Abstract 250: Interleukin-6 as potential predictive marker for therapeutic effect of Gefitinib in patients with advanced non-small-cell lung cancer harboring EGFR mutations
Authors: Tamura Tomoki , Hotta Katsuyuki , Kato Yuka , Tanaka Takehiro , Ichimura Kouichi , Oohashi Kadoaki , Ninomiya Takashi , Kubo Toshio , Ichihara Eiki , Tanimoto Mitsune , Kiura Katsuyuki 
Published: July 2016

Abstract
Background: Although epidermal growth factor receptor (EGFR) -tyrosine kinase inhibitors (TKIs) are the key drug in patients with EGFR-mutant (mt) Non-small-cell Lung Cancer (NSCLC), some of them can not respond well to its therapy. An overexpression of Interleukin (IL)-6 in tumor cells is postulated as a potential mechanism for such resistance or low sensitivity to EGFR-TKI in the preclinical models (PNAS 2010). Here, we evaluated clinically if tumor IL-6 level can be predictive for the effect of EGFR-TKI therapy, and evaluated the expression of IL-6 in EGFR-mt NSCLC cell-lines, and the effect of EGFR-TKI.
Methods: A total of 52 pts with advanced EGFR-mt NSCLC who had received gefitinib (G) were retrospectively assessed. The protein expression of IL-6 in the tumor cells was immunostained. Each specimen was assessed independently by 2 physicians (TT and YK) and 2 pathologists (KI and TT), and judged as positive if ≥ 50% of 100 tumor cells were stained positively (BJC 1999). Serum IL-6 level was measured by CLEIA in 11 (21%) of 52 pts.
Next we checked 13 EGFR-mt NSCLC cell lines. Enzyme linked immunosorbent assay (ELISA) and real time PCR (RT-PCR) of cell culture supernate were peformed.
Results: Patients demographics were as follows: 24 men; median age, 66 yrs; PS 0-1, 48; stage IV, 22; Ad, 49; exon19, 29. Of these, 24 (46%) and 28 (54%) were defined as IL-6-postitive (group P) and IL-6-negative (group N), respectively. Group P had worse PFS (75% v 92% at 6m; p &lt; 0.05), which was retained in the multivariate analysis (HR: 2.38; 95%CI: 1.00-5.68; p = 0.05). In contrast, PFS in the platinum-based chemotherapy did not differ in groups P and N (p = 0.47). The serum IL-6 level ranged from 0.75 to 23.80 pg/ml (median: 2.90 pg/ml), which correlated neither to that in the tumor cells (regression coefficient: 1.69, p = 0.29) nor PFS in gefitinib therapy (p = 0.44).
The IL-6 level in cell culture supernatant was ranged from 1.46 to 1219.75 pg/ml (median: 85.84 pg/ml). 2 of 13 cell lines showed especially high IL-6 level; IL-6 level of 11-18 was 1090.91 pg/ml and H1650 was 1219.75 pg/ml. RT-PCR also showed the high expression level of IL-6 mRNA in 11-18 and H1650 compared with other cell lines. 11-18 and H1650 showed low sensitivity to G therapy.
Conclusions: Pts in group P benefited less from G therapy.
In vitro experiment suggested that secretion of IL-6 may confer the less sensitivity to EGFR-TKIs. These data suggest that the expression of IL-6 lead to early acquisition of resistance to EGFR-TKIs in EGFR-mt tumors.
Citation Format: Tomoki Tamura, Katsuyuki Hotta, Yuka Kato, Takehiro Tanaka, Kouichi Ichimura, Kadoaki Oohashi, Takashi Ninomiya, Toshio Kubo, Eiki Ichihara, Mitsune Tanimoto, Katsuyuki Kiura. Interleukin-6 as potential predictive marker for therapeutic effect of Gefitinib in patients with advanced non-small-cell lung cancer harboring EGFR mutations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 250.