August 2016, Vol. 5, No. 6

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Liquid Biopsies Have High Correlation with Tissue Biopsy for Genetic Mutations

ASCO

Somatic alterations in circulating tumor (ct) DNA, ie, a liquid biopsy, are consistent with alterations found in tissue biopsy, with the exception of resistance mutations, in patients with advanced solid tumors, said Philip Mack, PhD.

The finding, which comes from a genomic analysis of blood samples from more than 15,000 patients with 50 different tumor types, suggests that tumor DNA shed in a patient’s blood may be informative when tissue biopsy is insufficient for genotyping, he said at the 2016 ASCO Annual Meeting.

In addition, the liquid biopsy may serve as a reliable method to periodically monitor disease progression, response to therapy, and development of resistance, said Dr Mack, Professor and Director of Molecular Pharmacology at the University of California Davis Comprehensive Cancer Center.

The following observations from the analysis provide insight into the clinical utility of plasma ctDNA analysis:

  • 49% of the cases had alterations for which FDA-approved targeted therapies exist
  • 27% of the cases had actionable resistance mutations detected
  • The ability of ctDNA to enhance and complement the initial biomarkers analysis in tissue was exemplified by an increase in the yield of 42% in tissue-insufficient or partially genotyped non–small cell lung cancer (NSCLC)

In the analysis, DNA was isolated from blood, and fragmented DNA was bar coded using a high-efficiency molecular tagging approach. Target capture was performed to identify regions of interest in 70 key cancer-associated genes. Sequence analysis was then performed, followed by variant calling that included missense mutations, small insertions and deletions, amplification events, and a limited number of fusions.

“One of the advantages of using next-generation sequencing in plasma is that it reports a fairly precise mutant allele frequency,” he said. “This allows you to easily discriminate the presence of germline polymorphisms from the somatic mutations, with a germline polymorphism occurring at 50% or 100% allele frequencies.”

This study included 15,191 patients with advanced cancers of the lung (37%), breast (14%), colon/rectum (10%), and other organs (39%). Each patient provided blood samples for analysis of ctDNA.

The accuracy of liquid biopsies was compared with tumor tissue samples. Some 83.4% of patients had alterations detected by ctDNA analysis, compared with 94% using published data from The Cancer Genome Atlas (TCGA).

Generally, blood was captured when patients’ cancer was in an advanced stage, usually during second-line treatment or later. In 49% of cases, mutations were identified that were associated with at least 1 FDA-approved therapy with an indication in cancer.

The patterns of genomic changes in ctDNA were compared with those found in 398 patients who underwent genetic testing of the tumor tissue. The positive predictive value for key abnormalities in EGFR, BRAF, KRAS, ALK, RET, and ROS1 by ctDNA ranged from 94.1% to 100%.

The same association was not true for subclonal mutations, which are associated with emergence of resistance mutations. Discordant resistance cases likely reflect the evolution of disease on therapy after initial tissue biopsy, he said.

“Circulating tumor DNA alteration patterns were highly similar in terms of the frequency and distribution of mutations between TCGA tissue and this series, with correlations of variant patterns ranging from 0.85 to 0.99,” he said. For example, correlations in mutation patterns between plasma and tissue typically ranged from 0.92 to 0.99. One exception was the detection in plasma of EGFR T790M resistance mutations in patients on EGFR inhibitor therapy that was absent in the tissue-based population data because the latter group had yet to receive treatment.

Overall, 27% of cases had potentially actionable resistance targets detected in ctDNA.

In a subset of 362 patients with NSCLC, tissue was insufficient for testing or partially tested in 63%. In these 362 patients, 120 had primary activating mutations in the tumor tissue. When plasma ctDNA analysis was added, an additional 51 patients were detected who had actionable biomarkers detected, an increase of 42%.

ASCO - August 5, 2016

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ASCO - August 5, 2016

CAR T-Cell Therapy Produces High Response Rates in Refractory B-Cell Malignancies

A durable complete response (CR) was achieved in a high proportion of adult patients with refractory B-cell malignancies who were treated with CD19+ chimeric antigen receptor (CAR) T cells made up of a defined 1:1 ratio of CD8+ and CD4+ cells. The data were presented by Cameron John Turtle, MBBS, [ Read More ]