The Emperor of All Maladies

by Siddhartha Mukherjee

  To choose a medical specialty is also to choose its cardinal bodily liquid. Hematologists have blood. Hepatologists have bile. Huggins had prostatic fluid: a runny, straw-colored mixture of salt and sugar meant to lubricate and nourish sperm. Its source, the prostate, is a small gland buried deep in the perineum, wrapped around the outlet of the urinary tract in men. (Vesalius was the first to identify it and draw it into human anatomy.) Walnut-shaped and only walnut-sized, it is yet ferociously the site of cancer. Prostate cancer represents a full third of all cancer incidence in men—sixfold that of leukemia and lymphoma. In autopsies of men over sixty years old, nearly one in every three specimens will bear some evidence of prostatic malignancy.

  But although an astoundingly common form of cancer, prostate cancer is also highly variable in its clinical course. Most cases are indolent—elderly men usually die with prostate cancer than die of prostate cancer—but in other patients the disease can be aggressive and invasive, capable of exploding into painful lesions in the bones and lymph nodes in its advanced, metastatic form.

  Huggins, though, was far less interested in cancer than in the physiology of prostatic fluid. Female hormones, such as estrogen, were known to control the growth of breast tissue. Did male hormones, by analogy, control the growth of the normal prostate—and thus regulate the secretion of its principal product, prostatic fluid? By the late 1920s, Huggins had devised an apparatus to collect precious drops of prostatic fluid from dogs. (He diverted urine away by inserting a catheter into the bladder and stitched a collection tube to the exit of the prostate gland.) It was the only surgical innovation that he would devise in his lifetime.

  Huggins now had a tool to measure prostatic function; he could quantify the amount of fluid produced by the gland. He found that if he surgically removed the testicles of his dogs—and thereby depleted the dogs of the hormone testosterone—the prostate gland involuted and shriveled and the fluid secretion dried up precipitously. If he injected the castrated dogs with purified testosterone, the exogenous hormone saved the prostate from shriveling. Prostate cells were thus acutely dependent on the hormone testosterone for their growth and function. Female sexual hormones kept breast cells alive; male hormones had a similar effect on prostate cells.

  Huggins wanted to delve further into the metabolism of testosterone and the prostate cell, but his experiments were hampered by a peculiar problem. Dogs, humans, and lions are the only animals known to develop prostate cancer, and dogs with sizable prostate tumors kept appearing in his lab during his studies. “It was vexatious to encounter a dog with a prostatic tumor during a metabolic study,” he wrote. His first impulse was to cull the cancer-afflicted dogs from his study and continue single-mindedly with his fluid collection, but then a question formed in his mind. If testosterone deprivation could shrink normal prostate cells, what might testosterone deprivation do to cancer cells?

  The answer, as any self-respecting cancer biologist might have informed him, was almost certain: very little. Cancer cells, after all, were deranged, uninhibited, and altered—responsive only to the most poisonous combinations of drugs. The signals and hormones that regulated normal cells had long been flung aside; what remained was a cell driven to divide with such pathological and autonomous fecundity that it had erased all memory of normalcy.

  But Huggins knew that certain forms of cancer did not obey this principle. Variants of thyroid cancer, for instance, continued to make thyroid hormone, the growth-stimulating molecule secreted by the normal thyroid gland; even though cancerous, these cells remembered their former selves. Huggins found that prostate cancer cells also retained a physiological “memory” of their origin. When he removed the testicles of prostate cancer–bearing dogs, thus acutely depriving the cancer cells of testosterone, the tumors also involuted within days. In fact, if normal prostate cells were dependent on testosterone for survival, then malignant prostate cells were nearly addicted to the hormone—so much so that the acute withdrawal acted like the most powerful therapeutic drug conceivable. “Cancer is not necessarily autonomous and intrinsically self-perpetuating,” Huggins wrote. “Its growth can be sustained and propagated by hormonal function in the host.” The link between the growth-sustenance of normal cells and of cancer cells was much closer than previously imagined: cancer could be fed and nurtured by our own bodies.

  Surgical castration, fortunately, was not the only means to starve prostate cancer cells. If male hormones were driving the growth of these cancer cells, Huggins reasoned, then rather than eliminate the male hormones, what if one tricked the cancer into thinking that the body was “female” by suppressing the effect of testosterone?

  In 1929, Edward Doisy, a biochemist, had tried to identify the hormonal factors in the estrous cycle of females. Doisy had collected hundreds of gallons of urine from pregnant women in enormous copper vats, then extracted a few milligrams of a hormone called estrogen. Doisy’s extraction had sparked a race to produce estrogen or its analogue in large quantities. By the mid-1940s, several laboratories and pharmaceutical companies, jostling to capture the market for the “essence of femininity,” raced to synthesize analogues of estrogen or find novel means to purify it efficiently. The two most widely used versions of the drug were diethylstilbestrol (or DES), an artificial estrogen chemically synthesized by biochemists in London, or Premarin, natural estrogen purified from horse’s urine in Montreal. (The synthetic analogue, DES, will return in a more sinister form in subsequent pages.)

  Both Premarin (its name derived from pregnant mare urine) and DES were initially marketed as elixirs to cure menopause. But for Huggins, the existence of synthetic estrogens suggested a markedly different use: he could inject them to “feminize” the male body and stop the production of testosterone in patients with prostate cancer. He called the method “chemical castration.” And once again, he found striking responses. As with surgical castration, patients with aggressive prostate cancer chemically castrated with feminizing hormones responded briskly to the therapy, often with minimal side effects. (The most prominent complaint among men was the occurrence of menopause-like hot flashes.) Prostate cancer was not cured with these steroids; patients inevitably relapsed with cancer that had become resistant to hormone therapy. But the remissions, which often stretched into several months, proved that hormonal manipulations could choke the growth of a hormone-dependent cancer. To produce a cancer remission, one did not need a toxic, indiscriminate cellular poison (such as cisplatin or nitrogen mustard).

  If prostate cancer could be starved to near-death by choking off testosterone, then could hormonal deprivation be applied to starve another hormone-dependent cancer? There was at least one obvious candidate—breast cancer. In the late 1890s, an adventurous Scottish surgeon named George Beatson, trying to devise new surgical methods to treat breast cancer, had learned from shepherds in the Scottish highlands that the removal of the ovaries from cows altered their capacity to lactate and changed the quality of their udders. Beatson did not understand the basis for this phenomenon (estrogen, the ovarian hormone, had not yet been discovered by Doisy), but intrigued by the inexplicable link between ovaries and breasts, Beatson had surgically removed the ovaries of three women with breast cancer.

  In an age before the hormonal circuits between the ovary and the breast were even remotely established, this was unorthodox beyond description—like removing the lung to cure a brain lesion. But to Beatson’s astonishment, his three cases revealed marked responses to the ovarian removal—the breast tumors shrank dramatically. When surgeons in London tried to repeat Beatson’s findings on a larger group of women, though, the operation led to a more nuanced outcome: only about two-thirds of all women with breast cancer responded.

  The hit-and-miss quality of the benefit mystified nineteenth-century physiologists. “It is impossible to tell beforehand whether any benefit will result from the operation or not, its effects being quite uncertain,” a surgeon wrote in 1902. How might the surgical removal of a faraway organ affect the g
rowth of cancer? And why, tantalizingly, had only a fraction of cases responded? The phenomenon almost brought back memories of a mysterious humoral factor circulating in the body—of Galen’s black bile. But why was this humoral factor only active in certain women with breast cancer?

  Nearly three decades later, Doisy’s discovery of estrogen provided a partial answer to the first question. Estrogen is the principal hormone secreted by the ovaries. As with testosterone for the normal prostate, estrogen was soon demonstrated to be a vital hormone for the maintenance and growth of normal breast tissue. Was breast cancer also fueled by estrogen from the ovaries? If so, what of Beatson’s puzzle: why did some breast cancers shrink with ovarian removal while others remained totally unresponsive?

  In the mid-1960s, working closely with Huggins, a young chemist in Chicago, Elwood Jensen, came close to solving Beatson’s riddle. Jensen began his studies not with cancer cells but with the normal physiology of estrogen. Hormones, Jensen knew, typically work by binding to a receptor in a target cell, but the receptor for the steroid hormone estrogen had remained elusive. Using a radioactively labeled version of the hormone as bait, in 1968 Jensen found the estrogen receptor—the molecule responsible for binding estrogen and relaying its signal to the cell.

  Jensen now asked whether breast cancer cells also uniformly possessed this receptor. Unexpectedly, some did and some did not. Indeed, breast cancer cases could be neatly divided into two types—ones with cancer cells that expressed high levels of this receptor and those that expressed low levels, “ER-positive” and “ER-negative” tumors.

  Jensen’s observations suggested a possible solution to Beatson’s riddle. Perhaps the marked variation of breast cancer cells in response to ovarian removal depended on whether the cancer cells expressed the estrogen receptor or not. ER-positive tumors, possessing the receptor, retained their “hunger” for estrogen. ER-negative tumors had rid themselves of both the receptor and the hormone dependence. ER-positive tumors thus responded to Beatson’s surgery, Jensen proposed, while ER-negative tumors were unresponsive.

  The simplest way to prove this theory was to launch an experiment—to perform Beatson’s surgery on women with ER-positive and ER-negative tumors and determine whether the receptor status of the cancer cells was predictive of the response. But the surgical procedure had fallen out of fashion. (Ovarian removal produced many other severe side effects, such as osteoporosis.) An alternative was to use a pharmacological means to inhibit estrogen function, a female version of chemical castration à la Huggins.

  But Jensen had no such drug. Testosterone did not work, and no synthetic “antiestrogen” was in development. In their dogged pursuit of cures for menopause and for new contraceptive agents (using synthetic estrogens), pharmaceutical companies had long abandoned the development of an antiestrogen, and there was no interest in developing an antiestrogen for cancer. In an era gripped by the hypnotic promise of cytotoxic chemotherapy, as Jensen put it, “there was little enthusiasm about developing endocrine [hormonal] therapies to treat cancer. Combination chemotherapy was [thought to be] more likely to be successful in curing not only breast cancer but other solid tumors.” Developing an antiestrogen, an antagonist to the fabled elixir of female youth, was widely considered a waste of effort, money, and time.

  Scarcely anyone paid notice, then, on September 13, 1962, when a team of talented British chemists from Imperial Chemical Industries (ICI) filed a patent for the chemical named ICI 46474, or tamoxifen. Originally invented as a birth control pill, tamoxifen had been synthesized by a team led by the hormone biologist Arthur Walpole and a synthetic chemist, Dora Richardson, both members of the “fertility control program” at the ICI. But even though structurally designed to be a potent stimulator of estrogen—its winged, birdlike skeleton designed to perch perfectly into the open arms of the estrogen receptor—tamoxifen had turned out to have exactly the opposite effect: rather than turning on the estrogen signal, a requirement for a contraceptive drug, it had, surprisingly, shut it off in many tissues. It was an estrogen antagonist—thus considered a virtually useless drug.

  Yet the connection between fertility drugs and cancer preoccupied Walpole. He knew of Huggins’s experiments with surgical castration for prostate cancer. He knew of Beatson’s riddle—almost solved by Jensen. The antiestrogenic properties of his new drug raised an intriguing possibility. ICI 46474 may be a useless contraceptive, but perhaps, he reasoned, it might be useful against estrogen-sensitive breast cancer.

  To test that idea, Walpole and Richardson sought a clinical collaborator. The natural site for such a trial was immediately apparent, the sprawling Christie Hospital in Manchester, a world-renowned cancer center just a short ride through the undulating hills of Cheshire from ICI’s research campus at Alderley Park. And there was a natural collaborator: Mary Cole, a Manchester oncologist and radiotherapist with a particular interest in breast cancer. Known affectionately as Moya by her patients and colleagues, Cole had a reputation as a feisty and meticulous physician intensely dedicated to her patients. She had a ward full of women with advanced, metastatic breast cancer, many of them hurtling inexorably toward their death. Moya Cole was willing to try anything—even an abandoned contraceptive—to save the lives of these women.

  Cole’s trial was launched at Christie in the late summer of 1969. Forty-six women with breast cancer were treated with tablets of ICI 46474. Cole expected little from the drug—at best, a partial response. But in ten patients, the response was almost immediately obvious. Tumors shriveled visibly in the breast. Lung metastases shrank. Bone pain flickered away and lymph nodes softened.

  Like Huggins’s prostate cancer patients, many of the women who responded to the drug eventually relapsed. But the success of the trial was incontrovertible—and the proof of principle historic. A drug designed to target a specific pathway in a cancer cell—not a cellular poison discovered empirically by trial and error—had successfully driven metastatic tumors into remission.

  Tamoxifen’s journey came full circle in a little-known pharmaceutical laboratory in Shrewsbury, Massachusetts. In 1973, V. Craig Jordan, a biochemist working at the lab of the Worcester Foundation (a research institute involved in the development of new contraceptives), investigated the pattern behind cancers that did or did not respond to tamoxifen therapy. Jordan used a simple molecular technique to stain breast cancer cells for the estrogen receptor that Elwood Jensen had discovered in Chicago, and the answer to Beatson’s riddle finally leapt out of the experiment. Cancer cells that expressed the estrogen receptor were highly responsive to tamoxifen, while cells that lacked the estrogen receptor did not respond. The reason behind the slippery, hit-and-miss responses in women with breast cancer observed in England nearly a century earlier was now clear. Cells that expressed the estrogen receptor could bind tamoxifen, and the drug, an estrogen antagonist, shut off estrogen responsiveness, thus choking the cells’ growth. But ER-negative cells lacked the receptor for the drug and thus were insensitive to it. The schema had a satisfying simplicity. For the first time in the history of cancer, a drug, its target, and a cancer cell had been conjoined by a core molecular logic.

  Halsted’s Ashes

  I would rather be ashes than dust.

  —Jack London

  Will you turn me out if I can’t get better?

  —A cancer patient to

  her physician, 1960s

  Moya Cole’s tamoxifen trial was initially designed to treat women with advanced, metastatic breast cancer. But as the trial progressed, Cole began to wonder about an alternative strategy. Typically, clinical trials of new cancer drugs tend to escalate inexorably toward sicker and sicker patients (as news of a novel drug spreads, more and more desperate patients lurch toward last-ditch efforts to save their lives). But Cole was inclined to journey in the opposite direction. What if women with earlier-stage tumors were treated with tamoxifen? If a drug could halt the progression of diffusely metastatic and aggressive stage IV cancers, might it work even be
tter on more localized, stage II breast cancers, cancers that had spread only to the regional lymph nodes?

  Unwittingly, Cole had come full circle toward Halsted’s logic. Halsted had invented the radical mastectomy based on the premise that early breast cancer needed to be attacked exhaustively and definitively—by surgically “cleansing” every conceivable reservoir of the disease, even when no visible cancer was present. The result had been the grotesque and disfiguring mastectomy, foisted indiscriminately on women with even small, locally restricted tumors to stave off relapses and metastasis into distant organs. But Cole now wondered whether Halsted had tried to cleanse the Augean stables of cancer with all the right intentions, but with the wrong tools. Surgery could not eliminate invisible reservoirs of cancer. But perhaps what was needed was a potent chemical—a systemic therapy, Willy Meyer’s dreamed-about “after-treatment” from 1932.

  A variant of this idea had already gripped a band of renegade researchers at the NCI even before tamoxifen had appeared on the horizon. In 1963, nearly a decade before Moya Cole completed her experiments in Manchester, a thirty-three-year-old oncologist at the NCI, Paul Carbone, had launched a trial to see if chemotherapy might be effective when administered to women after an early-stage primary tumor had been completely removed surgically—i.e., women with no visible tumor remaining in the body. Carbone had been inspired by the patron saint of renegades at the NCI: Min Chiu Li, the researcher who had been expelled from the institute for treating women with placental tumors with methotrexate long after their tumors had visibly disappeared.

  Li had been packed off in ignominy, but the strategy that had undone him—using chemotherapy to “cleanse” the body of residual tumor—had gained increasing respectability at the institute. In his small trial, Carbone found that adding chemotherapy after surgery decreased the rate of relapse from breast cancer. To describe this form of treatment, Carbone and his team used the word adjuvant, from the Latin phrase “to help.” Adjuvant chemotherapy, Carbone conjectured, could be the surgeon’s little helper. It would eradicate microscopic deposits of cancer left behind after surgery, thus extirpating any remnant reservoirs of malignancy in the body in early breast cancer—in essence, completing the Herculean cancer-cleansing task that Halsted had set for himself.