The Emperor of All Maladies: A Biography of Cancer (87 page)

Science embodies the human desire to understand nature; technology couples that desire with the ambition to control nature. These are related impulses—one might seek to understand nature in order to control it—but the drive to intervene is unique to technology. Medicine, then, is fundamentally a technological art; at its core lies a desire to improve human lives by intervening on life itself. Conceptually, the battle against cancer pushes the idea of technology to its far edge, for the object being intervened upon is our genome. It is unclear whether an intervention that discriminates between malignant and normal growth is even possible. Perhaps cancer, the scrappy, fecund, invasive, adaptable twin to our own scrappy, fecund, invasive, adaptable cells and genes, is impossible to disconnect from our bodies. Perhaps cancer defines the inherent outer limit of our survival. As our cells divide and our bodies age, and as mutations accumulate inexorably upon mutations, cancer might well be the final terminus in our development as organisms.

But our goals could be more modest. Above the door to Richard Peto’s office in Oxford hangs one of Doll’s favorite aphorisms: “Death in old age is inevitable, but death before old age is not.” Doll’s idea represents a far more reasonable proximal goal to define success in the War on Cancer. It is possible that we are fatally conjoined to this ancient illness, forced to play its cat-and-mouse game for the foreseeable future of our species. But if cancer deaths can be prevented before old age, if the terrifying game of treatment, resistance, recurrence, and more treatment can be stretched out longer and longer, then it will transform the way we imagine this ancient illness. Given what we know about cancer, even this would repre
sent a technological victory unlike any other in our history. It would be a victory over our own inevitability—a victory over our genomes.

To envision what such a victory might look like, permit a thought experiment. Recall Atossa, the Persian queen with breast cancer in 500 BC. Imagine her traveling through time—appearing and reappearing in one age after the next. She is cancer’s Dorian Gray: as she moves through the arc of history, her tumor, frozen in its stage and behavior, remains the same. Atossa’s case allows us to recapitulate past advances in cancer therapy and to consider its future. How has her treatment and prognosis shifted in the last four thousand years, and what happens to Atossa later in the new millennium?

First, pitch Atossa backward in time to Imhotep’s clinic in Egypt in 2500 BC. Imhotep has a name for her illness, a hieroglyph that we cannot pronounce. He provides a diagnosis, but “there is no treatment,” he says humbly, closing the case.

In 500 BC, in her own court, Atossa self-prescribes the most primitive form of a mastectomy, which is performed by her Greek slave. Two hundred years later, in Thrace, Hippocrates identifies her tumor as a
karkinos
, thus giving her illness a name that will ring through its future. Claudius Galen, in AD 168, hypothesizes a universal cause: a systemic overdose of black bile—trapped melancholia boiling out as a tumor.

A thousand years flash by; Atossa’s entrapped black bile is purged from her body, yet the tumor keeps growing, relapsing, invading, and metastasizing. Medieval surgeons understand little about Atossa’s disease, but they chisel away at her cancer with knives and scalpels. Some offer frog’s blood, lead plates, goat dung, holy water, crab paste, and caustic chemicals as treatments. In 1778, in John Hunter’s clinic in London, her cancer is assigned a stage—early, localized breast cancer or late, advanced, invasive cancer. For the former, Hunter recommends a local operation; for the latter, “remote sympathy.”

When Atossa reemerges in the nineteenth century, she encounters a new world of surgery. In Halsted’s Baltimore clinic in 1890, Atossa’s breast cancer is treated with the boldest and most definitive therapy thus far—radical mastectomy with a large excision of the tumor and removal of the
deep chest muscles and lymph nodes under the armpit and the collarbone. In the early twentieth century, radiation oncologists try to obliterate the tumor locally using X-rays. By the 1950s, yet another generation of surgeons learns to combine the two strategies, although tempered by moderation. Atossa’s cancer is treated locally with a simple mastectomy, or a lumpectomy followed by radiation.

In the 1970s, new therapeutic strategies emerge. Atossa’s surgery is followed by adjuvant combination chemotherapy to diminish the chance of a relapse. Her tumor tests positive for the estrogen receptor. Tamoxifen, the antiestrogen, is also added to prevent a relapse. In 1986, her tumor is further discovered to be
Her-2
amplified. In addition to surgery, radiation, adjuvant chemotherapy, and tamoxifen, she is treated with targeted therapy using Herceptin.

It is impossible to enumerate
the precise impact of these interventions on Atossa’s survival. The shifting landscape of trials does not allow a direct comparison between Atossa’s fate in 500 BC and her fate in 1989. But surgery, chemotherapy, radiation, hormonal therapy, and targeted therapy have likely added anywhere between seventeen and thirty years to her survival. Diagnosed at forty, say, Atossa can reasonably be expected to celebrate her sixtieth birthday.

In the mid-1990s, the management of Atossa’s breast cancer takes another turn. Her diagnosis at an early age and her Achaemenid ancestry raise the question of whether she carries a mutation in BRCA-1 or BRCA-2. Atossa’s genome is sequenced, and indeed, a mutation is found. She enters an intensive screening program to detect the appearance of a tumor in her unaffected breast. Her two daughters are also tested. Found positive for BRCA-1, they are offered either intensive screening, prophylactic bilateral mastectomy, or tamoxifen to prevent the development of invasive breast cancer. For Atossa’s daughters, the impacts of screening and prophylaxis are dramatic. A breast MRI identifies a small lump in one daughter. It is found to be breast cancer and surgically removed in its early, preinvasive stage. The other daughter chooses to undergo a prophylactic bilateral mastectomy. Having excised her breasts preemptively, she will live out her life free of breast cancer.

Move Atossa into the future now. In 2050, Atossa will arrive at her breast oncologist’s clinic with a thumb-size flash drive containing the entire sequence of her cancer’s genome, identifying every mutation in every gene. The mutations will be organized into key pathways. An algo
rithm might identify the pathways that are contributing to the growth and survival of her cancer. Therapies will be targeted against these pathways to prevent a relapse of the tumor after surgery. She will begin with one combination of targeted drugs, expect to switch to a second cocktail when her cancer mutates, and switch again when the cancer mutates again. She will likely take some form of medicine, whether to prevent, cure, or palliate her illness, for the rest of her life.

This, indubitably, is progress. But before we become too dazzled by Atossa’s survival, it is worthwhile putting it into perspective. Give Atossa metastatic pancreatic cancer in 500 BC and her prognosis is unlikely to change by more than a few months over twenty-five hundred years. If Atossa develops gallbladder cancer that is not amenable to surgery, her survival changes only marginally over centuries. Even breast cancer shows a marked heterogeneity in outcome. If Atossa’s tumor has metastasized, or is estrogen-receptor negative,
Her-2
negative, and unresponsive to standard chemotherapy, then her chances of survival will have barely changed since the time of Hunter’s clinic. Give Atossa CML or Hodgkin’s disease, in contrast, and her life span may have increased by thirty or forty years.

Part of the unpredictability about the trajectory of cancer in the future is that we do not know the biological basis for this heterogeneity. We cannot yet fathom, for instance, what makes pancreatic cancer or gallbladder cancer so markedly different from CML or Atossa’s breast cancer. What is certain, however, is that even the knowledge of cancer’s biology is unlikely to eradicate cancer fully from our lives. As Doll suggests, and as Atossa epitomizes, we might as well focus on prolonging life rather than eliminating death. This War on Cancer may best be “won” by redefining victory.

Atossa’s tortuous journey also raises a question implicit in this book: if our understanding and treatment of cancer keep morphing so radically in time, then how can cancer’s past be used to predict its future?

In 1997, the NCI director, Richard Klausner
, responding to reports that cancer mortality had remained disappointingly static through the nineties, argued that the medical realities of one decade had little bearing on the realities of the next. “There are far more good historians than there are
good prophets,” Klausner wrote. “It is extraordinarily difficult to predict scientific discovery, which is often propelled by seminal insights coming from unexpected directions. The classic example—Fleming’s discovery of penicillin on moldy bread and the monumental impact of that accidental finding—could not easily have been predicted, nor could the sudden demise of iron-lung technology when evolving techniques in virology allowed the growth of poliovirus and the preparation of vaccine. Any extrapolation of history into the future presupposes an environment of static discovery—an oxymoron.”

In a limited sense, Klausner is right. When truly radical discoveries appear, their impact is often not incremental but cataclysmic and paradigm-shifting. Technology dissolves its own past. The speculator who bought stock options in an iron-lung company before the discovery of the polio vaccine, or the scientist who deemed bacterial pneumonias incurable just as penicillin was being discovered, were soon shown to be history’s fools.

But with cancer, where no simple, universal, or definitive cure is in sight—and is never likely to be—the past is constantly conversing with the future. Old observations crystallize into new theories; time past is always contained in time future. Rous’s virus was reincarnated, decades later, in the form of endogenous oncogenes; George Beatson’s observation that removing ovaries might slow the growth of breast cancer, inspired by a Scottish shepherds’ tale, roars back in the form of a billion-dollar drug named tamoxifen; Bennett’s “suppuration of blood,” the cancer that launches this book, is also the cancer that ends this book.

And there is a subtler reason to remember this story: while the content of medicine is constantly changing, its
form
, I suspect, remains astonishingly the same. History repeats, but science reverberates. The tools that we will use to battle cancer in the future will doubtless alter so dramatically in fifty years that the geography of cancer prevention and therapy might be unrecognizable. Future physicians may laugh at our mixing of primitive cocktails of poisons to kill the most elemental and magisterial disease known to our species. But much about this battle will remain the same: the relentlessness, the inventiveness, the resilience, the queasy pivoting between defeatism and hope, the hypnotic drive for universal solutions, the disappointment of defeat, the arrogance and the hubris.

The Greeks used an evocative word to describe tumors,
onkos
, meaning “mass” or “burden.” The word was more prescient than they might have imagined. Cancer is indeed the load built into our genome, the leaden coun
terweight to our aspirations for immortality. But if one looks back even further behind the Greek to the ancestral Indo-European language, the etymology of the word
onkos
changes.
Onkos
arises from the ancient word
nek.
And
nek
, unlike the static
onkos
, is the active form of the word
load.
It means to carry, to move the burden from one place to the next, to bear something across a long distance and bring it to a new place. It is an image that captures not just the cancer cell’s capacity to travel—metastasis—but also Atossa’s journey, the long arc of scientific discovery—and embedded in that journey, the animus, so inextricably human, to outwit, to outlive and survive.