The Lynx Group

Liquid Biopsies Show High Correlation with Tissue Biopsy for Genetic Mutations

July 2016, Vol 7, No 6

With the exception of resistance mutations, somatic alterations in circulating tumor (ct) DNA (ie, a liquid biopsy) are consistent with alterations found in tissue biopsies of patients with advanced solid tumors, said Philip C. Mack, PhD, Director of Molecular Pharmacology, University of California Davis Comprehensive Cancer Center, Sacramento, at the 2016 American Society of Clinical Oncology (ASCO) annual meeting.

This finding comes from the largest study to date involving a genomic analysis of blood samples from more than 15,000 patients with 50 different tumor types, and suggests that tumor DNA shed into a patient’s blood may be informative when tissue biopsy is insufficient for genotyping, Dr Mack said.

“It’s actually very typical for tissue biopsies to be insufficient for comprehensive molecular analysis,” he said.

In addition, liquid biopsy may serve as a reliable method to periodically monitor disease progression, response to therapy, and the development of drug resistance, said Dr Mack.

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

  • 49% of the cases had alterations for which FDA-approved targeted therapies exist
  • 27% of the cases had actionable resistance mutations
  • 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).

Liquid Biopsy Detects Mutations in Multiple Cancers

In this analysis, DNA was isolated from blood, and fragmented DNA was barcoded using a high-efficiency molecular tagging approach. Target capture was conducted to identify regions of interest in 70 key cancer-associated genes. Sequence analysis was subsequently 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 mutated allele frequency. 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,” said Dr Mack.

This study included 15,191 patients with advanced NSCLC (37%), breast cancer (14%), colon or rectum cancer (6%), or other cancers (14%). Each patient provided blood samples for ctDNA analysis.

The accuracy of liquid biopsies in identifying mutations was assessed using tumor tissue samples. Overall, 83.4% of alterations were detected by ctDNA analysis compared with 94% of alterations identified using data from The Cancer Genome Atlas (TCGA).

DNA was isolated from blood samples when a patient’s cancer was in the advanced stage of the disease, typically during a second-line treatment or later. In 49% of the cases, the identified mutations were associated with at least 1 FDA-approved therapy.

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

This was not the case for subclonal mutations, which are associated with resistance mutations. Discordant resistance cases likely reflect the evolution of disease on therapy after the initial tissue biopsy.

“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,” Dr Mack said.

One exception was the detection of EGFR T790M resistance mutations in plasma in patients with NSCLC receiving EGFR inhibitor therapy that was absent in the tissue-based population data, because the latter group had yet to receive treatment.

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

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

Clinical Implications

Dr Mack noted that at the moment liquid biopsy is not an alternative to traditional tissue biopsy for an initial diagnosis of cancer, and should be used for patients who do not have sufficient tissue for tissue biopsy.

“At this point, we cannot dispense with that initial tumor biopsy. The initial biopsy and subsequent pathology are what allow us to determine what type of cancer it is."

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