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

by Siddhartha Mukherjee

  Dennis Slamon, a UCLA oncologist, attended Ullrich's talk that afternoon in 1986. The son of an Appalachian coal miner, Slamon had come to UCLA as a fellow in oncology after medical school at the University of Chicago. He was a peculiar amalgam of smoothness and tenacity, a "velvet jackhammer," as one reporter described him. Early in his academic life he had acquired what he called "a murderous resolve" to cure cancer, but thus far, it was all resolve and no result. In Chicago, Slamon had performed a series of exquisite studies on a human leukemia virus called HTLV-1, the lone retrovirus shown to cause a human cancer. But HTLV-1 was a fleetingly rare cause of cancer. Murdering viruses, Slamon knew, would not cure cancer. He needed a method to kill an oncogene.

  Slamon, hearing Ullrich's story of Her-2, made a quick, intuitive connection. Ullrich had an oncogene; Genentech wanted a drug--but an intermediate was missing. A drug without a disease is a useless tool; to make a worthwhile cancer drug, both needed a cancer in which the Her-2 gene was hyperactive. Slamon had a panel of cancers that he could test for Her-2 hyperactivity. A compulsive pack rat, like Thad Dryja in Boston, Slamon had been collecting and storing samples of cancer tissues from patients who had undergone surgery at UCLA, all saved in a vast freezer. Slamon proposed a simple collaboration. If Ullrich sent him the DNA probes for Her-2 from Genentech, Slamon could test his collection of cancer cells for samples with hyperactive Her-2--thus bridging the gap between the oncogene and a human cancer.

  Ullrich agreed. In 1986, he sent Slamon the Her-2 probe to test on cancer samples. In a few months, Slamon reported back to Ullrich that he had found a distinct pattern, although he did not fully understand it. Cancer cells that become habitually dependent on the activity of a gene for their growth can amplify that gene by making multiple copies of the gene in the chromosome. This phenomenon--like an addict feeding an addiction by ramping up the use of a drug--is called oncogene amplification. Her-2, Slamon found, was highly amplified in breast cancer samples, but not in all breast cancers. Based on the pattern of staining, breast cancers could neatly be divided into Her-2 amplified and Her-2 unamplified samples--Her-2 positive and Her-2 negative.

  Puzzled by the "on-off" pattern, Slamon sent an assistant to determine whether Her-2 positive tumors behaved differently from Her-2 negative tumors. The search yielded yet another extraordinary pattern: breast tumors that amplified Ullrich's gene tended to be more aggressive, more metastatic, and more likely to kill. Her-2 amplification marked the tumors with the worst prognosis.

  Slamon's data set off a chain reaction in Ullrich's lab at Genentech. The association of Her-2 with a subtype of cancer--aggressive breast cancer--prompted an important experiment. What would happen, Ullrich wondered, if Her-2 activity could somehow be shut off? Was the cancer truly "addicted" to amplified Her-2? And if so, might squelching the addiction signal using an anti-Her-2 drug block the growth of the cancer cells? Ullrich was tiptoeing around the afternoon experiment that Weinberg and Padhy had forgotten to perform.

  Ullrich knew where he might look for a drug to shut off Her-2 function. By the mid-1980s, Genentech had organized itself into an astonishing simulacrum of a university. The South San Francisco campus had departments, conferences, lectures, subgroups, even researchers in cutoff jeans playing Frisbee on the lawns. One afternoon, Ullrich walked to the Immunology Division at Genentech. The division specialized in the creation of immunological molecules. Ullrich wondered whether someone in immunology might be able to design a drug to bind Her-2 and possibly erase its signaling.

  Ullrich had a particular kind of protein in mind--an antibody. Antibodies are immunological proteins that bind their targets with exquisite affinity and specificity. The immune system synthesizes antibodies to bind and kill specific targets on bacteria and viruses; antibodies are nature's magic bullets. In the mid-1970s, two immunologists at Cambridge University, Cesar Milstein and George Kohler, had devised a method to produce vast quantities of a single antibody using a hybrid immune cell that had been physically fused to a cancer cell. (The immune cell secreted the antibody while the cancer cell, a specialist in uncontrolled growth, turned it into a factory.) The discovery had instantly been hailed as a potential route to a cancer cure. But to exploit antibodies therapeutically, scientists needed to identify targets unique to cancer cells, and such cancer-specific targets had proved notoriously difficult to identify. Ullrich believed that he had found one such target. Her-2, amplified in some breast tumors but barely visible in normal cells, was perhaps Kohler's missing bull's-eye.

  At UCLA, meanwhile, Slamon had performed another crucial experiment with Her-2 expressing cancers. He had implanted these cancers into mice, where they had exploded into friable, metastatic tumors, recapitulating the aggressive human disease. In 1988, Genentech's immunologists successfully produced a mouse antibody that bound and inactivated Her-2. Ullrich sent Slamon the first vials of the antibody, and Slamon launched a series of pivotal experiments. When he treated Her-2 overexpressing breast cancer cells in a dish with the antibody, the cells stopped growing, then involuted and died. More impressively, when he injected his living, tumor-bearing mice with the Her-2 antibody, the tumors also disappeared. It was as perfect a result as he or Ullrich could have hoped for. Her-2 inhibition worked in an animal model.

  Slamon and Ullrich now had all three essential ingredients for a targeted therapy for cancer: an oncogene, a form of cancer that specifically activated that oncogene, and a drug that specifically targeted it. Both expected Genentech to leap at the opportunity to produce a new protein drug to erase an oncogene's hyperactive signal. But Ullrich, holed away in his lab with Her-2, had lost touch with the trajectory of the company outside the lab. Genentech, he now discovered, was abandoning its interest in cancer. Through the 1980s, as Ullrich and Slamon had been hunting for a target specific to cancer cells, several other pharmaceutical companies had tried to develop anticancer drugs using the limited knowledge of the mechanisms driving the growth of cancer cells. Predictably, the drugs that had emerged were largely indiscriminate--toxic to both cancer cells and normal cells--and predictably, all had failed miserably in clinical trials. Ullrich and Slamon's approach--an oncogene and an oncogene-targeted antibody--was vastly more sophisticated and specific, but Genentech was worried that pouring money into the development of another drug that failed would cripple the company's finances. Chastened by the experience of others--"allergic to cancer," as one Genentech researcher described it--Genentech pulled funding away from most of its cancer projects.

  The decision created a deep rift in the company. A small cadre of scientists ardently supported the cancer program, but Genentech's executives wanted to focus on simpler and more profitable drugs. Her-2 was caught in the cross fire. Drained and dejected, Ullrich left Genentech. He would eventually join an academic laboratory in Germany, where he could work on cancer genetics without the fickle pressures of a pharmaceutical company constraining his science.

  Slamon, now working alone at UCLA, tried furiously to keep the Her-2 effort alive at Genentech, even though he wasn't on the company's payroll. "Nobody gave a shit except him," John Curd, Genentech's medical director, recalled. Slamon became a pariah at Genentech, a pushy, obsessed gadfly who would often jet up from Los Angeles and lurk in the corridors seeking to interest anyone he could in his mouse antibody. Most scientists had lost interest. But Slamon retained the faith of a small group of Genentech scientists, scientists nostalgic for the pioneering, early days of Genentech when problems had been taken on precisely because they were intractable. An MIT-educated geneticist, David Botstein, and a molecular biologist, Art Levinson, both at Genentech, had been strong proponents of the Her-2 project. (Levinson had come to Genentech from Michael Bishop's lab at UCSF, where he had worked on the phosphorylating function of src; oncogenes were stitched into his psyche.) Pulling strings, resources, and connections, Slamon and Levinson convinced a tiny entrepreneurial team to push ahead with the Her-2 project.

  Marginally funded, the work edged along, almost in
visible 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 oncologist 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 antibody.

  Drugs, Bodies, and Proof

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