243P - Liquid biopsy detection of KRAS and BRAF mutations may be useful as a prognostic or predictive marker

Date 28 September 2014
Event ESMO 2014
Session Poster Display session
Topics Translational Research
Presenter Takeshi Yamada
Citation Annals of Oncology (2014) 25 (suppl_4): iv58-iv84. 10.1093/annonc/mdu326
Authors T. Yamada1, H. Kan1, S. Matsumoto2, M. Koizumi1, A. Matsuda3, S. Shinji4, Y. Yokoyama5, A. Yamagishi6, T. Iwai7, S. Kitano8, M. Nakayama9, A. Watanabe10, E. Uchida11
  • 1Department Of Gastrointestinal And Hepato-biliary-pancreatic Surgery, Nippon Medical School, 113-8602 - Tokyo/JP
  • 2Surgery, Nippon Medical School Chiba Hokusoh Hospital, 2701694 - Chiba/JP
  • 3Surgery, Nippon Medical School Chiba Hokusoh Hospital, 270-1608 - Chiba/JP
  • 4Department Of Surgery, Nippon Medical School, 1138602 - Tokyo/JP
  • 5Department Of Digestive Surgery, Nippon Medical School, 1138602 - Tokyo/JP
  • 6Surgery, Nippon Medical School Hospital, 113-8 - Tokyo/JP
  • 7Department Of Gastrointestinal And Hepato-biliary-pancreatic Surgery, Nippon Medical School, 113-8603 - Tokyo/JP
  • 8Technical Research Institute, TOPPAN PRINTING CO., LTD, 3458508 - Saiatama/JP
  • 9Technical Research Institute, TOPPAN PRINTING CO., LTD, 3458508 - Saitama/JP
  • 10Divion Of Personalized Genetic Medicine, Nippon Medical School Hospital, 1138603 - Tokyo/JP
  • 11Department Of Gastrointestinal And Hepato-biliary-pancreatic Surgery, Nippon Medical School, 1038602 - Tokyo/JP

Abstract

Aim

Resistance to epidermal growth factor receptor (EGFR) blockade may occur by selection of pre-existing KRAS mutant clones or continuing mutagenesis caused by EGFR blockade. Serial biopsies to identify new mutations are invasive and risky, especially for cancers deep within the body. Liquid biopsy (LB) is a new method of molecular diagnosis using circulating tumor DNA in peripheral blood. Here, we evaluated KRAS and BRAF mutations using LB as a biomarker to predict the efficacy of EGFR blockade.

Methods

We enrolled 29 colorectal cancer patients (14 KRAS mutant and 15 KRAS wild in primary tumors) with distant metastases. Circulating tumor DNA was purified from 1 mL serum using the QIAamp Circulating Nucleic Acid Kit. We detected nine KRAS (G12A, G12R, G12D, G12C, G12S, G12V, G13D, Q61H, and Q61R) and one BRAF (V600E) mutations. We administered EGFR blockade to 8 patients with KRAS wild in their primary tumor and used computed tomography 3 months after starting EGFR blockade therapy to evaluate its effect. The study protocol was approved by the Ethics Review Committee of our institution. Written informed consent was obtained from each patient.

Results

KRAS mutations in circulating tumor DNA were detected in 86% of patients with KRAS mutation in their primary tumor but in 14% of patients without KRAS mutations in their primary tumors. We administered EGFR blockade to 12 patients. Nine patients with KRAS and BRAF wild in circulating tumor DNA had a good clinical response (1CR and 8PR). One patient with KRAS mutation (G13D) without BRAF mutation in circulating tumor DNA had partial response. Two patients with KRAS mutation (G13D and Q61R) without BRAF mutation in circulating tumor DNA had no clinical response. In a patient without KRAS or BRAF mutations in circulating tumor DNA, we detected KRAS mutation (G12C) in circulating tumor DNA 12 months after starting EGFR blockade. We detected radiographic evidence of disease progression 2 months after detecting KRAS mutation in circulating tumor DNA.

Conclusions

LB detection of KRAS and BRAF mutations is less-invasive and repeatable compared with current techniques and may be useful for identifying predictive markers of EGFR blockade and resistance to EGFR blockade.

Disclosure

All authors have declared no conflicts of interest.