The Emperor of All Maladies

by Siddhartha Mukherjee

Leukemia is cancer of the white blood cells—

felt I was slowly becoming inured to the deaths and the desolation—vaccinated against the constant emotional brunt.

Cancer cells grow faster, adapt better. They are more perfect versions of ourselves. The secret to battling cancer, then, is to find means to prevent these mutations from occurring in susceptible cells, or to find means to eliminate the mutated cells without compromising normal growth. The conciseness of that statement belies the enormity of the task. Malignant growth and normal growth are so genetically intertwined that unbraiding the two might be one of the most significant scientific challenges faced by our species.

Physicians of the Utmost Fame8 Were called at once; but when they came They answered, as they took their Fees, “There is no Cure for this Disease.”

Leukemia was a malignant proliferation of white cells in the blood. It was cancer in a molten, liquid form.

the only way out would be the way through.

The Nuremberg code for human experimentation, requiring explicit voluntary consent from patients, was drafted on August 9, 1947, less than a month before the PAA trial.

automaton. The notion of cancer

dying, even more than death, defines the illness.

Every generation of cancer cells creates a small number of cells that is genetically different from its parents. When a chemotherapeutic drug or the immune system attacks cancer, mutant clones that can resist the attack grow out. The fittest cancer cell survives.

Cancer thus exploits the fundamental logic of evolution unlike any other illness. If we, as a species, are the ultimate product of Darwinian selection, then so, too, is this incredible disease that lurks inside us.

Bruce Chabner wrote in an editorial, “the world of sport was shocked by the feat of Roger Bannister. . . . On May 6, 1954, he broke the four-minute barrier in the mile. While improving upon the world record by only a few seconds, he changed the complexion of distance running in a single afternoon. . . . Track records fell like ripe apples in the late 50s and 60s. Will the same happen in the field of cancer treatment?” Chabner’s analogy was carefully chosen. Bannister’s mile remains a touchstone in the history of athletics not because Bannister set an unbreachable record—currently, the fastest mile is a good fifteen seconds under Bannister’s. For generations, four minutes was thought to represent an intrinsic physiological limit, as if muscles could inherently not be made to move any faster or lungs breathe any deeper. What Bannister proved was that such notions about intrinsic boundaries are mythical. What he broke permanently was not a limit, but the idea of limits. So it was with Gleevec. “It proves a principle.1028 It justifies an approach,” Chabner continued. “It demonstrates that highly specific, non-toxic therapy is possible.” Gleevec opened a new door for cancer therapeutics. The rational synthesis of a molecule to kill cancer cells—a drug designed to specifically inactivate an oncogene—validated Ehrlich’s fantasy of “specific affinity.” Targeted molecular therapy for cancer was possible; one only needed to hunt for it by studying the deep biology of cancer cells.

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.)

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,”1032 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.

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.

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 decade1035, 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 watch...

Red Queen syndrome—moving incessantly just to keep in place—

“In the end,” as Vogelstein put it1048, “cancer genome sequencing validates a hundred years of clinical observations. Every patient’s cancer is unique because every cancer genome is unique. Physiological heterogeneity is genetic heterogeneity.” Normal cells are identically normal; malignant cells become unhappily malignant in unique ways.

old proverb runs, there are mountains beyond mountains.

Cancer, we have discovered, is stitched into our genome. Oncogenes arise from mutations in essential genes that regulate the growth of cells. Mutations accumulate in these genes when DNA is damaged by carcinogens, but also by seemingly random errors in copying genes when cells divide. The former might be preventable, but the latter is endogenous.