The Emperor of All Maladies: A Biography of Cancer (41 page)

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.

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 breast 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.’”

On an overcast morning in the winter of 1975, Bonadonna flew to Brussels to present his results at a conference of European oncologists. The trial had just finished its second year. But the two groups, Bonadonna reported, had clearly parted ways. Nearly half the women treated with no therapy had relapsed. In contrast, only a third of the women treated with the adjuvant regimen had relapsed. Adjuvant chemotherapy had prevented breast cancer relapses in about one in every six treated women.

The news was so unexpected that it was greeted by a stunned silence in the auditorium. Bonadonna’s presentation had shaken the terra firma of cancer chemotherapy. It was only on the flight back to Milan, ten thousand feet above the earth, that Bonadonna was finally inundated with questions about his trial by other researchers on his flight.

Gianni Bonadonna’s remarkable Milanese trial left a question almost begging to be answered. If adjuvant CMF chemotherapy could decrease relapses in women with early-stage breast cancer, then might adjuvant tamoxifen—the other active breast cancer drug established by Cole’s group—also decrease relapses in women with localized ER-positive breast cancer after surgery? Had Moya Cole been right about her instinct in treating early-stage breast cancer with antiestrogen therapy?

This was a question that Bernie Fisher, although embroiled in several other trials, could not resist trying to answer. In January 1977, five years after Cole had published her results on tamoxifen in metastatic cancer, Fisher recruited 1,891 women with estrogen receptor–positive (ER-positive) breast cancer that had spread only to the axillary nodes. He treated half with adjuvant tamoxifen and the other half with no tamoxifen. By 1981, the two groups had deviated sharply. Treatment with tamoxifen after surgery reduced cancer relapse rates by nearly 50 percent. The effect was particularly pronounced among women above fifty years old—a group most resistant to standard chemotherapy regimens and most likely to relapse with aggressive, metastatic breast cancer.

Three years later, in ’85, when Fisher reanalyzed the deviating curves of relapse and survival, the effect of tamoxifen treatment was even more dra
matic. Among the five-hundred-odd women older than fifty assigned to each group, tamoxifen had prevented fifty-five relapses and deaths. Fisher had altered the biology of breast cancer after surgery using a targeted hormonal drug that had barely any significant side effects.