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Promise of Liquid Biopsy as Clinical Tool Continues to Grow Among Cancer Researchers

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NEW YORK (GenomeWeb) – Enthusiasm for liquid biopsy tools and techniques is booming, as early adopters amass ever more promising validity and utility data, while new players enter the market hoping to advance novel methods for increasingly sensitive detection of cancer markers in blood and other body fluids.

This much was clear at the annual meeting of the American Association for Cancer Research last week in Philadelphia, which featured numerous symposia and presentations on the anticipated clinical potential of liquid biopsy across multiple technologies and disease areas, alongside heaps of new research presented in posters by both old and new faces in the field.

Initially a small pond, the liquid biopsy space is rapidly catching up to the overall cancer genomics field in its diversity. During the meeting, presenters highlighted a wide variety of techniques for analyzing both circulating tumor cells and circulating cell-free tumor DNA (ctDNA), and methods ranging from broad sequencing to more tightly targeted molecular assays with potential utility as companion diagnostics, in disease monitoring, or even for early cancer detection.

Many at the meeting expressed a sense that the analytical and even clinical validity of blood-based cancer testing has been, or is close to being proven, and the next steps for the field will be decidedly clinical in nature.

"There is enough evidence to say at this point … from concordance studies with tissue and plasma that there is no question that you can use blood to [analyze the genomics of a cancer]," Alberto Bardelli of the University of Turin said during a presentation at the conference.

He added that it also appears to him that the evidence is mounting that in some cases, especially in the context of the evolution of resistance to targeted drugs, liquid biopsy may actually be preferable to tumor testing, offering information relevant to clinical decision making and therapy above what can be gleaned by a single chunk of tissue.

In some areas, blood-based testing for cancer mutations or rearrangements is already taking off, at least as an adjunct to tissue analysis or in cases where tissue biopsies are not possible.

Several companies are currently offering, or working to launch liquid biopsy tests for alterations in genes like EGFR, ALK, and ROS1 to guide therapy for patients with non-small cell lung cancer.

Last year, San Diego-based Biocept launched its lab-developed test OncoCEE-LU to detect ALK fusions in lung cancer patients who don't have sufficient tumor biopsy material for analysis by conventional tests, and in January added another test for ROS1 rearrangements.

Qiagen also announced in January that it had received a CE-IVD mark for its therascreen EGFR RGQ Plasma PCR kit, a liquid biopsy assay co-developed by with AstraZeneca and intended to help physicians identify which advanced NSCLC patients without available tumor tissue are more likely to benefit from treatment with AstraZeneca's EGFR inhibitor Iressa (gefitinib).

At the AACR meeting, Exosome Diagnostics, a company developing liquid biopsy tests that utilize special technology to isolate transcriptomic and genetic material from circulating exosomes in addition to circulating cell-free DNA, presented a poster supporting the sensitivity of its EML4-ALK test for NSCLC patients, which it plans to make available to physicians by the end of this year. In addition to ALK, Exosome also plans to launch a liquid biopsy test for the T790M EGFR resistance marker.

But even beyond these companion diagnostics pioneers, evidence of the accuracy and clinical benefits offered by liquid biopsy for even broader analyses is also amassing rapidly.

Validity and utility

At the meeting, Guardant Health presented updated numbers on the validity of its laboratory-developed next-gen sequencing test, Guardant360 — which targets actionable mutations in 68 genes — in over 2,000 commercially tested cases.

The company also shared research from academic collaborations, highlighting its test's potential utility across different cancer types. Most interestingly, a study by researchers from MD Anderson suggested that Guardant's test increased the number of colorectal cancer patients referred to targeted therapy clinical trials over tumor tissue testing alone.

Guardant is not alone in pursuing a broader sequencing approach to catalogue multiple mutations in circulating tumor DNA.

Cambridge, UK startup Inivata is advancing an amplicon-based sequencing and data analysis method approach it calls TAm-Seq, while Johns Hopkins University spinout Personal Genome Diagnostics is developing an NGS-based liquid biopsy assay it calls PlasmaSelect.

PGD researchers shared data at the meeting on PlasmaSelect, which interrogates 63 well-established cancer genes, and which the company aims to bring through the US Food and Drug Administration as a clinical test within the next several years.

In dilution experiments, the company reported that it was able to detect genetic alterations with a limit of detection of 0.1 percent while maintaining high specificity. Blood-based and matched tissue biopsy specimens also demonstrated high concordance, the company reported, including alterations in both driver genes as well as those related to acquired resistance to targeted therapies.

PGD is also developing a more specific test, METDetect, for MET amplifications. In another poster at the meeting researchers reported on a study of 205 plasma samples from patients with gastric, lung, and esophageal cancer, in which they saw a concordance of more than 90 percent comparing MET amplification in plasma DNA to amplification status in patients' matched tumor tissue.

Numerous companies working with circulating tumor cells instead of ctDNA also shared results at the meeting, including Epic Sciences, which presented the first data that its platform for unbiased isolation of circulating tumor cells could allow next-gen sequencing to profile copy number variation among individual CTCs.

Researchers from Thermo Fisher and liquid biopsy company Cynvenio also presented a poster on how they have been using the AmpliSeq panel to sequence both DNA from isolated CTCs and ctDNA, a combined strategy that Cynvenio announced it was pursuing at the end of last year.

Importantly, the conference also saw data from highly anticipated moves into the liquid biopsy space by large companies that have already established themselves in tumor tissue testing, most notably two posters by Foundation Medicine, which has been discussing its plans to develop both CTC and ctDNA tests for some time.

In its poster on ctDNA analysis, company researchers used cell lines to spike samples at varying concentrations, and also compared calls in liquid samples to those from matched tumor tissue from 74 patients.

According to the company, tissue analysis identified at least one genomic alteration in 84 percent of the samples, but blood-based testing only found an alteration in 59 percent of the samples overall. However, according to the authors, concordance between tissue and blood results was much higher for metatstatic disease patients than for those with early-stage disease.

Additionally, the researchers saw several mutations in blood but not tissue, including variants linked to therapy resistance, supporting the potential of their liquid biopsy approach to identify evolving resistance mutations not observed in tissue.

Clinical potential

During a symposium highlighting many of these recent advances in the field, Johns Hopkins research Victor Velculescu gave an overview of his vision for liquid biopsy's near-term path into the clinic.

According to Velculescu, the furthest advanced and most readily applicable role for the technology is the profiling of circulating tumor cells or cell-free DNA as a way to monitor patients in the course of therapy — particularly the use of these tools for better, earlier indication of either response or emerging resistance to a particular treatment.

Following on this, the next logical step will be to couple this ability with analysis of the genomic landscape of circulating tumor cells or ctDNA to better understand the mechanisms of evolving resistance, and hopefully to guide treatment strategies to overcome these mechanisms, Velculescu said.

This, perhaps more than anything else, appears to illustrate the utility of liquid biopsy not just as a mirror of tissue biopsy, but as a tool that can detect unique and impactful information about a cancer that tissue testing cannot.

"You can now think about cancer genomes as not being static, but dynamic and changing over the course of therapy," Velculescu said.

According to conference presenters, early research in this area is already illustrating how this might be possible, for example in the context of MET amplification and resistance to EGFR inhibitors.

Velculescu's company Personal Genome Diagnostics is developing a MET amplification test based on its ctDNA sequencing methods.

During the conference, he said that the test, which is available through a CLIA lab, is being used not only in retrospective analyses, but prospectively, to enroll patients into clinical trials.

Other researchers highlighted various projects using liquid biopsy to investigate how subclonal cancer cell populations blossom and drive disease progress after targeted therapies kill off the more dominant clones. The hope is that this can illuminate strategies to combine drugs that affect the dominant mutated populations of cells and then also inhibit other subclonal populations from taking over.

Another promising avenue for liquid biopsy, according to Velculescu, is in improving clinicians' ability to predict the risk of recurrence in early-stage cancer patients whose tumors have been surgically removed. At another conference session, Luis Diaz, a colleague of Velculescu's at Johns Hopkins, also highlighted this idea of using liquid biopsy to redefine the idea of "minimal residual disease."

In many cancers, current clinical methods are limited in their ability to stratify the risk of early-stage patients after surgical resection. The potential benefit to patients of more accurate strategies is clear.

For example Velculescu said, in colorectal cancer, stage II patients are not commonly treated with adjuvant drug therapy. However, 30 percent recur after otherwise apparently curative surgery — vice versa for stage III patients who largely receive added treatment, though some may have been successfully treated with surgery alone.

Diaz and Velculescu have both researched whether the presence of ctDNA in patients after surgery can predict later disease recurrence, with promising results, as have other research groups.

For example, at the meeting, liquid biopsy firm Trovagene shared a study in which its researchers performed blinded retrospective analysis of blood and urine samples from 20 colorectal cancer patients who underwent either curative surgery for early stage disease or palliative surgery to remove metastases in later-stage disease.

A total of 193 plasma and urine samples archived for three for five years were tested, and a correct KRAS mutation that correlated with KRAS mutation in tissue was identified in 95 percent of evaluable baseline plasmas and 92 percent of evaluable baseline urine samples, the researchers reported.

Meanwhile, in all patients with curative intent surgery, ctDNA KRAS levels were undetectable in urine or plasma after surgery. In contrast, eight of the 10 patients who had incomplete or palliative surgery showed a ctDNA KRAS signal that remained detectable or increased after surgery.

Finally, both Velculescu and Diaz concluded in their talks that the most distant but perhaps most exciting clinical application of blood-based cancer genomics is early cancer detection.

"The holy grail for the field is using these types of non-invasive approaches for early detection," Velculescu said.

Promisingly, researchers have shown that ctDNA is detectable into the early stages of at least some already-diagnosed cancers, but it's also been clear from these studies, Velculescu said, that for true early detection it will be necessary to reach even lower limits of detection than is currently practical.

Encouragingly, he added, it looks like pushing this detection limit will be a relatively simple matter of additional sequencing, which though prohibitively expensive now, should become more and more practical in the future.

Diaz and his group are also working on methods to induce the release of more cancer DNA into circulation as a way of improving the sensitivity of liquid biopsy toward the same end.

Interest in early cancer detection also isn't limited to the cancer genomics space. Recently, prenatal testing companies have shared data showing that their chromosomal abnormality tests may also be able to pick up patterns of aneuploidy that indicate the presence of cancer in asymptomatic women.

Meanwhile, several NIPT firms are working on developing cancer detection tests using their various blood-based sequencing technologies.

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