summarize this "Historically, this has been done via imaging tests, such as CT scans, that
enable us to “see” a tumor. Radiation exposure notwithstanding, the main
issue is that these tests don’t have very high resolution. It’s very difficult for
these imaging technologies to discern a cancer smaller than about one
centimeter in diameter. Even if you assume that this one-centimeter nodule is
the only collection of cancer cells in the patient’s body (not a great
assumption; the mouse in the trap is rarely the only one in the house), you’re
still talking about more than a billion cancer cells by the time you reach the
threshold of traditional detection. If we could catch these recurrent cancers
sooner, we might have a better shot at keeping patients in remission—for the
same reasons that it’s easier to treat adjuvant versus metastatic cancer, as we
discussed a few pages ago.
Max and his colleagues came up with a wholly different method. Because
cancer cells are growing constantly, they tend to shed cellular matter,
including bits of tumor DNA, into the circulation. What if there were a blood
test that could detect this so-called cell-free DNA? We would already know
the genetic signature of the tumor from the surgery—that is, how the lung
cancer cells differ from normal lung cells. Thus, it should be possible to
screen for this cell-free DNA in a patient’s plasma and thereby determine the
presence of cancer.
Make no mistake about it, this is still akin to looking for a needle in a
haystack. In an early-stage cancer, which are the cancers we would most want
to find via liquid biopsies, we might be talking about 0.01 to 0.001 percent of
cell-free DNA coming from the cancer (or about one part in ten thousand to
one hundred thousand). Only with the help of next-generation, highthroughput DNA screening technology is this possible. These tests are
becoming more widely used in the postsurgical setting, but the technology is
still relatively young. The key is that you must know what you’re looking for
—the patterns of mutations that distinguish cancer from normal cells.
Some researchers are beginning to develop ways to use blood tests to
screen for cancer generally, in otherwise healthy people. This is an order of
magnitude more difficult, like looking for a needle in ten haystacks; worse, in
this case we don’t even know what the needle should look like. We don’t
know anything about the patient’s tumor mutation patterns, because we’re not
yet certain that they have cancer. Thus we must look for other potential
markers. One company leading the charge with this type of assay is called
Grail, a subsidiary of the genetic-sequencing company Illumina. The Grail
test, known as Galleri, looks at methylation patterns of the cell-free DNA,
which are basically chemical changes to the DNA molecules that suggest the
presence of cancer. Using very-high-throughput screening and a massive AI
engine, the Galleri test can glean two crucial pieces of information from this
sample of blood: Is cancer present? And if so, where is it? From what part of
the body did it most likely originate?
With any diagnostic test, a decision has to be made with respect to how to
calibrate, or tune, it. Is it going to be geared toward higher sensitivity or
higher specificity? Galleri has been validated against a database called the
Circulating Cell-free Genome Atlas (CCGA), which is based on blood
samples from more than fifteen thousand patients both with and without
cancer. In this study, the Galleri test proved to have a very high specificity,
about 99.5 percent, meaning only 0.5 percent of tests yielded a false positive.
If the test says you have cancer, somewhere in your body, then it is likely that
you do. The trade-off is that the resulting sensitivity can be low, depending on
the stage. (That is, even if the test says you don’t have cancer, you are not
necessarily in the clear.)
The thing to keep in mind here, however, is that this test still has much
higher resolution than radiographic tests such as MRI or mammogram. Those
imaging-based tests require “seeing” the tumor, which can happen only when
the tumor reaches a certain size. With Galleri, the test is looking at cell-free
DNA, which can come from any size tumor—even ones that remain invisible
to imaging tests.
One early observation of the CCGA study was that detectability was
associated not only with the stage of tumor, which would be expected (the
more advanced the tumor, the greater the likelihood of finding cell-free DNA
in the blood), but also with the subtype of tumor. For example, the detection
rate for stage I/II hormone receptor–positive breast cancer is about 25
percent, while the detection rate for stage I/II hormone receptor–negative
breast cancer is about 75 percent. What does this difference tell us? We know
that breast cancer is not a uniform disease and that the hormone receptor–
negative tumors are more lethal than hormone receptor–positive tumors.
Thus, the test proves more accurate in detecting the more lethal subtype of
breast cancer.
Liquid biopsies could be viewed as having two functions: first, to
determine cancer’s presence or absence, a binary question; and second and
perhaps more important, to gain insight into the specific cancer’s biology.
How dangerous is this particular cancer likely to be? The cancers that shed
more cell-free DNA, it seems, also tend to be more aggressive and deadly—
and are thus the cancers that we want to detect, and treat, as soon as possible.
This technology is still in its infancy, but I’m hopeful that pairing different
diagnostic tests ranging from radiographic (e.g., MRI) to direct visualization
(e.g., colonoscopy) to biological/genetic (e.g., liquid biopsy) will allow us to
correctly identify the cancers that need treatment the soonest, with the fewest
possible false positives.
The implications of this, I think, are seismic: if liquid biopsies deliver on
their promise, we could completely flip the time line of cancer so that we are
routinely intervening early, when we have a chance of controlling or even
eliminating the cancer—rather than the way we typically do it now, coming in
at a late stage, when the odds are already stacked against the patient, and
hoping for a miracle.
—
Of all the Horsemen, cancer is probably the hardest to prevent. It is probably
also the one where bad luck in various forms plays the greatest role, such as in
the form of accumulated somatic mutations. The only modifiable risks that
really stand out in the data are smoking, insulin resistance, and obesity (all to
be avoided)—and maybe pollution (air, water, etc.), but the data here are less
clear.
We do have some treatment options for cancer, unlike with Alzheimer’s
disease (as we’ll see in the next chapter), and immunotherapy in particular
has great promise. Yet our treatment and prevention strategies remain far less
effective than the tools that we have to address cardiovascular disease and the
spectrum of metabolic dysfunction from insulin resistance to type 2 diabetes.
Until we learn how to prevent or “cure” cancer entirely, something I do
not see happening in our lifetime, short of some miraculous breakthroughs,
we need to focus far more energy on early detection of cancer, to enable
better targeting of specific treatments at specific cancers while they are at
their most vulnerable stages. If the first rule of cancer is “Don’t get cancer,”
the second rule is “Catch it as soon as possible.”
This is why I’m such an advocate for early screening. It’s a simple truth
that treating smaller tumors with fewer mutations is far easier than if we wait
for the cancer to advance and potentially acquire mutations that help it evade
our treatments. The only way to catch it early is with aggressive screening.
This does come at significant cost, which is why Medicine 2.0 tends to be
more conservative about screening. There is a financial cost, of course, but
there is also an emotional cost, particularly of tests that may generate false
positives. And there are other, incidental risks, such as the slight risk from a
colonoscopy or the more significant risk from an unnecessary biopsy. These
three costs must be weighed against the cost of missing a cancer, or not
spotting it early, when it is still susceptible to treatment.
Nobody said this was going to be easy. We still have a very long way to
go. But there is finally hope, on multiple fronts—far more than when I was
training to become a cancer surgeon. More than fifty years into the War on
Cancer, we can finally see a path to a world where a cancer diagnosis
typically means an early detection of a treatable problem rather than a late
discovery of a grim one. Thanks to better screening and more effective
treatments such as immunotherapy, cancer could someday become a
manageable disease, perhaps no longer even qualifying as a Horseman.
"