The Emperor of All Maladies: A Biography of Cancer (80 page)

Outside the cloistered laboratories of Genentech, the controversy ignited a firestorm. San Francisco, of course, was no stranger to this issue of compassionate use versus focused research. In the late 1980s, as AIDS had erupted in the city, filling up Paul Volberding’s haunted Ward 5B with scores of patients, gay men had coalesced into groups such as ACT UP to demand speedier access to drugs, in part through compassionate use programs. Breast cancer activists saw a grim reflection of their own struggle in these early battles. As one newsletter put it, “
Why do women dying of breast cancer
have such trouble getting experimental drugs that could extend their lives? For years, AIDS activists have been negotiating with drug companies and the FDA to obtain new HIV drugs while the therapies were still in clinical trials. Surely women with metastatic breast cancer for whom standard treatments have failed should know about, and have access to, compassionate use programs for experimental drugs.”

Or, as another writer put it, “
Scientific uncertainty is no excuse
for inaction. . . . We cannot wait for ‘proof.’”

Marti Nelson, for one, certainly could not
afford to wait for proof. An outgoing, dark-haired gynecologist in California, Nelson had discovered a malignant mass in her breast in 1987, when she was just thirty-three.
She had had a mastectomy and multiple cycles of chemo, then returned to practicing medicine in a San Francisco clinic. The tumor had disappeared. The scars had healed. Nelson thought that she might have been cured.

In 1993, six years after her initial surgery, Nelson noticed that the scar in her breast had begun to harden. She waved it away. But the hardened line of tissue outlining her breast was relapsed breast cancer, worming its way insidiously along the scar lines and coalescing into small, matted masses in her chest. Nelson, who compulsively followed the clinical literature on breast cancer, had heard of
Her-2.
Reasoning presciently that her tumor might be
Her-2
positive, she tried to have her own specimen tested for the gene.

But Nelson soon found herself inhabiting a Kafkaesque nightmare. Her HMO insisted that because Herceptin was in investigational trials, testing the tumor for
Her-2
was useless. Genentech insisted that without
Her-2
status confirmed, giving her access to Herceptin was untenable.

In the summer of 1993, with Nelson’s cancer advancing daily and spewing out metastases into her lungs and bone marrow, the struggle took an urgent, political turn. Nelson contacted the Breast Cancer Action project, a local San Francisco organization connected with ACT UP, to help her get someone to test her tumor and obtain Herceptin for compassionate use. BCA, working through its activist networks, asked several laboratories in and around San Francisco to test Nelson’s tumor. In October 1994, the tumor was finally tested for
Her-2
expression at UCSF. It was strikingly
Her-2
positive. She was an ideal candidate for the drug. But the news came too late. Nine days later, still awaiting Herceptin approval from Genentech, Marti Nelson drifted into a coma and died. She was forty-one years old.

For BCA activists, Nelson’s death was a watershed event. Livid and desperate, a group of women from the BCA stormed through the Genentech campus on December 5, 1994, to hold a fifteen-car “funeral procession” for Nelson with placards showing Nelson in her chemo turban before her death. The women shouted and honked their horns and drove their cars through the manicured lawns. Gracia Buffleben, a nurse with breast cancer and one of the most outspoken leaders of the BCA, parked her car outside one of the main buildings and handcuffed herself to the steering wheel. A furious researcher stumbled out of one of the lab buildings and
shouted, “I’m a scientist working on the AIDS cure. Why are you here? You are making too much noise.” It was a statement that epitomized the vast and growing rift between scientists and patients.

Marti Nelson’s “funeral” woke Genentech up to a new reality. Outrage, rising to a crescendo, threatened to spiral into a public relations disaster. Genentech had a narrow choice: unable to silence the activists, it was forced to join them. Even Curd admitted, if somewhat begrudgingly, that the BCA was “a tough group [and] their activism is not misguided.”

In 1995, a small delegation of Genentech scientists and executives thus flew to Washington to meet Frances Visco, the chair of the National Breast Cancer Coalition (NBCC), a powerful national coalition of cancer activists, hoping to use the NBCC as a neutral intermediary between the company and the local breast cancer activists in San Francisco. Pragmatic, charismatic, and savvy, Visco, a former attorney, had spent nearly a decade immersed in the turbulent politics of breast cancer. Visco had a proposal for Genentech, but her terms were inflexible: Genentech had to provide an expanded access program for Herceptin. This program would allow oncologists to treat patients outside clinical trials. In return, the National Breast Cancer Coalition would act as a go-between for Genentech and its embittered and alienated community of cancer patients. Visco offered to join the planning committee of the phase III trials of Herceptin, and to help recruit patients for the trial using the NBCC’s extensive network. For Genentech, this was a long-overdue education. Rather than running trials
on
breast cancer patients, the company learned to run trials
with
breast cancer patients. (Genentech would eventually outsource the compassionate-access program to a lottery system run by an independent agency. Women applied to the lottery and “won” the right to be treated, thus removing the company from any ethically difficult decision-making.)

It was an uneasy triangle of forces—academic researchers, the pharmaceutical industry, and patient advocates—united by a deadly disease. Genentech’s next phase of trials involved large-scale, randomized studies on thousands of women with metastatic
Her-2
positive cancer, comparing Herceptin treatment against placebo treatment. Visco sent out newsletters from the NBCC to patients using the coalition’s enormous Listservs. Kay Dickersin, a coalition member and an epidemiologist, joined the Data Safety and Monitoring board of the trial, underscoring the new partnership between Genentech and the NBCC, between academic medicine and activism. And an all-star team of breast oncologists was assembled
to run the trial: Larry Norton from Sloan-Kettering, Karen Antman from Columbia, Daniel Hayes from Harvard, and, of course, Slamon from UCLA.

In 1995, empowered by the very forces that it had resisted for so long, Genentech launched three independent phase III trials to test Herceptin. The most pivotal of the three was a trial labeled 648, randomizing women newly diagnosed with metastatic breast cancer to standard chemotherapy alone versus chemotherapy with Herceptin added. Trial 648 was launched in 150 breast cancer clinics around the world. The trial would enroll 469 women and cost Genentech $15 million to run.

In May 1998, eighteen thousand cancer specialists flocked to Los Angeles to attend the thirty-fourth meeting of the American Society of Clinical Oncology, where Genentech would unveil the data from the Herceptin trials, including trial 648.
On Sunday, May 17
, the third day of the meeting, an expectant audience of thousands piled into the stuffy central amphitheater at the convention center to attend a special session dedicated to
Her-2/neu
in breast cancer. Slamon was slated to be the last speaker. A coil of nervous energy, with the characteristic twitch in his mustache, he stood up at the podium.

Clinical presentations at ASCO are typically sanitized and polished, with blue-and-white PowerPoint slides depicting the bottom-line message using survival curves and statistical analyses. But Slamon began—relishing this pivotal moment—not with numbers and statistics, but with forty-nine smudgy bands on a gel run by one of his undergraduate students in 1987. Oncologists slowed down their scribbling. Reporters squinted their eyes to see the bands on the gel.

That gel, he reminded his audience, had identified a gene with no pedigree—no history, no function, no mechanism. It was nothing more than an isolated, amplified signal in a fraction of breast cancer cases. Slamon had gambled the most important years of his scientific life on those bands. Others had joined the gamble: Ullrich, Shepard, Carter, Botstein and Levinson, Visco and the activists, pharma executives and clinicians and Genentech. The trial results to be announced that afternoon represented the result of that gamble. But Slamon wouldn’t—he couldn’t—rush to the end point of the journey without reminding everyone in the room of the fitful, unsanitized history of the drug.

Slamon paused for a theatrical moment before revealing the results of the trial.
In the pivotal 648 study
, 469 women had received standard cytotoxic chemotherapy (either Adriamycin and Cytoxan in combination, or Taxol) and were randomized to receive either Herceptin or a placebo. In every conceivable index of response, women treated with the addition of Herceptin had shown a clear and measurable benefit. Response rates to standard chemotherapy had moved up 150 percent. Tumors had shrunk in half the women treated with Herceptin compared to a third of women in the control arm. The progression of breast cancer had been delayed from four to seven and a half months. In patients with tumors heavily resistant to the standard Adriamycin and Cytoxan regimen, the benefit had been the most marked: the combination of Herceptin and Taxol had increased response rates to nearly 50 percent—a rate unheard of in recent clinical experience. The survival rate would also follow this trend. Women treated with Herceptin lived four or five months longer than women in the control group.

At face value, some of these gains might have seemed small in absolute terms—life extended by only four months. But the women enrolled in these initial trials were patients with late-stage, metastatic cancers, often heavily pretreated with standard chemotherapies and refractory to all drugs—women carrying the worst and most aggressive variants of breast cancer. (This pattern is typical: in cancer medicine, trials often begin with the most advanced and refractory cases, where even small benefits of a drug might outweigh risks.) The true measure of Herceptin’s efficacy would lie in the treatment of treatment-naive patients—women diagnosed with early-stage breast cancer who had never received any prior treatment.

In 2003, two enormous multinational studies
were launched to test Herceptin in early-stage breast cancer in treatment-naive patients. In one of the studies, Herceptin treatment increased breast cancer survival at four years by a striking 18 percent over the placebo group. The second study, although stopped earlier, showed a similar magnitude of benefit. When the trials were statistically combined, overall survival in women treated with Herceptin was increased by 33 percent—a magnitude unprecedented in the history of chemotherapy for
Her-2
positive cancer. “
The results,” one oncologist wrote
, were “simply stunning . . . not evolutionary, but revolutionary. The rational development of molecularly targeted therapies points the direction toward continued improvement in breast cancer therapy. Other targets and other agents will follow.”