From the Journals

CtDNA agrees (mostly) with tissue analysis in mCRC

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Clinic-ready, but not for all patients

Regarding next steps, several studies have now shown a high correlation between RAS testing in plasma versus tissue, and a better understanding of the technical and clinical characteristics of RAS ctDNA testing has helped in increasing the accuracy to almost 100%. With that, RAS ctDNA testing should be ready for its clinical use.

However, as clinicians, we need to remember that the goal of RAS testing is to select patients that will benefit from anti-EGFR therapy, and thus, a threshold of RAS detection in ctDNA that is clinically meaningful needs to be established in future studies.

In summary, Laurent-Puig et al. confirm the high correlation between tissue and ctDNA RAS testing, but more importantly they help by optimizing the limits for its clinical implementation. ctDNA RAS testing is ready for clinical use, but we now know that it may not be a good tool for a minority of patients with specific clinical characteristics.

Clara Montagut, MD, is with Hospital del Mar Medical Research Institute in Barcelona. Dana Tsui, PhD, and Luis Alberto Diaz Jr., MD, are with Memorial Sloan Kettering Cancer Center in New York. Dr. Montagut is an advisory consultant to Merck Serono and other companies. Dr. Diaz is a founder and shareholder of PapGene and Personal Genome Diagnostics and a consultant for Merck and others. Dr. Tsui is a former consultant of Inivata Ltd, and a contributor to patents on cell-free DNA detection methodologies, and may receive royalties related to the licenses of those patents to Inivata Ltd. Their remarks are adapted from an editorial (Ann Oncol. 2018 Feb 9. doi: 10.1093/annonc/mdy091).


 

FROM ANNALS OF ONCOLOGY

For identifying patients with metastatic colorectal cancer who might benefit from therapy with drugs targeted against the epidermal growth factor receptor (EGFR), analysis of plasma for circulating tumor DNA – aka “liquid biopsy” – is about as capable as and considerably faster than tissue analysis of RAS mutational status, investigators contend.

Among 412 chemotherapy-naive patients with metastatic colorectal cancer (mCRC) for whom both plasma and tissue samples were available, the kappa coefficient (a measure of acceptable concordance) between ctDNA RAS mutation detection and tissue-based analysis was 0.71, just over the minimum 0.7, and the accuracy of the liquid biopsy sampling was 85.2%, reported Pierre Laurent-Puig, MD, PhD, of Sorbonne University in Paris, and his colleagues.

“[E]ven if our results are limited to the techniques used with their analytic sensitivity, we show here for the first time in a prospective study an excellent concordance between plasma and tumor RAS mutation status in metastatic colorectal cancer patients, especially those with liver metastases. These results validate the routine use of plasma RAS analysis in patients with colorectal cancer and liver metastases,” they wrote. The report was published in Annals of Oncology.

The investigators found that ctDNA was more likely to yield inconclusive results in patients without liver metastases. In patients with liver metastases, the accuracy of the liquid biopsy using next-generation sequencing (NGS) alone to detect RAS mutations was 93.5%, and when detection of methylated biomarkers was added in, the accuracy was 97%.

In the AGEO RASANC prospective multicenter study, the investigators prospectively collected plasma samples from patients with mCRC and sent them to a central lab for analysis by NGS with the colon/lung cancer V2 Ampliseq panel and with digital polymerase chain reaction dPCR for genes associated with DNA methylation (WIF1 and NPY).

Matched tissue samples from the same patients were analyzed locally according to routine practice.

As noted before, the kappa coefficient was 0.71, indicating that agreement between the tests was at least 70% better than by chance alone.

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