The Use of Circulating Tumor DNA to Monitor and Predict Response to Treatment in Colorectal Cancer

Abstract

Background: Colorectal cancer is one of the most common cancers worldwide and has a high mortality rate following disease recurrence. Treatment efficacy is maximized by providing tailored cancer treatment, ideally involving surgical resection and personalized neoadjuvant and adjuvant therapies, including chemotherapy, radiotherapy and increasingly, targeted therapy. Early detection of recurrence or disease progression results in more treatable disease and is essential to improving survival outcomes. Recent advances in the understanding of tumor genetics have resulted in the discovery of circulating tumor DNA (ctDNA). A growing body of evidence supports the use of these sensitive biomarkers in detecting residual disease and diagnosing recurrence as well as enabling targeted and tumor-specific adjuvant therapies. Methods: A literature search in Pubmed was performed to identify all original articles preceding April 2019 that utilize ctDNA for the purpose of monitoring response to colorectal cancer treatment. Results: Ninety-two clinical studies were included. These studies demonstrate that ctDNA is a reliable measure of tumor burden. Studies show the utility of ctDNA in assessing the adequacy of surgical tumor clearance and changes in ctDNA levels reflect response to systemic treatments. ctDNA can be used in the selection of targeted treatments. The reappearance or increase in ctDNA, as well as the emergence of new mutations, correlates with disease recurrence, progression, and resistance to therapy, with ctDNA measurement allowing more sensitive monitoring than currently used clinical tools. Conclusions: ctDNA shows enormous promise as a sensitive biomarker for monitoring response to many treatment modalities and for targeting therapy. Thus, it is emerging as a new way for guiding treatment decisions—initiating, altering, and ceasing treatments, or prompting investigation into the potential for residual disease. However, many potentially useful ctDNA markers are available and more work is needed to determine which are best suited for specific purposes and for improving specific outcomes.

Evaluation of Circulating Tumor DNA for Methylated BCAT1 and IKZF1 to Detect Recurrence of Stage II/Stage III Colorectal Cancer (CRC)

“…Because earlier detection of CRC recurrence may facilitate potentially curable metastasectomy, the application of a more sensitive assay, such as one targeting hypermethylated BCAT1 and IKZF1 ctDNA, during surveillance might improve outcomes in recurrent CRC. Consistent with published data showing that methylation alterations to BCAT1 and IKZF1 can be identified in plasma well before radiographic recurrence (25,28,30,31,33), the current study demonstrated COLVERA positivity up to six months before imaging suggested recurrence. Nevertheless, without directly comparing results of regimented serial CEA and radiographic surveillance with serial ctDNA and radiographic surveillance, it is impossible to know whether application of ctDNA will lead to earlier radiographic detection and, most importantly, whether earlier radiographic detection will translate into improved cancer-related outcomes.…”

“…Consistent with prior studies (28), the current study showed that the specificity of CEA in the 295 patients without cancer recurrence was higher than that of COLVERA. However, the significance of a false positive result in the current study is unclear due to the relatively short follow-up period.…”

“…A growing body of evidence suggests that detecting cancer-specific genetic and epigenetic alterations in circulating cell free DNA (cfDNA) may be a highly sensitive and specific method of diagnosing cancer recurrence (21). Studies have shown the cfDNA technology can detect the presence of primary CRC (22)(23)(24)(25)(26)(27) as well as disease recurring after primary tumor resection (28)(29)(30). Multiple cfDNA assays have been developed and tested, including customized gene mutation panels derived from resected tumor samples and assays for specific methylation changes common to most colorectal tumors (24,29,31).…”

Prognostic and Predictive Molecular Biomarkers for Colorectal Cancer: Updates and Challenges

“…The potential for liquid biopsy in guiding treatment and monitoring the disease is compelling and may soon be translated to clinical practice. In recent years, ctDNA has been shown to be a powerful tool in (1) assessing the adequacy of surgical tumor clearance and thereby the risk of recurrence (2) in selecting the most appropriate targeted therapy and (3) in following responses to systemic treatments [73,74]. The reappearance or increase in ctDNA, along with the emergence of new mutations, is associated with recurrence, progression and resistance to therapy.…”

An easily adaptable validated risk score predicts cancer-specific survival in stage II colon cancer

“…Perineural invasion (PNI), high tumor budding and compromised surgical margin are also strong predictors of disease recurrence [3][4][5][6]. Circulating tumor DNA is a promising novel biomarker in colorectal cancer (CRC) and could be the most influential prognostic marker after radical surgery, but its predictive value has not yet been established [7][8][9].…”