HER2, Hollywood, and the Miner's Son: The Inspiring Journey Behind Herceptin, the First Monoclonal Antibody for Breast Cancer

As the world’s first monoclonal antibody drug for treating HER2-overexpressing metastatic breast cancer, Herceptin has provided safer and more effective treatment options to millions of female patients worldwide since its launch in 1998. Through more than a decade of collaborative efforts among researchers from academia, hospitals, and industry, this medication was finally made available to women in urgent need of effective therapy. As a landmark achievement that ushered in the new era of targeted therapies, the development of Herceptin is backed by a tortuous yet remarkable story. In 2019, Nobel Laureate Michael Brown remarked, “This victory stems from the collaboration between an academic clinician-scientist and a pharmaceutical company.”

On the morning of May 17, 1998, bright sunlight bathed the gray concrete buildings and empty parking lots surrounding Ninth Street. This was a scene unique to Los Angeles, with its vast expanse and flat terrain. The streets in downtown were deserted, yet the massive Los Angeles Convention Center was teeming with people. Men and women in suits, wearing name badges, hurried about in search of conference rooms. Journalists from media outlets such as People magazine and CNN navigated through the crowded corridors, seeking stories compelling enough to capture attention.

19,000 physicians and scientists, along with hundreds of journalists, gathered at the annual meeting of the American Society of Clinical Oncology (ASCO).

On the day of presentations that brought together the nation’s most distinguished cancer researchers, one scientist’s talk was particularly anticipated. Dr. Slamon, Director of the Revlon/UCLA Women’s Cancer Research Program, has attended countless academic conferences and addressed innumerable audiences. Although he may outwardly resemble the stereotypical researcher, he also frequently appears at high-profile fundraising galas and parties in Beverly Hills, mingling with Hollywood celebrities. Yet throughout Dr. Slamon’s entire career, no occasion has been more significant than today.

At the 9:00 a.m. press conference this morning, he will announce the latest clinical trial results for a new breast cancer drug named Herceptin. This can be said to be the crowning achievement of his life’s work.

Growing up in New Castle, Pennsylvania, Slamon had frequent encounters with doctors from an early age. This was not because he was frail or sickly, nor because his family members were renowned local physicians. Like most families who had guarded local industries in small towns for generations, Slamon’s father, Joseph, spent the majority of his life working in coal mines—tough, cautious, and dutiful. After miraculously surviving two mine collapse accidents, Joseph chose to retire, only to tragically lose a leg in a car accident.

House calls by physicians were a commonplace occurrence for this family, yet they left a profound impression on the young Slamon. Even at an early age, Slamon could perceive the professionalism of the medical community, observe how they alleviated patients’ suffering, and witness the respect his parents accorded them. Slamon found the profession truly captivating.

In the mining town of New Castle, pursuing higher education was often not a top priority; sons typically followed in their fathers’ footsteps by entering the mines or coalfields. Young Slamon did not take this path. “My parents never made me feel that there was something I couldn’t do. They always told me that if it was what I wanted, I could go for it.” His subsequent academic journey thus unfolded quite naturally. Slamon devoted himself to his studies and achieved outstanding results. During high school, he developed a strong interest in biology and began to consider how to integrate his passions for medicine and biology.

Dr. Slamon, who earned his M.D. and Ph.D. from the University of Chicago, came to UCLA in 1979 as a fellow in oncology. At that time, researchers had already begun to explore the potential role of genetic defects in cancer. Dr. Slamon was deeply interested in this field of research and secured a small grant from the school’s Jonsson Comprehensive Cancer Center to begin screening genes in his laboratory. This work involved multiple cell lines and animal models, making it a time-consuming and laborious endeavor.

After some time, Dr. Slamon began to ponder: given the already substantial workload, what if his team were to study human tumor cells? This seemingly logical idea was, in fact, highly risky at the time. Human tissue samples do not consist solely of cancerous cells; they also contain a significant number of normal cells. Therefore, great caution was required when interpreting the results.

In 1982, Dr. Slamon submitted a grant application to the National Institutes of Health (NIH) to establish a human tumor bank, aiming to screen discarded tissues from breast, prostate, colon, and lung cancers for specific genetic alterations. Unfortunately, this seemingly arduous and unrewarding proposal was rejected by the NIH. Undeterred, Dr. Slamon and his team secured support from the Jonsson Cancer Center Foundation and UCLA, allowing them to continue advancing the human tumor bank initiative.

Dr. Slamon’s persistence ultimately paid off. He understood that most oncogenes are mutated forms of genes that regulate cell growth and division, and that Dr. Ullrich, a German cancer researcher, had already isolated numerous growth-regulatory genes. Coinciding with Dr. Ullrich’s visit to UCLA for a lecture, Dr. Slamon seized the opportunity to engage him in discussion. Aware that Dr. Ullrich possessed the genes encoding growth factors and their receptors—chemical messengers responsible for transmitting signals for cellular growth and division within the body—Dr. Slamon sought to determine whether any of these genes were associated with cancer. The collection of cancerous tissue samples compiled by Dr. Slamon appeared to be ideal for investigating potential links between Dr. Ullrich’s growth factor genes and specific types of human cancer. Over dinner at a Thai restaurant in Santa Monica, the two researchers reached an agreement to collaborate: Dr. Ullrich would provide DNA samples from his gene library, and Dr. Slamon would attempt to match them with DNA extracted from his tumor sample collection.

Dr. Slamon, who was still in the early stages of his career, had limited research funding at his disposal. Consequently, he hired Levin, a freshman at UCLA, and taught her how to identify correlations between oncogenes and tumors. Now a physician, Dr. Levin practices as an oncologist in San Diego, yet she vividly recalls sleeping on the laboratory floor during her undergraduate years. In her recollection, extracting tumor DNA was a laborious task. It involved taking a small piece of tissue from tumors frozen in liquid nitrogen, grinding it up, extracting the DNA, and then examining each gene individually for abnormalities.

One Saturday afternoon in June 1986, the breakthrough came. “My heart began to race,” said Dr. Levin, when she discovered that the HER-2 gene matched a breast cancer tumor. “It was the Eureka moment every scientist dreams of.”

Meanwhile, academic and commercial laboratories across China are isolating new genes. In 1984, Dr. Weinberg, a scientist at MIT, discovered an important gene involved in the regulation of cell growth. That gene is HER-2/neu—human epidermal growth factor receptor 2.

Dr. Slamon had become even more convinced that his approach was logical, yet many of his peers remained skeptical. The research conducted in his laboratory was even likened to “looking for a needle in a haystack.” Dr. Slamon, of course, did not take such criticisms too seriously. In his view, while this analogy was not entirely without merit, once the team identified a mutation, they would be capable of undertaking more challenging tasks: isolating the gene and introducing it into breast cancer cells to determine whether it was truly associated with adverse outcomes. That, he believed, was the most exciting aspect of science.

Dr. Slamon and his team began extracting DNA from breast cancer tissues and posed the following questions: Has the HER-2/neu gene undergone alterations? Has its structure experienced some form of rearrangement? Has its expression pattern changed?

Evidence has confirmed this to be true. In cells, there is typically only one copy of HER-2, but Dr. Slamon discovered multiple copies in approximately 30% of breast cancer samples. “This gene produces a substance known as a growth factor receptor, which is a protein that acts like an antenna situated on the cell membrane, receiving signals from outside the cell that instruct it to grow.”

Then, Dr. Slamon compared female patients with this genetic variation to determine whether their tumors differed from those in women without HER-2. As expected, women with this variant had more aggressive breast cancer: standard treatments failed in all cases, their cancers metastasized more rapidly, and they had shorter survival times.

Dr. Slamon had higher expectations for further progress, but he had not yet proven that HER2 is the cause of uncontrolled cancer cell proliferation. This alteration might merely be a biomarker, what scientists refer to as an epiphenomenon occurring concurrently with the true culprit driving the cancer. “If we can understand what disruption in normal cells causes them to become cancerous,” said Dr. Slamon, “then we can develop smarter drugs that target only cancer cells without affecting healthy ones.”

Dr. Slamon began testing monoclonal antibodies from various biotechnology companies and university laboratories. During his collaboration with Dr. Ullrich, Dr. Slamon tested a monoclonal antibody developed by Genentech on cancer cells in petri dishes. When the monoclonal antibody was added to HER-2-positive breast cancer cells, the cancer cells stopped growing and dividing. When the researchers removed the antibody, the cancer cells resumed growth. The antibody had no effect on other cells in the petri dishes. The monoclonal antibody tested was Herceptin.

At that time, Dr. Slamon had sufficient data to proceed with clinical trials. In 1987, he and Dr. Ullrich published their findings in Science. However, Genentech, which held the rights to the drug, was reluctant to become heavily involved. Due to the frequent failures of previous cancer drug trials and the fact that chemotherapy and surgery remained the gold standard for cancer treatment at the time, Genentech exercised considerable caution regarding further collaboration.

Fortunately, there were still individuals willing to move forward alongside Dr. Slamon. At Genentech, a core team of scientists led by Dr. Shepard placed their trust in the scientific research conducted by Dr. Slamon and Dr. Ullrich. Even so, it took years of persistent persuasion by all parties involved to ensure the project’s continued operation. Whenever an opportunity arose, Dr. Slamon would fly from Los Angeles to San Francisco to present data to Genentech’s executives.

By 1989, Dr. Slamon had sensed that his research was drawing ever closer to its ultimate outcome. However, to break through the final barrier, he needed sufficient funding to accelerate and expand upon his findings. While research grants were certainly the optimal choice, the difficulty of the application process and the protracted approval cycles left him, despite his boundless energy, at a loss. Dr. Slamon stood at a critical juncture in his destiny.

When worrying about where to secure research funding, Lilly Tartikoff was certainly the last person Dr. Slamon would have thought of.

Sixteen years ago, Dr. Slamon saved the life of Lilly’s husband, Brandon Tartikoff, in his capacity as a physician. Brandon, then president of NBC, had unfortunately been diagnosed with Hodgkin’s lymphoma. Although his attending physicians at the time assured him that he had recovered, Dr. Slamon later discovered during follow-up examinations that Brandon still had active Hodgkin’s lymphoma and administered a more effective novel therapy. After Brandon’s recovery, a deeply grateful Lilly pledged to raise funds for Dr. Slamon’s research projects.

At that time, Dr. Slamon’s research on genes was just getting underway, and he never imagined that a Hollywood socialite would truly take an interest in the work being conducted in his laboratory.

In 1989, when Dr. Slamon felt he was just one step away from a breakthrough, he began exploring various unconventional avenues to secure research funding, including reaching out to Lilly. To Dr. Slamon’s great surprise, Lilly had been eagerly anticipating this opportunity. Lilly, who had previously served as a consultant in the cosmetics and beauty industry, believed she could approach a major corporation like Revlon—one that prided itself on appealing to everyday American women—to fund the team’s research into combating diseases that affect hundreds of thousands of women each year.

Although Lilly did not personally know Ronald O. Perelman, the New York tycoon and CEO of Revlon, she sincerely wrote a letter to introduce herself and advocate for Dr. Slamon. Initially, her efforts yielded no progress, but as if by fate, she happened to encounter Perelman while dining with friends. The determined Lilly spoke about Dr. Slamon’s important work, and Perelman agreed to send a Revlon representative to UCLA.

That summer, Jim Conroy, a special advisor to Revlon, met with Dr. Slamon and Dr. Glaspy. Dr. Glaspy was a scientist at the Jonsson Comprehensive Cancer Center, conducting research on bone marrow transplantation and nutrition-related studies associated with breast cancer. Dr. Slamon presented his findings on HER-2 to Conroy. He indicated that this genetic alteration might play a pivotal role in breast cancer, but further research was needed to substantiate this hypothesis. Meanwhile, he also expressed his intention to initiate testing of antibodies targeting HER-2.

At the conclusion of his remarks, Dr. Slamon cited a figure: if their laboratory had relied solely on federal grants, their progress would have been delayed by approximately three years. During that period, an additional 120,000 women might have died from breast cancer.

Dr. Glaspy was more direct: “The number of deaths could fill an entire football stadium.”

With a stroke of his pen, Perelman signed off on the funding for Dr. Slamon, establishing a three-year grant worth $800,000 annually, totaling $2.4 million. As financial support from a U.S. company to a single research team, this donation was unprecedented. Moreover, Perelman imposed no restrictions on the use of these research funds, allowing Dr. Slamon full discretion in their allocation.

What does $2.4 million in research funding actually mean? It would require four separate grants from the National Cancer Institute to reach a comparable scale, assuming all four were approved—a feat in itself, given how difficult it is to secure even a single grant. Yet Revlon resolved this issue with a single donation, eliminating the need to complete applications, submit proposals, or endure an eight- to twelve-month waiting period. This contribution enabled Dr. Slamon to pursue promising research leads almost immediately.

This success was made possible by the seamless collaboration between Lilly and Dr. Slamon. He delivered robust, credible, and compelling scientific findings, while she leveraged her capabilities and determination to raise millions of dollars for research. When Lilly needed support, Dr. Slamon would meet with CEOs of Fortune 500 companies or executives from Hollywood film studios, helping them understand the significance of this work and inspiring their emotional commitment to the cause. Meanwhile, Lilly organized a series of charitable fundraising events, such as the “Fire and Ice Ball” and the “Revlon Run/Walk.” In the years that followed, Lilly and Perelman jointly raised more than $17 million in total for Dr. Slamon, the Revlon/UCLA Women’s Cancer Research Program, and other women’s health research initiatives at UCLA.

In 1990, Dr. Slamon set out to answer the next critical question regarding HER2: Was it the defective gene that caused lethal tumors, or were other factors involved? To find the answer, researchers introduced HER2 into normal human breast cells. As expected, the cells grew more rapidly and exhibited more malignant behavior. The experiment was then repeated in mice, yielding entirely consistent results. Dr. Slamon demonstrated the link between HER2 and breast cancer.

One final challenge remained: Could researchers find a way to target HER2 and mitigate its overtly destructive effects? Dr. Slamon developed antibodies, invited other experts from academic and commercial pharmaceutical laboratories, and began systematically testing their effects on tumor cells. After more than a dozen attempts, Herceptin, produced by Genentech, proved effective.

Herceptin not only acts on HER-2-positive cells; when researchers applied the antibody to cells lacking this mutation, it had no effect. This is good news, demonstrating that the antibody is specific and unlikely to affect cells without this mutation. In mice, the results were entirely consistent: Herceptin inhibited tumor growth. Since the antibody had proven effective in laboratory studies, Dr. Slamon and Genentech met with the FDA and obtained approval to test the drug in patients with advanced breast cancer.

Dr. Slamon’s chances of success remained slim. When UCLA researchers initiated the Phase I clinical trial of Herceptin, many scientists—including some within Genentech itself—remained skeptical. After all, at that time, no antibody had ever succeeded in cancer treatment.

But Dr. Slamon’s intuition once again prevailed over the difficulties: early studies demonstrated that Herceptin was relatively safe. In the summer of 1995, the pivotal Phase III trial commenced. Ultimately, 940 critically ill yet hopeful women from more than 120 institutions worldwide participated in this groundbreaking study.

Fast-forward to the day before Thanksgiving in 1997. Dr. Slamon received an unexpected phone call at home. It was from Steve Shak, a research coordinator at Genentech. Steve’s exact words were that he “needed to meet with Dr. Slamon immediately.”

“Can you tell me what this is about?” Dr. Slamon asked.

“I’d rather tell you in person,” said Shak.

“It’s already late today, and tomorrow is Thanksgiving,” said Dr. Slamon. “How about Monday?”

“The best time is now.”

On Friday, Dr. Slamon met with Shak at a bar in Burbank Airport. Shak carried a briefcase filled with documents and charts containing information from the Phase III clinical trial. The results were nothing short of breathtaking. In this pivotal trial, 234 patients with advanced breast cancer who received the best available chemotherapy were compared with 235 women who received chemotherapy plus Herceptin. The addition of Herceptin significantly enhanced the efficacy of chemotherapy. Among the women receiving the experimental drug, nearly 50% experienced either complete disappearance of their cancer or at least a 50% reduction in tumor size. More importantly, their cancer did not recur as rapidly as had been expected.

The study also confirmed the lethality of HER-2-positive tumors. When paclitaxel, a chemotherapy agent then considered one of the best treatments for breast cancer, was used as monotherapy, only 16% of patients experienced improvement in their cancer. In contrast, under normal circumstances, at least 65% of patients respond positively to intensive chemotherapy.

Upon seeing these astonishing results, Dr. Slamon was unsure whether to laugh or cry, but he and Shak did share several drinks in succession.

Upon receiving these encouraging results, Dr. Slamon immediately called Lilly. Poignantly, Lilly’s husband, Brandon, had passed away a year earlier due to a recurrence of Hodgkin lymphoma. Although thrilled by the update, Lilly could not feel entirely at ease or joyful. “I celebrate for all women and am happy for Dr. Slamon. He is a natural visionary.”

Let us cast our minds back to 1998, at the annual meeting of the American Society of Clinical Oncology (ASCO).

Dr. Slamon sat at a long table alongside four other cancer experts, while the conference room was packed with television cameras and journalists. He had deliberately chosen a sharp, dark brown double-breasted suit for the occasion. As the last speaker, he waited his turn, occasionally glancing at his notes, his long fingers tightly gripping a bottle of mineral water.

Finally, Dr. Slamon slowly rose from his chair, his nearly 1.9-meter-tall frame unfolding as he made his way to the podium. Amidst the incessant clicking of cameras, he began to recount the story of HER2 and Herceptin in a steady, understated voice.

“One patient who took this medication for only 18 weeks survived for nearly six years.”

“Another patient still receiving this antibody has survived for five years.”

“For many patients, this therapy delayed disease progression by three months.”

Given that patients with this aggressive form of breast cancer typically die within 18 months, and sometimes in less than a year, the results presented by Dr. Slamon are remarkable.

Furthermore, although chemotherapy for breast cancer often produces many severe side effects, Herceptin’s side effects are relatively few and mild. Dr. Slamon told the attentive audience that the team was highly confident that better dosing regimens would be identified. The FDA is also expected to issue its decision on Herceptin by the end of this year. Once Herceptin receives FDA approval, it will very likely be used to treat early-stage breast cancer, potentially even at earlier stages than those seen in patients enrolled in the UCLA trial.

No one had ever succeeded in tackling the genetic mutations underlying cancer. This resilient UCLA scientist achieved that breakthrough. He has pioneered a new frontier in cancer treatment.

Dr. Slamon has made prudent use of the funds raised by Lilly to support subsequent groundbreaking research. Ronald O. Perelman’s generous funding is currently supporting nutritional studies in breast cancer patients, improving the success rate of bone marrow transplantation, and financing laboratory research on the P53 gene (which is mutated in 50% to 60% of ovarian cancer patients).

Dr. Slamon also leveraged these resources to educate women on the critical value of clinical trials to patients and medical research, while establishing a network of outreach programs at community clinics throughout Southern California.

“I truly don’t believe we succeeded because we were smarter than others; rather, we believed in something earlier than anyone else. We believed that developing new therapies by screening for genetic variations in tumors was an endeavor worth pursuing.”

In September 1998, Herceptin received FDA approval for market launch, fundamentally transforming the standard of care for breast cancer. Following its introduction, 85% of patients treated with Herceptin had an expected survival exceeding 10 years. Eight years later, in 2006, Herceptin was demonstrated in clinical trials to reduce the risk of postoperative cancer recurrence by 52% and mortality by 33% when used as adjuvant therapy.

Herceptin also delivered substantial returns for Genentech. Within just a few months of its market launch, sales reached $22 million; in the following year, they approached $190 million, and by 2004, annual sales surpassed $1 billion for the first time. In 2018, twenty years after the approval of its first indication, Herceptin’s global sales peaked at $7.1 billion. To date, this medication has provided treatment to more than 2.3 million female patients.

Herceptin is the first monoclonal antibody targeting an oncoprotein and the first monoclonal antibody used for breast cancer. The advent of Herceptin ushered in the era of targeted therapy.As of today, HER-2 remains one of the most prominent therapeutic targets.