Liquid Biopsy: Pathologists Dripping Blood

22. November 2016
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Working with tumour DNA from blood samples, doctors are succeeding in prying out the molecular characteristics of cancer without creating risks. The liquid biopsy might eventually even replace classic screenings, researchers hope.

At the last annual meeting of the American Society of Clinical Oncology, experts from around the world were in agreement: With liquid biopsy, physicians have a new tool at hand for more easily detecting cancers and better treating them. The basic principle has been known for decades: in the blood there is cell-free DNA (cfDNA) circulating which comes from dead cells. Malignancies result in larger amounts of nucleic acids. Intact tumour cells, in the form of ctcDNA (circulating tumour cell DNA), are present as well. Only through next generation sequencing techniques has it become possible to systematically use the method.

Minimising costs and risks

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Mark Jacobstein © Guardant Health

Mark Jacobstein, Chief User Engagement Officer at Guardant Health, explains some advantages of liquid biopsies to DocCheck. He mentions the risks associated with classic methods: “For example, 19.3 percent of all lung biopsies lead to adverse events such as pneumothorax, bringing along with it 14,600 US dollar expenses”.

Tissue biopsies have another disadvantage: “Due to the heterogeneity of tumours not all information may be comprehensively detected”, says Jacobstein. Investigations have shown that in nine biopsies of the same primary tumour, match-ups were shown in only 34 percent of all genetic variants, he says.

 

In many cases, doctors are more or less reluctant to search for specific features in the genome. “Although the current guidelines for NCCN oncologists advise that a broad molecular profiling be performed, so as to identify rare mutations, figures from practice reveal the problem”. Thus only 65 to 67 percent of patients were examined for ALK and EGFR mutations. And with non-small cell lung cancer, where there are currently seven clinically-relevant biomarkers, this figure according to Jacobstein is only 15 percent.

Here the researcher sees the strengths of using liquid biopsies. Geneticists search through blood samples for fragments of tumour DNA. Through the use of next-generation sequencing and bioinformatic algorithms, the secrets of nucleic acids are coaxed out. Doctors not only get information about genomic changes, but also instructions for clinical practice. These also takes in therapies with FDA approval or ongoing clinical trials.

More than a grain of salt’s difference

Oliver A. Zill, researcher at Guardant Health, pursued the question as to what extent the results of “liquid” and classic biopsies are able to be compared. The backdrop to this is the scepticism of some oncologists regarding the new method. They prefer to stick to proven techniques.

Together with colleagues, Zill examined the gene profiles of 15,191 patients. They were suffering from 50 different tumour diseases in advanced stages. Overall, 17,628 blood samples were available. All samples were examined with the ctDNA test “Guardant360” for changes in 70 genes. In addition tissue samples from 398 patients and data on the statistical distribution of mutations in the literature were also used. No differences were observed for all known driver mutations, such as those in the BRAF, EGFR or KRAS gene. In simpler language, this means that liquid biopsies can replace conventional methods, without any quality losses.

Yet it’s not just about replacing tissue biopsies. Zill found, for example, mutations in the EGFR gene which were associated with resistance to first and second generation EGFR inhibitors. This anomaly was not detectable in initial biopsies. Oncologists can intervene more quickly. Using established imaging procedures, they only see macroscopic changes after twelve to 18 months.

Making therapeutic success via blood test visible

Anja Lisa Riediger and Holger Sültmann of the German Cancer Research Center (DKFZ) Heidelberg have additionally also shown that the treatment success rate is able to be measured by liquid biopsy. The researchers examined blood samples from patients with lung cancer for up to two years. All study participants were treated with tyrosine kinase inhibitors. Riediger and Sültmann found several clinically relevant particularities.

The number of mutations changed over the course of clinical investigation. If immediately upon starting treatment a dramatic increase in the amount of mutant cfDNA occurs in the blood plasma, many cancer cells are found to have died. The tumour, it seems, responds well to the inhibitor. In the medium term, little or no cfDNA suggests that the disease is under control. If nucleic acid fragments suddenly reappear, a case is then strongly made that the condition has further progressed. This increase was even observed in part before the onset of clinical signs. “These results show that liquid biopsy is sensitive enough to detect tumour changes in real time”, according to a statement by the DKFZ.

Screening with blood tests – still part of the future

The range of possibilities is therewith far from exhausted. Mark Jacobstein criticises that classical cancer screenings are associated with a high rate of false positive results. Working together with colleagues, he has therefore initiated the PROJECT LUNAR trial. They are collectively investigating whether liquid biopsies are also suitable for early detection of cancers. In the long term, mammograms, colonoscopies or PAP tests might potentially be replaced, the researchers hope.

There is much to do

Despite all the good reviews this innovative process has some downsides. Pathologists examine malignant cells histologically as part of their diagnostic procedure. For example: in order to recognise when looking at breast cancers whether one is dealing with adenocarcinoma, invasive lobular cancer, or other types of tumours, classic biopsies are required. This classificatory step has implications for treatment and prognosis and unfortunately requires tissue samples. Liquid biopsies are still out of place here.

Professor Dr. Edgar Dahl of Aachen points out other weaknesses of the new method. Only 40 percent of all prostate or renal cell carcinoma cfDNA are detectable, he says. And due to the nature of the blood-brain barrier, cfDNA-detection is entirely unsuitable for brain tumours. The issue of quality assurance and reimbursement by statutory health insurance funds also needs to be discussed.

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Medicine, Oncology

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