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Liquid Biopsies Uncover Mutations That Develop During Tumor Progression

NEW YORK (GenomeWeb) – Researchers from the CORRECT trial have provided additional evidence that genomic analysis of liquid biopsies could be a viable approach for keeping tabs on tumor genotype evolution and matching clinically relevant mutations to therapeutics.

As reported in the Lancet Oncology yesterday, this international team of researchers compared certain genetic mutations in DNA obtained from more than 500 plasma samples from patients with metastatic colorectal cancer with those uncovered in DNA obtained from tissue biopsies.

"This is the first large clinical trial to compare liquid versus conventional tissue biopsy data, and the results show the former obtains more data on tumor mutations throughout the course of the disease, enabling us to better target therapy to the specificities of a patient's tumor," Josep Tabernero, head of the medical oncology department of Hospital Universitario Vall d'Hebron and study author, said in a statement.

The CORRECT trial was an international, multi-center, randomized, phase 3 trial that assigned 760 patients with metastatic adenocarcinoma of the colon or rectum — patients who had progressed on all standard therapies — to receive the multi-kinase inhibitor regorafenib (Bayer's Stivarga), or placebo.

Tabernero and his colleagues collected 503 liquid biopsy samples from patients for genotyping prior to the onset of the trial as well as tissue biopsy samples.

Both the liquid and tissue biopsy samples were analyzed using the emulsion PCR-based BEAMing (beads, emulsions, amplification, and magnetics) technology from Sysmex Inostics.

With this approach, the researchers found KRAS, PIK3CA, and BRAF mutations in 69 percent, 17 percent, and 3 percent of patients, respectively.

They compared these findings to matched archival samples, finding concordant mutation status between the liquid biopsy and tissue biopsy samples for 76 percent of patients for KRAS, 88 percent of patients for PIK3CA, and 97 percent of patients for BRAF mutations.

Much of the KRAS status discordance between the liquid biopsy and tissue biopsy samples was due to the detection of a mutation in the plasma, but not in the archival tissue sample.

Still, the mutations the researchers identified in the patient-matched tumor and normal samples were identical in 97 percent of the cases for KRAS mutations and 94 percent of cases for PIK3CA mutations.

Next-generation sequencing of 24 patients' tumor tissue showed full concordance with KRAS mutation status detected by the BEAMing approach, the researchers reported. This, they added, supports the robustness of the approach.

In addition, BEAMing analysis of fresh plasma DNA found KRAS mutations in nearly half of the patients who had previously received anti-EGFR therapy and whose archival tumor tissue DNA was KRAS wild-type also by BEAMing analysis, the researchers reported. This, they added, shows how liquid biopsy samples can be used to follow tumor evolution.

Regorafenib treatment, the researchers added, was associated with overall and progression-free survival in numerous patient subgroups based on genotype as well as protein biomarker status. They noted a trend toward clinical benefit for regorafenib based on KRAS and PIK3CA mutational status.

In particular, they reported a hazard ratio of 0.52 for wild-type KRAS and 0.51 for mutant KRAS, and an HR of 0.50 for wild-type PIK3CA and 0.54 for mutant PIK3CA for progression-free survival.

This suggests that liquid biopsies "could be a viable approach for non-invasive analysis of tumor genotype in real time and for the identification of potentially clinically relevant mutations that are not detected in archival tissue," Tabernero and his colleagues said in their paper.

They also noted in their paper that they received funding, input on study design and interpretation, as well as the study drug from Bayer HealthCare Pharmaceuticals.

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