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

by Siddhartha Mukherjee

  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 growth 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 a 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 better 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.

  But surgeons had no interest in getting help from anyone--least of all chemotherapists. By the mid-1960s, as radical surgery became increasingly embattled, most breast surgeons had begun to view chemotherapists as estranged rivals that could not be trusted with anything, least of all improving surgical outcomes. And since surgeons largely dominated the field of breast cancer (and saw all the patients upon diagnosis), Carbone could not ramp up his trial because he could barely recruit any patients. "Except for an occasional woman who underwent a mastectomy at the NCI . . . the study never got off the ground," Carbone recalled.

  But Carbone found an alternative. Shunned by surgeons, he now turned to the surgeon who had shunned his own compatriots--Bernie Fisher, the man caught in the controversial swirl of testing radical breast surgery. Fisher was instantly interested in Carbone's idea. Indeed, Fisher had been trying to run a trial along similar lines--combining chemotherapy with surgical mastectomy. But even Fisher could pick only one fight at a time. With his own trial, the NSABP-04 (the trial to test radical surgery versus nonradical surgery) barely limping along, he could hardly convince surgeons to join a trial to combine chemo and surgery in breas
t cancer.

  An Italian team came to the rescue. In 1972, as the NCI was scouring the nation for a site where "adjuvant chemotherapy" after surgery could be tested, the oncologist Gianni Bonadonna came to Bethesda to visit the institute. Suave, personable, and sophisticated, impeccably dressed in custom-cut Milanese suits, Bonadonna made an instant impression at the NCI. He learned from DeVita, Canellos, and Carbone that they had been testing combinations of drugs to treat advanced breast cancer and had found a concoction that would likely work: Cytoxan (a cousin of nitrogen mustard), methotrexate (a variant of Farber's aminopterin), and fluorouracil (an inhibitor of DNA synthesis). The regimen, called CMF, could be tolerated with relatively minimal side effects, yet was active enough in combination to thwart microscopic tumors--an ideal combination to be used as an adjuvant in breast cancer.

  Bonadonna worked at a large cancer center in Milan called the Istituto Tumori, where he had a close friendship with the chief breast surgeon, Umberto Veronesi. Convinced by Carbone (who was still struggling to get a similar trial launched in America), Bonadonna and Veronesi, the only surgeon-chemotherapist pair seemingly on talking terms with each other, proposed a large randomized trial to study chemotherapy after breast surgery for early-stage breast cancer. They were immediately awarded the contract for the NCI trial.

  The irony of that award could hardly have escaped the researchers at the institute. In America, the landscape of cancer medicine had become so deeply gashed by internal rifts that the most important NCI-sponsored trial of cytotoxic chemotherapy to be launched after the announcement of the War on Cancer had to be relocated to a foreign country.

  Bonadonna began his trial in the summer of 1973. By the early winter that year, he had randomized nearly four hundred women to the trial--half to no treatment and half to treatment with CMF. Veronesi was a crucial supporter, but there was still little interest from other breast surgeons. "The surgeons were not just skeptical," Bonadonna recalled. "They were hostile. [They] did not want to know. At the time there were very few chemotherapists, and they were not rated highly, and the attitude among surgeons was 'chemotherapists deliver drugs in advanced disease [while] surgeons operate and we have complete remission for the entire life of the patient. . . . Surgeons rarely saw their patients again, and I think they didn't want to hear about how many patients were being failed by surgery alone. It was a matter of prestige.'"