Snapshot of Cancer
Metastatic prostate cancer looks a lot different from cancer that is confined to the prostate. That’s because over time, as it develops the ability to spread beyond the prostate, cancer undergoes specific mutations.
How has it changed? The answer to this question is important, but it would require another biopsy to find out – something that is not an option for many patients. Good news: Investigators are testing a different way to look at evolving prostate cancer cells.
A liquid biopsy is a specialized blood test that captures circulating tumor cells (CTCs), cancer cells that have migrated into the bloodstream from the original tumor. Like a traditional biopsy, a liquid biopsy provides a snapshot – a look at what’s happening with the cancer at this point in time, on the molecular level.
It’s a lot easier and less painful to have blood drawn than to have a doctor stick a needle into bone or an organ. Thus, “liquid biopsies have the potential to be done more than once, not only to monitor the status of cancer, but the success of treatment,” says Duke University medical oncologist Andrew Armstrong, M.D., MSc. “If we are testing a new therapy and see the cancer cells go away, we can tell that the patient’s doing better. But we can also track the cancer, see what kind of cells are emerging, and point the patient toward a new therapy, like the ‘smart bomb’ – PSMA-targeted radioligand therapy.”
Unlike other blood tests (such as the 4K score or PHI, which look for certain biomarkers of prostate cancer), or germline genetic tests (which look for mutations of inherited genes), liquid biopsies measure the cancer directly. “Cancer is dynamic,” Armstrong explains; “it sends out little seeds of metastasis as it advances. Some of them never take root, and some of them do take hold and start to grow. But prostate cancer has no real way to get to the bone, liver, lungs, or other distant parts of the body without going through the blood.”
Armstrong sees strong evidence for the potential of liquid biopsies. “They can open up new avenues of treatment that we wouldn’t otherwise try.” For example: drugs called PARP inhibitors can be effective in men who have a mutation in certain genes involved in DNA repair (primarily the BRCA2 gene). This mutation can be inherited (and if so, is present at the time of diagnosis), but it can also occur on its own as cancer progresses. This means that a man who was initially found to have no mutations in BRCA2 (and, therefore, not eligible for a PARP inhibitor) might, over the course of time, be tested again and found to have a mutation. “And then suddenly, you’ve got a new medicine available to help this man that he couldn’t have benefitted from before.”
In-depth analysis
A CTC test can provide information that is missing from other types of blood and genetic tests. Think of a river after a flood, full of debris. Similarly, metastatic cancer leaves debris floating in the bloodstream: fragments of genetic material, as well as whole tumor cells. Standard tests, Armstrong notes, focus on DNA and look for mutated genes. “But we’re missing a lot of information by just concentrating on DNA. The tumor also has RNA and proteins,” including, for example, prostate specific membrane antigen (PSMA). “The expression of the PSMA protein on the prostate cancer cell surface is not predictable by a blood test. You can only pick it up by looking at the cell itself” – under a microscope, or using a liquid biopsy. “Another way to determine the expression of PSMA is the PSMA-PET scan, but the liquid biopsy can add complementary information,” such as whether a man is likely to benefit from PSMA-targeting radioligand therapy.
Armstrong has been testing a liquid biopsy in clinical trials to help determine which men are likely to respond to PSMA-targeted therapy. This assay looks at circulating tumor cells (CTCs) from prostate cancer that have escaped to the bloodstream. “Outside the U.S., PET scans are really cheap,” Armstrong adds, “but in the U.S., they are very expensive. If a PSMA-focused liquid biopsy can help determine which men will benefit from radioligand therapy, it would be well worth it.” Further research is needed before this liquid biopsy can become commercially available, and a larger trial is planned (see below).
Expanding to new types of therapies
“The potential of liquid biopsy for prostate cancer opens up a whole field,” he says. “Precision medicine has transformed my practice and my patients’ lives, because it’s offering hope. New imaging, such as PSMA-PET, and more specific tests are opening doors that were previously closed to many patients, giving them access to precision treatments including PARP inhibitors, immunotherapy, and PSMA-targeted therapy. I think the future is going to see a greater expansion: more targeted therapies, more radioligand therapies, and more antibody drug conjugates (ADCs).”
Like the PSMA-targeted radioligands, ADCs use molecular targets to find and kill cancer: in this case, antibodies, which are linked to a cancer-killing “payload.” The antibodies don’t look for cancer itself, but for nearby antigens: trouble-causing invaders (such as proteins on the cancer cell surface) that stimulate an immune response. PSMA is one such antigen; others are under investigation.
Armstrong advises patients to ask their doctors about precision tests that are already available, and about participating in clinical trials that require liquid biopsy (tests that are not yet standard of care, looking for genetic features such as PTEN loss and androgen receptor variants) as an entry criterion. “A broad liquid biopsy may open the door to a range of options.”
Are any liquid biopsies for prostate cancer commercially available as we speak? Yes, says Armstrong. “They use ctDNA (circulating tumor DNA) to look for mutations in genes like BRCA2 and mismatch repair enzymes. These are important for clinical care and to guide the use of PARP inhibitors like olaparib” (just approved in combination with abiraterone) and pembrolizumab (for patients with metastatic castrate-resistant prostate cancer who have tumors with high microsatellite instability).
“What we are trying to do with the CTC precision liquid biopsies like the PSMA assay is to extend beyond these to identify more precision tests to guide therapy. This remains an active area of research, and our new trial, called ATOMIC, will start in July to look at how PSMA CTC expression predicts the benefits of PSMA Lu177 radioligand therapy.”
