Siddhartha Mukherjee - The Emperor of All Maladies: A Biography of Cancer

by Siddhartha Mukherjee

  The second controversy also has its antecedents in the 1960s. Since the publication of Rachel Carson's Silent Spring in 1962, environmental activists have stridently argued that the indiscriminate overuse of pesticides is partially responsible for the rising incidence of cancer in America. This theory has spawned intense controversy, activism, and public campaigns over the decades. But although the hypothesis is credible, large-scale human-cohort experiments directly implicating particular pesticides as carcinogens have emerged slowly, and animal studies have been inconclusive. DDT and aminotriazole have been shown to cause cancer in animals at high doses, but thousands of chemicals proposed as carcinogens remain untested. Again, an integrated approach is needed. The identification of key activated pathways in cancer cells might provide a more sensitive detection method to discover carcinogens in animal studies. A chemical may not cause overt cancer in animal studies, but may be shown to activate cancer-linked genes and pathways, thus shifting the burden of proof of its potential carcinogenicity.

  In 2005, the Harvard epidemiologist David Hunter argued that the integration of traditional epidemiology, molecular biology, and cancer genetics will generate a resurgent form of epidemiology that is vastly more empowered in its ability to prevent cancer. "Traditional epidemiology," Hunter reasoned, "is concerned with correlating exposures with cancer outcomes, and everything between the cause (exposure) and the outcome (a cancer) is treated as a 'black box.' . . . In molecular epidemiology, the epidemiologist [will] open up the 'black box' by examining the events intermediate between exposure and disease occurrence or progression."

  Like cancer prevention, cancer screening will also be reinvigorated by the molecular understanding of cancer. Indeed, it has already been. The discovery of the BRCA genes for breast cancer epitomizes the integration of cancer screening and cancer genetics. In the mid-1990s, building on the prior decade's advances, researchers isolated two related genes, BRCA-1 and BRCA-2, that vastly increase the risk of developing breast cancer. A woman with an inherited mutation in BRCA-1 has a 50 to 80 percent chance of developing breast cancer in her lifetime (the gene also increases the risk for ovarian cancer), about three to five times the normal risk. Today, testing for this gene mutation has been integrated into prevention efforts. Women found positive for a mutation in the two genes are screened more intensively using more sensitive imaging techniques such as breast MRI. Women with BRCA mutations might choose to take the drug tamoxifen to prevent breast cancer, a strategy shown effective in clinical trials. Or, perhaps most radically, women with BRCA mutations might choose a prophylactic mastectomy of both breasts and ovaries before cancer develops, another strategy that dramatically decreases the chances of developing breast cancer. An Israeli woman with a BRCA-1 mutation who chose this strategy after developing cancer in one breast told me that at least part of her choice was symbolic. "I am rejecting cancer from my body," she said. "My breasts had become no more to me than a site for my cancer. They were of no more use to me. They harmed my body, my survival. I went to the surgeon and asked him to remove them."

  The third, and arguably most complex, new direction for cancer medicine is to integrate our understanding of aberrant genes and pathways to explain the behavior of cancer as a whole, thereby renewing the cycle of knowledge, discovery, and therapeutic intervention.

  One of the most provocative examples of a cancer cell's behavior, inexplicable by the activation of any single gene or pathway, is its immortality. Rapid cellular proliferation, or the insensitivity to growth-arresting signals, or tumor angiogenesis, can all largely be explained by aberrantly activated and inactivated pathways such as ras, Rb, or myc in cancer cells. But scientists cannot explain how cancers continue to proliferate endlessly. Most normal cells, even rapidly growing normal cells, will proliferate over several generations and then exhaust their capacity to keep dividing. What allows a cancer cell to keep dividing endlessly without exhaustion or depletion generation upon generation?

  An emerging, although highly controversial, answer to this question is that cancer's immortality, too, is borrowed from normal physiology. The human embryo and many of our adult organs possess a tiny population of stem cells that are capable of immortal regeneration. Stem cells are the body's reservoir of renewal. The entirety of human blood, for instance, can arise from a single, highly potent blood-forming stem cell (called a hematopoietic stem cell), which typically lives buried inside the bone marrow. Under normal conditions, only a fraction of these blood-forming stem cells are active; the rest are deeply quiescent--asleep. But if blood is suddenly depleted, by injury or chemotherapy, say, then the stem cells awaken and begin to divide with awe-inspiring fecundity, generating cells that generate thousands upon thousands of blood cells. In weeks, a single hematopoietic stem cell can replenish the entire human organism with new blood--and then, through yet unknown mechanisms, lull itself back to sleep.

  Something akin to this process, a few researchers believe, is constantly occurring in cancer--or at least in leukemia. In the mid-1990s, John Dick, a Canadian biologist working in Toronto, postulated that a small population of cells in human leukemias also possess this infinite self-renewing behavior. These "cancer stem cells" act as the persistent reservoir of cancer--generating and regenerating cancer infinitely. When chemotherapy kills the bulk of cancer cells, a small remnant population of these stem cells, thought to be intrinsically more resistant to death, regenerate and renew the cancer, thus precipitating the common relapses of cancer after chemotherapy. Indeed, cancer stem cells have acquired the behavior of normal stem cells by activating the same genes and pathways that make normal stem cells immortal--except, unlike normal stem cells, they cannot be lulled back into physiological sleep. Cancer, then, is quite literally trying to emulate a regenerating organ--or perhaps, more disturbingly, the regenerating organism. Its quest for immortality mirrors our own quest, a quest buried in our embryos and in the renewal of our organs. Someday, if a cancer succeeds, it will produce a far more perfect being than its host--imbued with both immortality and the drive to proliferate. One might argue that the leukemia cells growing in my laboratory derived from the woman who died three decades earlier have already achieved this form of "perfection."

  Taken to its logical extreme, the cancer cell's capacity to consistently imitate, corrupt, and pervert normal physiology thus raises the ominous question of what "normalcy" is. "Cancer," Carla said, "is my new normal," and quite possibly cancer is our normalcy as well, that we are inherently destined to slouch towards a malignant end. Indeed, as the fraction of those affected by cancer creeps inexorably in some nations from one in four to one in three to one in two, cancer will, indeed, be the new normal--an inevitability. The question then will not be if we will encounter this immortal illness in our lives, but when.

  * Thus far, the full sequencing of ALL genomes has not been completed. The alterations described are deletions or amplifications of genes. Detailed sequencing may reveal an increase in the number of mutated genes.

  * Mice filter out many of the carcinogenic components of tar. Asbestos incites cancer by inducing a scar-forming, inflammatory reaction in the body. Bacteria don't generate this reaction and are thus "immune" to asbestos.

  Atossa's War

  We aged a hundred years and this descended

  In just one hour, as at a stroke

  --Anna Akhmatova,

  "In Memoriam, July 19, 1914"

  It is time, it is time for me too to depart. Like an old man who has outlived his contemporaries and feels a sad inner emptiness, Kostoglotov felt that evening that the ward was no longer his home, even though . . . there were the same old patients asking the same old questions again and again as though they had never been asked before: . . . Will they cure me or won't they? What other remedies are there that might help?

  --Aleksandr Solzhenitsyn, Cancer Ward

  On May 17, 1973, seven weeks after Sidney Farber's death in Boston, Hiram Gans, an old friend, stood up at the memorial service to read some li
nes from Swinburne's "A Forsaken Garden":

  Here now in his triumph where all things falter,

  Stretched out on the spoils that his own hand spread,

  As a god self-slain on his own strange altar,

  Death lies dead.

  It was--careful listeners might have noted--a peculiar and deliberate inversion of the moment. It was cancer that was soon to be dead--its corpus outstretched and spread-eagled ceremonially on the altar--death lying dead.

  The image belongs very much to Farber and his era, but its essence still haunts us today. In the end, every biography must also confront the death of its subject. Is the end of cancer conceivable in the future? Is it possible to eradicate this disease from our bodies and our societies forever?

  The answers to these questions are embedded in the biology of this incredible disease. 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. Cancer is a flaw in our growth, but this flaw is deeply entrenched in ourselves. We can rid ourselves of cancer, then, only as much as we can rid ourselves of the processes in our physiology that depend on growth--aging, regeneration, healing, reproduction.

  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 represent 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 algorithm 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 Atos
sa'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?