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Fast Moving Field

  • Liquid biopsies move toward the clinic

    From Paths of Progress 2020
    By Richard Saltus
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  • Cancers found in early stages are more likely to be successfully treated or cured. Unfortunately, there are few accurate, widely applicable tests for early detection of major cancers: All too often, patients are diagnosed only after they develop symptoms – when their tumors are larger and harder to treat.

    However, scientists are making rapid strides in detecting early signs of cancer in a blood sample, potentially opening a new era of non-invasive cancer screening that could save many lives. These tests, known as liquid biopsies, leverage the fact that cancers shed bits of DNA into the bloodstream, where they can be measured using increasingly sensitive and powerful technologies.

    This form of cancer detection needs further development and validation before it can be used routinely, but some clinical trials have yielded impressive results. One such liquid biopsy test demonstrated that it could spot more than 50 types of cancer and identify the tumors' location in the body with high accuracy. In addition, it gave "false positive" readings in less than 1% of cases.

    Consequently, there is growing optimism that liquid biopsies may have an important role in early cancer detection, as well as helping guide therapy.

    "The goal is to make cancer screening more efficient, ideally with one-stop shopping, to identify clinically important cancers at a curable stage, while at the same time minimizing the risks of over-testing, over-diagnosis, and anxiety," says Deborah Schrag, MD, MPH, chief of Dana-Farber's Division of Population Sciences.

    A Revolution in Precision Oncology?

    The gold standard of cancer diagnosis has long been the traditional tumor biopsy. In these procedures, cells or tissues are removed from the body and examined by pathologists to confirm the presence of cancer, characterize the types of cells in the tumor, and sometimes identify alterations such as mutations that can be used to guide therapy. These biopsies usually require an invasive procedure, can be uncomfortable, and may involve hard-to-access areas of the body, such as the brain or deep in the abdomen.

    There are many potential advantages to liquid biopsies, which take advantage of tumor-derived DNA that is shed into the bloodstream or other body fluids. Instead of a surgical biopsy, a liquid biopsy is much easier on the patient — a simple blood draw. Because they aren't invasive or painful, liquid biopsies can be repeated frequently — for example, to determine how well a treatment is working, or to monitor the patient for cancer recurrences, or to look for changes in the makeup of the cancer.

    "It's a new way to look at how tumor genomics are changing over time," says Brian Crompton, MD, a pediatric oncologist at Dana-Farber/Boston Children's Cancer and Blood Disorders Center. "You could do a blood draw as often as necessary" in a child, rather than needing to repeat an invasive tumor biopsy.

    Crompton has shown that tumor DNA from five common pediatric solid tumors can be measured in the blood. He says the findings of liquid biopsies potentially could be used to predict which patients will respond well to treatments and tailor therapies to these findings. New studies suggest that liquid biopsies could improve on current methods for detecting recurrences of cancer in patients who have completed treatment.

    Researchers at Dana-Farber and the Broad Institute of MIT and Harvard designed custom blood biopsy tests for breast cancer patients based on the DNA sequence of the person's tumor. They then looked for tumor DNA in stored samples of blood from the patients, in a retrospective analysis going back 13 years. The scientists detected cancer DNA in the blood samples an average of 18 months — and as long as three years — before a metastatic recurrence of the cancer was diagnosed by standard monitoring.

    "In the future, if we can find those patients with residual cancer early enough, determine whether they would benefit from another course of therapy, and give them an effective additional treatment, we could potentially change the course of their disease," said Heather Parsons, MD, MPH, a physician-scientist in breast oncology at Dana-Farber.

    Studies also suggest liquid biopsies have potential to detect when a tumor is becoming resistant to treatment. They're also being investigated as a way to determine which cancers are susceptible to immunotherapy treatment, and ones that probably are not.

    Liquid biopsies can be carried out remotely — by sending a blood draw kit to individuals across the country, as is being done in a Dana-Farber study called PROMISE. In addition, compared with a surgical biopsy that samples only a particular piece of tumor tissue, liquid biopsies collect DNA fragments from tumors throughout the body.

     Geoffrey Oxnard, MD
    Geoffrey Oxnard, MD

    Currently, liquid biopsies are used in specific situations to guide therapy. According to Geoffrey Oxnard, MD, Dana-Farber oncologist and liquid biopsy researcher these blood tests are now standard for patients with advanced lung cancer to determine if the tumor contains a particular mutation that can be targeted by a precision drug.

    Oxnard says, "We're using these tests more and more often in addition to tumor analysis to look for mutations we can effectively target." Now the question is, "can we next apply these technologies for early cancer detection?"

    To do so, a test would have to be able to spot tell-tale DNA from many types of tumors — some of which are more likely to shed tumor DNA than others — and not yield false positives.

    Two studies using liquid biopsies are in progress at Dana-Farber. One, PROMISE, is enrolling individuals to determine if they have precursor blood conditions, such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma, that can progress to multiple myeloma.

    Dana-Farber's Center for the Prevention of Progression (CPOP) is studying potential interventions to block the transformation of precursor conditions into myeloma. Individuals in the PROMISE study will be followed with serial liquid biopsies which the scientists will examine only for research purposes for signs of the precursor state morphing into multiple myeloma. The patients in the study will be monitored by their own oncologists who will diagnose any change in their status.

    Catherine Marinac, PhD, an investigator on the PROMISE study, says the trial is enrolling individuals who self-identify as being Black or African-American, who have a higher risk of multiple myeloma, as well as individuals who have a first-degree relative with a plasma cell disorder such as multiple myeloma or its precursor conditions. So far, she says, the study has screened more than 1,329 individuals and found 164 who tested positive for a precursor disorder to multiple myeloma.

    The other clinical trial, called Pathfinder, is sponsored by GRAIL Inc. It is testing an early detection liquid biopsy method which has shown that it can detect more than 50 types of cancer in a blood sample, across various stages. Results from prior studies suggest the test is particularly good at detecting high mortality cancers and cancers types not covered by current cancer screening approaches.

    The test is being offered to patients age 50 and older at Dana-Farber and hospitals in the Partners HealthCare network who are asymptomatic and otherwise presumed to be cancer-free but have a slightly higher risk of a positive result. This includes individuals who have a history of smoking, an inherited cancer risk, or a personal history of cancer, with definitive treatment more than three years ago. Patients who test positive in this study will be informed and recommended to undergo standard diagnostic workups to determine whether cancer is present or if the initial result was a "false positive," says Marinac, who is collaborating with Oxnard, the principal investigator of the study.

    Oxnard said the test "is not finding every cancer, but it may have the ability to find the dangerous cancers that urgently need treatment."

    The GRAIL test is not available outside the clinical trial, which is being offered at several centers around the country and aims to enroll about 6,200 participants. "To some extent, this is a feasibility study to understand the risks and benefits of this novel technology," says Oxnard.

    Hunting Cancer Signals in a Blood Sample

    Although it's long been known that blood and other body fluids contain free-floating cells and DNA from tumors, only in the past few years have methods become powerful enough to detect them in minuscule amounts and separate them from normal cells and DNA. GRAIL's method is based on targeted methylation sequencing. Methylation is a chemical change that applies tiny tags to DNA to regulate whether genes are turned on or off. Methods that determine the methylation state of genes in a fragment of DNA can reveal whether it comes from a tumor — and even where the tumor is probably located.

    Development of this test required a massive study and the use of artificial intelligence algorithms to create the cancer signatures detected in the blood sample. In Fall 2019, Oxnard reported encouraging results from a GRAIL analysis of 2,301 patients with and without cancer.

    Oxnard said the liquid biopsy technique was able to "detect the majority of cancers, especially high-risk cancers" with a false positive rate of less than 1% — meaning that just one person in 100 would be falsely informed that cancer was present. The sensitivity ranged from 59% to 86%, depending on cancer type, and the test could specify the tissue of origin (where the cancer developed) in 90% of cases. The test was able to detect only 34% of stage I cancers — the earliest stage — but that increased to 88% in stage II, 84% in stage III, and 92% in stage IV. "It's not finding every cancer," says Oxnard. "But it is finding the dangerous cancers."

    A more recent report in early 2020 on a subset of the GRAIL study focused on gastrointestinal cancers (cancers of the esophagus, stomach, pancreas, gallbladder, liver, bile duct, colon, and rectum) which were projected to account for 26% of cancer deaths in 2019. Brian Wolpin, MD, MPH, director of Dana-Farber's Gastrointestinal Cancer Center, reported that more than 80% of those cancers at all stages were detected with a false-positive rate of less than 1%, and the location was predicted with approximately 90% accuracy.

    "In patients with early stage gastrointestinal cancers (stages I, II, and III), we could detect 71% with the liquid biopsy test," Wolpin says. "These are particularly important cancers to identify, as prompt intervention has the potential to treat them most effectively."

    Dealing with Positive and Negative Test Results

    A key question is how doctors and patients will follow up if a positive test is reported. "Diagnostic tests are generally different for different malignancies," Wolpin said. "Thus, we will need to learn the most efficient ways to evaluate for cancer in our patients if a liquid biopsy test is reported as positive."

    This point raises a host of issues that go along with the fast pace of progress in liquid biopsy research, says J. Leonard Lichtenfeld, MD, MACP, deputy chief medical officer for the American Cancer Society. "We run the risk of having an available test that people use without it being meaningful," he says. "Does it tell us anything? Does it make a difference?"

    Lichtenfeld notes that not all cancers are aggressive; some are so slow-growing they would never need treatment. "We don't know yet whether screenings with liquid biopsy could help doctors learn how aggressive a cancer is," he says. "One of the keys in this discovery process is not only to find the cancer cell or the mutated DNA fragment circulating in the blood, but also to find out whether that particular person's cancer is going to be a problem. To me, that's going to be an even bigger challenge."

    Schrag agrees that significant issues abound. "We don't want to create a population of worried, anxious people getting blood tests every five minutes" to look for cancer. On the other hand, she notes, a negative result of a liquid biopsy screening test doesn't mean cancer is not present, and such results "shouldn't lead people to skip" the standard screening tests that are recommended for different population groups, like colonoscopies or mammograms.

    While these dilemmas exist, the fact remains that in just the past few years, advances in detecting and understanding the significance of tumor DNA in the blood have opened the way for a revolution in cancer diagnosis, prediction, and treatment.

Posted on June 18, 2020

  • Precision Cancer Medicine
  • Immunotherapy
  • Lung Cancers
  • Gastrointestinal Cancer
  • Breast Cancer
  • Multiple Myeloma