Abstract 5696: Emerging KRAS mutation can play a considerable role to get acquired resistance to EGFR blockade
Authors: Yamada Takeshi , Takahashi Goro , Iwai Takuma , Takeda Kouki , Koizumi Michihiro , Matsuda Akihisa , Shinji Seiichi , Yokoyama Yasuyuki , Hotta Masahiro , Hara Keisuke , Matsumoto Satoshi , Ohta Keiichiro , Uchida Eiji 
Published: July 2017

Background: Epidermal growth factor receptor (EGFR) blockade can achieve considerable tumor shrinkage in patients with metastatic colorectal cancer (CRC). However, most patients who benefit from EGFR blockade acquire resistance within a year. It was previously reported that nine of 24 (38%) patients whose tumors initially exhibited wild type KRAS developed detectable mutations in KRAS in their sera after acquiring resistance to EGFR blockade. However, the mechanisms of this acquired resistance remain unclear. In this study, we aimed to identify the mechanisms underlying acquired resistance to EGFR blockade by using circulating cell-free (ccf)DNA to track emerging KRAS, BRAF and S492R mutations during chemotherapy.

Methods: We enrolled 29 patients with metastatic CRC and no RAS mutations in their primary tumors. Patients were treated with first-line systemic chemotherapy that included EGFR blockade. We purified ccfDNA from 1 mL of serum from each patient before they started chemotherapy, and every 2-3 months during chemotherapy until disease progression. We detected KRAS (codons 12, 13, 61, and 146), BRAF (V600E) and S492R mutations using digital polymerase chain reaction.

Results: KRAS mutations were detected in the ccfDNA of three of the 29 patients (10%) before chemotherapy. The response rate was 86% (25/29); the four non-responders were the three patients with KRAS mutations, and another who exhibited ccfDNA BRAF mutations before starting chemotherapy. All patients with no KRAS or BRAF mutations in their ccfDNA before chemotherapy responded to the chemotherapy (25/25). Of these 25 initially responsive patients, 13 (52%) acquired resistance. We detected emerging KRAS mutations in the ccfDNA of 11 of these 13 patients (84%); eight of these patients had multiple mutations. We also detected BRAF mutations in six patients (46%); none of the patients had solo BRAF mutations. Five patients (38%) had S492R mutations; one had mutations in S492R only. Only one patient had no KRAS, BRAF or S492R mutations.

Discussion: EGFR blockade has no beneficial effect in patients with KRAS or BRAF mutations in their ccfDNA prior to starting chemotherapy. Emergence of KRAS, BRAF or S492R mutations that were undetectable before the start of chemotherapy may be a mechanism underlying acquisition of resistance to EGFR blockade. Notably, emerging KRAS mutations were detected in most of the patients (84%) who acquired resistance. This indicates that the emergence of KRAS mutations may play a considerable role in the acquisition of resistance to EGFR blockade.

Citation Format: Takeshi Yamada, Goro Takahashi, Takuma Iwai, Kouki Takeda, Michihiro Koizumi, Akihisa Matsuda, Seiichi Shinji, Yasuyuki Yokoyama, Masahiro Hotta, Keisuke Hara, Satoshi Matsumoto, Keiichiro Ohta, Eiji Uchida. Emerging KRAS mutation can play a considerable role to get acquired resistance to EGFR blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5696. doi:10.1158/1538-7445.AM2017-5696