The Emperor of All Maladies: A Biography of Cancer (40 page)

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
pre
gnant
ma
re ur
in
e) 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 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.