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

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

doi:10.1038/s41598-019-55939-5

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.

Highlights

2 (HER2) amplification, and hepatocyte growth factor overexpression, have been reported in NSCLC10–12
We observed the potential implications of heregulin expression in EGFR-TKI–treated NSCLC patients who harbored EGFR-activating mutations
The efficacy of 1st-generation EGFR-TKIs was less durable in patients with high soluble heregulin (sHRG) plasma levels than in patients with low sHRG plasma levels

Summary

Introduction

2 (HER2) amplification, and hepatocyte growth factor overexpression, have been reported in NSCLC10–12. MET aberrant expression leads to activation of HER3 and its downstream pathway, suggesting that HER3 plays a key role in EGFR-TKI resistance[10]. Based on these findings, it is imperative that novel treatment strategies are clinically investigated to overcome EGFR-TKI resistance. Second-generation EGFR-TKIs were shown to significantly improve progression-free survival (PFS) as well as overall survival compared to first-generation EGFR-TKIs in patients with advanced NSCLC harboring EGFR-activating mutations[13,14]. Osimertinib significantly improves PFS in EGFR-TKI-naïve patients with NSCLC harboring EGFR-activating mutations compared to first-generation EGFR-TKIs15. In contrast to 1st-generation EGFR-TKIs, 2nd-generation EGFR-TKIs such as afatinib or dacomitinib, unique pan-HER family inhibitors, have been shown preclinically to overcome heregulin-mediated resistance[28]. First- and second-generation of EGFR-TKIs were assessed to determine their efficacy in patients with high heregulin expression

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