--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."
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. K
ay 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."
On the evening of May 17, 1998, after Slamon had announced the results of the 648 study to a stunned audience at the ASCO meeting, Genentech threw an enormous cocktail party at the Hollywood Terrace, an open-air restaurant nestled in the hills of Los Angeles. Wine flowed freely, and the conversation was light and breezy. Just a few days earlier, the FDA had reviewed the data from the three Herceptin trials, including Slamon's study, and was on the verge of "fast-tracking" the approval of Herceptin. It was a poignant posthumous victory for Marti Nelson: the drug that would likely have saved her life would become accessible to all breast cancer patients--no longer reserved for clinical trials or compassionate use alone.
"The company," Robert Bazell, the journalist, wrote, "invited all the investigators, as well as most of Genentech's Her-2 team. The activists came too: Marilyn McGregor and Bob Erwin [Marti Nelson's husband] from San Francisco and Fran Visco from the National Breast Cancer Coalition."
The evening was balmy, clear, and spectacular. "The warm orange glow of the setting sun over the San Fernando Valley set the tone of the festivities. Everyone at the party would celebrate an enormous success. Women's lives would be saved and a huge fortune would be made."
Only one person was conspicuously missing from the party--Dennis Slamon. Having spent the afternoon planning the next phase of Herceptin trials with breast oncologists at ASCO, Slamon had jumped into his run-down Nissan and driven home.
A Four-Minute Mile
The nontoxic curative compound remains undiscovered but not undreamt.
--James F. Holland
Why, it is asked, does the supply of new miracle drugs lag so far behind, while biology continues to move from strength to strength . . .? There is still the conspicuous asymmetry between molecular biology and, say, the therapy of lung cancer.
--Lewis Thomas,
The Lives of a Cell, 1978
In the summer of 1990, as Herceptin entered its earliest trials, another oncogene-targeted drug began its long journey toward the clinic. More than any other medicine in the history of cancer, more even than Herceptin, the development of this drug--from cancer to oncogene to a targeted therapy and to successive human trials--would signal the arrival of a new era in cancer medicine. Yet to arrive at this new era, cancer biologists would again need to circle back to old observations--to the peculiar illness that John Bennett had called a "suppuration of blood," that Virchow had reclassified as weisses Blut in 1847, and that later researchers had again reclassified as chronic myeloid leukemia or CML.
For more than a century, Virchow's weisses Blut had lived on the peripheries of oncology. In 1973, CML was suddenly thrust center stage. Examining CML cells, Janet Rowley identified a unique chromosomal aberration that existed in all the leukemia cells. This abnormality, the so-called Philadelphia chromosome, was the result of a translocation in which the "head" of chromosome twenty-two and the "tail" of chromosome nine had been fused to create a novel gene. Rowley's work suggested that CML cells possess a distinct and unique genetic abnormality--possibly the first human oncogene.
Rowley's observation launched a prolonged hunt for the mysterious chimeric gene produced by the 9:22 fus
ion. The identity of the gene emerged piece by piece over a decade. In 1982, a team of Dutch researchers in Amsterdam isolated the gene on chromosome nine. They called it abl.* In 1984, working with American collaborators in Maryland, the same team isolated abl's partner on chromosome twenty-two--a gene called Bcr. The oncogene created by the fusion of these two genes in CML cells was named Bcr-abl. In 1987, David Baltimore's laboratory in Boston "engineered" a mouse containing the activated Bcr-abl oncogene in its blood cells. The mouse developed the fatal spleen-choking leukemia that Bennett had seen in the Scottish slate-layer and Virchow in the German cook more than a century earlier--proving that Bcr-abl drove the pathological proliferation of CML cells.
As with the study of any oncogene, the field now turned from structure to function: what did Bcr-abl do to cause leukemia? When Baltimore's lab and Owen Witte's lab investigated the function of the aberrant Bcr-abl oncogene, they found that, like src, it was yet another kinase--a protein that tagged other proteins with a phosphate group and thus unleashed a cascade of signals in a cell. In normal cells, the Bcr and abl genes existed separately; both were tightly regulated during cell division. In CML cells, the translocation created a new chimera--Bcr-abl, a hyperactive, overexuberant kinase that activated a pathway that forced cells to divide incessantly.
In the mid-1980s, with little knowledge about the emerging molecular genetics of CML, a team of chemists at Ciba-Geigy, a pharmaceutical company in Basel, Switzerland, was trying to develop drugs that might inhibit kinases. The human genome has about five hundred kinases (of which, about ninety belong to the subclass that contains src and Bcr-abl). Every kinase attaches phosphate tags to a unique set of proteins in the cell. Kinases thus act as molecular master-switches in cells--turning "on" some pathways and turning "off" others--thus providing the cell a coordinated set of internal signals to grow, shrink, move, stop, or die. Recognizing the pivotal role of kinases in cellular physiology, the Ciba-Geigy team hoped to discover drugs that could activate or inhibit kinases selectively in cells, thus manipulating the cell's master-switches. The team was led by a tall, reserved, acerbic Swiss physician-biochemist, Alex Matter. In 1986, Matter was joined in his hunt for selective kinase inhibitors by Nick Lydon, a biochemist from Leeds, England.
Siddhartha Mukherjee - The Emperor of All Maladies: A Biography of Cancer Page 51