NEW YORK (GenomeWeb) – With evidence building that monitoring a tumor's mutational landscape can be done by evaluating circulating tumor DNA or circulating tumor cells, companies are increasingly looking to move into the liquid biopsy market.
Over the last several years, researchers have published a number of studies demonstrating that next-generation sequencing of ctDNA or CTCs can give a representative picture of a patient's tumor.
As a result, a few startup companies and spinouts from academic research teams performing such methods have sprung up, including Guardant Health, Personal Genome Diagnostics, and Inivata. Chronix Biomedical is also offering an NGS-based ctDNA test for patients in Germany as a supplemental prostate specific antigen test.
However, over the last month, the larger players in cancer genomics have all announced their intentions to get into the market, as well.
At the JP Morgan Healthcare Conference in San Francisco earlier this month, Illumina, Sequenom, and Foundation Medicine all mentioned plans for developing liquid biopsy tests. Meantime, Thermo Fisher Scientific signed a distribution agreement with Cynvenio for its LiquidBiopsy platform that extracts and isolates CTCs from a blood draw and prepares them for genomic analysis. Qiagen's PCR-based test to assess EGFR mutation status from ctDNA in non-small cell lung cancer received CE-IVD marking, and the company continues to develop technologies to enable both PCR- and NGS-based analysis of ctDNA, CTCs, and RNA found in exosomes. In addition, Trovagene aims to distinguish itself by developing tests that can analyze tumor DNA in either blood or urine.
Illumina, which also announced new sequencing platforms, said that is planning to develop research-use-only kits in 2015 for ctDNA analysis and will operate a laboratory-developed test to gather clinical evidence for a regulatory submission.
Foundation Medicine also said that it plans to develop a test that would potentially analyze both ctDNA and CTCs. "Both areas are important for cancer care depending on clinical indication," CEO Michael Pellini said in a presentation at the JP Morgan conference. He said that the company would talk further about its strategy in this area later in the year, adding that one of the company's goals is to show the clinical value of being able to analyze ctDNA and CTCs. Chief Medical Officer Vincent Miller added that one application could be to analyze tumors that are inaccessible by biopsy.
Sequenom aims to use its expertise in cell-free DNA to develop a ctDNA assay. At the JP Morgan conference, CEO Bill Welch said that the company has built up a clinical advisory board that has been working to develop the company's oncology strategy, and that it plans to launch a RUO test to early-access users in the second half of the year that will analyze ctDNA in advanced cancer patients with solid tumors, patients with metastatic disease, and patients whose tumor cannot be biopsied.
Thermo Fisher and Cynvenio
Earlier this month, Thermo Fisher and Cynvenio signed a distribution agreement for Cynvenio's LiquidBiopsy platform, which isolates and quantifies CTCs from a blood sample.
The companies plan to combine the LiquidBiopsy platform with Thermo's Ion Chef for sample prep and the Ion Torrent PGM 318 chip and AmpliSeq Cancer Hot Spot Panel v2 to sequencing 2,800 gene mutations.
Cynvenio has CLIA certification for its LiquidBiopsy service, but Jason Johnson, director of product management, sample preparation solutions at Thermo, told GenomeWeb that Thermo would sell kits as RUO products, beginning in the first quarter of this year. The goal is to offer a complete solution from blood collection through analysis, he said.
In addition, while Cynvenio's service currently includes only analysis of CTCs, in collaboration with Thermo, the companies plan to include both CTC and ctDNA analysis. Cynvenio has already demonstrated that it can do this with its current platform and has showed that the two approaches could be complementary.
Johnson said that customers will be able to purchase the complete kit with the LiquidBiopsy platform, Ion Chef, AmpliSeq panel, and PGM, or existing PGM customers could purchase just the LiquidBiopsy platform.
The initial market will be comprehensive cancer centers and for translational research, he added.
Last year, Trovagene made its first commercial entry into the NGS liquid biopsy market with a KRAS test that screens for seven mutations. Trovagene runs the test on Illumina's MiSeq from its CAP-accredited, CLIA-certified laboratory in San Diego.
The company has also been inking a number of collaborations in recent months, including one this week with Genomac Research Institute, and ones earlier this month with City of Hope and the University of California, San Diego, to use its Precision Cancer Monitoring platform.
CEO Toni Schuh and CSO Mark Erlander spoke with GenomeWeb at the JP Morgan conference this month about the company's technology and its plans going forward.
Trovagene seeks to distinguish itself from others looking to tap into the liquid biopsy market by developing technology that can analyze cell-free nucleic acids from plasma, serum, or urine.
"Everybody who develops solutions for detection of mutations in tissue is venturing into cell-free DNA," Schuh said. However, the majority of those companies are analyzing cell-free DNA in blood. "Our clinical differentiation is that our assays can work on any specimen, including urine," he said. Urine is a more ideal clinical sample than blood, Schuh said, because it can be collected in large volumes and does not require the patient to travel to the hospital.
Initially, the company was working primarily with droplet digital PCR, but it is transitioning to NGS, Schuh said.
Trovagene has already processed around 3,000 clinical samples in 15 months and its technology is currently being evaluated in around 30 clinical studies, the largest of which are recruiting up to 1,000 patients, Schuh said.
Those studies will help support the company's development of IVDs, Erlander said, adding that the firm is currently developing a roadmap for bringing its products through FDA clearance. "We're starting now to evaluate how that path would look," he said. In addition, he said the company is developing LDTs, such as its KRAS test.
The company is platform agnostic, Schuh said, and the goal is to develop cleared tests that could run on any NGS system, although initially the tests would be cleared for NGS systems that have FDA clearance.
The firm's clinical studies are prospective and analyze cell-free DNA in blood and urine, Erlander said. "We believe that by being versatile and agnostic for specimen type gives us greater flexibility," he said, although, he thinks that ultimately urine will be a more preferred sample because "we believe that high frequency testing will not be possible with blood."
However, he said, DNA is typically more fragmented in urine, making testing a bit more difficult. That is one reason why Trovagene's assays currently look at just a handful of mutations, as opposed to tens or hundreds of genes, Erlander said.
Qiagen is relying on its position as a leader in sample prep technology, as well as having a CE-IVD marked liquid biopsy test that uses PCR to analyze EGFR mutation status from ctDNA in lung cancer patients, to market products in the liquid biopsy space.
Michael Kazinski, senior director of global product management for liquid biopsy at Qiagen, told GenomeWeb that the company is developing products for CTCs, ctDNA, and even exosomes — circulating microvessicles that contain RNA.
Kazinski said that Qiagen's products will work with PCR or NGS solutions from all the major platform providers.
Qiagen is developing "complete solution offerings, along the whole workflow starting from DNA isolation," he said. Already, Qiagen markets a number of sample prep kits for such testing, and it is also developing a bioinformatics offering, Kazinski said. Eventually, Qiagen aims to bring its liquid biopsy products through in vitro diagnostic validation, he added.
The firm last year expanded on an agreement with Exosome Diagnostics to develop noninvasive IVDs based on Exosome's methods for purifying nucleic acids from exosomes and Qiagen's sample prep technologies.
Kazinski said that although the exosomes are an "upcoming" application, analyzing RNA from exosomes serve as an important complement to analyzing mutations in ctDNA. In order to use mutational profiling to choose a targeted therapy for a cancer patient, it is important to make sure that the mutation being targeted is actually being expressed. Studies have shown that while sequencing genomic DNA from tumors is a good way to identify potentially targetable mutations, RNA-seq data has found that those mutations are not always expressed. Similarly, when analyzing ctDNA to guide treatment, it will be important to make sure that the targeted mutations are actually being expressed. Analyzing tumor RNA from exosomes is one way to do that noninvasively.