Abstract 1504: Usefulness of peripheral blood for monitoring of acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC
Authors: Kobayashi Naomi , Sueoka-Aragane Naoko , Umeguchi Hitomi , Nakamura Tomomi , Sato Akemi , Komiya Kazutoshi , Takeda Yuji , Hayashi Shinichiro , Sueoka Eisaburo , Kimura Shinya 
Published: May 2015

Determination of mechanisms of acquired resistance to molecular targeted therapy such as EGFR tyrosine kinase inhibitors (EGFR-TKI) is indispensable for overcoming the resistance to the treatment. According to the results using re-biopsy, EGFR T790M mutation, and overexpression of hepatocyte growth factor (HGF) are major mechanisms of acquired resistance to EGFR-TKI in non-small cell lung cancer. Since the biological characteristics of cancer cells could be altered during treatment, it is necessary to clarify the molecular events in each individual on time point of acquired resistance to EGFR-TKI for selection of the appropriate treatment. Considering that, we chose peripheral blood for monitoring molecular alterations contributing to the resistance to EGFR-TKI such as T790M and HGF overexpression. Since amount of circulating tumor DNA (ctDNA) is small, we have newly developed a fully-automated sensitive method, mutation-biased PCR and quenched probe (MBP-QP) system for detection of T790M. HGF was quantified using ELISA. Using these systems, we retrospectively analyzed T790M and HGF levels in peripheral blood in 36 non-small cell lung cancer patients who were treated with EGFR-TKI.

Before treatment of EGFR-TKI, HGF levels in plasma samples were less than lower limit of HGF quantification, 100 pg/ml, in 4 patients, and ranged up to 381 pg/ml. T790M was not detected with ctDNA in any patients. The progression free survival (PFS) time and overall survival (OS) time were compared between two groups, high HGF group (more than median) and low HGF group (median and less than that), was investigated. There were no differences of PFS and OS between two populations, suggesting that HGF level in plasma before treatment with EGFR-TKI was neither a predictive marker for anti-cancer effect of EGFR-TKI nor a prognostic marker among these population. Sixteen sets of plasma before treatment of EGFR-TKI and after acquired resistance were obtained. Plasma HGF levels ranged from 90 to 680, and 79 to 1235 pg/ml before treatment of EGFR-TKI, and after acquired resistance, respectively. The ratio of HGF levels after acquired resistance to before treatment was 0.52 to 7.3, and 6 patients showed elevation of HGF 1.5 times and more than that. T790M was detected with plasma DNA in 9 patients after acquired resistance to EGFR-TKI. Eleven of 16 patients (69%) showed either HGF elevation (1.5-fold≦) or T790M with plasma, and both elevations were observed in 4 patients (25%) , which were equivalent to the results using re-biopsy reported in other laboratories. These results of retrospective analysis suggest that quantification of HGF and detection of T790M using peripheral blood are promising systems for monitoring the mechanisms of acquired resistance to EGFR-TKI.

Citation Format: Naomi Kobayashi, Naoko Sueoka-Aragane, Hitomi Umeguchi, Tomomi Nakamura, Akemi Sato, Kazutoshi Komiya, Yuji Takeda, Shinichiro Hayashi, Eisaburo Sueoka, Shinya Kimura. Usefulness of peripheral blood for monitoring of acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1504. doi:10.1158/1538-7445.AM2014-1504