Urinary measurement of circulating tumor DNA for treatment monitoring and prognosis of metastatic colorectal cancer patients

2018 ◽  
Vol 57 (2) ◽  
pp. 268-275 ◽  
Author(s):  
Tao Song ◽  
Fei Mao ◽  
Li Shi ◽  
Xuemei Xu ◽  
Zirong Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Treatment Response ◽  
Clinical Relevance ◽  
Growth Factor Receptor ◽  
Circulating Tumor Dna ◽  
Treatment Monitoring ◽  
Total Dna ◽  
Urine Specimens ◽  
Good Agreement

Abstract Background Solid tumor tissue testing is the gold standard for molecular-based assays for metastatic colorectal cancer (mCRC). This poses challenges during treatment monitoring. Total DNA derived from urine specimens offers clear advantages to track the disease dynamics. Our study aims to evaluate the sensitivity for total DNA recovered from urine and its clinical relevance to mCRC. Methods KRAS mutations in urine specimens were examined in 150 mCRC patients. Baseline concordance was established to determined clinical relevance. The total DNA quantities were also prospectively examined in serial samplings during treatment. Results Analysis of the genetic mutations showed good agreement for baseline samples. Matched tumor and urine specimens’ molecular profiles were observed to have 90% concordance. Comparing with healthy volunteers, we established a cutoff of 8.15 ng that demonstrated elevated total DNA levels was associated with mCRC patients (sensitivity: 90.7%; specificity: 82.0%). For patients treated with chemotherapy or anti-epidermal growth factor receptor inhibitors, DNA quantity mirrored early treatment response. Survival analysis showed that patients with sustained elevated quantities of KRAS mutations had poorer outcome. Conclusions Total urine DNA offers a viable complement for mutation profiling in mCRC patients, given the good agreement with matched tumor samples. Our study also established that this is specific based on the results from healthy individuals. Serial monitoring of total DNA levels allowed early prediction to treatment response and was effective to identify high risk patients. This is potentially useful to complement current disease management.

scholarly journals Clinical relevance of circulating tumor DNA assessed through deep sequencing in patients with metastatic colorectal cancer

2018 ◽  
Vol 8 (1) ◽  
pp. 408-417 ◽  
Author(s):  
Hiroki Osumi ◽  
Eiji Shinozaki ◽  
Yoshinori Takeda ◽  
Takeru Wakatsuki ◽  
Takashi Ichimura ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Deep Sequencing ◽  
Clinical Relevance ◽  
Circulating Tumor Dna ◽  
Tumor Dna

scholarly journals Undetectable RAS-Mutant Clones in Plasma: Possible Implication for Anti-EGFR Therapy and Prognosis in Patients With RAS-Mutant Metastatic Colorectal Cancer

2020 ◽  
pp. 1070-1079 ◽  
Author(s):  
Mohamed Bouchahda ◽  
Raphael Saffroy ◽  
Abdoulaye Karaboué ◽  
Jocelyne Hamelin ◽  
Pasquale Innominato ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Survival Rates ◽  
Growth Factor Receptor ◽  
Complete Response ◽  
Median Number ◽  
Circulating Tumor Dna ◽  
Survival Times ◽  
Viral Oncogene ◽  
Viral Oncogene Homolog

PURPOSE Combining cetuximab with chemotherapy provides clinical benefit to 60% of the patients with RAS wild-type ( RAS-wt) metastatic colorectal cancer (mCRC). This pilot study investigated the efficacy of cetuximab-based chemotherapy in a sample of patients (40%) with RAS mutation ( RAS-mt) in their primary tumor whose circulating tumor DNA (ctDNA) was RAS-wt. MATERIALS AND METHODS The occurrence of Kirsten rat sarcoma viral oncogene homolog ( KRAS), neuroblastoma rat sarcoma viral oncogene homolog (NRAS), V-raf murine sarcoma viral oncogene homolog B1 ( BRAF), and PI3KCA mutations was determined in ctDNA by using a new ultrasensitive analysis based on mass spectrometry detection. All consenting patients with confirmed RAS-mt mCRC had disease progression on previous chemotherapy that contained no anti–epidermal growth factor receptor (EGFR). The patients with RAS-wt ctDNA received cetuximab + fluorouracil, leucovorin, and irinotecan (FOLFIRI), whereas those with RAS-mt ctDNA were treated with the oncologist’s choice of therapy. RESULTS Of 16 registered patients, 11 were male and five female. They were age 48 to 81 years, and they had unresectable metastatic adenocarcinoma from the colon (n = 11) or rectum (n = 5), with a median of two metastatic sites. They had received a median number of three previous chemotherapy protocols. Plasma genotyping identified RAS-mt in seven patients (44%) and RAS-wt in nine patients (56%). In the patients with wt ctDNA, objective tumor response rate was 50.0%, including one complete response and four partial responses after a median number of 6 courses of cetuximab + FOLFIRI (range, 1 to 16 courses). Two of the nine patients had stable disease, and two had progressive disease. No grade 3 to 4 toxicities were encountered. One-year survival rates were 60.0% for the patients with RAS-wt ctDNA and 17.9% for those with RAS-mt ctDNA. Median overall survival times were not reached and 4.7 months, respectively. CONCLUSION Patients with RAS-mt mCRC whose plasma biopsies contained RAS-wt could benefit from cetuximab-based therapy, a hypothesis to be tested in a prospective randomized trial.

scholarly journals Biomarker-Guided Anti-Egfr Rechallenge Therapy in Metastatic Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1941
Author(s):  
Davide Ciardiello ◽  
Giulia Martini ◽  
Vincenzo Famiglietti ◽  
Stefania Napolitano ◽  
Vincenzo De Falco ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Current Knowledge ◽  
Growth Factor Receptor ◽  
Circulating Tumor Dna ◽  
Clinical Activity ◽  
First Line ◽  
First Line Therapy ◽  
Novel Biomarkers ◽  
Third Line

The prognosis of patients with metastatic colorectal cancer (mCRC) who progressed to the first and the second lines of treatment is poor. Thus, new therapeutic strategies are needed. During the last years, emerging evidence suggests that retreatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MAbs) in the third line of mCRC patients, that have previously obtained clinical benefit by first-line therapy with anti-EGFR MAbs plus chemotherapy, could lead to prolonged survival. The rationale beyond this “rechallenge” strategy is that, after disease progression to first line EGFR-based therapy, a treatment break from anti-EGFR drugs results in RAS mutant cancer cell decay, restoring the sensitivity of cancer cells to cetuximab and panitumumab. In fact, rechallenge treatment with anti-EGFR drugs has shown promising clinical activity, particularly in patients with plasma RAS and BRAF wild type circulating tumor DNA, as defined by liquid biopsy analysis at baseline treatment. The aim of this review is to analyze the current knowledge on rechallenge and to investigate the role of novel biomarkers that can guide the appropriate selection of patients that could benefit from this therapeutic strategy. Finally, we discuss on-going trials and future perspectives.

scholarly journals Small EVs-Associated DNA as Complementary Biomarker to Circulating Tumor DNA in Plasma of Metastatic Colorectal Cancer Patients

2021 ◽  
Vol 14 (2) ◽  
pp. 128
Author(s):  
Silvia Galbiati ◽  
Francesco Damin ◽  
Dario Brambilla ◽  
Lucia Ferraro ◽  
Nadia Soriani ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Digital Pcr ◽  
Extracellular Vesicle ◽  
Circulating Tumor Dna ◽  
Mutation Status ◽  
Promising Practice ◽  
Colorectal Cancer Patients ◽  
Tumor Dna

It is widely accepted that assessing circular tumor DNA (ctDNA) in the plasma of cancer patients is a promising practice to evaluate somatic mutations from solid tumors noninvasively. Recently, it was reported that isolation of extracellular vesicles improves the detection of mutant DNA from plasma in metastatic patients; however, no consensus on the presence of dsDNA in exosomes has been reached yet. We analyzed small extracellular vesicle (sEV)-associated DNA of eleven metastatic colorectal cancer (mCRC) patients and compared the results obtained by microarray and droplet digital PCR (ddPCR) to those reported on the ctDNA fraction. We detected the same mutations found in tissue biopsies and ctDNA in all samples but, unexpectedly, in one sample, we found a KRAS mutation that was not identified either in ctDNA or tissue biopsy. Furthermore, to assess the exact location of sEV-associated DNA (outside or inside the vesicle), we treated with DNase I sEVs isolated with three different methodologies. We found that the DNA inside the vesicles is only a small fraction of that surrounding the vesicles. Its amount seems to correlate with the total amount of circulating tumor DNA. The results obtained in our experimental setting suggest that integrating ctDNA and sEV-associated DNA in mCRC patient management could provide a complete real-time assessment of the cancer mutation status.

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