Treatment monitoring in metastatic colorectal cancer patients by quantification and KRAS genotyping of circulating cell-free DNA

Abstract

Treatment of metastatic colorectal cancer (CRC) has continuously improved over the last decade. However, disease monitoring remains underdeveloped and mostly dependent on imaging e.g. RECIST 1.1 criteria. The genetic landscape of individual cancers and subsequently occurring treatment-induced evolution remain neglected in current surveillance strategies. Novel biomarkers demand minimally invasive and repetitive tracking of the cancer mutagenome for therapy stratification and to make prognostic predictions. Carcinoembryonic antigen (CEA), a routinely used tumor marker for CRC, does not meet these goals and thus prevents its use as a reliable monitoring tool. A tumor-derived fraction of circulating cell-free DNA (cfDNA), isolated from blood samples, may bypass the limitations of currently available biomarkers and could be a tool for noninvasive disease monitoring. Here, total cfDNA levels differentiated a cohort of metastatic CRC patients from healthy controls. Furthermore, we correlated cfDNA during chemotherapy of 27 stage IV patients with clinical parameters to establish its prognostic and predictive value. Indeed, cfDNA levels in chemotherapy naive patients correlate with the tumor burden and CEA values at diagnosis and increase upon disease progression during 1st and 2nd line treatment. Moreover, we confirm the possibility of cfDNA-based genotyping of KRAS to early detect the emergence of resistance during chemotherapy. These data indicate that repetitive quantitative and mutational analysis of cfDNA might complement current treatment standards but may have also limited value in some patients.

Circulating tumour-derived DNA in metastatic soft tissue sarcoma

“…In addition cfDNA levels in the STS patients were shown to positively correlate with patient disease burden, but only fairly weakly (R 2 =0.26). In other malignancies the strength of this correlation varies [ 19 , 20 ], and interestingly when those patients in our cohort with evidence of ctDNA were analysed separately, the strength of the correlation seen rose (see Figure 2 ) suggesting that a significant proportion of cfDNA in these cases was both tumour derived and released into the circulation in a linear correlation with disease burden. During the follow up period six of the 11 patients enrolled died of their disease.…”

Total circulating cell-free DNA as a prognostic biomarker in metastatic colorectal cancer before first-line oxaliplatin-based chemotherapy

“…One study on advanced lung cancer found no significant correlation between cfDNA and metabolic tumor volume or total lesion glycolysis as estimated by positron emission tomography/ computed tomography [20]. Others have found that baseline cfDNA levels in treatment naive mCRC patients correlate with radiologic disease burden, but this trend could not be observed at time of disease progression and subsequent therapy lines [21].…”

The diagnostic accuracy of circulating free DNA for the detection of KRAS mutation status in colorectal cancer: A meta‐analysis

“…A total of 5032 studies were excluded after primary screening, and 94 articles were selected for further assessment of eligibility. By rigorous evaluation, 28 studies met the inclusion criteria and were included in our present meta‐analysis. In the study reported by Taly and another study by Xu, KRAS status was detected by two different methods, and Morgan detected KRAS status both in serum and plasma, and the data from two different methods and two samples were analyzed as two independent studies.…”