Quantitative Cell Free DNA, KRAS and BRAF mutations in Plasma from Patients with Metastatic Colorectal Cancer during Treatment with Cetuximab and Irinotecan
Menée sur 108 patients atteints d'un cancer colorectal métastatique, cette étude évalue la faisabilité d'analyser les mutations de l'ADN libre circulant pour prédire la réponse à un traitement combinant cetuximab et irinotecan
Purpose The present study investigated the levels of circulating cell-free DNA (cfDNA) in plasma from metastatic colorectal cancer (mCRC) patients 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 PS and organ function. Treatment consisted of irinotecan 350 mg/m2 q3w and weekly cetuximab 250 mg/m2 until progression or unacceptable toxicity. A quantitative polymerase chain reaction (qPCR) method was developed to asses the number of cfDNA alleles, KRAS and BRAF mutation alleles plasma at baseline. Results The study included 108 patients. Only 3 patients were positive for BRAF mutations. The majority of KRAS mutations detected in tumors were also found in plasma (32/41 (78%)). Plasma cfDNA and plasma mutant KRAS levels (pmKRAS) were strongly correlated (r = 0.85, p<10-4). The disease control (DC) rate was 77% in patients with low cfDNA (<25 percentile) and 30% in patients with high cfDNA (>75% percentile (p=0.009)). Patients with pmKRAS levels higher than the 75% percentile had a DC rate of 0% compared to 42% in patients with pmKRAS below (p=0.048). Cox analysis confirmed the prognostic importance of both cfDNA and pmKRAS. High levels were clear indicators of a poor outcome. Conclusion 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.
Clinical Cancer Research , résumé, 2012