Circulating Tumor Cells and Circulating Tumor DNA Detection in Potentially Resectable Metastatic Colorectal Cancer: A Prospective Ancillary Study to the Unicancer Prodige-14 Trial

Abstract

The management of patients with colorectal cancer (CRC) and potentially resectable liver metastases (LM) requires quick assessment of mutational status and of response to pre-operative systemic therapy. In a prospective phase II trial (NCT01442935), we investigated the clinical validity of circulating tumor cell (CTC) and circulating tumor DNA (ctDNA) detection. CRC patients with potentially resectable LM were treated with first-line triplet or doublet chemotherapy combined with targeted therapy. CTC (Cellsearch®) and Kirsten RAt Sarcoma (KRAS) ctDNA (droplet digital polymerase chain reaction (PCR)) levels were assessed at inclusion, after 4 weeks of therapy and before LM surgery. 153 patients were enrolled. The proportion of patients with high CTC counts (≥3 CTC/7.5mL) decreased during therapy: 19% (25/132) at baseline, 3% (3/108) at week 4 and 0/57 before surgery. ctDNA detection sensitivity at baseline was 91% (N=42/46) and also decreased during treatment. Interestingly, persistently detectable KRAS ctDNA (p = 0.01) at 4 weeks was associated with a lower R0/R1 LM resection rate. Among patients who had a R0/R1 LM resection, those with detectable ctDNA levels before liver surgery had a shorter overall survival (p < 0.001). In CRC patients with limited metastatic spread, ctDNA could be used as liquid biopsy tool. Therefore, ctDNA detection could help to select patients eligible for LM resection.

Fractionated small cell‐free DNA increases possibility to detect cancer‐related gene mutations in advanced colorectal cancer

“…Results of this study indicate that the fractionation of cfDNA from CRC patients offers sensitive genetic detection by dPCR and NGS analysis, which would provide a less-invasive method to obtain the genetic tumor profiles. The sensitivity of cfDNA in detecting tumor mutations is currently reported to be 51-97% with digital PCR (dPCR) 13,18,19,[24][25][26][27]39 and 35-86% with NGS. 19,22,23,28,40,41 In our study, the sensitivity in detecting mutations in cfDNA from serum using dPCR was 85% and 93% when cut-off values of MAFs were set at >0% and >0.1%, respectively.…”

“…Recently, liquid biopsy, a process that identifies the presence of tumor genetic abnormalities using cell-free DNA (cfDNA), [9][10][11] circulating tumor cells, [12][13][14] and microRNA [15][16][17] that are extracted from body fluids such as plasma, serum, and urine, is gaining significant attention because of its less-invasive method to obtain genetic profiles. 11 In fact, and owing to its profound advantages, liquid biopsy is expected to be used clinically in cases such as early tumors detection, 18,19 tumor monitoring, [20][21][22][23][24] treatment effect prediction, 20 detection of drug resistance, and as a sensitivity marker.…”

Liquid biopsy in endometrial cancer

“…There is no consensus when comparing ctDNA, CTCs, and primary tumor [12] ; the results change depending on the tumor analyzed and the procedure adopted for biomarkers isolation and characterization. For example, these results include 92% for KRAS in colon cancer comparing ctDNA and primary tissue [13] , "good correlation" between CTs and ctDNA in colon [14] , and "higher accuracy of ctDNA as prognostic biomarker" in comparison to CTC in overall evaluation in cancer [15] .…”

Liquid Biopsy: Emergence of an Alternative Cancer Detection Method

“…Targeted liquid biopsies that utilize polymerase chain reaction amplification of target sequences for cancer detection are being explored in multiple cancers in a similar vein to the Cobas system. For example, the PRODIGE‐14 trial of metastatic colorectal cancer utilized both ctDNA and circulating tumor cells to categorize patients as eligible for surgical resection of liver metastases 9 . In neuroblastoma, a cancer with limited opportunities for tissue retrieval, targeted liquid biopsy approaches offer a noninvasive alternative for monitoring disease progression and establishing prognosis 10 .…”