Last week on OncoBites, Beth Rogoski of PhDoodles shared with us the story of liquid biopsies, blood tests that can be used to detect cancer and evaluate treatments. Today, in a follow-up piece, we’ll go into more detail as to what technologies are making their way to market, how liquid biopsies can be used to inform therapy, and what drawbacks we still face.
As Beth discussed, one big break in science this year was in liquid biopsies for early cancer screenings. Recently published studies indicate that liquid biopsies that can be used to diagnose cancer are getting more promising with each passing year. Using previously published data on DNA and protein biomarkers and samples from over 1,000 cancer patients and 800 healthy patients, researchers at Johns Hopkins developed CancerSEEK, a liquid biopsy that analyzes blood samples for over 2,000 genetic mutations and 8 tumor-associated proteins that they identified as specific to tumors. Using CancerSEEK, researchers were able to identify 70% of cancer cases among patients with different types of colorectal, ovarian, pancreatic, and lung cancers that all currently lack good screening tests. The false-positive rate was less than 1%. This could be a groundbreaking step in making cancer screening more widespread–blood samples can be drawn at any medical facility, a stark contrast to CT scans and MRIs, which are expensive and require hospital visits. Currently, rural patients or patients in underserved communities may have to travel long distances to reach the care they need just to diagnose their cancers, and liquid biopsies would alleviate a great deal of that hassle. The current estimated cost of CancerSEEK is about $500 per test— a lot kinder on the wallet and the body than the aggressive therapies needed to fight cancer when it is caught at later stages (although it is, of course, only an early estimate). It would also mean that more patients could potentially opt to screen regularly, especially if they have family histories of risk, increasing the likelihood of catching tumors early. CancerSEEK was also able to predict the site of cancer about 80% of the time, a key piece of information in the diagnosis and initial treatment of cancer. More studies are currently underway in high-risk patient populations as the developers work to move CancerSEEK into the clinic. Similarly, a liquid biopsy analyzing DNA in patient blood samples for mutations correlated to 20 different types of cancer, produced by Grail Inc., is raising billions of dollars and recruiting patients for clinical studies. Between the two, it is likely that liquid biopsies will be making their way into clinics in a matter of years.
While the FDA has recently announced that liquid biopsies are a priority by granting it “breakthrough device” status–meaning that it will work closely with developers to ensure thorough but rapid testing and keep clinical trial costs down–the tests we discussed today are not yet ideal. The tests themselves would likely take weeks to process, too slow for patients who are experiencing symptoms. And while earlier cancer detection would save millions of lives, neither CancerSEEK nor the Grail test is currently robust enough to detect Stage I cancer, the very early form, even half the time, on average. The robustness of the test increases as cancer grows and metastasizes, but so does the risk to patients, so the best case scenario would be to detect cancer before metastasis. This makes the false-negative rate rather high–that is, over half the patients with Stage 1 cancer would be told they do not have cancer at all. This does vary by cancer type; liver cancer is nearly always detected by Stage I, but Stage 1 esophageal cancer is only detected about 20% of the time, according to their findings. This leaves a lot of patients at risk but with a false sense of security, which, in the case of cancer, can be deadly.
As we’ve discussed before on OncoBites, checkpoint inhibitors have made a huge splash in oncology, most famously with former president Jimmy Carter’s remission from melanoma-related brain metastases a few years ago. And while Keytruda and other therapies have given hope to many patients, they don’t work for everyone. You see, checkpoint therapies help the immune system fight cancer by curbing a tumor’s ability to disguise itself as normal, healthy tissue. However, this only works if the immune system has a way of recognizing that the undisguised tumor is a threat in the first place. For this to happen, tumors must express abnormal proteins called tumor-associated antigens, which signal that something is wrong. Some cancers have lots of these antigens, but others do not, and it can vary from person to person. Until recently, doctors had to use trial and error to see if checkpoint inhibitors would be a viable therapy for each individual patient. Unfortunately, it can take weeks to months to see the results of a drug on a patient’s tumor, which makes using drugs that don’t fit the tumor profile costly to patient survival.
Thankfully, new diagnostic tests are being developed that measure how many mutations a cancer cell carries, which correlates to the number of abnormal proteins expressed and can better predict whether checkpoint therapies will work before being prescribed. These tests are called tumor-mutational burden tests, or TMB tests, and recent studies on thousands of patients have shown that not only does tumor mutational burden correlate with better responses to checkpoint inhibitors as predicted, and but that TMB tests can also be done on blood samples rather than tumor tissue. These liquid biopsies are key because they are less invasive and can be done much more easily. Only just over half of patients in the tissue TMB studies had enough tissue from a biopsy to take the test; that is simply unsustainable in the clinic. Blood tests avoid this issue, though they come with their own challenges and are not ready to hit the market just yet. It’s likely that in a few years, however, a blood TMB test will be available to help clinicians determine the best treatment for their patient’s specific cancer.
All in all, the improvements in cancer screenings are vast, and we seem poised to enter a new era of liquid biopsies for cancer diagnosis and personalized treatments in the near future, but we aren’t there yet. Soon, however, the key to detecting and understanding cancer could lie in a single vial of blood, drawn in minutes in a doctor’s office. Oncology is a race against time, and any test that can buy a little more time–by detecting cancer early, or narrowing down locations, or determining susceptibility to immunotherapy–is a test that can save lives. I, for one, am excited to see what the future of liquid biopsy holds.
Garber, K. (2018). Blood test may predict cancer immunotherapy benefit. Science.
Cohen, J.D., Li, L., Wang, Y., Thoburn, C., Afsari, B., Danilova, L., Douville, C., Javed, A.A., Wong, F., Mattox, A. and Hruban, R.H. (2018). Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science, p.3247.