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Spotting Cancer in a Vial of Blood
The answers Bert Vogelstein needed and feared were in the blood sample.
Vogelstein is among the most highly cited scientists in the world. He was described, in the 1980s, as having broken into “the cockpit of cancer” after he and coworkers at Johns Hopkins University showed for the first time exactly how a series of DNA mutations, adding up silently over decades, turn cells cancerous. Damaged DNA, he helped prove, is the cause of cancer.
Now imagine you could see these mutations—see cancer itself—in a vial of blood. Nearly every type of cancer sheds DNA into the bloodstream, and Vogelstein’s laboratory at Johns Hopkins has developed a technique, called a “liquid biopsy,” that can find the telltale genetic material.
The technology is made possible by instruments that speedily sequence DNA in a blood sample so researchers can spot tumor DNA even when it’s present in trace amounts. The Hopkins scientists, working alongside doctors who treat patients in Baltimore’s largest oncology center, have now studied blood from more than a thousand people. They say liquid biopsies can find cancer long before symptoms of the disease arise.
This particular blood sample, though, was personal. It was from Vogelstein’s brother, an orthopedic surgeon one year younger. He was fighting skin cancer, and the disease was already spreading. There was hope he’d respond to a new type of drug, but the treatment causes swelling, and it’s difficult to tell from an x-ray or CT scan whether the cancer is melting away or not. So Vogelstein used his lab’s new technology. If the cancer DNA had disappeared from the blood, they might celebrate. If it was still there, maybe he could steer his brother to some last-ditch drug.
“We tried to guide the treatment. That was the hope, anyway,” says Vogelstein. His voice tightens. He doesn’t say what happened next.
The obituary of Barry Vogelstein, born in Baltimore, appeared on July 3, 2013.
We’re not winning the war on cancer, and the death of Vogelstein’s brother shows why. Too many cancers are caught when they have become incurable. Each year, $91 billion is spent on cancer drugs worldwide, but most of those medicines are given to patients when it’s too late. The newest treatments, created at staggering expense, cost $10,000 a month and often extend life by only a few weeks. Pharmaceutical firms develop and test more drugs for late-stage cancer than for any other kind of disease.
“We as the public and as scientists have been entranced by this idea of curing advanced cancers,” says Vogelstein. “That is society’s Plan A. I don’t think that has to be the case.” There are other ways to reduce cancer deaths: wearing sunscreen, not smoking, and getting screened to catch cancer early. To Vogelstein, all these preventive steps represent “Plan B” because they receive so much less attention and funding. Yet when prevention works, it has better results than any drug. In the United States, the chance of dying from colorectal cancer is 40 percent lower than it was in 1975, a decrease mostly due to colonoscopy screening. Melanoma skin cancer, too, is treatable with surgery if caught early. “We think Plan B needs to be Plan A,” says Vogelstein.
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| Bert Vogelstein |
The new blood tests could make that possible. For the first time, Hopkins researchers say, they are within reach of a general screening tool that could be used to scan broadly—perhaps at an annual physical—for molecular traces of cancer in people with no symptoms. “We think we’ve solved early detection,” says Victor Velculescu, a Hopkins researcher who runs a lab in the building next to Vogelstein’s.
Making such screening a routine practice in medicine will be challenging. One difficulty is that while the test may detect the presence of cancer DNA in the body, physicians might not know where the tumor is, how dangerous it is, or even whether it is worth treating. “We have to be cautious about how we talk about that,” says Daniel Haber, director of the Massachusetts General Hospital Cancer Center. He believes the DNA blood tests are “far from ready” and says very large studies will be needed to prove that they are useful. “There is a huge bar to get over,” he says.
Despite such skepticism, the technology is gaining attention. Tony Dickherber, head of the Innovative Molecular Analysis Technologies Program at the National Cancer Institute, says the idea of scanning blood for tumor DNA was “fringe at best” only three years ago. But now labs and companies from California to London are jumping in, producing a stream of improvements to the blood screening technology and new data supporting it. “People are starting to think that [Vogelstein] is right—this could be the best way to do early diagnosis,” he says. “[It] could be done much more widely than other screening technology we have, and you could screen for an incredible range of cancers.”
In February, doctors from Hopkins and 23 other institutions provided the largest survey yet of their findings. They studied the tumors of 846 patients with 15 different types of cancer. They found tumor DNA in the blood of more than 80 percent of patients with advanced cancers, the kind that have spread, and about 47 percent of those whose cancer was still localized and at the earliest stage. In advanced colorectal cancer, the DNA was always seen.
For the first time, Hopkins researchers say, they are within reach of a general screening tool that could be used to scan broadly—perhaps at an annual physical—for molecular traces of cancer in people with no symptoms.
The results might not at first appear impressive. A test that misses half the time? The benefit is that the tests are “exquisitely specific,” according to Velculescu. If you do have tumor DNA, it appears, so far, that you also have cancer. That could give DNA screening the edge over current tests for prostate and breast cancer, which frequently produce false positives. “It’s normal to have circulating DNA in the blood; it is not normal to have circulating DNA that matches a tumor,” says Stefanie Jeffrey, chief of surgical oncology research at Stanford University.
To Vogelstein, the blood tests mean it may be possible to catch more than half of cancers early on, and potentially cure them with surgery. “If there were a drug that cured half of cancer you’d have a ticker-tape parade in New York City,” he says.
Early Days
President Nixon’s War on Cancer was launched in 1971, when Vogelstein was in medical school. Years of frustration followed as drugs failed to make much of a dent in cancer deaths. What has changed is that now we know what causes cancer. Vogelstein’s work in the 1980s, carried out with colleague Kenneth Kinzler, helped demonstrate the crucial role of mutated genes in the disease. And scientists have now assembled a list of more than 150 genes that appear to be the key drivers. Even though cancer’s genetic landscape is complex, all the DNA mutations do one thing: they allow some cells to keep multiplying when normal cells would die. The resulting imbalance is cancer.
For pharmaceutical companies, this insight and the gene list have been the launching point for billion-dollar efforts to develop new drugs for advanced cancers. But to Vogelstein, the knowledge that DNA mutations cause cancer has always also meant something different: that it should be possible to spot the telltale changes early on, well before the disease is usually diagnosed. And in oncology, it’s a truism: the sooner you detect cancer, the better your chances.
Consider colorectal cancer, the type Vogelstein has studied most closely. It begins with a single mutation to a gene called APC. Yet it takes on average 30 years from that point for the cells to acquire several other DNA mutations they need in order to spread and kill. About 600,000 people die from colorectal cancer each year. “Nearly all of them will die only because their cancer was not detected in the first 27 years of the tumor’s existence,” Vogelstein says. “That is a huge window to intervene in this process.”
The problem has been that until the blood tests, there was no very easy way to look for these mutations. Vogelstein has been working on early-detection schemes since the 1990s, when he began looking for tumor DNA in urine and stool, using the laborious methods available at that time. He believes prevention and screening still receive too little attention, putting him, even now, in an “absolute minority” of researchers. He estimates that 100 times as many research dollars go toward drugs as toward these strategies.
This may explain why, despite his preëminence, Vogelstein seems to have a chip on his shoulder. The Hopkins research group, which includes several other well-known researchers, is quick to publish new ideas, but it often makes the effort to shoot down scientific concepts that are trendy elsewhere. Any young scientist who want to work there, according to the lab’s traditions, must first present his or her earlier scientific work while wearing a Burger King crown.
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| Luis Diaz |
The lab’s work on the blood tests has been led by Luis Diaz, an oncologist who has become Vogelstein’s protégé. He hit on the idea of testing blood for cancer DNA in 2005, while researching whether a flesh-eating bacterium could be used to eradicate tumors. The work involved transplanting human cancers into mice, and Diaz recalls that he “needed a way to monitor the tumors in the mouse without killing it.” He and a colleague decided that they might be able to do that with a blood test. Soon they saw the level of human DNA bouncing down and up as the treatment worked or failed. If they could monitor DNA from a human tumor in mice, wouldn’t it work in humans, too?
The idea wasn’t entirely new. It’s been known since 1948 that free-floating DNA circulates in our veins and arteries. It’s normally a waste product of dead cells. But tumors also shed DNA into the blood. The portion of DNA in the blood that comes from tumors can be as high as 87 percent in a person dying from cancer, but often the amount is vanishingly small.
When Diaz began looking at the question, all this was not yet fact but muddy possibility. To develop the liquid biopsy, the Hopkins scientists first had to invent ways to pick out the tumor DNA from an overwhelming background of normal DNA. Working with blood donated by patients with colorectal cancer whom Diaz was treating in Baltimore, the researchers initially tracked only four cancer genes. Yet they could see that the tumor DNA in the blood would disappear quickly—even within a day—after these patients had surgery or drug treatments. Healthy control subjects never tested positive. “We realized this test can ask and answer the question ‘Do I have cancer?’” says Diaz.
Hopkins believes its test may be more sensitive than any tool doctors have now—at least for cancers that are too small to be seen with an imaging machine. Vogelstein estimates that a tumor has to contain at least 10 million cells, making it about as big as the head of a pin, to shed a detectable amount of DNA. To be visible on an MRI, by contrast, a tumor needs to be about 100 times that size, containing at least one billion cells.
The Hopkins physicians have begun using the DNA tests in an effort to determine whether malignant cells remain behind in patients whose tumors have been surgically removed. Working with Peter Gibbs, an Australian oncologist, they have scanned blood samples from 250 patients who have been operated on for early-stage colon cancer. Most of these people will turn out to be cured, but up to 30 percent are expected to suffer a relapse because not all the tumor cells were removed. The problem is that doctors don’t know which patients will relapse. “The surgeon will say, ‘Don’t worry—we got it all,’” says Diaz. “It’s frustrating to me, because then I have to tell the patient, ‘We don’t really know if you are cured.’” Survivors can get caught in a state of limbo, uncertain whether their disease is coming back, possibly in a more dangerous form. And the situation can drag on for years.
Patients could be frightened, doctors uncertain how to act. “The idea of screening healthy people and telling them ‘Oh, look, there is cancer somewhere but we don’t know where it is’—well, that would be the death of the whole [idea],” says one oncologist.
The patients in Australia are checked for tumor DNA in their blood six weeks after surgery. So far, the researchers say, they have correctly identified about half the people who later relapsed. In the future, says Vogelstein, these patients could be flagged to receive chemotherapy, probably saving at least a third of them. Yet the limits of the test are also apparent, since it still missed half the patients whose cancer later reappeared.
Diaz says this may be because whatever cancer cells remain aren’t giving off enough DNA to detect. “We may have hit the biological limits,” he says. However, the cancer DNA could rise to detectable levels over time, and retesting patients periodically could pick that up. Even though Hopkins’s testing remains experimental, Diaz says he has enough confidence in it to tell some patients they are still sick and others that they are probably healed. “Six to eight weeks later, we can tell them if they are cured,” he says. “It’s very satisfying.”
Mass Screening
Vogelstein says his ultimate goal is to turn the blood tests into a way to routinely screen everyone for cancer. The Hopkins researchers believe they have a version of the test that can do that. Instead of tracking a few key cancer genes, they sequence a person’s entire genome using DNA from the blood sample. This lets them count how often chunks of genetic material are misplaced or appear scrambled. A large amount of rearranged DNA is a molecular side effect seen only on the chromosomes of cancer cells—a tip-off that cancer is present. But a full genome sequence is still expensive. “If a person has cancer, you don’t mind spending $5,000 on a DNA test. But you can’t have a test that costs $1,000 that you can do at an annual physical,” says Vogelstein. “The goal is to get the technology cheap enough to use in screening.”
That could take time. The cost of DNA sequencing has been falling very rapidly, yet a $100 genome—the price that might be low enough for a general screening test—could be 10 years away. In the meantime, Hopkins has begun several studies, mostly on individuals predisposed to cancer, to determine whether the techniques can catch tumors early in healthy people. One involves 800 people at risk for pancreatic cancer. In these unusual cases, people have cysts on the pancreas that sometimes turn into cancer but sometimes don’t. The clinical trial began following patients in 2012, and the researchers will get their first look at the results late this year.
Pancreatic cancer is a good test case for early screening. It’s not a very common cancer, but it’s the fourth-highest cause of cancer deaths in the United States, because it’s cured only 4 percent of the time. If detected very early, before it spreads, the survival rate rises to about 25 percent. (Apple founder Steve Jobs died of a different type of pancreatic cancer, called a neuroendocrine tumor, at age 56.)
But extending the DNA tests to everyone is an enormous leap. Haber, the Mass. General oncologist, says the technology, as currently conceived, might tell a doctor if cancer is present. But unlike an imaging scan or a biopsy, it could leave you guessing where in the body it is. Patients would be frightened, doctors uncertain how to act. “The idea of screening healthy people and telling them ‘Oh, look, there is cancer somewhere but we don’t know where it is’—well, that would be the death of the whole [idea],” Haber says.
Medicine has a precedent of handling predictive tests poorly. Consider the PSA test, which detects a protein linked to prostate cancer. Not only does the test produce false positives a majority of the time, but some of the tumors it actually detects are so slow-growing that they aren’t worth treating. Millions of men have ended up getting treated for cancers that ultimately wouldn’t have affected them. By one estimate, for every 47 men who had their prostates removed, a single cancer death was avoided. Studies by researchers at Dartmouth College suggest that mammography also leads to overdiagnosis and overtreatment. About 25 percent of breast cancers discovered, and treated, would not have caused any symptoms. “You test everyone and end up treating people for diseases that would never have mattered, either because they wouldn’t have progressed or because people die of something else,” says Jonathan Skinner, a health economist at Dartmouth. “The downside of early screening can be very high.”
At Hopkins, however, Velculescu says he’s hopeful that mass DNA screening for cancer will become a reality. “If you can’t make a difference, then maybe you would want to remain ignorant,” he says. “But I can’t imagine that knowing about cancer wouldn’t help patients. Maybe we won’t dramatically act on every piece of information. Maybe we don’t do anything. But with these tests, it would be so easy to keep doing them and say to the patient, ‘Let’s see how it develops.’”
So far, companies aren’t talking loudly about broad screening for cancer in seemingly healthy patients. For now, Personal Genome Diagnostics, a diagnostic testing startup that Diaz and Velculescu founded, and several competitors, like Boreal Genomics and Guardant Health, offer liquid biopsies only to patients who are fighting late-stage cancer. For those patients, the tests might reveal whether a treatment is working in time to try something else if it’s not. Another valuable use of the technology is to track the specific DNA mutations driving a patient’s tumors.
Since many new cancer medications are “targeted”—they block specific molecular processes—patients get them only if their tumor is the kind expected to respond. Doctors can already use DNA tests on chunks of tumor obtained through tissue biopsies. But the noninvasive blood tests could be easier and safer, allowing patients to be evaluated more frequently. Since cancer DNA is constantly mutating, that could help patients switch drugs when appropriate.
To Helmy Eltoukhy, the CEO of Guardant, liquid biopsies are “a huge idea” with many applications. For commercial and medical reasons, his company so far is marketing the tests only to people who have cancer. But he says early screening tests are on his company’s road map. “It’s obviously the Holy Grail,” he says. “Imagine the applications, and that is what we are working on.”
I asked both Vogelstein, who is 65, and Velculescu, who is 44, if they had ever tested themselves. Both said no. Yet overall, men in the United States have a 40 percent chance of developing cancer sometime, and the odds rise with age. If these researchers haven’t sought the screening, it seems questionable that the broader public will be eager to do it either. For a screening test to be performed widely as a public health measure, the entire medical community will have to participate, and that will take a great deal of time.
Vogelstein isn’t naïve. We’ll still need new drugs to treat people who develop cancer anyway. But he remains convinced that the best way to beat late-stage cancer is to prevent it from happening. When I offered my condolences to Vogelstein on the death of his brother, he waved them aside. “This is why we do the work,” he says. “A hundred years from now, when cancer and death from cancer is a lot less common, a lot of that is going to be due to early detection, not because we can cure a body riddled with tumors.”
This story was updated on August 13 to clarify that Steve Jobs did not have the kind of pancreatic cancer that Hopkins researchers are trying to detect in the trial of 800 patients.
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Finding Cancer Cells in the Blood
Technologies that can pull tumor cells from patients’ blood are giving researchers an unprecedented look at cancer.
By Susan Young Rojahn on July 16, 2013
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| Liquid biopsy: A microfluidic chip is able to capture circulating tumor cells. |
In the near future, oncologists may be using a finger-size plastic chip with tiny channels to extract a dozen or so cancer cells from a sample of a patient’s blood. Those cells, called circulating tumor cells, could then be screened for genetic disruptions that an oncologist could target with drugs best suited to attacking the tumor. Continued sampling would give doctors a way to monitor whether a treatment is working and decide whether to add or change a drug as the malady evolves.
Dozens of companies are vying for success in this market, which is expected to reach $7.9 billion in the next few years, but so far only one device, sold by a Johnson & Johnson subsidiary, has received FDA approval. That current technology is not able to detect circulating tumor cells when they’re present only in very small numbers, says Daniel Haber, director of the Massachusetts General Hospital Cancer Center, and cannot capture the full diversity of cells that escape from different tumor types in patients. But advances are already proven in labs and may be making their way to clinics in the next few years, experts say.
Working with biomedical engineer Mehmet Toner and his team at MGH, Haber is developing their latest chip into a commercial product. The new chip design can pull out any cancer cell that might be floating in the blood and keep it alive so pathologists can do genomic and molecular tests on it (see “Device Finds Stray Cancer Cells in Patients’ Blood”). The results of such tests are valuable because pharmaceutical companies are increasingly developing cancer drugs with specific molecular targets in mind. These targeted therapies stand to improve cancer treatment. Cancer genomics company Foundation Medicine says that as many as 70 percent of tumors it analyzes carry genetic signatures that can inform treatment (see “Cancer Genomics”).
Although the scientific and medical community has long known that cancer spreads through the bloodstream, there has been no way to capture the circulating tumor cells. “These are rare cells in the midst of 100 billion other cells,” says Toner. “Microfluidics gave us an opportunity to more precisely manipulate the blood and see if these cells are there in a useful number.”
A subset of circulating tumor cells in a patient are thought to seed metastases. “In the end, a subpopulation of these cells ends up killing patients,” Toner says. “Finding these cells in patients in real time has tremendous application for monitoring the genotype of the cancer and for early detection.”
The technology gives doctors the ability to monitor cancer over time. “Right now, after a patient is diagnosed with cancer, we don’t usually re-biopsy patients,” says Haber, who is using the devices experimentally to define genetic mutations in lung cancer and match those mutations to therapies. But as a cancer grows and spreads in the body, it changes: “We can’t assume it has the same abnormalities it had at first.”
“We see the direction of cancer treatment as the ability to monitor the molecular changes in the disease over time,” says Nicholas Dracopoli, head of oncology biomarkers at Janssen, J&J’s pharmaceutical branch.
The MGH device and some others in development isolate rare cancer cells by discarding all red blood cells and white blood cells, which typically outnumber circulating tumor cells by the billions. Any cancerous cells would then be left in a life-friendly liquid, from which they can be grabbed individually and studied.
Other versions of the technology, including the device that J&J currently sells, capture the cells on a physical surface, usually through a coating of antibodies that recognize proteins on the cell membranes of some, but not all, cancers.
Beyond the potential to improve cancer treatment, devices that can capture circulating tumor cells could help biologists uncover the secrets of cancer’s deadly spread. “The question of how cancer metastasizes and spreads has never really been understood because we didn’t have the tools to study it,” says Haber. “This is the first time that you are looking at cancer cells in transit. They aren’t there long, but they are there.”
Working with biomedical engineer Mehmet Toner and his team at MGH, Haber is developing their latest chip into a commercial product. The new chip design can pull out any cancer cell that might be floating in the blood and keep it alive so pathologists can do genomic and molecular tests on it (see “Device Finds Stray Cancer Cells in Patients’ Blood”). The results of such tests are valuable because pharmaceutical companies are increasingly developing cancer drugs with specific molecular targets in mind. These targeted therapies stand to improve cancer treatment. Cancer genomics company Foundation Medicine says that as many as 70 percent of tumors it analyzes carry genetic signatures that can inform treatment (see “Cancer Genomics”).
Although the scientific and medical community has long known that cancer spreads through the bloodstream, there has been no way to capture the circulating tumor cells. “These are rare cells in the midst of 100 billion other cells,” says Toner. “Microfluidics gave us an opportunity to more precisely manipulate the blood and see if these cells are there in a useful number.”
A subset of circulating tumor cells in a patient are thought to seed metastases. “In the end, a subpopulation of these cells ends up killing patients,” Toner says. “Finding these cells in patients in real time has tremendous application for monitoring the genotype of the cancer and for early detection.”
The technology gives doctors the ability to monitor cancer over time. “Right now, after a patient is diagnosed with cancer, we don’t usually re-biopsy patients,” says Haber, who is using the devices experimentally to define genetic mutations in lung cancer and match those mutations to therapies. But as a cancer grows and spreads in the body, it changes: “We can’t assume it has the same abnormalities it had at first.”
J&J has partnered with MGH to develop the new chip into a commercial product.
The MGH device and some others in development isolate rare cancer cells by discarding all red blood cells and white blood cells, which typically outnumber circulating tumor cells by the billions. Any cancerous cells would then be left in a life-friendly liquid, from which they can be grabbed individually and studied.
Other versions of the technology, including the device that J&J currently sells, capture the cells on a physical surface, usually through a coating of antibodies that recognize proteins on the cell membranes of some, but not all, cancers.
Beyond the potential to improve cancer treatment, devices that can capture circulating tumor cells could help biologists uncover the secrets of cancer’s deadly spread. “The question of how cancer metastasizes and spreads has never really been understood because we didn’t have the tools to study it,” says Haber. “This is the first time that you are looking at cancer cells in transit. They aren’t there long, but they are there.”
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