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June 19, 2017

Liquid Biopsy Guides New Prostate Cancer Drug Trial

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    New three-in-one blood test opens door to precision medicine for prostate cancer. [The Institute of Cancer Research, London]

    It’s been no secret that screening methods to detect prostate cancer have been woefully lacking and largely inconsistent with respect to the results they provide. Yet, with the rise in validated biomarkers and advanced diagnostics coupled with next-generation sequencing methods, new liquid biopsy assays are guiding physician treatment options. Now, a group of investigators at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust have developed a three-in-one blood test that could transform the treatment of advanced prostate cancer through the use of precision drugs designed to target mutations in the BRCA genes.

    "Blood tests for cancer promise to be truly revolutionary,” noted Paul Workman, Ph.D., chief executive of The Institute of Cancer Research, London. “They are cheap and simple to use, but most importantly, because they aren't invasive, they can be employed or applied to routinely monitor patients to spot early if treatment is failing—offering patients the best chance of surviving their disease.”

    The research team was able to isolate cancer DNA in a patient’s bloodstream and determine which men with advanced prostate cancer were likely to benefit from treatment with a new class of drugs called poly(ADP-ribose) polymerase (PARP) inhibitors—specifically the drug olaparib. Moreover, the scientists were able to use the test to analyze DNA in the blood after treatment had started, so people who were not responding could be identified and switched to an alternative therapy in as little as four to eight weeks. The third aspect of the new test came when the research team was able to monitor a patient's blood throughout treatment, quickly picking up signs that the cancer was evolving genetically and might be becoming resistant to the drugs.

    Findings from the new study were published recently in Cancer Discovery in an article entitled “Circulating Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition.”

    "Our study identifies, for the first time, genetic changes that allow prostate cancer cells to become resistant to the precision medicine olaparib,” explained senior study investigator Johann de Bono, M.D., professor of cancer research at The Institute of Cancer Research, London, and consultant medical oncologist at The Royal Marsden NHS Foundation Trust. "From these findings, we were able to develop a powerful, three-in-one test that could in future be used to help doctors select treatment, check whether it is working, and monitor the cancer in the longer term. We think it could be used to make clinical decisions about whether a PARP inhibitor is working within as little as four to eight weeks of starting therapy.”

    The investigators are optimistic that the new test could help to extend or save lives by targeting treatment more effectively, while also reducing the side effects of treatment and ensuring patients don't receive drugs that are unlikely to do them any good. Additionally, the new study is also the first to identify which genetic mutations prostate cancers use to resist treatment with olaparib. The test could potentially be adapted to monitor treatment with PARP inhibitors for other cancers.

    "Not only could the test have a major impact on the treatment of prostate cancer, but it could also be adapted to open up the possibility of precision medicine to patients with other types of cancer as well," Dr. de Bono remarked.

    In the study, researchers at the ICR and The Royal Marsden collected blood samples from 49 men at The Royal Marsden with advanced prostate cancer enrolled in the TOPARP-A Phase II clinical trial of olaparib. Olaparib is good at killing cancer cells that have errors in genes that have a role in repairing damaged DNA such as BRCA1 or BRCA2. Some patients respond to the drug for years, but in other patients, the treatment either fails early, or the cancer evolves resistance. Evaluating the levels of cancer DNA circulating in the blood, the researchers found that patients who responded to the drug had a median drop in the levels of circulating DNA of 49.6% after only eight weeks of treatment, whereas cancer DNA levels rose by a median of 2.1% in patients who did not respond.

    Men whose blood levels of DNA had decreased at eight weeks after treatment survived an average of 17 months, compared with only 10.1 months for men whose cancer DNA levels remained high.

    "This is another important example where liquid biopsies—a simple blood test as opposed to an invasive tissue biopsy—can be used to direct and improve the treatment of patients with cancer," commented David Cunningham, Ph.D., director of clinical research at The Royal Marsden NHS Foundation Trust.

    The researchers also performed a detailed examination of the genetic changes that occurred in cancer DNA from patients who had stopped responding to olaparib. They found that cancer cells had acquired new genetic changes that canceled out the original errors in DNA repair—particularly in the genes BRCA2 and PALB2—that had made the cancer susceptible to olaparib in the first place.

    "To greatly improve the survival chances of the 47,000 men diagnosed with prostate cancer each year, it's clear that we need to move away from the current one-size-fits-all approach to much more targeted treatment methods,” concluded Matthew Hobbs, Ph.D., deputy director of research at Prostate Cancer UK. “The results from this study and others like it are crucial as they give an important understanding of the factors that drive certain prostate cancers, or make them vulnerable to specific treatments.”

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