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.
Highlights
Colorectal cancer (CRC) is the third most common cancer worldwide (Ferlay et al, 2015)
Baseline methylated vimentin correlated with tumor volume (R = 0.75, p < 0.0001) Reduction in ctDNA correlated significantly with the best percentage tumor change (p = 0.001, r = 0.414) CT size correlates with ctDNA levels; in 1 patient with 8 mets, size on CT correlated with ctDNA levels ctDNA level correlated with radiographic changes ctDNA, circulating tumor DNA; ddPCR, droplet digital PCR; HR, hazard ratio; MAF, mutant allele frequency; mCRC, metastatic colorectal cancer; OS, overall survival; PFS, progression free survival; 95% CI, 95% confidence interval
In 144 eligible patients, it was found that with adjustment for gender, stage, carcinoembryonic antigen (CEA) levels and the use of adjuvant chemotherapy, a positive ctDNA post-neoadjuvant therapy was highly predictive for disease recurrence (HR 6.0, 95% CI 2.2–16.0)
Summary
Colorectal cancer (CRC) is the third most common cancer worldwide (Ferlay et al, 2015). Adjuvant therapies are indicated for later stage disease (usually stage IIB and above) as determined by pathological tumor staging (with radiological diagnosis of metastatic disease). Treatments are improving for late stage CRC, and early detection of recurrence maximizes treatment options and is associated with improved survival (Pita-Fernandez et al, 2015). 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. 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
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