Abstract
Circulating tumor DNA (ctDNA) may reveal dynamic tumor status during therapy. We conducted serial ctDNA analysis to investigate potential association with clinical outcome in metastatic colorectal cancer (mCRC) patients receiving chemotherapy. Tissue KRAS/NRAS wild-type mCRC patients were enrolled and treated with first-line cetuximab-containing chemotherapy. ctDNA isolated from plasma were analyzed by next generation sequencing (NGS) with 16 targeted gene panel. Among 93 patients, 84 (90.3%) had at least 1 somatic mutation in baseline ctDNA samples (average 2.74). Five patients with KRAS or NRAS hotspot mutation in the ctDNA showed significantly worse progression-free survival (PFS) (p = 0.029). Changes in average variant allele frequency (VAF) in ctDNA showed significant correlation with tumor size change at the time of first response evaluation (p = 0.020) and progressive disease (PD) (p = 0.042). Patients whose average VAF decreased below cutoff (< 1%) at the first evaluation showed significantly better PFS (p < 0.001), and the average VAF change further discriminated the PFS in the patients in partial response (p = 0.018). At the time of PD, 54 new mutations including KRAS and MAP2K1 emerged in ctDNA. ctDNA sequencing can provide mutation profile that could better reflect tumor mutation status and predict treatment outcome.
Highlights
Tumor DNA with specific genetic alterations is present as minor sub-clones in the cell-free fraction of the peripheral blood[1,2,3]
We have collected serial Circulating tumor DNA (ctDNA) samples from metastatic colorectal cancer (mCRC) patients at the start, in the middle, and the end of chemotherapy and analyzed mutation profiles of the ctDNA samples by applying targeted deep sequencing with next generation sequencing (NGS) platform. ctDNA analysis was able to detect baseline mutations related to resistance to anti-EGFR treatment, and serial analysis have shown that changes in average variant allele frequency (VAF) in ctDNA were associated with the response to treatment and have revealed a few emerging mutations at the time of resistance
CtDNA analysis was able to detect additional KRAS and NRAS mutations that were not detected by conventional tumor tissue analysis, and the cases with newly detected RAS mutations showed poor response to cetuximab-containing chemotherapy
Summary
Tumor DNA with specific genetic alterations is present as minor sub-clones in the cell-free fraction of the peripheral blood[1,2,3]. CtDNA analysis makes tumor analysis possible in the patients whose tissue specimens are otherwise impossible to obtain, for medical or anatomical reasons. It makes it feasible to obtain multiple specimens repeatedly. We aimed at evaluating the potential association of the results of ctDNA analysis with clinical outcome in metastatic cancer patients, and the feasibility of application of ctDNA analysis to actual patients. We prospectively registered tissue-proven RAS wild-type metastatic colorectal cancer patients and collected blood samples before, during and after palliative 1st line chemotherapy with cetuximab-containing regimen
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