A multicentre, prospective study of plasma circulating tumour DNA test for detecting RAS mutation in patients with metastatic colorectal cancer

Abstract

BACKGROUND: OncoBEAM TM RAS CRC kit using BEAMing technology is a circulating tumour DNA (ctDNA) test for detecting plasma RAS mutational status in metastatic colorectal cancer (mCRC). We conducted a multicentre, prospective study to investigate the concordance of the RAS mutational status between plasma ctDNA and tumour tissue DNA. METHODS: mCRC patients without prior anti-EGFR antibodies or regorafenib treatment were enroled. Plasma-and tissue-based RAS mutational status were determined by BEAMing, respectively. RESULTS: A total of 280 patients from eight institutions were eligible. The overall agreement between plasma-and tissue-based analyses was 86.4%, with a positive percent agreement of 82.1% and negative percent agreement of 90.4%. From logistic regression analysis, lung metastasis alone indicated the most significant factor associated with discordance. The agreement between plasma-and tissue-based analyses was 64.5% in patients with lung metastasis alone (n = 31) indicating lower amount of ctDNA. Among the cases with lung metastasis alone, all plasma-and tissue-based analyses were perfectly concordant in cases with ≥20 mm of maximum lesion diameter or ≥10 lesions. CONCLUSION: The clinical validity of OncoBEAM TM RAS CRC kit was confirmed. Careful attention should be paid for mCRC patients with lung metastases alone having fewer metastases or smaller diameter lesions.

Assessing the Concordance of Genomic Alterations between Circulating-Free DNA and Tumour Tissue in Cancer Patients

“…KRAS mutations arise in 50% of metastatic colorectal cancer (mCRC) cases, which can affect the response to EGFR pathway-targeted therapeutics [30]. In multiple studies of mCRC, cohorts of patients were tested for RAS status using standard-of-care PCR and ddPCR (BEAMing) or similar technologies for tissue and cfDNA, yielding 86.4-92% concordance rates [31][32][33]. In excess of 85% of lung cancers are classified as NSCLC, with several actionable alterations of EGFR and ALK contributing to its pathogenesis [34,35].…”

“…In the field of breast cancer, circulating tumour cells and cfDNA are promising analytes for prediction of survival and response to therapy [17,20,42,43]. An important cfDNA biomarker of breast cancer, hotspot mutations in ESR1, predicts resistance to endocrine therapy [32]. Takeshita et al, compare ESR1 mutation status of 35 cfDNA and matched tumour tissue in patients with metastatic breast cancer using ddPCR and find an overall concordance rate of 74.3% (26/35) [44].…”

“…The location, size and vascularity of the tumour can affect the accessibility of tumour DNA to the circulation, and hence impact tumour fraction [62][63][64]. Therefore, these biological factors can affect the release of tumour DNA in the blood, impacting their representation and detectability in cfDNA [31,32]. For instance, García-Foncillas et al, in a study of metastatic colorectal cancer, report that when SGAs (such as RAS mutations) of cfDNA and liver metastasis were compared, a higher concordance rate was obtained than that of cfDNA and lung metastasis [65].…”

Analysis of colorectal cancer‐related mutations by liquid biopsy: Utility of circulating cell‐free DNA and circulating tumor cells

“…In cohort 2, the RAS mutant allele was detected in ccfDNA of all patients in whom the allele was detected in ctcDNA, and VAF of ccfDNA was significantly higher than that of ctcDNA. According to the results of previous studies, detection rates of RAS mutations using ccfDNA are considered to be higher than that using ctcDNA . However, the present study is the first to show the superiority of ccfDNA by direct comparison.…”

“…According to the results of previous studies, detection rates of RAS mutations using ccfDNA [25][26][27][28] are considered to be higher than that using ctcDNA. 29,30 However, the present study is the first to show the superiority of ccfDNA by direct comparison.…”