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Newer, less invasive tests are helping scientists isolate genomic alterations.
MATTHEW TOBIN - PHOTO BY ELIZABETH HORNE
In early 2016, Matthew Tobin came down with a headache and persistent cough that lasted for months. When his doctor ordered an X-ray to test for pneumonia, it revealed a spot on his lung. After a tissue biopsy, doctors gave him the devastating diagnosis: lung cancer.
But to know the exact type of lung cancer — what its genetic characteristics were — Tobin’s oncology team at Dana-Farber Cancer Institute in Boston would have to wait a week or more to get results from the tissue sample. They suggested a relatively new option: a liquid biopsy, or blood sample, from which they might be able to quickly isolate the cancer’s genetic markers.
“We had results within a couple days of my giving the blood sample,” says Tobin, 50, a Massachusetts attorney in private practice. He tested positive for epidermal growth factor receptor (EGFR) gene mutation and also had metastatic disease, which made him a good candidate for a drug, Tarceva (erlotinib), that targets this receptor. “The day I got my results, I walked out of Dana-Farber with a targeted drug. Within days, I felt better. Within weeks, we had started to turn the tide.”
Not long ago, liquid biopsies were once the province of theory and hope. Now they are becoming part of the standard of care in lung cancer.
“We’ve been making a ton of headway on precision therapies and genomics,” explains Geoffrey Oxnard, M.D., Tobin’s oncologist at Dana-Farber and an assistant professor of medicine at Harvard Medical School. “But it’s not that easy to connect a patient to a drug. It’s not that easy to get tumor to test in all patients. With the convenience of liquid biopsy, there’s no excuse not to offer precision therapy and genomics to all your patients with lung cancer.”
In 2016, the Food and Drug Administration approved the first liquid biopsy test, to screen the blood plasma of patients with metastatic non-small cell lung cancer who may have particular mutations in the EGFR gene. But experts say this technique is being used in many different lung cancer scenarios. Specific genetic drivers, or suspected drivers, can be detected in more than half of lung cancers, studies show.
Second- and even third-line therapies have increased median progression-free survival rates two to three times longer than in patients receiving traditional chemotherapy. And liquid biopsies make it easier to test whether the cancer of a patient will react well to these new anti-tumor agents, experts say.
“Liquid biopsies are just another way of identifying molecular markers,” says Philip Mack, Ph.D., director of molecular pharmacology at the University of California, Davis. “But with a liquid biopsy, you can take a sample anytime. You can look to see how a tumor has evolved over time. You can test whether the tumor is developing resistance. It’s the next frontier of cancer research. We need to put a lot more energy into doing rigorous clinical trials that take advantage of liquid biopsies.”
Lung cancer is the leading cause of cancer deaths overall. Each year, more people die of lung cancer than of colon, breast and prostate cancers combined. Unfortunately, most cases of the disease are not diagnosed in early stages, when the disease typically causes no symptoms. And treatment options remain confusing for stage 3, locally advanced lung cancers. It’s unclear how to predict when and whether these patients will progress and whether it makes sense to use treatments designed for patients with metastatic disease.
In the past several years, researchers have made great strides in understanding the biology of lung cancer. This, in turn, has identified several genetic mutations — BRAF, EGFR — and genetic rearrangements — ALK and ROS1 — that mutation-specific drugs have been designed to target, usually in metastatic, or stage 4, patients. Other genetic aberrations, such as MET, HER2, NTRK and RET, may indicate drugs that can be used off-label in some patients with lung cancer.
However, most tumors develop resistance to these new agents. In some instances, there are then specific treatment options for patients who have developed certain genetic markers.
The challenge in all of this is that until recently, each treatment crossroad required a tissue biopsy. And tissue biopsies are limited by location and quantity.
With tissue biopsies, it may be difficult to get a clear picture of a person’s systemic disease burden. What if there’s not enough tissue to do all the tests needed? (According to experts, this happens in 25 percent of cases.) What if the genetics, and thus the drug markers, differ within one tumor or between different metastatic sites? What if the tumor location or locations — say, in the bone or liver — make tissue biopsy dangerous or impossible, as is the case for 31 percent of patients with lung cancer? What if a patient is too sick to endure a stressful tissue biopsy?
“If we do a liquid biopsy and find markers in the blood, we can put the patient on a particular drug. This avoids repeat (tissue) biopsies. That is really being used every day clinically,” says Maximilian Diehn, M.D., Ph.D., assistant professor at Stanford University School of Medicine.
So how does a liquid biopsy differ from a more traditional tissue biopsy? Most patients with cancer have experienced a tissue biopsy, and it’s never very pleasant: a local or general anesthetic, sometimes positioned uncomfortably in some sort of imaging machine, incisions or instruments that remove a small cylinder of tissue, soreness, recovery time. Then both patient and oncology team must wait for laborious lab work: setting, staining, slicing, then microscopic analysis and second opinions that may take a week or two.
As with any surgical procedure, there is always the risk of infection and bleeding when a tissue biopsy is taken. And in some patients with lung cancer, tissue biopsies may be impossible because of the location of the tumor, or there may be too great a risk of serious side effects, such as a collapsed lung.
Liquid biopsies, in contrast, simply mean a needle stick in the vein.
KAREN LOSS threw the first pitch at the Washington Nationals game in August to raise lung cancer awareness. - COURTESY KAREN LOSS / THE WASHINGTON NATIONALS
Karen Loss, 58, pushed for a liquid biopsy when her pathology team ran out of tumor tissue to test, and they felt a second tissue biopsy was too risky. “It was just a few vials of blood,” says Loss, a security specialist from McLean, Virginia. “It was an easy prep on my part, no fasting. In the end, I came up negative for any markers, but I’m glad I did it.”
The test requires a sample of blood, or in some cases urine or cerebrospinal fluid, to scan for pieces of circulating tumor DNA (ctDNA) that have sloughed off when tumor cells die. Then technicians can use techniques that make the ctDNA replicate, or amplify, certain sections of DNA with a lab procedure called polymerase chain reaction. Once the marker is amplified, it can be detected.
There are various methods for doing this: Some use fluorescence or a panel of several dozen genes thought to drive cancer growth.
Next-generation sequencing (NGS) analyzes millions or billions of DNA sequences that can provide a broad picture of the cancer’s genetic makeup. If you think of DNA as a book with a lot of sentences, NGS scans billions of lines of DNA code for a spelling or grammar error that may tag it as tumor DNA.
If the lab techs run out of tumor sample, it’s not difficult to go back for more because the liquid biopsy procedure is not very invasive, specialists say. Even better, clinicians can test more frequently and safely to see how a cancer may be changing in response to treatment or other factors.
“This sounds complicated, but the genetics of metastases in the bone can differ from the mets in liver,” says Mack. “With liquid biopsy, you can get a more global picture of the mutations out there.”
This can be particularly useful for patients with lung cancer. Patients eventually develop resistance to targeted therapies, but now oncologists can scan ctDNA for certain changes, such as the T790M mutation in the EGFR gene, which can be treated with Tagrisso (osimertinib).
Tobin took Tagrisso after his tumor became resistant and harbored the T790M mutation. He has since started a course of traditional chemotherapy.
While lung cancer specialists are optimistic about the role of liquid biopsy in lung cancer treatment, they caution that a lot of work remains. The NGS tests are still expensive, and not all insurance plans cover this technique. And liquid biopsies still detect ctDNA only about 70 to 80 percent of the time. If possible, oncologists try to compare the results of liquid biopsy with a more traditional tissue sample.
“You can’t trust a negative result,” says Oxnard. “You need to fall back on the tumor sample as backup.”
Further, the scans aren’t yet sensitive enough to reliably detect ctDNA when the cancer is still early-stage. And in some studies, people whose liquid biopsy showed a cancer driver did not end up developing a full-blown malignancy. And for those who do, not all types of lung cancer shed DNA that can be detected by liquid biopsy.
Even more confounding, when ctDNA is compared with DNA from a tissue sample, studies have shown that there are often differences. Experts aren’t yet sure what this means: Is it because the cancer is spinning out different DNA changes? Is it a problem with the test? Or is it something else?
More clinical studies are needed to answer these and many other questions and to provide enough data to prove the usefulness of liquid biopsies in different areas of lung cancer care, says Diehn.
“Going forward, we need to simultaneously go in two directions,” Oxnard says. “In one direction, we need to make liquid biopsy more sensitive, more broad. And the other direction we need is to make liquid biopsy cheaper, more focused, more nimble.”
Either way, patients with lung cancer and, over time, a growing number of malignancies are likely to encounter more liquid biopsies in the clinic.