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Circulating tumor DNA in metastatic colorectal cancer: Real-time monitoring of disease evolution and treatment response
Background
Colorectal cancer (CRC) is the third most common cancer worldwide and ranks second in terms of mortality. Approximately 20% of CRCs are diagnosed in the metastatic stage. Metastatic CRC (mCRC) is characterized by a worse prognosis, with a 5-year survival rate of less than 20%. Plasma circulating tumor DNA (ctDNA) is a valuable resource for tumor baseline characterization and for monitoring of residual disease during treatment, however it is not yet introduced in mCRC routine clinical practice. In this retrospective exploratory study, we evaluated the utility of ctDNA analysis in a series of 53 mCRC patients treated with chemotherapy plus bevacizumab in first-line.
Methods
Forty-six patients were characterized for RAS and BRAF status on tumor tissue before the start of treatment: 67% of patients were RAS-mutated (28 KRAS, 3 NRAS), 20% were BRAF mutated and 13% were RAS/BRAF wild-type. Plasma was collected at baseline, at first clinical evaluation, during treatment and at disease progression. ctDNA analysis was performed using Oncomine Colon cfDNA Assay on Ion S5 instrument (Thermofisher). An average coverage of 38.000X was reached, which corresponded to 2.500X molecular coverage per sample.
Results
Concordance rate between tumor tissue and ctDNA mutational calls was >94%. The highest mutant allele frequency (MAF) for each sample was considered as the measure of released ctDNA. Baseline MAF was found associated with longer progression free survival (PFS) (P=0.026) and overall survival (OS) (P=0.044). At first evaluation, MAF decreased and the release of ctDNA was not detectable in 55% of cases. The entity of MAF reduction with respect to baseline was found strongly associated with both PFS (P=0.0094) and OS (P=0.0096). In almost all patients, the same mutations were identified at baseline and progression. In 6 cases the driver mutations were not found at progression, while in 7 patients additional TP53, PIK3CA and APC mutations were identified. Interestingly, in four patients, the increase of released ctDNA could be detected 3 months before the indication of radiological progression by clinicians.
Conclusions
The mutational analysis performed on ctDNA is useful for mCRC molecular characterization, and quantitative variations of released ctDNA are associated with clinical outcomes. Together these results support the use of liquid biopsy for both molecular characterization and tumor response monitoring in mCRC patients.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosures
All authors have declared no conflicts of interest.
