The Emperor of All Maladies: A Biography of Cancer (79 page)

Marginally funded, the work edged along, almost invisible to Genentech’s executives. In 1989, Mike Shepard, an immunologist at Genentech, improved the production and purification of the
Her-2
antibody. But the purified mouse antibody, Slamon knew, was far from a human drug. Mouse antibodies, being “foreign” proteins, provoke a potent immune response in humans and make terrible human drugs. To circumvent that response, Genentech’s antibody needed to be converted into a protein that more closely resembled a human antibody. This process, evocatively called “humanizing” an antibody, is a delicate art, somewhat akin to translating a novel;
what matters is not just the content, but the ineffable essence of the antibody—its form. Genentech’s resident “humanizer” was Paul Carter, a quiet, twenty-nine-year-old Englishman who had learned the craft at Cambridge from Cesar Milstein, the scientist who had first produced these antibodies using fused immune and cancer cells. Under Slamon’s and Shepard’s guidance, Carter set about humanizing the mouse antibody. In the summer of 1990, Carter proudly produced a fully humanized
Her-2
antibody ready to be used in clinical trials. The antibody, now a potential drug, would soon be renamed Herceptin, fusing the words
Her-2
,
intercept
, and
inhibitor.
^*

Such was the halting, traumatic birth of the new drug that it was easy to forget the enormity of what had been achieved. Slamon had identified
Her-2
amplification in breast cancer tissue in 1987; Carter and Shepard had produced a humanized antibody against it by 1990. They had moved from cancer to target to drug in an astonishing three years, a pace unprecedented in the history of cancer.

In the summer of 1990, Barbara Bradfield, a forty-eight-year-old woman from Burbank, California, discovered a mass in her breast and a lump under her arm. A biopsy confirmed what she already suspected: she had breast cancer that had spread to her lymph nodes. She was treated with a bilateral mastectomy followed by nearly seven months of chemotherapy. “
When I was finished with all that
,” she recalled, “I felt as if I had crossed a river of tragedy.”

But there was more river to ford
: Bradfield’s life was hit by yet another incommensurate tragedy. In the winter of 1991, driving on a highway not far from their house, her daughter, twenty-three years old and pregnant, was killed in a fiery accident. A few months later, sitting numbly in a Bible-study class one morning, Bradfield let her fingers wander up to the edge of her neck. A new grape-size mass had appeared just above her collarbone. Her breast cancer had relapsed and metastasized—almost certainly a harbinger of death.

Bradfield’s oncologist in Burbank offered her more chemotherapy, but she declined it. She enrolled in an alternative herbal-therapy program and bought a vegetable juicer and planned a trip to Mexico. When her oncolo
gist asked if he could send samples of her breast cancer to Slamon’s lab at UCLA for a second opinion, she agreed reluctantly. A faraway doctor performing unfamiliar tests on her tumor sample, she knew, could not possibly affect her.

One afternoon in the summer of 1991, Bradfield received a phone call from Slamon. He introduced himself as a researcher who had been analyzing her slides. Slamon told Bradfield about
Her-2
. “
His tone changed,” she recalled
. Her tumor, he said, had one of the highest levels of amplified
Her-2
that he had ever seen. Slamon told her that he was launching a trial of an antibody that bound
Her-2
and that she would be the ideal candidate for the new drug. Bradfield refused. “
I was at the end of my road
,” she said, “and I had accepted what seemed inevitable.” Slamon tried to reason with her for a while, but found her unbending. He thanked her for her consideration and rang off.

Early the next morning, though, Slamon was back on the telephone. He apologized for the intrusion, but her decision had troubled him all night. Of all the variants of
Her-2
amplification that he had encountered, hers had been truly extraordinary; Bradfield’s tumor was chock-full of
Her-2
, almost hypnotically drunk on the oncogene. He begged her once again to join his trial.

“
Survivors look back and see omens
, messages they missed,” Joan Didion wrote. For Bradfield, Slamon’s second phone call was an omen that was not missed; something in that conversation pierced through a shield that she had drawn around herself.
On a warm August morning in 1992
, Bradfield visited Slamon in his clinic at UCLA. He met her in the hallway and led her to a room in the back. Under the microscope, he showed her the breast cancer that had been excised from her body, with its dark ringlets of
Her-2
labeled cells. On a whiteboard, he drew a step-by-step picture of an epic scientific journey. He began with the discovery of
neu
, its rediscovery in Ullrich’s lab, the struggles to produce a drug, culminating in the antibody stitched together so carefully by Shepard and Carter. Bradfield considered the line that stretched from oncogene to drug. She agreed to join Slamon’s trial.

It was an extraordinarily fortunate decision. In the four months between Slamon’s phone call and the first infusion of Herceptin, Bradfield’s tumor had erupted, spraying sixteen new masses into her lung.

Fifteen women, including Bradfield, enrolled in Slamon’s trial at UCLA in 1992. (The number would later be expanded to thirty-seven.) The drug was given for nine weeks, in combination with cisplatin, a standard chemotherapy agent used to kill breast cancer cells, both delivered intravenously. As a matter of convenience, Slamon planned to treat all the women on the same day and in the same room. The effect was theatrical; this was a stage occupied by a beleaguered set of actors. Some women had begged and finagled their way into Slamon’s trial through friends and relatives; others, such as Bradfield, had been begged to join it. “All of us knew that we were living on borrowed time,” Bradfield said, “and so we felt twice as alive and lived twice as fiercely.” A Chinese woman in her fifties brought stash after stash of traditional herbs and salves that she swore had kept her alive thus far; she would take oncology’s newest drug, Herceptin, only if she could also take its most ancient drugs with it. A frail, thin woman in her thirties, recently relapsed with breast cancer after a bone marrow transplant, glowered silently and intensely in a corner. Some treated their illness reverentially. Some were bewildered, some too embittered to care. A mother from Boston in her midfifties cracked raunchy jokes about her cancer. The daylong drill of infusions and blood tests was exhausting. In the late evening, after all the tests, the women went their own ways. Bradfield went home and prayed. Another woman soused herself with martinis.

The lump on Bradfield’s neck—the only tumor in the group that could be physically touched, measured, and watched—became the compass for the trial. On the morning of the first intravenous infusion of the
Her-2
antibody, all the women came up to feel the lump, one by one, running their hands across Bradfield’s collarbone. It was a peculiarly intimate ritual that would be repeated every week. Two weeks after the first dose of the antibody, when the group filed past Bradfield, touching the node again, the change was incontrovertible. Bradfield’s tumor had softened and visibly shrunk. “We began to believe that something was happening here,” Bradfield recalled. “Suddenly, the weight of our good fortune hit us.”

Not everyone was as fortunate as Bradfield. Exhausted and nauseous one evening, the young woman with relapsed metastatic cancer was unable to keep down the fluids needed to hydrate her body. She vomited through the night and then, too tired to keep drinking and too sick to understand the consequences, fell back into sleep. She died of kidney failure the next week.

Bradfield’s extraordinary response continued. When the CT scans were repeated two months into the trial, the tumor in her neck had virtually disappeared, and the lung metastases had also diminished both in number and size. The responses in many of the thirteen other women were more ambiguous. At the three-month midpoint of the trial, when Slamon reviewed the data with Genentech and the external trial monitors, tough decisions clearly needed to be made. Tumors had remained unchanged in size in some women—not shrunk, but static: was this to be counted as a positive response? Some women with bone metastasis reported diminished bone pain, but pain could not objectively be judged. After a prolonged and bitter debate, the trial coordinators suggested dropping seven women from the study because their responses could not be quantified. One woman discontinued the drug herself. Only five of the original cohort, including Bradfield, continued the trial to its six-month end point. Embittered and disappointed, the others returned to their local oncologists, their hopes for a miracle drug again dashed.

Barbara Bradfield finished eighteen weeks of therapy in 1993. She survives today. A gray-haired woman with crystalline gray-blue eyes, she lives in the small town of Puyallup near Seattle, hikes in the nearby woods, and leads discussion groups for her church. She vividly remembers her days at the Los Angeles clinic—the half-lit room in the back where the nurses dosed the drugs, the strangely intimate touch of the other women feeling the node in her neck. And Slamon, of course. “Dennis is my hero,” she said. “I refused his first phone call, but I have never, ever, refused him anything since that time.” The animation and energy in her voice crackled across the phone line like an electrical current. She quizzed me about my research. I thanked her for her time, but she, in turn, apologized for the distraction. “Get back to work,” she said, laughing. “There are people waiting for discoveries.”

*
Ullrich actually found the human homolog of the mouse
neu
gene. Two other groups independently discovered the same gene.

*
The drug is also known by its pharmacological name Trastuzumab; the “ab” suffix is used to denote the fact that this is an
a
nti
b
ody.

Dying people don’t have time or energy
. We can’t keep doing this one woman, one drug, one company at a time.

—Gracia Buffleben

It seemed as if we had
entered a brave new world of precisely targeted, less toxic, more effective combined therapies.

—
Breast Cancer Action Newsletter
, 2004

By the summer of 1993, news of Slamon’s early-phase trial had spread like wildfire through the community of breast cancer patients, fanning out through official and unofficial channels. In waiting rooms, infusion centers, and oncologists’ offices, patients spoke to other patients describing the occasional but unprecedented responses and remissions. Newsletters printed by breast cancer support groups whipped up a frenzy of hype and hope about Herceptin. Inevitably, a tinderbox of expectations was set to explode.

The issue was “compassionate use.”
Her-2
positive breast cancer is one of the most fatal and rapidly progressive variants of the disease, and patients were willing to try any therapy that could produce a clinical benefit. Breast cancer activists pounded on Genentech’s doors to urge the release of the drug to women with
Her-2
positive cancer who had failed other therapies. These patients, the activists argued, could not wait for the drug to undergo interminable testing; they wanted a potentially lifesaving medicine
now.
“
True success happens
,” as one writer put it in 1995, “only when these new
drugs actually enter bodies.”

For Genentech, though, “true success” was defined by vastly different imperatives. Herceptin had not been approved by the FDA; it was a molecule in its infancy. Genentech wanted carefully executed early-phase trials—not just new drugs entering bodies, but carefully monitored drugs entering carefully monitored bodies in carefully monitored trials. For the next phase of Herceptin trials launched in 1993, Genentech wanted to stay small and focused.
The number of women enrolled in these trials
had been kept to an absolute minimum: twenty-seven patients at Sloan-Kettering, sixteen at UCSF, and thirty-nine at UCLA, a tiny cohort that the company intended to follow deeply and meticulously over time. “
We do not provide . . . compassionate use
programs,” Curd curtly told a journalist. Most doctors involved in the early-phase trials agreed. “
If you start making exceptions
and deviating from your protocol,” Debu Tripathy, one of the leaders of the UCSF trial, said, “then you get a lot of patients whose results are not going to help you understand whether a drug works or not. All you’re doing is delaying . . . being able to get it out into the public.”