Cancer doesn’t always stay in one place. Often tumor cells break free and ride the bloodstream, settling in distant organs and changing the course of the disease. Cancer cells can escape even when the original tumor is small, and some cancer cells mutate or change, outwitting even the most sophisticated treatment. Once cancer spreads and morphs into metastatic disease, it becomes much more difficult to treat and to survive.
“Cancer is very clever and unfortunately evolves a way to resist treatment,” says Davina Gale, who manages the U.K. laboratory of Nitzan Rosenfeld, a team that’s working to use tumor DNA to find mutations responsible for resistance to chemotherapy and then translate the data into a test useful to doctors and cancer patients.
Over the past decades, researchers have taken advantage of the fact that cancer uses the bloodstream as a sort of highway to metastasis. By fishing a sample of offending cells, or tumor DNA, out of the bloodstream, it’s now possible to eavesdrop on what tumors have planned. The idea is to turn a simple blood draw into a “liquid biopsy.” Such tests are emerging as a critical tool for certain cancers.
“Blood can tell a lot about what’s going on with cancer,” says Alison Allan, a cancer metastasis expert at the University of Western Ontario in Canada. Researchers like Allan are using liquid biopsies to analyze mutations in circulating tumor cells (or CTCs). These are the tumor cells cruising through the bloodstream. By profiling the genomes of CTCs, Allan and others aim to figure out which genes are responsible for metastasis, information that can potentially lead to new cancer drugs designed to block those mutations. Tests for CTCs are already available and covered by insurance.
The earlier doctors can learn when and how cancer spreads, and when a treatment has stopped working, the earlier doctors can try a different treatment. Taking repeat biopsies is not practical for many reasons. They’re expensive, invasive, painful, and can be risky. A blood test, or a liquid biopsy, can show in real time what the cancer genome happens to be doing, especially in cases where there is not enough tumor tissue for a biopsy, or when the first line of treatment has failed, causing cancer to spread. Tumors are genetically complex, meaning that they contain a mix of cells with different mutations — researchers call this mix “heterogeneity.” Because of this heterogeneity, the tumor cells circulating in the bloodstream likely have very different mutations from tumor cells confined to an organ. Using liquid biopsies to help understand these differences will help explain, for instance, why some tumors are so aggressive and why others stay in one place.
Liquid biopsies do not diagnose cancer, since people with early-stage cancer are less likely to have CTCs in their bloodstream. The tests in use today are aimed at patients whose cancer has spread to other organs from the primary tumor. Used in parallel with other diagnostic testing, such as imaging, liquid biopsies can help oncologists make better treatment decisions.
The test works in two ways. The first method, which has been around for nearly 10 years, counts the number of CTCs in the bloodstream. Scientists have known about the existence of CTCs for more than 100 years, but it took some leaps of technology to separate the tumor cells from the normal cells well enough to get an accurate count. They’re rare, as few as one in several million cells, but people without cancer should not have any CTCs in the bloodstream, says Jorge Villacian, chief medical officer of Janssen Diagnostics, a subsidiary of Johnson & Johnson.
In 2004, the U.S. Food and Drug Administration cleared the company’s CellSearch CTC test for use in monitoring patients with metastatic breast cancer. Today the test is also used for malignancies in prostate and colon cancer. Although any number of CTCs in a cancer patient’s bloodstream is not a good sign, plenty of research shows that patients with a higher number of CTCs have a worse prognosis. “Their cancer progresses more quickly, and survival is shortened,” Villacian says.
Once doctors turn to CellSearch, their patients’ cancer has already morphed into metastatic disease. Doctors use the CTC count along with other diagnostic tests, such as imaging, and then make treatment decisions based on the combined results. A high CTC count in certain cancers lets doctors know whether a patient will do better or worse than prior patients and can tell doctors that their patients’ current therapy may not be effective in their particular cancer, information that may prompt doctors to find another treatment protocol for these patients. A change in CTC count, one that goes from high to low, can tell doctors that treatment is working well and can also signal that the patient will do well on treatment, compared to prior patients. The test costs around $350, depending on the lab where it is administered.
What a CTC count cannot tell doctors is why the cancer is resistant to therapy. Mutations driving resistance can be different for different cancers and within the same cancer. It is possible to use the CTCs to analyze the DNA and profile different genetic mutations. This additional information could one day provide enough detailed information to help personalize cancer treatment. Janssen Diagnostics is funding such research, and labs across the world are undertaking this endeavor as well.
The earlier doctors can test to determine if there are CTCs or tumor DNA in the bloodstream, the earlier they’ll be able to evaluate whether treatment is working or monitor patients more carefully. “Theoretically, one cancer cell in the bloodstream can cause a recurrence,” says Gerald Linette, an oncologist at Washington University School of Medicine in St. Louis. In melanoma, for example, once the cancer has spread, it’s considered incurable.
With melanoma, if surgical removal of the mole eliminates all of the cancer and if lymph nodes are negative, survival exceeds 95 percent. If even one lymph node is positive, survival rates drop dramatically. Patients with lymph node-positive melanoma have few options when it comes to monitoring the status of their disease. Invasive biopsies can be done only so many times because the cost gets prohibitive and the disease reaches the point at which additional biopsies are not cost-effective, Linette says. Currently, metastatic melanoma patients are monitored every three months via physical exam. “Even imaging has been shown not to be cost-effective in prolonging survival, but it’s the best we have right now,” Linette says.
That could change soon. A new test on the market offers a more detailed analysis than counting CTCs. This method uses a blood test to analyze tumor DNA floating in the bloodstream. Guardant Health of Redwood City, California, unveiled the test last February, and it has been validated for breast, lung, colorectal, melanoma, and prostate cancer. The test, Guardant360, probes cancer DNA in the bloodstream for genomic alterations in 54 genes that are already known to play a critical role in cancer. Because the genomic makeup of cancer continues to evolve in response to treatment, sometimes causing it to become resistant to that therapy, the test tells doctors what’s happening in real time with the cancer and may provide guidance on what treatment to try next. Although pricing has not yet been disclosed, Guardant will work with insurance providers to minimize patient out-of-pocket expenses.
Another form of noninvasive biopsy under development is molecular urine testing. Created by Trovagene, this technology analyzes circulating tumor DNA in the urine and is currently on the market for BRAF and KRAS mutations and is undergoing clinical evaluation for other areas. Since urine samples are easy to obtain, the test creates convenience for the patient, especially when multiple biopsies are needed or not possible.
To date, the development and use of liquid biopsies has significantly enhanced our understanding of the metastatic spread of cancer and how tumor cells change their molecular characteristics. But liquid biopsies won’t work for all tumor types because not all tumor types shed DNA or tumor cells into the bloodstream. Also, cancer is a heterogeneous disease, meaning, for example, that for every 10 women with breast cancer, you’ll get essentially 10 kinds of breast cancer.
The genetic makeup of cells within a single tumor can also be vastly different. Even for many solid cancers, researchers don’t know enough about which mutations might be the ones signaling problems with the treatment. There are some known mutations for certain cancers that can signal what’s going on with therapy, but that’s not true for all cancers. The idea, researcher Allan says, is to look for a change in status. If a mutation shows up that wasn’t around in the first place, that can mean the therapy has stopped working.
One day, liquid biopsies may indeed be able to diagnose cancer, once the technology is sensitive enough to detect even lower concentrations of circulating tumor DNA or CTCs. “The greatest value for these tests will be as prognostic tools or predictive tools,” Allan says.
For instance, researchers hope to use the test to figure out whether cancer is responding to treatment — sometimes, imaging isn’t the most accurate way to answer that question. Even after, say, one month of treatment, a patient can return for a follow-up image only to find that the tumor hasn’t changed in size.
“But that doesn’t mean that the patient isn’t responding to treatment,” says Elaine Mardis, co-director of The Genome Institute at Washington University and a professor of genetics and molecular microbiology. The treatment can seep into the tumor and destroy the cancer, but the immune cells designed to clear dead cells just haven’t had time to clear away the dead cells and shrink the tumor, making it look like the cancer isn’t responding, when, in fact, treatment may be working. Right now, liquid biopsies are not sensitive enough for this type of analysis. In the future, once this aspect of the test is accurate enough, stopping treatment on a cancer patient who no longer needs it will not only save money, but it will also save a person from unnecessary side effects.
In some patients, treatment decisions can be difficult to make, especially for those whose doctors are not certain if cancer has metastasized yet and the oncologist needs to make a choice that can place the patient between overtreatment and under-treatment. Liquid biopsies are already a critical tool. As the technology becomes more sensitive, this blood test is poised to reveal the best-targeted therapy and track the disease as it evolves. A better understanding of tumor biology will spark more effective, more individualized therapies.
“Liquid biopsies hold tremendous promise as a minimally invasive, real-time way to assess these molecular changes in individual patients,” Allan says. Which, she concludes, will help doctors “treat them effectively using a personalized medicine approach.”