko","family":"Tanizaki","sequence":"additional","affiliation":[]},{"given":"Kaoru","family":"Tanaka","sequence":"additional","affiliation":[]},{"given":"Masayuki","family":"Takeda","sequence":"additional","affiliation":[]},{"given":"Kazuko","family":"Sakai","sequence":"additional","affiliation":[]},{"given":"Koichi","family":"Azuma","sequence":"additional","affiliation":[]},{"given":"Yasutaka","family":"Chiba","sequence":"additional","affiliation":[]},{"given":"Shinji","family":"Atagi","sequence":"additional","affiliation":[]},{"given":"Kazuto","family":"Nishio","sequence":"additional","affiliation":[]},{"given":"Isamu","family":"Okamoto","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1284-9776","authenticated-orcid":false,"given":"Kazuhiko","family":"Nakagawa","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2019,12,20]]},"reference":[{"key":"55939_CR1","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.jtho.2015.10.002","volume":"11","author":"C Zhou","year":"2016","unstructured":"Zhou, C. & Yao, L. D. Strategies to improve outcomes of patients with EGFR-mutant non\u2013small cell lung cancer: review of the literature. J Thorac Oncol. 11, 174\u2013186 (2016).","journal-title":"J Thorac Oncol."},{"key":"55939_CR2","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1007\/s10147-006-0583-4","volume":"11","author":"T Mitsudomi","year":"2006","unstructured":"Mitsudomi, T., Kosaka, T. & Yatabe, Y. Biological and clinical implications of EGFR mutations in lung cancer. Int J Clin Oncol. 11, 190\u2013198 (2006).","journal-title":"Int J Clin Oncol."},{"key":"55939_CR3","doi-asserted-by":"publisher","first-page":"2380","DOI":"10.1056\/NEJMoa0909530","volume":"362","author":"M Maemondo","year":"2010","unstructured":"Maemondo, M. et al. North-East Japan Study Group. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 362, 2380\u20132388 (2010).","journal-title":"N Engl J Med."},{"key":"55939_CR4","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/S1470-2045(09)70364-X","volume":"11","author":"T Mitsudomi","year":"2010","unstructured":"Mitsudomi, T. et al. West Japan Oncology Group. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 11, 121\u2013128 (2010).","journal-title":"Lancet Oncol."},{"key":"55939_CR5","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1056\/NEJMoa0810699","volume":"361","author":"TS Mok","year":"2009","unstructured":"Mok, T. S. et al. Gefitinib or carboplatin\u2013paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 361, 947\u2013957 (2009).","journal-title":"N Engl J Med."},{"key":"55939_CR6","doi-asserted-by":"publisher","first-page":"1497","DOI":"10.1126\/science.1099314","volume":"304","author":"JG Paez","year":"2004","unstructured":"Paez, J. G. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 304, 1497\u2013500 (2004).","journal-title":"Science."},{"key":"55939_CR7","doi-asserted-by":"publisher","first-page":"2129","DOI":"10.1056\/NEJMoa040938","volume":"350","author":"TJ Lynch","year":"2004","unstructured":"Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 350, 2129\u20132139 (2004).","journal-title":"N Engl J Med."},{"key":"55939_CR8","doi-asserted-by":"publisher","first-page":"75ra26","DOI":"10.1126\/scitranslmed.3002003","volume":"3","author":"L Sequist","year":"2011","unstructured":"Sequist, L. et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 3, 75ra26 (2011).","journal-title":"Sci Transl Med."},{"key":"55939_CR9","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1056\/NEJMoa044238","volume":"352","author":"S Kobayashi","year":"2005","unstructured":"Kobayashi, S. et al. EGFR mutation and resistance of non-small cell lung cancer to gefitinib. N Engl J Med. 352, 786\u2013792 (2005).","journal-title":"N Engl J Med."},{"key":"55939_CR10","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1126\/science.1141478","volume":"316","author":"JA Engelman","year":"2007","unstructured":"Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. 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Cancer Res. 68, 9479\u20139487 (2008).","journal-title":"Cancer Res."},{"key":"55939_CR13","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1016\/S1470-2045(16)30033-X","volume":"17","author":"K Park","year":"2016","unstructured":"Park, K. et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 17, 577\u2013589 (2016).","journal-title":"Lancet Oncol."},{"key":"55939_CR14","doi-asserted-by":"publisher","first-page":"1454","DOI":"10.1016\/S1470-2045(17)30608-3","volume":"18","author":"YL Wu","year":"2017","unstructured":"Wu, Y. L. et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 18, 1454\u20131466 (2017).","journal-title":"Lancet Oncol."},{"key":"55939_CR15","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1056\/NEJMoa1713137","volume":"378","author":"JC Soria","year":"2018","unstructured":"Soria, J. C. et al. FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non\u2013small-cell lung cancer. N Engl J Med. 378, 113\u2013125 (2018).","journal-title":"N Engl J Med."},{"key":"55939_CR16","doi-asserted-by":"publisher","first-page":"4702","DOI":"10.1038\/onc.2008.109","volume":"27","author":"D Li","year":"2008","unstructured":"Li, D. et al. BIBW2992, an irreversible EGFR\/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene. 27, 4702\u20134711 (2008).","journal-title":"Oncogene."},{"key":"55939_CR17","doi-asserted-by":"publisher","first-page":"11924","DOI":"10.1158\/0008-5472.CAN-07-1885","volume":"67","author":"JA Engelman","year":"2007","unstructured":"Engelman, J. A. et al. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res. 67, 11924\u201311932 (2007).","journal-title":"Cancer Res."},{"key":"55939_CR18","doi-asserted-by":"publisher","first-page":"3335","DOI":"10.1200\/JCO.2012.45.0981","volume":"31","author":"N Katakami","year":"2013","unstructured":"Katakami, N. et al. LUX-Lung 4: A Phase II trial of afatinib in patients with advanced non\u2013small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 31, 3335\u20133341 (2013).","journal-title":"J Clin Oncol."},{"key":"55939_CR19","doi-asserted-by":"crossref","first-page":"68123","DOI":"10.18632\/oncotarget.19243","volume":"8","author":"K Tanaka","year":"2017","unstructured":"Tanaka, K. et al. Acquisition of the T790M resistance mutation during afatinib treatment in EGFR tyrosine kinase inhibitor\u2013na\u00efve patients with non\u2013small cell lung cancer harboring EGFR mutations. Oncotarget. 8, 68123\u201368130 (2017).","journal-title":"Oncotarget."},{"key":"55939_CR20","doi-asserted-by":"publisher","first-page":"1689","DOI":"10.1056\/NEJMoa1411817","volume":"372","author":"PA J\u00e4nne","year":"2015","unstructured":"J\u00e4nne, P. A. et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 372, 1689\u20131699 (2015).","journal-title":"N Engl J Med."},{"key":"55939_CR21","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1158\/2159-8290.CD-14-0337","volume":"4","author":"DA Cross","year":"2014","unstructured":"Cross, D. A. et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 4, 1046\u20131061 (2014).","journal-title":"Cancer Discov."},{"key":"55939_CR22","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.ccr.2006.05.024","volume":"10","author":"BB Zhou","year":"2006","unstructured":"Zhou, B. B. et al. Targeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancer. Cancer Cell. 10, 39\u201350 (2006).","journal-title":"Cancer Cell."},{"key":"55939_CR23","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1016\/j.ebiom.2015.02.005","volume":"2","author":"J Mendella","year":"2015","unstructured":"Mendella, J. et al. Clinical translation and validation of a predictive biomarker for patritumab, an anti-human epidermal growth factor receptor 3 (HER3) monoclonal antibody, in patients with advanced non-small cell lung cancer. EBioMedicine. 2, 264\u2013271 (2015).","journal-title":"EBioMedicine."},{"key":"55939_CR24","doi-asserted-by":"publisher","first-page":"24267","DOI":"10.1074\/jbc.M115.657270","volume":"290","author":"C Capparelli","year":"2015","unstructured":"Capparelli, C., Rosenbaum, S., Berger, A. C. & Aplin, A. E. Fibroblast-derived neuregulin 1 promotes compensatory ErbB3 receptor signaling in mutant BRAF melanoma. J Biol Chem. 290, 24267\u201324277 (2015).","journal-title":"J Biol Chem."},{"key":"55939_CR25","doi-asserted-by":"publisher","first-page":"267","DOI":"10.2174\/1574892811666160418123221","volume":"11","author":"H Kawakami","year":"2016","unstructured":"Kawakami, H. & Yonesaka, K. HER3 and its ligand, heregulin, as targets for cancer therapy. Recent Pat Anticancer Drug Discov. 11, 267\u2013274 (2016).","journal-title":"Recent Pat Anticancer Drug Discov."},{"key":"55939_CR26","doi-asserted-by":"publisher","first-page":"2358","DOI":"10.1007\/s00018-007-7120-0","volume":"64","author":"M Breuleux","year":"2007","unstructured":"Breuleux, M. Role of heregulin in human cancer. Cell Mol Life Sci. 64, 2358\u20132377 (2007).","journal-title":"Cell Mol Life Sci."},{"key":"55939_CR27","doi-asserted-by":"publisher","first-page":"878","DOI":"10.1038\/onc.2015.142","volume":"35","author":"K Yonesaka","year":"2016","unstructured":"Yonesaka, K. et al. Anti-HER3 monoclonal antibody patritumab sensitizes refractory non-small cell lung cancer to the epidermal growth factor receptor inhibitor erlotinib. Oncogene. 35, 878\u2013886 (2016).","journal-title":"Oncogene."},{"key":"55939_CR28","doi-asserted-by":"publisher","first-page":"33602","DOI":"10.18632\/oncotarget.5286","volume":"6","author":"K Yonesaka","year":"2015","unstructured":"Yonesaka, K. et al. The pan-HER family tyrosine kinase inhibitor afatinib overcomes HER3 ligand heregulin-mediated resistance to EGFR inhibitors in non-small cell lung cancer. Oncotarget. 6, 33602\u201333611 (2015).","journal-title":"Oncotarget."},{"key":"55939_CR29","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.cllc.2014.09.008","volume":"16","author":"Y Zhang","year":"2015","unstructured":"Zhang, Y. et al. Impact of smoking status on EGFR-TKI efficacy for advanced non\u2013small-cell lung cancer in EGFR mutants: a meta-analysis. Clin Lung Cancer. 16, 144\u2013151.e1 (2015).","journal-title":"Clin Lung Cancer."},{"doi-asserted-by":"crossref","unstructured":"Ramalingam, S. S. et al. Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): final overall survival analysis. Ann Oncol. 30, Supplement 5 (2019).","key":"55939_CR30","DOI":"10.1093\/annonc\/mdz394.076"},{"key":"55939_CR31","doi-asserted-by":"publisher","first-page":"99ra86","DOI":"10.1126\/scitranslmed.3002442","volume":"3","author":"K Yonesaka","year":"2011","unstructured":"Yonesaka, K. et al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med. 3, 99ra86 (2011).","journal-title":"Sci Transl Med."},{"key":"55939_CR32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.lungcan.2016.12.018","volume":"105","author":"K Yonesaka","year":"2017","unstructured":"Yonesaka, K. et al. Circulating heregulin level is associated with the efficacy of patritumab combined with erlotinib in patients with non-small cell lung cancer. 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Eur J Cancer. 45, 228\u2013247 (2009).","journal-title":"Eur J Cancer."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-55939-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-55939-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-55939-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T17:38:11Z","timestamp":1671298691000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-55939-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,20]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["55939"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-55939-5","relation":{},"ISSN":["2045-2322"],"issn-type":[{"type":"electronic","value":"2045-2322"}],"subject":[],"published":{"date-parts":[[2019,12,20]]},"assertion":[{"value":"19 May 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 December 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 December 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Dr. Iwama reports personal fees from AstraZeneca. Atagi reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from MSD, grants and personal fees from Chugai, grants and personal fees from AstraZeneca, grants and personal fees from Taiho, grants and personal fees from Ono, grants and personal fees from Pfizer, grants and personal fees from Bristol-Myers Squibb, personal fees from Hisamitsu. Azuma reports personal fees from Boehringer Ingelheim, personal fees from AstraZeneca. Hayashi reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from AstraZeneca, grants from Chugai. Nishio reports grants from Boehringer Ingelheim. Takahama reports personal fees from Boehringer Ingelheim, personal fees from AstraZeneca. Takeda reports personal fees from Boehringer Ingelheim. Tanaka reports personal fees from Boehringer Ingelheim, personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb, personal fees from MSD Oncology. Tanizaki reports personal fees from Boehringer Ingelheim, personal fees from AstraZeneca, personal fees from Taiho Pharmaceutical, personal fees from Bristol-Myers Squibb, personal fees from Eli Lilly, personal fees from MSD Oncology. Dr. Okamoto reports grants and personal fees from AstraZeneca, grants and personal fees from Taiho Pharmaceutical, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Ono Pharmaceutical, grants and personal fees from MSD Oncology, grants and personal fees from Lilly, grants from Astellas Pharma, grants and personal fees from Bristol-Myers Squibb, grants from Novartis, grants and personal fees from Chugai Pharma, personal fees from Pfizer, grants from AbbVie. Yonesaka reports grants and personal fees from Boehringer Ingelheim. Nakagawa reports grants and personal fees from AstraZeneca, grants and personal fees from Taiho Pharmaceutical, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Ono Pharmaceutical, grants and personal fees from MSD Oncology, grants and personal fees from Lilly, grants and personal fees from Astellas Pharma, grants and personal fees from Bristol-Myers Squibb, grants from Novartis, grants and personal fees from Chugai Pharma, personal fees from Pfizer, grants from AbbVie, grants and personal fees from Takeda Pharma, grants and personal fees from Daiichi-sankyo.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"19501"}}