Research Papers:

Monitoring circulating tumor DNA revealed dynamic changes in KRAS status in patients with metastatic colorectal cancer

Yuji Takayama, Koichi Suzuki _, Yuta Muto, Kosuke Ichida, Taro Fukui, Nao Kakizawa, Hideki Ishikawa, Fumiaki Watanabe, Fumi Hasegawa, Masaaki Saito, Shingo Tsujinaka, Kazushige Futsuhara, Yasuyuki Miyakura, Hiroshi Noda, Fumio Konishi and Toshiki Rikiyama

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Oncotarget. 2018; 9:24398-24413. https://doi.org/10.18632/oncotarget.25309

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Yuji Takayama1, Koichi Suzuki1, Yuta Muto1, Kosuke Ichida1, Taro Fukui1, Nao Kakizawa1, Hideki Ishikawa1, Fumiaki Watanabe1, Fumi Hasegawa1, Masaaki Saito1, Shingo Tsujinaka1, Kazushige Futsuhara1, Yasuyuki Miyakura1, Hiroshi Noda1, Fumio Konishi2 and Toshiki Rikiyama1

1Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan

2Department of Surgery, Nerima-Hikarigaoka Hospital, Nerima-ku, Tokyo 179-0072, Japan

Correspondence to:

Koichi Suzuki, email: [email protected]

Keywords: liquid biopsy; circulating tumor DNA; colorectal cancer; KRAS; droplet digital PCR

Received: December 27, 2017     Accepted: April 13, 2018     Published: May 11, 2018


KRAS mutated circulating tumor DNA (MctDNA) can be monitored in the blood of patients with metastatic colorectal cancer (mCRC), but dynamic changes have not been determined. Four hundred and fifty-seven plasma samples were collected prospectively from 85 mCRC patients who underwent chemotherapy. MctDNA in plasma was detected by droplet digital PCR, and the percentage of MctDNA in total circulating cell-free DNA was calculated. KRAS assessment in tumor tissues showed 29 patients with the mutant-type (MT) and 56 patients with the wild-type (WT). Twenty-three of 29 MT patients (79.3%) and 28 of 56 WT patients (50.0%) showed MctDNA. Emergence of MctDNA was recognized during treatments with various drugs. Regardless of KRAS status in tumor tissues, patients with MctDNA in blood showed poor progression-free survival with first-line treatment. Median percentage of MctDNA accounted for 10.10% in MT patients and 0.22% in WT patients. These differences between MT and WT likely affected patterns of changes in MctDNA. KRAS monitoring identified dynamic changes in MctDNA, such as continuous, intermittent, and transient changes (quick elevation and disappearance). Emergence of MctDNA involved drug resistance, except for transient changes, which were seen in WT patients and likely corresponded with the drug response. Transient changes could be involved in recovery of sensitivity to anti-EGFR antibody in WT patients. Monitoring MctDNA during various treatments showed dynamic changes in KRAS status and could provide useful information for determining treatments for patients with mCRC.

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