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

Abstract

Background: Metastatic colorectal cancer (mCRC) is a heterogeneous disease where prognosis is dependent both on tumor biology and host factors. Total circulating cell-free DNA (cfDNA) has shown to harbor prognostic information in mCRC, although less is known about the biological correlates of cfDNA levels in this patient group. The primary objective was to evaluate the prognostic value of pretreatment cfDNA in patients receiving the first-line oxaliplatin-based chemotherapy for mCRC, by using a predefined upper limit of normal (ULN) from a cohort of presumed healthy individuals. The secondary objective was to model cfDNA levels as a function of predefined tumor and host factors. Patients and methods: This was a retrospective post hoc study based on a prospective multicenter phase III trial, the NORDIC-VII study. DNA was purified from 547 plasma samples and cfDNA quantified by a droplet digital PCR assay (B2M, PPIA) with controls for lymphocyte contamination. Main clinical end point was overall survival (OS). Results: cfDNA was quantified in 493 patients, 54 were excluded mainly due to lymphocyte contamination. Median cfDNA level was 7673 alleles/ml (1050-1 645 000) for B2M and 5959 alleles/ml (555-854 167) for PPIA. High cfDNA levels were associated with impaired outcome; median OS of 16.6 months for levels above ULN and 25.9 months for levels below ULN (hazard ratio ¼ 1.83, 95% confidence interval 1.51-2.21, P < 0.001). The result was confirmed in multivariate OS analysis adjusting for established clinicopathological characteristics. A linear regression model predicted cfDNA levels from sum of longest tumor diameters by RECIST, the presence of liver metastases and systemic inflammatory response as measured by interleukin 6 (F(6, 357) ¼ 62.7, P < 0.001). Conclusion: cfDNA holds promise as a minimally invasive and clinically relevant prognostic biomarker in mCRC before initiating first-line oxaliplatin-based chemotherapy and may be a complex entity associated with tumor burden, liver metastases and systemic inflammatory response.

The tumor burden of metastatic colorectal cancer patients at initial diagnosis, pre- versus post-Covid-19 lockdown

“…We speculate that patient triage could be performed based on the quick assessment of tumor burden and the testing of biomarkers with predictive and prognosis value (such as immunohistochemistry for mismatch repair proteins; mutation analysis for KRAS, NRAS, and BRAF) . For this purpose, we believe that cirDNA analysis revealing qualitative (tumor molecular profiling) or quantitative information 8,20 21,39,13 may represent an ideal tool, as previously reported 16,19,40 .…”

“…Numerous works report that tumors secrete DNA into the blood stream in quantities proportional to their masses 10,11,12 especially in the case of metastatic colorectal cancer (mCRC) 10,13,14,15 . Thus, cirDNA offers analytical and clinical advantages over conventional antigenic biomarkers such as CEA, and may be considered as a surrogate marker of disease progression, at least in mCRC 16,13,17,14,18,19 (Suppl. Fig.…”

Circulating Tumor DNA Is Capable of Monitoring the Therapeutic Response and Resistance in Advanced Colorectal Cancer Patients Undergoing Combined Target and Chemotherapy

“…Therefore, it is vital to detect these gene mutations in an individualized manner. We believe this strategy can support the establishment of reasonable treatment plan for each patient (11)(12)(13)(14).…”

Prognostic Value of the Pace of Tumor Progression as Assessed by Serial 18F-FDG PET/CT Scan and Liquid Biopsy in Refractory Colorectal Cancer: The CORIOLAN Trial

“…To assess this, we analyzed a group of patients that were highly representative of the chemorefractory CRC population with regard to baseline characteristics, treatments received and overall prognosis. Importantly, we used a number of imaging and circulating parameters that, while not routinely tested in clinical practice, have all previously been reported to be reliable markers of tumor burden and indicators of CRC prognosis, with an ever-increasing interest for their potential clinical applications [ 10 , 11 , 12 , 16 ]. Despite the sound rationale, however, our hypothesis was not confirmed, the dynamics of any of the tested markers being associated with survival.…”