summarize this "This experience informs our three-part strategy for dealing with cancer.
Our first and most obvious wish is to avoid getting cancer at all, like the
centenarians—in other words, prevention. But cancer prevention is tricky,
because we do not yet fully understand what drives the initiation and
progression of the disease with the same resolution that we have for
atherosclerosis. Further, plain bad luck seems to play a major role in this
largely stochastic process. But we do have some clues, which is what we’ll
talk about in the next two sections.
Next is the use of newer and smarter treatments targeting cancer’s
manifold weaknesses, including the insatiable metabolic hunger of fastgrowing cancer cells and their vulnerability to new immune-based therapies,
the outcome of decades of work by scientists like Steve Rosenberg. I feel that
immunotherapy, in particular, has enormous promise.
Third, and perhaps most importantly, we need to try to detect cancer as
early as possible so that our treatments can be deployed more effectively. I
advocate early, aggressive, and broad screening for my patients—such as
colonoscopy (or other colorectal cancer screening) at age forty, as opposed to
the standard recommendation of forty-five or fifty—because the evidence is
overwhelming that it’s much easier to deal with most cancers in their early
stages. I am also cautiously optimistic about pairing these tried-and-true
staples of cancer screening with emerging methods, such as “liquid biopsies,”
which can detect trace amounts of cancer-cell DNA via a simple blood test.
Five decades into the war on cancer, it seems clear that no single “cure” is
likely to be forthcoming. Rather, our best hope likely lies in figuring out
better ways to attack cancer on all three of these fronts: prevention, more
targeted and effective treatments, and comprehensive and accurate early
detection.
What Is Cancer?
One major reason why cancer is so deadly—and so scary—is that we still
know relatively little about how it begins and why it spreads.
Cancer cells are different from normal cells in two important ways.
Contrary to popular belief, cancer cells don’t grow faster than their
noncancerous counterparts; they just don’t stop growing when they are
supposed to. For some reason, they stop listening to the body’s signals that tell
them when to grow and when to stop growing. This process is thought to
begin when normal cells acquire certain genetic mutations. For example, a
gene called PTEN, which normally stops cells from growing or dividing (and
eventually becoming tumors), is often mutated or “lost” in people with
cancer, including about 31 percent of men with prostate cancer and 70
percent of men with advanced prostate cancer. Such “tumor suppressor”
genes are critically important to our understanding of the disease.
The second property that defines cancer cells is their ability to travel from
one part of the body to a distant site where they should not be. This is called
metastasis, and it is what enables a cancerous cell in the breast to spread to the
lung. This spreading is what turns a cancer from a local, manageable problem
to a fatal, systemic disease.
Beyond these two common properties, however, the similarities among
different cancers largely end. One of the biggest obstacles to a “cure” is the
fact that cancer is not one single, simple, straightforward disease, but a
condition with mind-boggling complexity.
About two decades ago, the National Cancer Institute launched a huge
and ambitious study called The Cancer Genome Atlas, whose goal was to
sequence cancer tumor cells in hopes of finding the precise genetic changes
that cause various types of cancer, such as breast, kidney, and liver cancer.
Armed with this knowledge, scientists would be able to develop therapies
targeted at these exact mutations. As one of the scientists who proposed the
project said, “These are the starting blocks that we need to develop a cure.”
But the early results of The Cancer Genome Atlas, published in a series of
papers beginning in 2008, revealed more confusion than clarity. Rather than
uncovering a definite pattern of genetic changes driving each type of cancer,
the study found enormous complexity. Each tumor had more than one
hundred different mutations, on average, and those mutations almost
appeared to be random. A handful of genes emerged as drivers, including
TP53 (also known as p53, found in half of all cancers), KRAS (common in
pancreatic cancer), PIC3A (common in breast cancer), and BRAF (common
in melanoma), but very few if any of these well-known mutations were shared
across all tumors. In fact, there didn’t seem to be any individual genes that
“caused” cancer at all; instead, it seemed to be random somatic mutations that
combined to cause cancers. So not only is breast cancer genetically distinct
from colon cancer (as the researchers expected), but no two breast cancer
tumors are very much alike. If two women have breast cancer, at the same
stage, their tumor genomes are likely to be very different from each other.
Therefore, it would be difficult if not impossible to devise one treatment for
both women based on the genetic profile of their tumors. Rather than
revealing the shape of the forest, then, The Cancer Genome Atlas merely
dragged us deeper into the maze of the trees.
Or so it seemed at the time. Ultimately, genome sequencing has proved to
be a very powerful tool against cancer—just not in the way that was
envisioned two decades ago.
—
Even when we treat a local cancer successfully, we can never be sure that it’s
entirely gone. We have no way of knowing whether cancer cells may have
already spread and are lurking in other organs, waiting to establish a foothold
there. It is this metastatic cancer that is responsible for most cancer deaths. If
we want to reduce cancer mortality by a significant amount, we must do a
better job of preventing, detecting, and treating metastatic cancers.
With a few exceptions, such as glioblastoma or other aggressive brain
tumors, as well as certain lung and liver cancers, solid organ tumors typically
kill you only when they spread to other organs. Breast cancer kills only when
it becomes metastatic. Prostate cancer kills only when it becomes metastatic.
You could live without either of those organs. So when you hear the sad story
of someone dying from breast or prostate cancer, or even pancreatic or colon
cancer, they died because the cancer spread to other, more critical organs
such as the brain, the lungs, the liver, and bones. When cancer reaches those
places, survival rates drop precipitously.
But what causes cancer to spread? We don’t really know, and we are
unlikely to find out anytime soon because only about 5 to 8 percent of US
cancer research funding goes to the study of metastasis. Our ability to detect
cancer metastasis is also very poor, although I do believe we are on the verge
of some key breakthroughs in cancer screening, as we’ll discuss later. Most of
our energy has been focused on treating metastatic cancer, which is an
extremely difficult problem. Once cancer has spread, the entire game changes:
we need to treat it systemically rather than locally.
Right now, this usually means chemotherapy. Contrary to popular belief,
killing cancer cells is actually pretty easy. I’ve got a dozen potential
chemotherapy agents in my garage and under my kitchen sink. Their labels
identify them as glass cleaner or drain openers, but they would easily kill
cancer cells too. The problem, of course, is that these poisons will also
slaughter every normal cell in between, likely killing the patient in the
process. The game is won by killing cancers while sparing the normal cells.
Selective killing is the key.
Traditional chemotherapy occupies a fuzzy region between poison and
medicine; the mustard gas used as a weapon during World War I was a direct
precursor to some of the earliest chemotherapy agents, some of which are
still in use. These drugs attack the replicative cycle of cells, and because
cancer cells are rapidly dividing, the chemo agents harm them more severely
than normal cells. But many important noncancerous cells are also dividing
frequently, such as those in the lining of the mouth and gut, the hair follicles,
and the nails, which is why typical chemotherapy agents cause side effects
like hair loss and gastrointestinal misery. Meanwhile, as cancer researcher
Robert Gatenby points out, those cancer cells that do manage to survive
chemotherapy often end up acquiring mutations that make them stronger, like
cockroaches that develop resistance to insecticides.
The side effects of chemo might seem at the outset to be a fair trade for a
“chance for a few more useful years,” as the late author Christopher Hitchens
noted in his cancer memoir Mortality. But as his treatment for metastatic
esophageal cancer dragged on, he changed his mind. “I lay for days on end,
trying in vain to postpone the moment when I would have to swallow. Every
time I did swallow, a hellish tide of pain would flow up my throat,
culminating in what felt like a mule kick in the small of my back….And then
I had an unprompted rogue thought: If I had been told about all this in
advance, would I have opted for the treatment?”
Hitchens was experiencing the primary flaw of modern chemotherapy: It
is systemic, but still not specific enough to target only cancerous cells and not
normal healthy cells. Hence the horrible side effects he suffered. Ultimately,
successful treatments will need to be both systemic and specific to a
particular cancer type. They will be able to exploit some weakness that is
unique to cancer cells, while largely sparing normal cells (and, obviously, the
patient). But what might those weaknesses be?
Just because cancer is powerful does not mean it is invincible. In 2011,
two leading cancer researchers named Douglas Hanahan and Robert
Weinberg identified two key hallmarks of cancer that may lead—and in fact
have led—to new treatments, as well as potential methods of reducing cancer
risk. The first such hallmark is the fact that many cancer cells have an altered
metabolism, consuming huge amounts of glucose. Second, cancer cells seem
to have an uncanny ability to evade the immune system, which normally hunts
down damaged and dangerous cells—such as cancerous cells—and targets
them for destruction. This second problem is the one that Steve Rosenberg
and others have been trying to solve for decades.
Metabolism and immune surveillance excite me because they are both
systemic, a necessary condition for any new treatment to combat metastatic
cancers. They both exploit features of cancer that are potentially more
specific to tumors than simply runaway cell replication. But neither the
metabolic nor the immune-based approaches to cancer are exactly new:
dogged researchers have been laying the groundwork for progress in both of
these areas for decades.
"