Herceptin – The Rational Discovery & Development of the First Commercially Successful Oncogene-targeting Drug

*Note: The following is an adaptation of various excerpts from the book The Emperor of All Maladies by Siddhartha Mukherjee.

The First Drug to Target an Oncogene

Before the 1980s, the armamentarium of cancer therapy was largely built around two fundamental vulnerabilities of cancer cell:

  1. The first was that most cancers originate as local diseases before they spread systemically. Surgery and radiation therapy exploit this vulnerability.
  2. The second vulnerability was the rapid growth rate of some cancer cells.

Most chemotherapy drugs discovered before the 1980s target this second vulnerability. Antifolates interrupt metabolism of folic acid and starve all sales of a crucial nutrient required for cell division. Nitrogen mustard and cisplatin chemically react with DNA, and DNA-damaged cells cannot duplicate their genes and thus cannot divide. Vincristine, the periwinkle poison, thwarts the ability of a cell to construct the molecular “scaffold” required for all cells to divide.

Growth may be the hallmark of cancer, but it is equally the hallmark of life. A poison directed at cellular growth, such as vincristine or cisplatin, eventually attacks normal growth, and cells that grow most rapidly in the body begin to bear the collateral cost of chemotherapy. Hair falls out. Blood involutes. The lining of the skin and gut sloughs off.

The discoveries of cancer biology in the 1980s offered a vastly more nuanced view of these vulnerabilities. Three new principals emerged, representing three new Achilles’ heels of cancer.

First, cancer cells are driven to grow because of the accumulation of mutations in their DNA. These mutations activate internal proto-oncogenes and inactivate tumor suppressor genes, thus unleashing the “accelerators” and “brakes” that operate during normal cell division. Targeting these hyperactive genes, while sparing their modulated normal precursors, might be a novel means to attack cancer cells more discriminately. Second, proto-oncogenes and tumor suppressor genes typically lie at the hubs of cellular signaling pathways.  Third, the relentless cycle of mutation, selection, and survival creates a cancer cell that has acquired several additional properties besides uncontrolled growth. These include the capacity to resist death signals, to metastasize throughout the body, and to incite the growth of blood vessels. The “hallmarks of cancer” are not invented by the cancer cell; they’re typically derived from the corruption of similar processes that occur in the normal physiology of the body.

Until the late 1980s, no drug had reversed and oncogene’s activation or a tumor suppressor’s inactivation. Even tamoxifen, the most specific cancer-targeted drug discovered to date, worked by attacking the dependence of certain breast cancer cells on estrogen. In 1986 the discovery of the first oncogene-targeting drug would instantly galvanize cancer medicine.

The disease that stood at the pivotal crossroads of oncology was a rare variant of leukemia called acute promyelocytic leukemia – APL. The disease had a distinct characteristic: the cells in this form of cancer do not merely divide rapidly, they are also strikingly frozen in immature development. Normal white blood cells developing in the bone marrow undergo a series of maturation steps to develop into fully functional adult cells. One such intermediate cell is termed a promyelocyte, an adolescent cell on the verge of becoming functionally mature. APL is characterized by the malignant proliferation of these immature promyelocytes. Normal promyelocytes are loaded with toxic enzymes and granules that are usually released by adult white blood cells to kill viruses, bacteria, and parasites. Moody, mercurial, and jumpy, the cells of APL can release their poisonous granules on a whim – precipitating massive bleeding or simulating a septic reaction in the body.

Since the early 1970s scientist had hunted for a chemical that might force these cells to mature. Scores of drugs had been tested on APL cells in test tubes but only one that stood out – retinoic acid and oxidized form of vitamin A. Researchers have found however that retinoic acid was a vexingly unreliable reagent. One batch might mature APL cells while another batch of the same chemical might fail. In the summer of 1985 Laurent Degos, a hematologist at St. Louis Hospital, met up with Zhen Yi Wang, head of a Chinese team in Shanghai that was also treating APL patients.

Retinoic acid comes in two closely-related molecular forms called cis-retinoic acid and trans-retinoic acid. Of the two forms cis-retinoic acid had been the most intensively tested and it had produced flickering, transient responses. But Wang and Degos wondered if trans-retinoic acid was the true maturation agent. Perhaps, they thought, unreliable responses seen in the old experiments had been due to variations in amount of the trans-retinoic form present in each batch of retinoic acid. Wang new of a pharmaceutical factory outside Shanghai that could produce pure trans-retinoic acid without the admixture of cis-retinoic acid.

A trial was launched in 1986 with 24 patients. Twenty-three experienced dazzling responses. Leukemic promyelocytes in the blood underwent a brisk maturation into white blood cells. Having fully matured, the cancer cells began to die out. Acute promyelocytic leukemia still relapsed in some patients, typically about three to four months after treatment with trans-retinoic acid, but by 1993 Wang and Dagos concluded that 75% of their patients treated with the combination of trans-retinoic acid and standard chemotherapy would never relapse, a percentage unheard-of in the history of APL.

In 1984 Janet Rowley, a Chicago cytologist, had identified a unique translocation in the chromosomes of APL cells – a fragment of a gene from chromosome 15 fused with a fragment of a gene from chromosome 17. This created an activated chimeric oncogene, which drove the proliferation of promyelocytes and blocked their maturation, thus creating the peculiar syndrome of APL. The APL oncogene, scientists found, encodes a protein that is tightly bound by trans retinoic acid. This binding immediately extinguishes the oncogene signal in APL cells, thereby explaining the rapid powerful remissions observed in Shanghai.

From Genes to Drugs

Wang and Degos first stumbled on trans-retinoic acid through inspired guesswork and only later discovered that the molecule could directly target an oncogene. Was is possible to instead start from an oncogene and then develop a drug that targets it? Robert Weinberg’s lab had already begun that converse journey.

By the early 1980s, Weinberg’s lab had perfected a technique to isolate cancer-causing genes directly out of cancer cells. Using Weinberg’s technique, researchers had isolated dozens of new oncogenes from cancer cells. In 1982, a postdoctoral scientist named Lakshmi Charon Padhy reported the isolation of yet another such oncogene from a rat tumor called a neuroblastoma. Weinberg christened the gene neu, naming after the type of cancer that harbored this gene.

The product of the neu gene was a protein that was  tethered to the cell membrane with a large fragment that hung outside of the cell, freely accessible to a drug. In 1981, while isolating his gene, Padhy had created an antibody against the neu protein. Although his discovery was published in a high-profile scientific journal, few scientists noticed that he might have stumbled on a potential anticancer drug.

In the summer of 1984, a team of researchers collaborating with Weinberg discovered the human homolog of the neu gene. Noting its resemblance to another growth-modulating gene discovered previously – the Human EGF Receptor (HER) – the researchers called the gene Her-2. While the neu gene, discovered in an academic laboratory, faded into obscurity, Her-2 was discovered on the sprawling campus of the biopharmaceutical company Genentech. For Weinberg, neu represented a route to understanding the fundamental biology of neuroblastoma. For Genentech, however, Her-2 represented a route to developing a new drug.

The Nature of Her-2

It was under the aegis of a target discovery program that Axel Ullrich, a German scientist working at Genentech, rediscovered Weinberg’s gene – Her-2/neu, the oncogene tethered to the cell membrane. However, Genentech faced a significant dilemma. The drugs that Genentech had successfully synthesized thus far were designed to treat human diseases in which a protein or a signal was abest – insulin for diabetics, clotting factors for hemophiliacs, growth hormone for dwarfs. An oncogene was the opposite – not a missing protein, but a signal in overabundance.

Dennis Slamon, a UCLA oncologist, was a particular 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. He attended the University of Chicago medical school, where Slamon had performed a series of studies on a human leukemia virus called HTLV-1, the lone retrovirus shown to cause human cancer.

In the summer of 1986, Slamon attended a seminar given by Ullrich at UCLA at which the isolation of Her-2 was described in the context of Weinberg’s work. With the intention of finding a method to kill the oncogene, Slamon proposed a simple collaboration. If Ullrich sent his the DNA probes for Her-2 from Genentech, Slamon would test his collection of cancer cells for samples with Her-2 hyperactivity, thus bridging the gap between the oncogene and a human cancer.

In 1986, Ullrich agreed and sent Slamon the probes. In a few months, Slamon reported the back a distinct pattern he found. Cancer cells that had become habitually dependent on the activity of a gene for their growth could amplify that gene by increasing its rate of transcription – a phenomenon now referred to as oncogene amplification. Based on a pattern of staining, breast cancers could be divided into Her-2 positive and Her-2 negative samples. Upon further investigation, Slamon determined that Her-2 positive breast tumors tended to be more aggressive, more metastatic, and more likely to kill.

What would happen, Ullrich wondered, if Her-2 activity could somehow be shut off? One afternoon, Ullrich walked into the Immunology Division at Genentech and inquired as to whether someone in immunology might be able to design an antibody to bind Her-2 and possibly erase its signalling.

The Immunology Gambit

In the mid-1970s, two immunibiologists 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. To exploit antibodies therapeutically, scientists needed to identify targets unique to cancer cells, and such cancer-specific targets had proved notoriously difficult to identify. Her-2 was, perhaps, Kohler’s missing bullet.

At UCLA, meanwhile, Slamon had implanted Her-2 positive 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 attempted to treat Her-2 positive breast cancer cells in a dish. 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. Her-2 inhibition worked in an animal model. Slamon and Ullrich now had all three essential ingredients for a targeted cancer therapy: (1) an oncogene, (2) a form of cancer that specifically activated that oncogene, (3) and a drug that specifically inactivated that target.

A Change in Landscape

Through the 1980s, as Ullrich and Slamon had been hunting for a target specific to cancer, several other 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. For these reasons, Genentech was abandoning its interest in cancer. They were worried that pouring money into the development of another drug that failed would cripple the company’s finances.

Drained and dejected, Ullrich left the harsh constraints of the pharmaceutical industry and, ultimately, joined an academic lab in Germany. 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 payroll. An MIT-educated geneticist, David Botstein, and a molecular biologist, Art Levinson, both at Genentech, had been strong proponents of the Her-2 project. Slamon and Levinson convinced a tiny entrepreneurial team to push ahead with the Her-2 project.

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 for 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, therefore, make terrible human drugs. To circumvent that response, Genentech’s antibody needed to be converted into a protein that more closel resembled a human antibody. The process, evocatively called “humanizing” an antibody, is a delicate art, somewhat akin to translating a novel.

In 1990, Paul Carter, Genentech’s resident “humanizer”, proudly produced a fully humanized Her-2 antibody ready to be used in clinical trials. That antibody, now a potential drug, would soon be renamed Herceptin, fuzing the words Her-2, intercept, and inhibitor. Slamon had identified Her-2 amplification in breast cancer tissue in 1987; Carter and Shepard had produced a humanized antibody against it by 1900. They had moved from cancer to target to drug in an astonishing three years, a pace unprecedented in the history of cancer.

From Lab to Clinic

In the summer of 1990, a biopsy confirmed that Barbara Bradford, a 48-year old woman from Burbank, CA, had breast cancer that had spread to her lymph nodes. The was treated with a bilateral mastectomy followed by nearly seven months of chemotherapy. A year later, she found that her breast cancer had metastasized – almost certainly a harbinger of death.

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. One afternoon in the winter of 1991, Bradford received a phone call from Slamon. 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 to Her-2 and that she would be an ideal candidate. Branford refused.

On a warm August in 1992, she visited Slamon in his clinic in UCLA with a change of heart. She agreed to join Slamon’s trial. In the four months between Slamon’s phone call and the first infusion of Herceptin, Bradfield’s tumor had erupted, spraying 16 new masses into her lung.

Fifteen women, including Bradford, enrolled in Slamon’s trial at UCLA in 1992. The number would later be expanded to 37. The drug was given for 9 weeks, in combination with cisplatin, both delivered intravenously. At the 13-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.

After a long and bitter debate, the trial coordinators suggested dropping 7 women from the study because their responses could not be quantified. Only five women of the original cohort, including Bradfield, continued the trial to its 6-month endpoint. Barbara Bradfield finished 18 weeks of therapy in 1993. She survives today.

The Sociopolitical Catalyst

By the summer of 1993, news of Slamon’s early-phase trial speard like wildfire through the community of breast cancer patients, fanning out through official and unofficial channels. Newsletters printed by breast cancer support groups whipped up a frenzy of hype and hope about Herceptin. Breast cancer activists pounded on Genentech’s doors to urge the release of the drug to women with Her-2 positive breast cancer who had failed other therapies, advocating for “compassionate use”.

For Genentech, through, “true success” was defined by vastly different imperatives. Herceptin had not been approved by the FDA. 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: 27 patients in Sloan-Kettering, 16 at UCSF, and 39 at UCLA.

Outside of the cloistered laboratories of Genentech, the controversy ignited a firestorm. San Francisco was no stranger to the issue of compassionate use versus focused research. In the late 1980s, as AIDS had erupted in the city, gay men had coalesced into groups such as ACT UP to demand speedier access to drugs, in part through compassionate use programs. For years, AIDS activists had been negotiating with drug companies and the FDA to obtain new HIV drugs while the therapies were still in clinical trials. As one writer put it, “scientific uncertainty is no excuse for inaction…we cannot wait for proof”.

Marti Nelson, a gynecologist in California, had discovered a malignant mass in her breast in 1987. After a mastectomy and multiple cycles of chemotherapy her tumors subsided, only to return in 1993. Reasoning that her tumor might be Her-2 positive, she tried to have her own specimen tested for the gene. 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.

Nelson contacted Breast Cancer Action project, a local San Francisco organization connected with ACT UP, to help get someone to test her turmo and obtain Herceptin for compassionate use. On October 1994, the tumor was tested for Her-2 expression at UCSF and showed to be strikingly Her-2 positive. Nine days later, still awaiting Herceptin approval from Genentech, Mart Nelson drifted into a coma and died.

For BCA, Nelson’s death was a watershed event. Her 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.

In 1995, a small delegation of Genentech scientists and executives flew to Washington to meet Frances Visco, the chair of the National Breast Cancer Coalition (NBCC), a powerful national coalition of cancer activists. Genentech agreed to provide expanded access programs for Herceptin in a program that would allow oncologists to treat patients outside of clinical trials. In return, the NBCC would act as a neutral intermediary between the company and the local breast cancer activists in San Francisco. Visco joined to planning committee of the phase III trials of Herceptin, and helped to recruit patients for the trial using NBCC’s extensive network. Rather than running trials on breast cancer patients, the company learned to run trials  with breast cancer patients.

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 trials was a trial labeled 648, randomizing women newly diagnosed with metastatic breast cancer to 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 ad cost Genentech $15 million to run.

A Grand Unveiling

On May 1998, eighteen thousand cancer specialists flocked to Los Angeles to attend to 34th meeting of the American Society of Clinical Oncology (ASCO), where Genentech would unveil the data from the Herceptin trials. Clinical presentations at ASCO were typically sanitized and polished, with blue-and-white PowerPoint slides depicting bottom-line messages using survival curves and statistical analyses.

However, Slamon began – relishing this pivotal moment – not with numbers and statistics, but with 49 smudgy bands on a gel run by one of his undergraduate students in 1987. That gel, he reminded his audience, had identified a gene with no pedigree – no history, no function, and no mechanism. Slamon wouldn’t – he couldn’t – rush to the endpoint of the journey without reminding everyone in the room of the fitful, unsanitized history of the drug.

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 or response, women treated with the addition of Herceptin had shown a clear and measurable benefit. Response rates to standard chemotherapy had moved up 150%. Tumors had shrunk in half the women treated compared to a third of the women in the control arm. The progression of cancer had been delayed from 4 to 7.5 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% – a rate unheard of in recent clinical experience. The survival rate would also follow this trend. Women treated with Herceptin lived 4-5 months longer that women in the control group.

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, after four years, by about 18% above the placebo group. The second study, showed similar magnitude of benefit. When the trials were statistically combined, overall survival in women treated with Herceptin was increased by 33% – a magnitude unprecedented in the history of chemotherapy for Her-2 positive breast 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.”


  1. Image: http://random42.com/monoclonal-antibody-0
  2. Mukherjee, Siddhartha. “The emperor of all maladies.” London: Fourth (2011): 9-105.