Liquid Biopsies May Soon Prevent Countless Unnecessary Surgical Ones
If you're not a specialist or a researcher, you likely don't know much about the history of testing for prostate cancer. Chances are you know about the prostate-specific antigen (PSA) test, which looks for protein markers in the blood to determine whether you may have the disease, and the controversy about its efficacy. Elevated PSA levels often indicate early-stage prostate cancer, though testing inaccuracies are common.
However, Mayo Clinic urologist Toby Kohler, M.D., advises everything should be judged in context. Since prostate cancer is the second most common cancer among men in the U.S., the Food and Drug Administration's approval of the PSA test as a monitoring tool in 1986 was, at the time, considered a massive step in fighting a disease that killed far too many otherwise healthy men. In 1994, the FDA approved the test for diagnostic purposes.
"Suddenly, not only could we detect it, we found it earlier and we saved a lot of lives," Kohler said.
Pros and cons of PSA tests
The initial problem with the testing was that all elevated PSAs were treated the same, regardless of aggressiveness, Kohler explained. This led to too many surgeries and radiation treatments, which in turn caused loss of function, including sexual and urinary. These complications might have been caused by treatment of non-aggressive or non-life-threatening cancer.
A fairly broad research consensus today suggests PSA testing may reduce mortality in younger men. But for men older than 75, it's highly unlikely to matter because treating prostate cancer in elderly men seldom prolongs their life.
However, Kohler explained that urologists have evolved their methodologies, and he believes patients shouldn't fear the PSA test.
'We used to take this giant sample, as if the cancer could be everywhere, which is not very intelligent. Now, with MRI, we can target the area very precisely.'
"There's this fear that PSA itself caused us to do bad things, to push for surgery or radiation treatment," he said.
Physicians now know how to more accurately score the likelihood of an aggressive cancer, and biopsies, which may also cause complications, can be far more targeted using magnetic resonance imaging (MRI), he added.
"We used to take this giant sample, as if the cancer could be everywhere, which is not very intelligent," Kohler said. "Now, with MRI, we can target the area very precisely, and the MRI itself lets us know whether or not we can be more conservative on the treatment."
Yes, MRIs have greatly improved the accuracy of both cancer diagnosis and subsequent biopsies, according to Eric Klein, M.D., a urologist and researcher for the past 32 years, and the chairman of the Glickman Urological & Kidney Institute at the Cleveland Clinic.
But he believes there's great hope for a new kind of test that could be far more accurate than the PSA: liquid biopsies.
Liquid biopsies are tests done on blood samples to look for cancer cells. In some ways, they're already in use, because clinicians now look for specific protein markers within the PSA test itself, Klein explained.
"There are specific blood-based markers that give us a better idea of the aggressiveness of any cancer, and we've learned quite a lot in the last 10 to 15 years," he said, meaning doctors can have more faith in being conservative and watching, rather than actively treating, low-grade cancers.
Klein and his colleagues have been working on a new blood-based diagnostic test called the IsoPSA test. It is awaiting FDA approval and is already being used by the Cleveland Clinic. (Klein made the point that while the Cleveland Clinic has a financial interest in IsoPSA, he does not.)
The problem with the standard PSA test is it looks for the presence and concentration of a protein that's in everyone's blood, Klein explained. An elevated PSA level could be indicative of cancer, but it's not causal, so it doesn't necessarily mean cancer is present; therefore, the PSA test is still leading to too many biopsies. A prostate biopsy removes tissue or cells from the body to be analyzed for the presence of cancer.
The IsoPSA test looks at the chemical structure of the proteins, which allows for a more accurate diagnosis of cancer.
"Cancer cells look funny," Klein said. "They're shortened and they have other changes. They have sugars hooked to them and that sort of thing."
There are dozens—Klein said maybe hundreds or even thousands—of different kinds of PSA molecules in the bloodstream, and they are specifically related to cancer. Being able to use these molecules in diagnosis overcomes the limitation that the PSA test is prostate-specific but not cancer-specific.
Klein explained that a forthcoming study on the IsoPSA test found a reduction of about 45 percent in the need for biopsies on patients who underwent an IsoPSA test rather than a conventional PSA test.
But there's more progress needed from liquid biopsies, he noted.
More advancements to come
In patients with slow-growing cancers, physicians would prefer to watch and evaluate what's going on.
"But we have a real challenge in figuring out who has progressed to the next level and needs treatment," Klein said.
He pointed to a New York company called miR Scientific and its development of a new kind of urine biopsy that looks at the RNA molecules, which are tightly linked to the biology of cancer. RNA, or ribonucleic acid, is a molecule similar to DNA, but is single-stranded rather than double-stranded. In initial studies, this test has shown better than 90 percent sensitivity for predicting the presence of high-grade cancers in men whose cancer is already being monitored, which Klein considers a significant breakthrough.
Even more progress is on the horizon, and not just in diagnosing prostate cancer. Klein recently co-wrote a study on a blood test called Galleri, which looks for DNA shards that remain from dead tumor cells.
"We're circulating tumor DNA when tumor cells die, and using next-generation sequencing, we can detect more than 50 kinds of cancers, including cancers like ovarian and pancreatic, which have high death rates because detection is so late," Klein said.
This kind of testing is critical because it can tell clinicians which organ the cancer has impacted and when a cancer treatment may no longer be effective, he added.
"It's really exciting, because you can monitor treatment across all cancers," Klein said.
Circulating tumor DNA comes from cancerous cells and tumors, and is found in the bloodstream. Klein said a patient would be monitored as they underwent treatment, which should typically result in a substantial decrease in the amount of circulating tumor DNA. Then, doctors would monitor the patient with serial blood tests; if they start to see signs of more circulating tumor DNA—even before X-rays turn positive—they have more time to try different treatments in an effort to rid the person of cancer.
Klein believes cancer research of all kinds is radically changing for the first time in decades because these emerging forms of tests, especially genetic ones, have three benefits: They are noninvasive, they far more accurately predict whether someone is endangered by a particular cancer, and they eliminate most of the numerous false positives that have beleaguered screenings to date.
These advancements are obviously encouraging news for anyone who has been touched by cancer, and a sign of more progress to come in the near future. Men facing a possible prostate cancer diagnosis should talk to their doctor about all screening options available to them.