A final note: I said CML was a "rare" disease, and that was true in the era before Gleevec. The incidence of CML remains unchanged from the past: only a few thousand patients are diagnosed with this form of leukemia every year. But the prevalence of CML--the number of patients presently alive with the disease--has dramatically changed with the introduction of Gleevec. As of 2009, CML patients treated with Gleevec survive an average of thirty years after their diagnosis. Based on that survival figure, Hagop Kantarjian estimates that within the next decade, 250,000 people will be living with CML in America, all of them on targeted therapy. Druker's drug will alter the national physiognomy of cancer, converting a once-rare disease into a relatively common one. (Druker jokes that he has achieved the perfect inversion of the goals of cancer medicine: his drug has increased the prevalence of cancer in the world.) Given that most of our social networks typically extend to about one thousand individuals, each of us, on average, will know one person with this leukemia who is being kept alive by a targeted anticancer drug.
*Abl, too, was first discovered in a virus, and later found to be present in human cells--again recapitulating the story of ras and src. Once more, a retrovirus had "pirated" a human cancer gene and turned into a cancer-causing virus.
* Gleevec, the commercial name, is used here because it is more familiar to patients. The scientific name for CGP57148 is imatinib. The drug was also called STI571.
The Red Queen's Race
"Well, in our country," said Alice, still panting a little, "you'd generally get to somewhere else--if you ran very fast for a long time, as we've been doing."
"A slow sort of country!" said the Queen. "Now, here, you see, it takes all the running you can do, to keep in the same place. If you want to get somewhere else, you must run at least twice as fast as that!"
--Lewis Carroll,
Through the Looking-Glass
In August 2000, Jerry Mayfield, a forty-one-year-old Louisiana policeman diagnosed with CML, began treatment with Gleevec. Mayfield's cancer responded briskly at first. The fraction of leukemic cells in his bone marrow dropped over six months. His blood count normalized and his symptoms improved; he felt rejuvenated--"like a new man [on] a wonderful drug." But the response was short-lived. In the winter of 2003, Mayfield's CML stopped responding. Moshe Talpaz, the oncologist treating Mayfield in Houston, increased the dose of Gleevec, then increased it again, hoping to outpace the leukemia. But by October of that year, there was no response. Leukemia cells had fully recolonized his bone marrow and blood and invaded his spleen. Mayfield's cancer had become resistant to targeted therapy.
Now in the fifth year of their Gleevec trial, Talpaz and Sawyers had seen several cases like Mayfield's. They were rare. The vast proportion of CML patients maintained deep, striking remissions on the drug, requiring no other therapy. But occasionally, a patient's leukemia stopped responding to Gleevec, and Gleevec-resistant leukemia cells grew back. Sawyers, having just entered the world of targeted therapy, swiftly entered a molecular world beyond targeted therapy: how might a cancer cell become resistant to a drug that directly inhibits its driving oncogene?
In the era of nontargeted drugs, cancer cells were known to become drug-resistant through a variety of ingenious mechanisms. Some cells acquire mutations that activate molecular pumps. In normal cells, these pumps extrude natural poisons and waste products from a cell's interior. In cancer cells, these activated pumps push chemotherapy drugs out from the interior of the cell. Spared by chemotherapy, the drug-resistant cells outgrow other cancer cells. Other cancer cells activate proteins that destroy or neutralize drugs. Yet other cancers escape drugs by migrating into reservoirs of the body where drugs cannot penetrate--as in lymphoblastic leukemia relapsing in the brain.
CML cells, Sawyers discovered, become Gleevec-resistant through an even wilier mechanism: the cells acquire mutations that specifically alter the structure of Bcr-abl, creating a protein still able to drive the growth of the leukemia but no longer capable of binding to the drug. Normally, Gleevec slips into a narrow, wedgelike cleft in the center of Bcr-abl--like "an arrow pierced through the center of the protein's heart," as one chemist described it. Gleevec-resistant mutations in Bcr-abl change the molecular "heart" of the Bcr-abl protein so that the drug can no longer access the critical cleft in the protein, thus rendering the drug ineffective. In Mayfield's case, a single alteration in the Bcr-abl protein had rendered it fully resistant to Gleevec, resulting in the sudden relapse of leukemia. To escape targeted therapy, cancer had changed the target.
To Sawyers, these observations suggested that overcoming Gleevec resistance with a second-generation drug would require a very different kind of attack. Increasing the dose of Gleevec, or inventing closely related molecular variants of the drug, would be useless. Since the mutations changed the structure of Bcr-abl, a second-generation drug would need to block the protein through an independent mechanism, perhaps by gaining another entry point into its crucial central cleft.
In 2005, working with chemists at Bristol-Myers Squibb, Sawyers's team generated another kinase inhibitor to target Gleevec-resistant Bcr-abl. As predicted, this new drug, dasatinib, was not a simple structural analogue of Gleevec; it accessed Bcr-abl's "heart" through a separate molecular crevice on the protein's surface. When Sawyers and Talpaz tested dasatinib on Gleevec-resistant patients, the effect was remarkable: the leukemia cells involuted again. Mayfield's leukemia, fully resistant to Gleevec, was forced back into remission in 2005. His blood count normalized again. Leukemia cells dissipated out of his bone marrow gradually. In 2009, Mayfield still remains in remission, now on dasatinib.
Even targeted therapy, then, was a cat-and-mouse game. One could direct endless arrows at the Achilles' heel of cancer, but the disease might simply shift its foot, switching one vulnerability for another. We were locked in a perpetual battle with a volatile combatant. When CML cells kicked Gleevec away, only a different molecular variant would drive them down, and when they outgrew that drug, then we would need the next-generation drug. If the vigilance was dropped, even for a moment, then the weight of the battle would shift. In Lewis Carroll's Through the Looking-Glass, the Red Queen tells Alice that the world keeps shifting so quickly under her feet that she has to keep running just to keep her position. This is our predicament with cancer: we are forced to keep running merely to keep still.
In the decade since the discovery of Gleevec, twenty-four novel drugs have been listed by the National Cancer Institute as cancer-targeted therapies. Dozens more are in development. The twenty-four drugs have been shown to be effective against lung, breast, colon, and prostate cancers, sarcomas, lymphomas, and leukemias. Some, such as dasatinib, directly inactivate oncogenes. Others target oncogene-activated pathways--the "hallmarks of cancer" codified by Weinberg. The drug Avastin interrupts tumor angiogenesis by attacking the capacity of cancer cells to incite blood-vessel growth. Bortezomib, or Velcade, blocks an internal waste-dispensing mechanism for proteins that is particularly hyperactive in cancer cells.
More than nearly any other form of cancer, multiple myeloma, a cancer of immune-system cells, epitomizes the impact of these newly discovered targeted therapies. In the 1980s, multiple myeloma was treated by high doses of standard chemotherapy--old, hard-bitten drugs that typically ended up decimating patients about as quickly as they decimated the cancer. Over a decade, three novel targeted therapies have emerged for myeloma--Velcade, thalidomide, and Revlimid--all of which interrupt activated pathways in myeloma cells. Treatment of multiple myeloma today involves mixing and matching these drugs with standard chemotherapies, switching drugs when the tumor relapses, and switching again when the tumor relapses again. No single drug or treatment cures myeloma outright; myeloma is still a fatal disease. But as with CML, the cat-and-mouse game with cancer has extended the survival of myeloma patients--strikingly in some cases. In 1971, about half the patients diagnosed with multiple myeloma died within twenty-four months of diagnosis; the other half died by the tenth
year. In 2008, about half of all myeloma patients treated with the shifting armamentarium of new drugs will still be alive at five years. If the survival trends continue, the other half will continue to be alive well beyond ten years.
In 2005, a man diagnosed with multiple myeloma asked me if he would be alive to watch his daughter graduate from high school in a few months. In 2009, bound to a wheelchair, he watched his daughter graduate from college. The wheelchair had nothing to do with his cancer. The man had fallen down while coaching his youngest son's baseball team.
In a broader sense, the Red Queen syndrome--moving incessantly just to keep in place--applies equally to every aspect of the battle against cancer, including cancer screening and cancer prevention. In the early winter of 2007, I traveled to Framingham in Massachusetts to visit a study site that will likely alter the way we imagine cancer prevention. A small, nondescript Northeastern town bound by a chain of frozen lakes in midwinter, Framingham is nonetheless an iconic place writ large in the history of medicine. In 1948, epidemiologists identified a cohort of about five thousand men and women living in Framingham. The behavior of this cohort, its habits, its interrelationships, and its illnesses, has been documented year after year in exquisite detail, creating an invaluable longitudinal corpus of data for hundreds of epidemiological studies. The English mystery writer Agatha Christie often used a fictional village, St. Mary Mead, as a microcosm of all mankind. Framingham is the American epidemiologist's English village. Under sharp statistical lenses, its captive cohort has lived, reproduced, aged, and died, affording a rare glimpse of the natural history of life, disease, and death.
The Framingham data set has spawned a host of studies on risk and illness. The link between cholesterol and heart attacks was formally established here, as was the association of stroke and high blood pressure. But recently, a conceptual transformation in epidemiological thinking has also been spearheaded here. Epidemiologists typically measure the risk factors for chronic, noninfectious illnesses by studying the behavior of individuals. But recently, they have asked a very different question: what if the real locus of risk lies not in the behaviors of individual actors, but in social networks?
In May 2008, two Harvard epidemiologists, Nicholas Christakis and James Fowler, used this notion to examine the dynamics of cigarette smoking. First, Fowler and Christakis plotted a diagram of all known relationships in Framingham--friends, neighbors, and relatives, siblings, ex-wives, uncles, aunts--as a densely interconnected web. Viewed abstractly, the network began to assume familiar and intuitive patterns. A few men and women (call them "socializers") stood at the epicenter of these networks, densely connected to each other through multiple ties. In contrast, others lingered on the outskirts of the social web--"loners"--with few and fleeting contacts.
When the epidemiologists juxtaposed smoking behavior onto this network and followed the pattern of smoking over decades, a notable phenomenon emerged: circles of relationships were found to be more powerful predictors of the dynamics of smoking than nearly any other factor. Entire networks stopped smoking concordantly, like whole circuits flickering off. A family that dined together was also a family that quit together. When highly connected "socializers" stopped smoking, the dense social circle circumscribed around them also slowly stopped as a group. As a result, smoking gradually became locked into the far peripheries of all networks, confined to the "loners" with few social contacts, puffing away quietly in the distant and isolated corners of the town.
The smoking-network study offers, to my mind, a formidable challenge to simplistic models of cancer prevention. Smoking, this model argues, is entwined into our social DNA just as densely and as inextricably as oncogenes are entwined into our genetic material. The cigarette epidemic, we might recall, originated as a form of metastatic behavior--one site seeding another site seeding another. Soldiers brought smoking back to postwar Europe; women persuaded women to smoke; the tobacco industry, sensing opportunity, advertised cigarettes as a form of social glue that would "stick" individuals into cohesive groups. The capacity of metastasis is thus built into smoking. If entire networks of smokers can flicker off with catalytic speed, then they can also flicker on with catalytic speed. Sever the ties that bind the nonsmokers of Framingham (or worse, nucleate a large social network with a proselytizing smoker), and then, cataclysmically, the network might alter as a whole.
This is why even the most successful cancer-prevention strategies can lapse so swiftly. When the Red Queen's feet stop spinning even temporarily, she does not maintain her position; the world around her, counter-spinning, pushes her off-balance. So it is with cancer prevention. When antitobacco campaigns lose their effectiveness or penetrance--as has recently happened among teens in America or in Asia--smoking often returns like an old plague. Social behavior metastasizes, eddying out from its center toward the peripheries of social networks. Mini-epidemics of smoking-related cancers are sure to follow.
The landscape of carcinogens is not static either. We are chemical apes: having discovered the capacity to extract, purify, and react molecules to produce new and wondrous molecules, we have begun to spin a new chemical universe around ourselves. Our bodies, our cells, our genes are thus being immersed and reimmersed in a changing flux of molecules--pesticides, pharmaceutical drugs, plastics, cosmetics, estrogens, food products, hormones, even novel forms of physical impulses, such as radiation and magnetism. Some of these, inevitably, will be carcinogenic. We cannot wish this world away; our task, then, is to sift through it vigilantly to discriminate bona fide carcinogens from innocent and useful bystanders.
This is easier said than done. In 2004, a rash of early scientific reports suggested that cell phones, which produce radio frequency energy, might cause a fatal form of brain cancer called a glioma. Gliomas appeared on the same side of the brain that the phone was predominantly held, further tightening the link. An avalanche of panic ensued in the media. But was this a falsely perceived confluence of a common phenomenon and a rare disease--phone usage and glioma? Or had epidemiologists missed the "nylon stockings" of the digital age?
In 2004, an enormous British study was launched to confirm these ominous early reports. "Cases"--patients with gliomas--were compared to "controls"--men and women with no gliomas--in terms of cell phone usage. The study, reported in 2006, appeared initially to confirm an increased risk of right-sided brain cancers in men and women who held their phone on their right ear. But when researchers evaluated the data meticulously, a puzzling pattern emerged: right-sided cell phone use reduced the risk of left-sided brain cancer. The simplest logical explanation for this phenomenon was "recall bias": patients diagnosed with tumors unconsciously exaggerated the use of cell phones on the same side of their head, and selectively forgot the use on the other side. When the authors corrected for this bias, there was no detectable association between gliomas and cell phone use overall. Prevention experts, and phone-addicted teenagers, may have rejoiced--but only briefly. By the time the study was completed, new phones had entered the market and swapped out old phones--making even the negative results questionable.
The cell phone case is a sobering reminder of the methodological rigor needed to evaluate new carcinogens. It is easy to fan anxiety about cancer. Identifying a true preventable carcinogen, estimating the magnitude of risk at reasonable doses and at reasonable exposures, and reducing exposure through scientific and legislative intervention--keeping the legacy of Percivall Pott alive--is far more complex.
"Cancer at the fin de siecle," as the oncologist Harold Burstein described it, "resides at the interface between society and science." It poses not one but two challenges. The first, the "biological challenge" of cancer, involves "harnessing the fantastic rise in scientific knowledge . . . to conquer this ancient and terrible illness." But the second, the "social challenge," is just as acute: it involves forcing ourselves to confront our customs, rituals, and behaviors. These, unfortunately, are not customs or behaviors that lie at the peripheries of our society or sel
ves, but ones that lie at their definitional cores: what we eat and drink, what we produce and exude into our environments, when we choose to reproduce, and how we age.
Thirteen Mountains
"Every sickness
is a musical problem,"
so said Novalis,
"and every cure
a musical solution."
--W. H. Auden
The revolution in cancer research can be summed up in a single sentence: cancer is, in essence, a genetic disease.
--Bert Vogelstein
When I began writing this book, in the early summer of 2004, I was often asked how I intended to end it. Typically, I would dodge the question or brush it away. I did not know, I would cautiously say. Or I was not sure. In truth, I was sure, although I did not have the courage to admit it to myself. I was sure that it would end with Carla's relapse and death.
I was wrong. In July 2009, exactly five years after I had looked down the microscope into Carla's bone marrow and confirmed her first remission, I drove to her house in Ipswich, Massachusetts, with a bouquet of flowers. It was an overcast morning, excruciatingly muggy, with a dun-colored sky that threatened rain but would not deliver any. Just before I left the hospital, I glanced quickly at the first note that I had written on Carla's admission to the hospital in 2004. As I had written that note, I recalled with embarrassment, I had guessed that Carla would not even survive the induction phase of chemotherapy.
Siddhartha Mukherjee - The Emperor of All Maladies: A Biography of Cancer Page 53
