Herceptin: A Breast Cancer Breakthrough

Rebecca J. Anderson, PhD

In the summer of 1990, Barbara Bradfield, a 48-yearold former school teacher in Burbank, Calif., discovered a mass in her breast and a lump under her arm (1, 2). Only a few months earlier, her mammogram had failed to detect them “It grew that fast” (2). A biopsy confirmed she had breast cancer, and it had spread to her lymph nodes.

Lacking confidence in her original doctors’ approach, Barbara took matters into her own hands. She searched and found a more amiable oncologist in Burbank. He prescribed six months of chemotherapy to shrink the tumor, followed by a bilateral mastectomy. Then, more chemotherapy and radiation for nearly seven months. The treatment ended in the spring of 1991 (1, 2). In August 1992,

Barbara felt a spongy grape-sized mass above her collarbone (1, 2). A biopsy confirmed that her cancer had returned, and a CAT scan revealed another lesion in her lung. Her Burbank doctor suggested high-dose chemotherapy. But chemotherapy had not worked the first time, and there was no reason to think it would work now. “Done with that,” she said. “If I’m going to die, I don’t want to die bald and throwing up” (2)

Instead, Barbara considered alternative treatments, like nutritional supplements, psychotherapy, and homeopathy. She enrolled in a herbal therapy program, drank vegetable juices, and planned a trip to a clinic in Mexico (1, 2).

Something neu

A decade earlier, Robert Weinberg at the Massachusetts Institute of Technology perfected a technique for isolating cancer-causing genes (called oncogenes) from cancer cells. In 1982, one of his postdoctoral fellows, Lakshmi Padhy, found an interesting oncogene in a rat neuroblastoma tumor (1, 2). Because it came from neuroblastoma, Weinberg named the

oncogene “neu.”

Most oncogenes coded for proteins that were sequestered inside the cell, but neu was different. The neu-generated protein was on the cell membrane surface, making it much more accessible to drug treatment. As part of his research, Padhy had created an antibody against this neu protein (1, 3). It would have been easy for Padhy and Weinberg to take the next step: to see if this antibody bound to the neu protein and hampered growth of the cancer cells. But they didn’t.

Likewise, other researchers failed to see the significance of Padhy’s results, which were published in the prestigious journal, Cell. Weinberg later said, “It would have been an overnight test…If I had been more studious and more focused…I would have made that connection” (1).

They Saw HER Standing There

Axel Ullrich, a universally recognized master gene cloner, received his doctorate in Germany. In 1975, he joined the Biochemistry Department of the University of California San Francisco. In neighboring UCSF labs, Harold Varmus (later, Director of the National Institutes of Health (NIH)) and Michael Bishop were conducting their Nobel Prize research on oncogenes, and Herb Boyer (later, a co-founder of Genentech) was developing innovative genetic engineering techniques (2, 3).

One of Ullrich’s early successes at UCSF was to isolate the gene that produces insulin (2). By incorporating this human gene into a bacterial genome, the bacteria became little insulin-producing factories, and that greatly facilitated the production of human insulin.

In 1977, Ullrich and several of his UCSF colleagues moved to South San Francisco to work at newly founded Genentech (2). Ullrich’s first cancer research involved epidermal growth factor (EGF). Mike Waterfield, a protein chemist in London, asked Ullrich to work backwards from the EGF receptor protein to

identify the gene that codes for it (2, 3)

Ullrich and Waterfield continued collaborating, and in 1984, they offered the first evidence connecting growth factors to cancer (2, 3). In fact, almost all oncogenes are mutated forms of the genes that regulate cell growth and division.

Ullrich and his Genentech team looked for DNA sequences that were similar to Waterfield’s human EGF receptor gene (which was designated as EGFR, or Her-1). The first look-alike gene they discovered was named Her-2 (human EGF receptor gene 2) (2-4).

When Ullrich cloned the protein that was produced by the Her-2 gene, it turned out to be the same protein that Padhy had identified on the mouse neuroblastoma cells. Ullrich had independently rediscovered the gene corresponding to Weinberg’s neu oncogene (1, 2, 4)

In the early years after this discovery, the gene was commonly known as Her-2/neu, in deference to both Weinberg and Ullrich’s work (2). Now, most researchers and clinicians simply call it HER2.

In the summer of 1986, Ullrich presented a seminar at UCLA on his HER2 findings and acknowledged Weinberg’s prior work. Among those in the audience was Dennis Slamon, a UCLA oncologist who was already searching for ways to cure cancer (1, 2).

Mining Coal, Then Cancer

Dennis Slamon came from a family of Appalachian coal miners. Scholarships allowed him to attend college and the MD-PhD program at the University of Chicago. His 1975 doctoral dissertation was in cell biology, and after his residency, in 1979, he joined the Department of Hematology-Oncology at UCLA (2).

A tall, gentle man, Slamon was a down-to-earth and accessible physician (5). His patients described him as caring and attentive. In 1982, a medical school friend referred a patient to him. The patient, Brandon Tartikoff, was 30 years old, head of television entertainment at NBC, and had been unsuccessfully treated for Hodgkin’s disease for four years (2)

Slamon was just a junior faculty member with limited experience and was reluctant to see Tartikoff. But he thought he could handle a “simple” case of Hodgkin’s disease. He prescribed an aggressive course of experimental chemotherapy. After a year and 9 cycles of drug treatment, Tartikoff went into remission and remained healthy for the next 15 years (2).

Clinical Proof

Slamon treated patients with all forms of cancer, but he was most energized and animated when talking about his laboratory research and its clinical applications. One reporter called him a “velvet jackhammer” for his combination of smoothness and tenacity (1). His active research team of technicians, students, postdoctoral fellows, and colleagues were laser-focused on finding a superior cancer treatment (2, 6).

In 1982 (the same year that Weinberg’s lab isolated the neu oncogene), Slamon submitted a grant proposal to NIH for funds to build a bank of human tumor cells (5). He wanted to screen the cells for specific genetic alterations. NIH turned down his proposal, but Slamon pressed ahead anyway. With support from the Jonsson Cancer Center Foundation and UCLA, he collected tumor cells that had been discarded after surgery for breast, prostate, colon, and lung cancer (1, 5)

Slamon was screening specifically for genes that regulate cell growth in those tumors (2, 5, 6). So, Ullrich’s seminar at UCLA in 1986 particularly piqued his interest.

That evening at a Thai restaurant in Santa Monica, Slamon and Ullrich forged a unique but very productive collaboration (2). Ullrich would provide samples of DNA from his gene collection, and Slamon would try to match them to the DNA he had extracted from his banked tumor cells. The goal was to identify which growth factor genes, if any, caused cancer (1, 2).

Ullrich did not inform Genentech of this collaboration, but he protected the company’s patent rights by coding the samples that he sent to Slamon (2). After several months of systematic research, Slamon found a match with certain breast and ovarian cancers (1-3). Ullrich then revealed that the gene was HER2.

In most cases, a gene mutation causes the production of either a defective protein or no protein at all. To Ullrich and Slamon’s surprise, the breast and ovarian cancer cells produced the normal HER2 protein, but it was produced in abnormally high amounts. This overexpression amplified the protein’s effect, and the cells grew out of control. That is, they became cancerous. When copies of the HER2 gene were incorporated into normal cells in tissue culture, they were transformed into malignant cells (2)

Slamon had over 30 breast cancer tumors in his collection, but he did not know the patients’ outcomes. On the other hand, William McGuire in San Antonio had a sizeable collection of tumors and the corresponding women’s medical histories (2, 3)

Slamon and McGuire collaborated and found that the HER2 gene was amplified in 25-30% of the human breast cancer tumors in their collection (7, 8). Also, the women whose tumors carried multiple copies of the HER2 gene relapsed more quickly and died sooner than those whose tumors contained only one copy (7, 8).

Making a Drug

Although their results appeared in Science in 1987, the scientific community, for the most part, was not interested. Nevertheless, Ullrich and his small group of Genentech researchers continued their work, hoping to develop an anti-cancer drug (2). A compound (such as an antibody) that bound to the HER2 receptor on the cell’s surface would impede signal transduction and, hopefully, suppress the tumor’s growth (4).

At Ullrich’s request, scientists in Genentech’s Immunology Division produced a series of mouse monoclonal antibodies against the HER2 protein (2, 3). Their top pick was 4D5. It bound selectively to the HER2 receptor protein and not to other closely related human EGF receptors (3-6)

When Ullrich and Slamon added 4D5 to HER2-cancer cells in tissue culture, the cells stopped growing and became normal (1, 2, 5). When they washed away the monoclonal antibody, the cancerous growth returned. Also, as they hoped, 4D5 had no effect on other cells in the tissue culture.

The next step was testing the antibody in an animal model. In collaboration with Pepino Giovanella in Houston, Slamon injected 4D5 into mice, and their overexpressed HER2 tumors shrank (1, 2). There was no effect in mice whose tumors did not overexpress HER2. Other researchers confirmed their findings.

Genentech Hesitates

Genentech owned the rights to this promising 4D5 antibody, but the company’s executives were not interested in investing in another cancer drug (2).

In 1982 (while Padhy was discovering the neu oncogene and Slamon was submitting his failed grant proposal to NIH), Genentech perfected Ullrich’s genetically engineered insulin. This recombinant human insulin was the company’s first major accomplishment. But rather than marketing it, they licensed the technology to Eli Lilly, a major insulin manufacturer (2).

The company had invested heavily in gene-based cancer treatments, but the clinical trials failed (2). Other biotech companies had investigated monoclonal antibodies to treat cancer, but their attempts also failed. Genentech executives doubted that any monoclonal antibody could penetrate a solid tumor (4). And at best, the 4D5 antibody would benefit only one-quarter of breast cancer patients—those whose tumors overexpressed HER2.

Genentech had disbanded its oncology clinical trial staff and pulled funding from most of its cancer projects. There was no interest in pouring millions of dollars into another long-shot cancer drug. Frustrated by Genentech’s decision, Ullrich left the company to pursue his research elsewhere (1, 2).

“It’s Real”

Mike Shepard took over the HER2 lab program, and his small cadre of ardent Genentech scientists persevered. Despite limited resources, they improved the production and purification of 4D5 (1-3). By 1989, Shepard’s team and Slamon knew this was a promising new therapy for breast cancer.

While Shepard kept lobbying unsuccessfully for support from Genentech’s senior management, Slamon pushed even harder from outside the company (1, 2) . He did not have the resources to develop the drug himself. A persistent gadfly, he repeatedly phoned the Genentech executives and often flew to San Francisco, using all his skills to charm them (1, 2) . “You’ve got something real here. If you don’t want to make it, license it out” (2)

Mike Shepard

Along with his persistent lobbying, Slamon forged ahead in his own lab. And his professional stature was growing. In 1988, he became director of clinical research at the Jonsson Comprehensive Cancer Center at UCLA, one of NIH’s research centers. In 1991, he was named chief of the Division of HematologyOncology at UCLA School of Medicine (6). And money was no longer a problem.

Lilly Tartikoff, Brandon’s wife, was grateful for Slamon’s care of her husband and wanted to contribute to his research. For several years, Slamon resisted, not wanting to take advantage of a wealthy patient. But Lilly persisted and Slamon finally relented (2).

Lilly reached out to Ronald Perelman, chairman of the cosmetic firm Revlon, which prided itself on appealing to ordinary American women. She thought it was reasonable and a public service for Revlon to support research of a disease that primarily affects women (5). Revlon’s executives did their due diligence by visiting Slamon and were impressed.

In 1989, Revlon pledged $800,000 per year for three years, a total of $2.4 million ($5.8 in today’s currency). It was an unprecedented level of support from an American corporation for a single scientific group, and the funds were unrestricted (5, 6).

The Revlon Women’s Cancer Research program was established at UCLA with Slamon as its director (5) Lilly also launched a series of fundraisers, tapping into her extensive network of Hollywood entertainers, who all made generous donations. Slamon was now bringing in more research money than any other UCLA faculty member (2).

Flipping the Switch

In late 1989, Shepard and Slamon finally convinced a vice president on Genentech’s development committee (whose mother had developed breast cancer) to champion the HER2 project. “Just like that, one man flipped the switch on HER2” (2).

Because 4D5 was a mouse monoclonal antibody, it would be recognized as foreign by the patient’s immune system. Even if it successfully inhibited the HER2 receptor on the tumor cells, it would be rapidly destroyed. Repeated administration would trigger a stronger immune response and probably inactivate 4D5 before it reached the tumor.

Coincidently, Genentech and a few other companies were developing a new technology to “humanize” monoclonal antibodies (2). Paul Carter, a 29-year-old Englishman, learned the technique in England and had recently joined Genentech.

In January 1990, Carter began work to produce a hybrid gene that coded for a “humanized” version of 4D5. It would retain just the bits of 4D5 that bind to the HER2 receptor and replace the rest with human antibody sequences (3, 4). Hopefully, the humanized antibody would not cause an inflammatory response.

Proving the Concept

Unfortunately, Genentech’s revenues were not keeping pace with its research expenses. The company marketed three products. Human growth factor, which prevented dwarfism in children, was never a big seller. Pulmozyme, a treatment for cystic fibrosis, was another specialty product. And Activase

(t-PA) dissolved blood clots to prevent heart attacks, but studies were showing that t-PA was no better than a competing drug that sold for one-tenth the price (2)

In February 1990, Roche Holding, Ltd., paid $2.1 billion for 60% of Genentech’s stock, with an option to buy the remaining shares over several years. One of the new owner’s actions was to cut the HER2 budget (2).

Genentech’s senior management defied that budget cut and continued to support HER2 (2). They authorized $3 million, which supplemented Slamon’s Revlon funds, to begin clinical testing. Slamon had already established a network of doctors in southern California who would refer patients to him. He thought he could conduct the bulk of the HER2 clinical trials at UCLA (2)

As part of the planning for the clinical trials, Genentech and Slamon developed clinical diagnostic tests to detect HER2. They needed to confirm that the women’s tumors overexpressed HER2, which was a requirement for enrollment (4)

While awaiting delivery of Carter’s humanized antibodies, they tested 4D5 in volunteers. Because of the anticipated immune response, 4D5 could be given to each woman only once. The trial enrolled 20 women with highly advanced breast or ovarian cancer, and they all overexpressed HER2 (2).

This “proof-of-concept” trial confirmed that a radiolabeled form of 4D5 bound selectively to the women’s HER2 cancer cells and caused no side effects (2, 4, 5).

Humanizing HER

Paul Carter made a series of humanized antibodies. One of them bound to the HER2 receptor three-times more tightly than 4D5. In tissue culture, it blocked proliferation of the HER2-positive breast cancer cells as effectively as 4D5 (3, 4). Preclinical tests showed that this humanized antibody, which was named trastuzumab, was non-toxic to animals.

Genentech wanted influential oncologists to conduct the Phase I trial and administer trastuzumab as a single treatment. Slamon, unfortunately, was not yet considered “influential,” and he wanted to give trastuzumab in combination with cisplatin. Cisplatin was a harsh drug and useless against breast cancer, but Slamon had shown that it enhanced the effect of the HER2 antibody in lab tests. At Genentech, Shepard confirmed those results, and he also advocated using the cisplatin-trastuzumab combo (2)

The HER2 clinical team compromised. The influential oncologists at Sloan Kettering and UCSF tested trastuzumab alone in women with advanced HER2positive breast cancer. At UCLA, Slamon was allowed to test trastuzumab in combination with cisplatin (2)

Barbara Agrees

In the summer of 1992, when Barbara Bradfield rejected her oncologist’s suggestion for a second round of chemotherapy, he asked her permission to send samples of her cancer cells to Slamon at UCLA (1). She said, “I don’t care. Go ahead” (2). She had plans to spend three weeks at a cancer clinic in Tijuana.

Shortly before she left, Slamon called and said that her tumor had one of the highest levels of amplified HER2 that he had ever seen. She was an ideal candidate for the Phase I trial, but she politely turned him down (1, 2)

The next morning, Slamon called again. Her decision had troubled him all night, and he urged her to reconsider (1, 2). He invited her to his lab at UCLA, where he convincingly described his research and the Phase I protocol in detail. Women would receive a three-month regimen of trastuzumab and cisplatin. Barbara decided to sign up.

At this point, Barbara’s lung tumor had metastasized to 16 new lesions, in addition to her neck tumor. The Phase I trial was designed to assess only safety, but within two weeks, Barbara’s neck tumor visibly shrank. After two months of treatment, it disappeared completely, and the lesions in her lungs had been reduced from 16 to about five (1, 2)

At the end of the three-month trial, Slamon and Genentech decided that the drug combination worked well enough to extend treatment for another three months, at least for some of the participants, including Barbara. Her extraordinary response continued. She eventually discontinued cisplatin because it caused nerve pain and hearing loss (2). Repeated tests showed her to be totally cancer-free (1, 2)

Not everyone was as fortunate as Barbara. Although half of the women experienced benefits, if temporarily, only five of the original 15 volunteers completed the 6-month trial. The results at Sloan Kettering and UCSF with trastuzumab alone were similar (2). Considering that these women were all thought to be beyond any treatment, the temporary remissions were powerful evidence of efficacy (1, 2).

The Phase I trial also demonstrated that repeated administration of trastuzumab did not trigger an immune response. And, it lacked the harsh side effects of chemotherapy drugs.

Things Get Active

By the summer of 1993, as Genentech was planning the Phase II trial, news of the Phase I results raced through the community of breast cancer patients, especially in San Francisco. Desperate women pressed Genentech for access to this new drug (1, 2)

Genentech resisted the pressure. Allowing women who did not fit the protocol’s strict enrollment criteria could severely compromise the data and might even invalidate the results. The Phase II trial was kept small and focused: 27 patients at Sloan Kettering, 16 at UCSF, and 39 at UCLA (1, 2)

But the activists’ protests and demonstrations created a public relations headache. Genentech realized they were dealing with an emotional and political issue that would not be appeased or deflected with intellectual and scientific responses. In early 1995, they acknowledged that the activists had a valid point of view and invited representatives to join the HER2 team as advisors (1, 2). They also agreed to permit compassionate drug access.

The problem was that supplies of trastuzumab were limited, and the clinical testing was already highly complex (2). The solution was a lottery. HER2-positive patients who had failed other treatment applied to the lottery, and about a dozen designated hospitals across the country treated the lottery “winners,” who were chosen at random. In exchange for the drug, the participating hospitals agreed to follow a specific protocol, guaranteeing that Genentech would get data on each woman (1, 2).

To avoid ethically difficult decision-making, Genentech outsourced management of this compassionate access program to an independent company (1). More than 300 women got the drug through the lottery, in parallel with Genentech’s clinical trials. In fact, data from the lottery patients ultimately helped Genentech win FDA approval (2)

The Critical Trials

While the Phase III trials were being planned, Genentech’s marketing department settled on a market-friendly trade name for trastuzumab. They named it Herceptin®: “Her” from the gene’s name and the obvious connection to a woman’s disease, “cept” for the drug’s ability to intercept the HER2 target protein, and “in” for its inhibitory action (1, 2)

The Phase III clinical program consisted of three trials. Trial 648 was the largest and would provide definitive data. As such, it would be randomized, double-blind, and placebo controlled.

Two smaller trials of 200 patients each would provide supporting data and were open-labeled. Trial 649 enrolled women whose metastatic disease had failed to respond to chemotherapy, and they received Herceptin alone. Trial 650 enrolled women who had newly diagnosed metastatic disease but did not want any chemotherapy. They were also offered Herceptin alone.

Because Genentech lacked experience in running Phase III clinical trials and had no oncologists on staff, Covance (a clinical research organization) was contracted to establish the trial infrastructure, recruit investigators, and monitor the clinical sites. By June 1995, Covance had set up 99 clinical sites in the US, seven in Canada, 33 in Europe, 10 in Australia, and

one in New Zealand (2)

In February 1995, Ginger Empey, a 50-year-old nurse in Bakersfield, CA, was diagnosed with breast cancer, and it had metastasized to her liver, ribs, and spine (2, 9). Unfortunately, surgery and chemotherapy in Bakersfield had no effect. Then, with Stage Four cancer, she received several rounds of chemotherapy at UCLA. There was no improvement, and the paclitaxel chemotherapy caused permanent nervous system damage (9). In June, her UCLA oncologist said, “Get your affairs in order” (9). A few days later, she called Dennis Slamon’s group.

Through her cancer support group, Ginger had learned about Slamon’s research and clinical trials (9). She submitted her tumor cells, which were highly HER2positive and qualified her for Trial 649. Unfortunately, arrangements for starting the trial were progressing slowly that summer. Ginger persisted. “I got real frisky” (9). She repeatedly called Slamon’s clinical coordinator and pushed the clinic to implant the infusion port, so she would be ready for her first treatment (9).

Finally, on August 31, 1995, Ginger received her first Herceptin infusion, the first patient in Trial 649. With that, Genentech’s Phase III program officially began (2). After 12 weeks, Ginger’s tumors had shrunk by 25%, and each following checkup showed them shrinking further (9)

Fairly quickly, other women around the world also enrolled in Trial 649 (2). Unfortunately, the pivotal 648 trial was having serious problems.

Problems and Solutions

At the end of 1995, only 21 of the required 480 patients had enrolled in Trial 648 (2, 10). The original protocol randomly divided women who were newly diagnosed with metastatic breast cancer into two groups. Half of them got chemotherapy plus Herceptin. The other half received chemotherapy plus a placebo infusion (11). The treating physicians monitored the patients for evidence of disease progression, at which point they were guaranteed access to Herceptin (10)

The FDA had insisted on a placebo arm and blinded evaluations, to ensure that the tumors were assessed impartially. But many patients disliked being subjected to the onerous infusion procedures when they might not be getting this new and promising drug (2).

Genentech also worried that doctors would be tempted to prematurely declare disease progression, so that the patient could be switched to Herceptin (10). Individual patients might benefit from the premature switch, but this could endanger Genentech’s ability to draw definitive conclusions about Herceptin’s efficacy.

To encourage enrollment, the Genentech team, in conjunction with Covance, made a number of changes to the 648 protocol. The biggest changes (in the summer of 1996) were to make the trial essentially open-label and to ensure that patients received a placebo for the shortest possible time. To eliminate bias by the treating physicians (who now knew the treatments of each patient), tumor evaluations were handled by an independent panel (2, 10).

This independent Tumor Response Evaluation Committee consisted of 10 radiologist-oncologist pairs, who did not know which patients were receiving Herceptin (2). The radiologists read the X-ray films, and the oncologists evaluated the lesions and assigned a response category using standardized definitions. Covance established procedures for checking inter-reader variation and ensuring that each pair of reviewers used the same criteria for assessing disease progression (10)

Covance also handled all of the logistics regarding shipment of materials and communications. The Committee’s assessments were fully integrated into the treating physicians’ activities, and information and decisions flowed seamlessly between the reviewers and the clinical sites (10)

Genentech and Covance managed to convince FDA officials, who were initially cool to the protocol changes (2) Those changes increased the enrollment rate by 500%, and all patients were enrolled by March 1997. Because of its success, this innovative solution inspired use of similar Committees in clinical trials of other drugs (10).

Race to The Finish

At that time, the average woman treated for metastatic breast cancer would suffer a recurrence 9 months after beginning treatment. Based on that, the Genentech statisticians calculated that they would need to follow all the women for 12 months to determine whether Herceptin offered any meaningful benefit (2, 10).

But because HER2-positive tumors were particularly aggressive, the women in the placebo group were experiencing cancer recurrence far more rapidly. As a result, the trial reached the time-to-progression endpoint faster. Trial 648 concluded five months earlier than the statisticians had originally calculated (2, 10)

The day after Thanksgiving 1997, Steven Shak, Genentech’s Herceptin team leader, flew to Los Angeles carrying a bulky briefcase. In the cocktail lounge of the Burbank Airport, Shak showed Slamon the final Phase III clinical results (2, 5).

Nearly twice as many women given the combination of Herceptin and chemotherapy saw their tumors shrink or disappear, compared to those taking chemotherapy alone (11). The Herceptin combination increased the time to disease progression by 65% (11).

For women who were taking paclitaxel (the most powerful breast cancer drug available at that time) as their chemotherapy agent, the results were especially impressive. Clinicians knew that when paclitaxel was given alone, it shrank tumors in only 16% of women (2) But nearly 50% of the women taking the combination of Herceptin and paclitaxel benefitted, a response rate unheard of in the investigators’ clinical experience (1,

11). And unlike chemotherapy, Herceptin had relatively few and comparatively mild side effects.

Shak also briefed investigators at the US National Cancer Institute (NCI). Throughout Genentech’s clinical trials, NCI had shown little interest in Herceptin, but they were impressed with the Phase III results. NCI agreed to take over management of the Herceptin compassionate access program. Its network of 32 comprehensive cancer care centers and several military hospitals offered women a broader choice of locations for receiving Herceptin until the FDA approved the drug (2).

The ASCO Show

Genentech submitted the Herceptin application to the FDA on May 1, 1998. Two weeks later, Slamon and Genentech’s Herceptin team gathered in Los Angeles for the 34th annual meeting of the American Society of Clinical Oncology (ASCO) (2)

On Sunday afternoon, May 17, 1998, most of the 18,000 ASCO delegates packed into the convention center’s massive amphitheater for a special session, “Her-2/ neu in breast cancer” (1, 2). A panel of four speakers presented the preclinical and clinical results. Slamon spoke last and summarized the results of the pivotal 648 trial, along with anecdotes about Herceptin’s lifesaving effect in patients like Ginger Empey and Barbara Bradfield.

Ginger had paid her own way to attend the ASCO meeting. For her, it was thrilling to mingle among the scientists and doctors and thank them personally. She was approaching 3 years of Herceptin treatment and remained cancer-free. “I had gotten my life back again” (2)

Barbara had taken Herceptin for only 18 months and was the longest survivor among all the trial participants, now more than 6 years (1, 2, 5). Like Ginger, she had been getting phone calls from desperate women who were unable to get into the clinical trials. With Herceptin’s approval, she said, “At least now it’s going to be possible to tell them…what to ask for, and they’ll be able to get it” (2).

Five months later, on September 25, 1998, the FDA approved Herceptin.

It Gets Better

Like most cancer clinical trials, Genentech’s Herceptin trials enrolled patients with metastasized and refractory tumors, where even small benefits of a drug would outweigh the risks. But the real value of Herceptin would come from treating women with early-stage breast cancer and who had never received any prior treatment (1).

In 2003, NCI launched two large multinational trials to examine this question (12). When combined, the results of the two trials showed that the overall survival of women treated with Herceptin was increased by 33%, an unprecedented benefit in the history of chemotherapy for HER2-positive cancer (1, 12). And Herceptin cut the rates of recurrence in half (12).

In 2006, FDA approved Herceptin for use in patients with early-stage breast cancer, before or after surgery, and either alone or in conjunction with adjuvant (radiation or chemotherapy) treatment (3). From the beginning, investigators noted that patients with the highest HER2 overexpression (like Barbara and Ginger) benefitted most from Herceptin treatment (11). Unfortunately, in some cases, women saw their cancer disappear in the lungs, liver, and bones, only to spring up as brain tumors (2). Recently, new small molecule HER2 inhibitors such as tucatinib penetrate the brain more effectively than Herceptin and have shown some efficacy against brain metastases (13)

Another strategy has also enhanced the efficacy against HER2-positive tumors: linking Herceptin to a “payload” chemotherapy drug. Herceptin seeks out the tumor and binds to the HER2 receptors on the cell surface. The chemotherapy drug is then uncoupled from Herceptin and kills the tumor cells (14, 15). This dual-action compound provides a large therapeutic index with limited systemic toxicity (3).

Herceptin-payload drugs like Enhertu® have proven effective against both advanced metastatic HER2- positive breast cancer and “HER2-low” tumors (3, 14, 15) These newly defined “HER2-low” tumors have HER2 expression that is intermediate between the traditional definitions of HER2-positive and HER2-negative, and account for 50-60% of all breast cancers (13-15).

Turning Point

Herceptin marked several major milestones in medicine. It was the first humanized monoclonal antibody approved for clinical use. For the first time, a drug had successfully attacked a genetic alteration in cancer, and it served as a model for many subsequent targeted therapies (3, 5).

This also marked the first time that the FDA had coordinated and simultaneously approved two products that were dependent on each other: Herceptin and the HER2 diagnostic test kit, HercepTest®. HercepTest was needed to identify women whose breast cancer tumors overexpressed HER2, because only they would benefit from Herceptin treatment.

Today, it is possible to profile every patient’s tumor for genomic alterations. Investigators and regulatory authorities now expect clinical trials of a molecularly targeted therapy to screen patients using genomic diagnostic tests (3).

Because Herceptin lacked the horrendous side effects (hair loss, nausea, infertility, etc.) that limits the use of chemotherapy drugs, it could theoretically be administered indefinitely. Ginger, for example, took Herceptin for more than 10 years and was then considered “cured” (9)

Finally, Herceptin opened the door for a new class of biologic drugs: monoclonal antibodies that were directed against diseases requiring long-term treatment. Newer monoclonal antibodies such as pertuzumab were developed with broader HER2/HER3 binding efficacy. And other types of non-immunogenic monoclonal antibodies have been developed to treat inflammatory diseases, osteoporosis, high cholesterol, infectious diseases, and many other conditions.

Over the years, Barbara and Ginger appeared in news articles about Herceptin, inspiring women to seek treatment (2). They have now remained cancerfree for more than 25 years. In 2019, Dennis Slamon, Mike Shepard, and Axel Ullrich received the LaskerDeBakey Clinical Medical Research Award for their invention of Herceptin (4).

References

1. Mukherjee S (2010) The emperor of all maladies. Scribner, New York.

2. Bazell R (1998) Her-2: The making of Herceptin, a revolutionary treatment for breast cancer. Random House, New York.

3. Sawyers CL (2019) Herceptin: A first assault on oncogenes that launched a revolution. Cell 179: 8-12.

4. Strauss E (2019) Herceptin—a targeted antibody therapy for breast cancer. Lasker Award for 2019; available from: https://laskerfoundation.org/ winners/herceptin-a-targeted-antibody-therapy-for-breast-cancer/.

5. Gable M (January 1, 2000) The culprit is cancer. UCLA Magazine; available from: https://newsroom.ucla.edu/magazine/cancer-dennis-slamonherceptin-her-2.

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Biosketch:

Rebecca J. Anderson holds a bachelor’s in chemistry from Coe College and earned her doctorate in pharmacology from Georgetown University. She has 25 years of experience in pharmaceutical research and development and now works as a technical writer. Her most recent book is Nevirapine and the Quest to End Pediatric AIDS. Email rebeccanderson@msn.com

In the next issue of The Pharmacologist…

Dr. Anderson will feature veterinary pharmacology. Don't miss the September 2023 issue.