Changes in mutational status during third‐line treatment for metastatic colorectal cancer—Results of consecutive measurement of cell free DNA, KRAS and BRAF in the plasma. Issue 9 (17th April 2014)

• Record Type: Journal Article
• Authors: Spindler, Karen‐Lise Garm; Pallisgaard, Niels; Andersen, Rikke Fredslund; Jakobsen, Anders
• Is Part Of: International journal of cancer. Volume 135:Issue 9(2014:Nov. 01)
• Page Start: 2215
• Page End: 2222
• Publication Date: 2014-04-17
• Subjects: Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.28863
• Languages: English
• ISSNs: 0020-7136

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p> <italic>KRAS</italic> and <italic>BRAF</italic> mutations are responsible for primary resistance to epidermal growth factor receptor (EGFR) MoAbs in metastatic colorectal cancer (mCRC), but it is unknown what causes wildtype (wt) patients to develop resistance during treatment. We measured circulating free DNA (cfDNA), <italic>KRAS</italic> and <italic>BRAF</italic> in plasma and report the changes during third line treatment with cetuximab and irinotecan. One‐hundred‐and‐eight patients received irinotecan 350 mg/m<sup>2</sup> q3w and weekly cetuximab (250 mg/m<sup>2</sup>) until progression (RECIST) or unacceptable toxicity. cfDNA and number of mutated <italic>KRAS</italic>/<italic>BRAF</italic> alleles in plasma at baseline and before each cycle was analyzed by an in‐house qPCR. cfDNA and p<italic>KRAS</italic> levels decreased from baseline to cycle three and increased at time of progression (<italic>p</italic> = 0.008). The decrease was larger in responding patients than in non‐responding (<italic>p</italic> < 0.05). Two patients with primary mutant disease had different types of mutations detected in the plasma, including synchronous <italic>KRAS</italic> and <italic>BRAF</italic>. Twelve patients had a primary <italic>KRAS</italic> mutant tumor, but wild‐type disease according to baseline plasma analysis, eight of these obtained stabilization of disease. In five patients with primary wt disease a mutation appeared in plasma before radiological evidence of progression. Loss of mutations may explain observed benefit of treatment in primary mutant disease, whereas appearance of mutations during therapy may be responsible for acquired resistance in primary wt disease. Benefit from EGFR MoAbs may be influenced by the quantitative level of mutational alleles rather than by mutational status alone, and plasma levels of cfDNA, <italic>KRAS</italic> and <italic>BRAF</italic> could be used to monitor patients during treatment.</p> </abstract>