Heregulin expression and its clinical implication for patients with EGFR-mutant non-small cell lung cancer treated with EGFR-tyrosine kinase inhibitors

Kimio Yonesaka, Eiji Iwama, Hidetoshi Hayashi, Shinichiro Suzuki, Ryoji Kato, Satomi Watanabe, Takayuki Takahama, Junko Tanizaki, Kaoru Tanaka, Masayuki Takeda, Kazuko Sakai, Koichi Azuma, Yasutaka Chiba, Shinji Atagi, Kazuto Nishio, Isamu Okamoto, Kazuhiko Nakagawa

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Abstract

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard therapy for EGFR-mutant non-small cell lung cancer (NSCLC). 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 EGFR-mutant NSCLC treated with EGFR-TKIs. Soluble heregulin was immunologically measured in plasma from EGFR-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 1st-generation and 29 with 2nd-generation EGFR-TKIs. Soluble heregulin levels varied (range: 274–7,138 pg/mL, median: 739 pg/mL). Among patients treated with 1st-generation EGFR-TKIs, those with high heregulin (n = 20, >800 pg/mL) had a tendency for shorter PFS than those with low heregulin (n = 24, <800 pg/mL), with median PFS of 322 and 671 days, respectively. Cox proportional hazards model also indicated a trend toward resistance against 1st-generation EGFR-TKIs (HR: 1.825, 95% CI: 0.865–4.318) but not against 2nd-generation EGFR-TKIs. Soluble heregulin potentially correlates with resistance to EGFR-TKIs but not 2nd-generation EGFR-TKIs in patients with EGFR-mutant NSCLC.

Original languageEnglish
Article number19501
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

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