The Emperor of All Maladies: A Biography of Cancer (76 page)

Berry’s answer was a long-due emollient to a field beset by squabbles between the advocates of prevention and the proponents of chemotherapy. When Berry assessed the effect of each intervention independently using statistical models, it was a satisfying tie: both cancer prevention and chemotherapy had diminished breast cancer mortality equally—12 percent for mammography and 12 percent for chemotherapy, adding up to the observed 24 percent reduction in mortality. “
No one,” as Berry said
, paraphrasing the Bible, “had labored in vain.”

These were all deep, audacious, and meaningful victories borne on the backs of deep and meaningful labors. But, in truth, they were the victories of another generation—the results of discoveries made in the fifties and sixties. The core conceptual advances from which these treatment strategies arose predated nearly all the significant work on the cell biology of cancer. In a bewildering spurt over just two decades, scientists had unveiled a fantastical new world—of errant oncogenes and tumor suppressor genes that accelerated and decelerated growth to unleash cancer; of chromosomes that could be decapitated and translocated to create new genetic chimeras, of cellular pathways corrupted to subvert the death of cancer. But the
therapeutic
advances that had led to the slow attrition of cancer mortality made no use of this novel biology of cancer. There was new science on one hand and old medicine on the other. Mary Lasker had once searched for an epochal shift in cancer. But the shift that had
occurred seemed to belong to another epoch.

Mary Lasker died of heart failure
in 1994 in her carefully curated home in Connecticut—having removed herself physically from the bristling epicenters of cancer research and policymaking in Washington, New York, and Boston. She was ninety-three years old. Her life had nearly spanned the most transformative and turbulent century of biomedical science. Her potent ebullience had dimmed in her last decade. She spoke rarely about the achievements (or disappointments) of the War on Cancer. But she had expected cancer medicine to have achieved more during her lifetime—to have taken a more assertive step toward Farber’s “universal cure” for cancer and marked a more definitive victory in the war. The complexity, the tenacity—the sheer magisterial force of cancer—had made even its most committed and resolute opponent seem circumspect and humbled.

In 1994, a few months after Lasker’s death,
the cancer geneticist Ed Harlow captured
both the agony and the ecstasy of the era. At the end of a weeklong conference at the Cold Spring Harbor Laboratory in New York pervaded by a giddy sense of anticipation about the spectacular achievements of cancer biology, Harlow delivered a sobering assessment: “Our knowledge of . . . molecular defects in cancer has come from a dedicated twenty years of the best molecular biology research. Yet this information does not translate to any effective treatments nor to any understanding of why many of the current treatments succeed or why others fail. It is a frustrating time.”

More than a decade later, I could sense the same frustration in the clinic at Mass General. One afternoon, I watched Tom Lynch, the lung cancer clinician, masterfully encapsulate carcinogenesis, cancer genetics, and chemotherapy for a new patient, a middle-aged woman with bronchoalveolar cell cancer. She was a professor of history with a grave manner and a sharp, darting mind. He sat across from her, scribbling a picture as he spoke. The cells in her bronchus, he began, had acquired mutations in their genes that had allowed them to grow autonomously and uncontrollably. They had formed a local tumor. Their propensity was to acquire further mutations that might allow them to migrate, to invade tissues, to metastasize. Chemotherapy with Carboplatin and Taxol (two standard
chemotherapy drugs), augmented with radiation, would kill the cells and perhaps prevent them from migrating to other organs to seed metastases. In the best-case scenario, the cells carrying the mutated genes would die, and her cancer would be cured.

She watched Lynch put his pen down with her quick, sharp eyes. The explanation sounded logical and organized, but she had caught the glint of a broken piece in the chain of logic. What was the connection between this explanation and the therapy being proposed? How, she wanted to know, would Carboplatin “fix” her mutated genes? How would Taxol know which cells carried the mutations in order to kill them? How would the mechanistic explanation of her illness connect with the medical interventions?

She had captured a disjunction all too familiar to oncologists. For nearly a decade, practicing cancer medicine had become like living inside a pressurized can—pushed, on one hand, by the increasing force of biological clarity about cancer, but then pressed against the wall of medical stagnation that seemed to have produced no real medicines out of this biological clarity.
In the winter of 1945, Vannevar Bush
had written to President Roosevelt, “The striking advances in medicine during the war have been possible only because we had a large backlog of scientific data accumulated through basic research in many scientific fields in the years before the war.”

For cancer, the “backlog of scientific data” had reached a critical point. The boil of science, as Bush liked to imagine it, inevitably produced a kind of steam—an urgent, rhapsodic pressure that could only find release in technology. Cancer science was begging to find release in a new kind of cancer medicine.

*
Jimmy began chemo in the Children’s Hospital in 1948, but was later followed and treated in the Jimmy Fund Building in 1952.

*
Surgery’s contribution could not be judged since surgery predated 1990, and nearly all women are treated surgically.

In the story of Patroclus

No one survives, not even Achilles

Who was nearly a god.

Patroclus resembled him; they wore

The same armor

—Louise Glück

The perfect therapy has not been developed
. Most of us believe that it will not involve toxic cytotoxic therapy, which is why we support the kinds of basic investigations that are directed towards more fundamental understanding of tumor biology. But . . . we must do the best with what we now have.

—Bruce Chabner to Rose Kushner

In the legend, Achilles was quickly dipped into the river Styx, held up only by the tendon of his heel. Touched by the dark sheath of water, every part of his body was instantly rendered impervious to even the most lethal weapon—except the undipped tendon. A simple arrow targeted to that vulnerable heel would eventually kill Achilles in the battlefields of Troy.

Before the 1980s, the armamentarium of cancer therapy was largely built around two fundamental vulnerabilities of cancer cells. The first is that most cancers originate as local diseases before they spread systemically. Surgery and radiation therapy exploit this vulnerability. By physically excising locally restricted tumors before cancer cells can spread—or by searing cancer cells with localized bursts of powerful energy using X-rays—surgery and radiation attempt to eliminate cancer en bloc from the body.

The second vulnerability is the rapid growth rate of cancer cells. Most chemotherapy drugs discovered before the 1980s target this second vulnerability. Antifolates, such as Farber’s aminopterin, interrupt the metab
olism of folic acid and starve all cells of a crucial nutrient required for cell division. Nitrogen mustard and cisplatin chemically react with DNA, and DNA-damaged cells cannot duplicate their genes and thus cannot divide. Vincristine, the periwinkle poison, thwarts the ability of a cell to construct the molecular “scaffold” required for all cells to divide.

But these two traditional Achilles’ heels of cancer—local growth and rapid cell division—can only be targeted to a point. Surgery and radiation are intrinsically localized strategies, and they fail when cancer cells have spread beyond the limits of what can be surgically removed or irradiated. More surgery thus does not lead to more cures, as the radical surgeons discovered to their despair in the 1950s.

Targeting cellular growth also hits a biological ceiling because normal cells must grow as well. Growth may be the hallmark of cancer, but it is equally the hallmark of life. A poison directed at cellular growth, such as vincristine or cisplatin, eventually attacks normal growth, and cells that grow most rapidly in the body begin to bear the collateral cost of chemotherapy. Hair falls out. Blood involutes. The lining of the skin and gut sloughs off. More drugs produce more toxicity without producing cures, as the radical chemotherapists discovered to their despair in the 1980s.

To target cancer cells with novel therapies, scientists and physicians needed new vulnerabilities that were unique to cancer. The discoveries of cancer biology in the 1980s offered a vastly more nuanced view of these vulnerabilities. Three new principles emerged, representing three new Achilles’ heels of cancer.

First, cancer cells are driven to grow because of the accumulation of mutations in their DNA. These mutations activate internal proto-oncogenes and inactivate tumor suppressor genes, thus unleashing the “accelerators” and “brakes” that operate during normal cell division. Targeting these hyperactive genes, while sparing their modulated normal precursors, might be a novel means to attack cancer cells more discriminately.

Second, proto-oncogenes and tumor suppressor genes typically lie at the hubs of cellular signaling pathways. Cancer cells divide and grow because they are driven by hyperactive or inactive signals in these critical pathways. These pathways exist in normal cells but are tightly regulated. The potential dependence of a cancer cell on such permanently activated pathways is a second potential vulnerability of a cancer cell.

Third, the relentless cycle of mutation, selection, and survival creates a cancer cell that has acquired several additional properties besides
uncontrolled growth. These include the capacity to resist death signals, to metastasize throughout the body, and to incite the growth of blood vessels. These “hallmarks of cancer” are not invented by the cancer cell; they are typically derived from the corruption of similar processes that occur in the normal physiology of the body. The acquired dependence of a cancer cell on these processes is a third potential vulnerability of cancer.

The central therapeutic challenge of the newest cancer medicine, then, was to find, among the vast numbers of similarities in normal cells and cancer cells, subtle differences in genes, pathways, and acquired capabilities—and to drive a poisoned stake into that new heel.

It was one thing to identify an Achilles’ heel—and quite another to discover a weapon that would strike it. Until the late 1980s, no drug had reversed an oncogene’s activation or a tumor suppressor’s inactivation. Even tamoxifen, the most specific cancer-targeted drug discovered to that date, works by attacking the dependence of certain breast cancer cells on estrogen, and not by directly inactivating an oncogene or oncogene-activated pathway. In 1986, the discovery of the first oncogene-targeted drug would thus instantly galvanize cancer medicine. Although found largely serendipitously, the mere existence of such a molecule would set the stage for the vast drug-hunting efforts of the next decade.

The disease that stood at the pivotal crossroads of oncology was yet another rare variant of leukemia called acute promyelocytic leukemia—APL. First identified as a distinct form of adult leukemia in the 1950s, the disease has a distinct characteristic: the cells in this form of cancer do not merely divide rapidly, they are also strikingly frozen in immature development. Normal white blood cells developing in the bone marrow undergo a series of maturational steps to develop into fully functional adult cells. One such intermediate cell is termed a promyelocyte, an adolescent cell on the verge of becoming functionally mature. APL is characterized by the malignant proliferation of these immature promyelocytes. Normal promyelocytes are loaded with toxic enzymes and granules that are usually released by adult white blood cells to kill viruses, bacteria, and parasites. In promyelocytic leukemia, the blood fills up with these toxin-loaded promyelocytes. Moody, mercurial, and jumpy, the cells of APL can release their poisonous granules on a whim—precipitating massive bleeding or simulating a septic reaction in the body. In APL, the pathological prolif
eration of cancer thus comes with a fiery twist. Most cancers contain cells that refuse to stop growing. In APL, the cancer cells also refuse to grow up.