Quantitative cell-free DNA, KRAS, and BRAF mutations in plasma from patients with metastatic colorectal cancer during treatment with cetuximab and irinotecan

Karen Lise Garm Spindler*, Niels Pallisgaard, Ivan Vogelius, Anders Jakobsen

*Corresponding author

Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

Abstract

Purpose: The present study investigated the levels of circulating cell-free DNA (cfDNA) in plasma from patients with metastatic colorectal cancer (mCRC) in relation to third-line treatment with cetuximab and irinotecan and the quantitative relationship of cfDNA with tumor-specific mutations in plasma. Experimental Design: Inclusion criteria were histopathologically verified chemotherapy-resistant mCRC, adequate Eastern Cooperative Oncology Group performance status, and organ function. Treatment consisted of irinotecan being administered at 350 mg/m 2 for 3 weeks and weekly administration of 250 mg/m 2 cetuximab until progression or unacceptable toxicity. A quantitative PCR method was developed to assess the number of cfDNA alleles and KRAS and BRAF mutation alleles in plasma at baseline. Results: The study included 108 patients. Only three patients were positive for BRAF mutations. The majority of KRAS mutations detected in tumors were also found in the plasma [32 of 41 (78%)]. Plasma cfDNA and plasma mutant KRAS levels (pmKRAS) were strongly correlated (r=0.85, P < 10 -4). The disease control rate was 77% in patients with low cfDNA (<25% quartile) and 30% in patients with high cfDNA [>75% quartile (P=0.009)]. Patients with pmKRAS levels higher than 75% had a disease control rate of 0% compared with 42% in patients with lower pmKRAS (P = 0.048). Cox analysis confirmed the prognostic importance of both cfDNA and pmKRAS. High levels were clear indicators of a poor outcome. Conclusions: KRAS analysis in plasma is a viable alternative to tissue analysis. Quantitative levels of cfDNA and pmKRAS are strongly correlated and hold promise of clinical application.

OriginalsprogEngelsk
TidsskriftClinical Cancer Research
Vol/bind18
Udgave nummer4
Sider (fra-til)1177-1185
Antal sider9
ISSN1078-0432
DOI
StatusUdgivet - 15 feb. 2012
Udgivet eksterntJa

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