Perseverance

“This part’s tough. It always gets me,” says Lisa, fighting back tears. She pauses for a moment as she retells the story of her second breast cancer diagnosis. After years in remission, it was back. And this time it had spread to her liver, lungs and bones. “In my mind I’m like: ‘You’re screwed. It’s everywhere. You can’t compete with this.’”

Lisa discusses her second breast cancer diagnosis

But after her terminal diagnosis, Lisa is alive. Small tumors remain throughout her body, and she still has stage IV breast cancer, but thankfully she’s been given more time to spend with her three sons. “I’m so glad,” she says. “Their hearts were broken when I got sick again.”

The information in this story represents a specific point in time when this article was published. The story is not being updated and no representation should be made concerning Lisa's current condition. The story should not be used as a substitute for professional medical advice.

For the last 30 years, scientists, doctors and patients have been engaged in a war against Lisa’s particular type of breast cancer – an especially aggressive form of the disease known as HER2-positive. Developing medicines to treat it has been an exceedingly difficult task and over the course of those decades, there were many moments when it seemed they could not succeed. Though the battle is far from over, the progress they have made not only gave hope to Lisa and others, but also helped to fundamentally change the way we fight cancer.

Cancer has been an all-too-common, formidable enemy for centuries.¹ Often caused by genetic alterations within our own DNA, it’s highly complex and extremely difficult to treat.

The discovery in 1976 that cancer-causing genes – or oncogenes – are present in our own cells signified a huge leap forward in our understanding of the disease.² But despite that breakthrough, in the years that followed, many unanswered questions remained. For example, scientists and oncologists still didn’t know why some people with cancer fared better than others on the available treatments.

Dennis Slamon M.D., Ph.D., director of clinical and translational research, University of California, Los Angeles, Jonsson Comprehensive Cancer Center

“It was frustrating,” says Dennis Slamon, M.D., Ph.D., director of clinical and translational research at the University of California, Los Angeles, Jonsson Comprehensive Cancer Center. “We had to pretty much look at the disease with a one-size-fits-all approach. We had one or two different regimens that we used for these patients and they had good outcomes or bad outcomes.”

He was determined to understand why. The oncogene discovery had opened the door to an exciting period in cancer research and by the early 1980s, scientists had already begun to build a clearer picture of the role that certain genes might play in cancer growth.³

A few hundred miles away in South San Francisco scientists at Genentech, including Art Levinson and Axel Ullrich, had been successful in cloning a number of cell growth-regulating genes as the company worked to develop medicines for a variety of different diseases.^4,5 Slamon was aware of their work and, along with oncologist Dr. Bill McGuire at the University of Texas at San Antonio, they teamed up to understand whether any of these genes might play a role in cancer. 

Using DNA probes that the Genentech team had created to identify the genes, they performed a series of experiments to see if any of them might be over-expressed in cancer tumors. One, in particular, stood out.

The gene, called HER2^6-10 instructs cells in the body to form receptors on their surface that send signals telling them to grow and divide.¹¹ It’s part of the normal mechanism that regulates the growth, division and repair of healthy cells. But in some of the breast cancer tumors, there seemed to be higher than normal levels of the gene.

In fact, they saw that about a quarter of the breast cancer tumors had an excess of HER2.^12,13 This meant each cell didn’t just have the standard of about 20,000 HER2 receptors but up to 2 million of them, triggering the cancer cells to replicate out of control and the tumors to grow.¹¹ People with this over-expression had what would eventually become known as “HER2-positive” breast cancer.

And thanks to the detailed medical histories that McGuire had collected on each sample in his tumor bank¹⁴ the team could see that, on average, women with these tumors had not responded as well to treatment. Their cancer had recurred more quickly and they also died more quickly. It appeared that having too many HER2 receptors didn’t just contribute to breast cancer; it was potentially the driver behind one of the most aggressive and deadly forms.¹²

The scientists had identified an enemy: HER2 was a new target in the war against breast cancer.

But how do you attack a target you’ve only just begun to understand? Determining a mechanism that could drive a specific type of cancer was a huge step forward for research, but it was only the first step. Creating a medicine to slow or stop it wasn’t going to be easy.

Mark Sliwkowski, distinguished staff scientist, Genentech

The scientists at Genentech believed that monoclonal antibodies – man-made copies of proteins that the body’s immune system creates to fight off bacteria and viruses – could be an answer. They were able to build mouse versions of these antibodies that would bind to the HER2 receptors on breast cancer cells and help block them from transmitting growth signals.^15,16 If these antibodies worked in people, they might not only stop tumors from growing, but possibly even shrink them.

It was an idea that scientists had been considering since the 1970s¹⁷ when “there was great hope that this would be the future of medicine,” says Paul Carter, now a senior director and staff scientist at Genentech. Unfortunately, no one was able to make it work in clinical trials. The trouble was, the human immune system saw mouse antibodies as foreign objects and rejected them. As a result, tests with these antibodies had been disappointing and showed little promise.^18,19

Paul Carter, senior director and staff scientist, Genentech

To get around that problem, Carter, together with colleagues Michael Shepard, Len Presta and their teams, took the sections of the mouse antibody that would bind to HER2 and grafted them onto a human antibody, cleverly disguising it so it wouldn’t be rejected – a so-called “humanized antibody.”²⁰

“I think people were actually astonished,” Carter says about revealing their research to management. “At the time there were very few examples of this having been done anywhere. There was real surprise.”

Success in the lab is one thing, but there were reservations about moving forward with developing a medicine based on Carter’s creation. All of the logic and evidence at the time suggested that it was too risky. The technology behind monoclonal antibodies was questionable. HER2 had only recently been identified as a potential target in cancer. And Genentech had never successfully developed a cancer medicine before. In fact, one of its first experimental cancer therapies had just failed in clinical trials.²¹ It seemed completely irrational that a small biotech startup would invest in a development program in such an uncharted area.

To get the body of evidence they’d need for Food and Drug Administration (FDA) approval of the medicine, the company would have to engage in large-scale clinical trials. Even if those were successful, could they manufacture enough of these antibodies to meet the need? Not only was there a huge difference in size between these and more common small-molecule medicines like aspirin, they were also far more complex than any of the large-molecule medicines Genentech had already developed.

For a period of time, the answer to the question of whether or not to develop the medicine was: No. Genentech decided the project wasn’t going forward.

“We were kind of stunned,” said Gail Lewis Phillips, a senior research associate at the time. “It’s not the kind of thing we expected and not what we wanted to hear.”

Gail Lewis Phillips, senior scientist, Genentech

That decision, however, was later reversed. There were a variety of reasons why. Scientists like Levinson and Shepard, who had worked so hard on the research, were determined not to give up; Dennis Slamon came by the offices regularly, stopping folks in the halls to talk about how impressive the data were; and Bill Young, a vice president who had recently learned his mother had breast cancer, became an advocate for the HER2 program. He knew that patients desperately needed more treatment options.

The development program for the antibody that would eventually become HerceptinⓇ (trastuzumab)  [Important Safety Information] was now official: It had funding and was moving forward. But no one on the team could have imagined the challenges that lay ahead. It would be years before they could build enough evidence to demonstrate the veracity of their breakthrough to the outside world.

In 1991 Barbara’s breast cancer was in remission. At the time she was mourning the loss of her daughter to a car accident. Cancer was the least of her worries. And then she discovered a lump in her throat near the collarbone. “I knew what that meant. I wasn’t surprised it came back,” she says.

Instead of seeking additional treatment, Barbara was going to Mexico, off for a vacation to get ready to say goodbye. Her doctor said he was sending her information to an oncologist in California working on understanding cancer genes. “I said, ‘I don’t care, do whatever you want.’” She had stage IV cancer; it had spread to her lungs. She says, “I already thought I was dying.”

Not long after, Barbara received a call from Dennis Slamon. Would she be interested in participating in a clinical trial for a potential new medicine? He explained to her what HER2 was and its role in her type of breast cancer, as well as the risks of participating in a clinical trial. “He sounded so logical,” Barbara recalls. “And then my husband made me go. ‘You have nothing to lose,’ he said.”

And so Barbara became one of the first women in the world to take the medicine that would become Herceptin. In the six years following the first trial, more than 900 others would volunteer to participate in clinical studies designed to better understand whether it was safe and whether it could help patients.²²

Today, Barbara is the only surviving member of the initial group of 15 women who participated in the first trial. Her outcome is far from typical. One of her fellow participants died from kidney failure within the first weeks of starting treatment. Another found the process too emotionally overwhelming, couldn’t handle the side effects anymore, and withdrew from the trial. “Being the only survivor is very emotional. We girls all pretty much bonded with the treatment. The whole attitude of everybody was we wanted to be part of something that would find a way to help,” she says.

Dennis Slamon M.D., Ph.D., director of clinical and translational research, University of California, Los Angeles, Jonsson Comprehensive Cancer Center

Slamon refers to all of those women as his colleagues. “That whole group left an amazing impression on me,” he says. “They’d played a critical role in this major part of history, this grand experiment about whether this targeted therapy would work. Everybody talks about targeted therapy today. Back then, there was no such thing.”

As the trials were being conducted, Genentech was inundated with requests from other breast cancer patients for Herceptin, hoping it could potentially help them. But the medicine hadn’t yet been proven safe and effective with enough data for FDA approval. Not to mention the simple fact that supply at the time was extremely limited; they were only able to produce enough for the clinical trials. The challenge of large-scale manufacturing for a medicine so complex had become a problem even before it was approved.

Nonetheless, Herceptin was a beacon of hope for metastatic breast cancer patients who had exhausted all other options. They weren’t going to give up, and they were outspoken about their need. Some even came down to Genentech with picket signs to campaign for access.^5,23 The company decided it would have to find a solution.

So in 1995 Genentech worked with patient advocates to set up one of the first FDA-approved expanded access programs for a cancer medicine. It would allow certain people who weren’t eligible for the trial to receive Herceptin before its approval.^5,23 According to patient advocate Bob Erwin, who worked with the company on the design and whose wife had succumbed to breast cancer, “Genentech pioneered the program at great cost to itself – not so much financial but stress, time and having to withstand a lot of negative critiques” as they worked out a way to fairly allocate their very limited supplies. However, looking back, “their overall positive experience caused other companies to look at programs like this more favorably.”

In 1998 results of the large Phase III trial needed for FDA approval were finally revealed and questions about the safety and efficacy of the medicine were answered. The data showed that in some cases treatment with Herceptin could result in a risk of serious heart problems. Doctors would need to monitor their patients’ heart function closely throughout and after treatment.  [Important Safety Information]

Gail Lewis Phillips, senior scientist, Genentech

But there was also some very positive news that finally justified the years of hard work. Adding Herceptin to chemotherapy had been shown to slow the progression of HER2-positive metastatic breast cancer.^24,25  [Important Safety Information]

Upon receiving the news, distinguished staff scientist Mark Sliwkowski walked into Lewis Phillips’ office. All he said to her was, “It worked.” She knew immediately what he was talking about. “It was a big deal,” she says. “We were jumping up and down and hugging each other.”

The first personalized treatment for cancer had arrived.²⁶ In 1998 Herceptin was approved in combination with paclitaxel chemotherapy by the FDA for HER2-positive metastatic breast cancer. [Important Safety Information] But in reality, scientists at Genentech were just beginning to understand the role of HER2 in cancer. And there were a lot of unanswered questions. For example, could they help some people live longer by treating them earlier – before their cancer had spread to other parts of the body? There was still so much more to be done to help people with the disease.

And so they pushed forward with new trials for Herceptin in early stage HER2-positive breast cancer, hoping that treating people earlier might help stop their cancer from returning or reaching a more advanced stage. The results, revealed during the American Society of Clinical Oncology (ASCO) annual meeting in 2005, were hailed as a huge success.

The data showed that, in combination with a type of chemotherapy, Herceptin cut the risk of people’s cancer coming back by half, compared to the chemo alone.²⁷  [Important Safety Information] Oncologists, scientists and researchers remember vividly the moment when the trial results were presented. From the podium, George Sledge, M.D., now chief of medical oncology at Stanford University Medical Center, summed up the data in one brief, but powerful statement: “Ladies and gentlemen, biology has spoken and we should listen.”²⁸

But for a small group of scientists at Genentech, that ASCO meeting was bittersweet. Despite the overwhelming joy of knowing Herceptin could help people with early breast cancer, there was also a disappointment.

As they had continued to study the role of HER2 they learned that it is not the only receptor on the surface of a cell that triggers growth and division: There are actually four different HER receptors, and in order to efficiently move those growth messages along, the receptors have to pair up.²⁹ They discovered that one of the original mouse antibodies they had created at the same time as Herceptin showed promise in stopping this pairing and blocking the growth messages in a different way.³⁰ Perhaps, they thought, a medicine derived from this antibody might help slow the growth of other types of cancer where HER2 was not over-expressed. [Important Safety Information]

Early studies in the lab suggested that idea might prove to be true. And so the Genentech team collaborated with colleagues at long-term partner Roche to carry out clinical trials for this potential medicine and begin the long, hard work of understanding how it behaved in the human body.

Unfortunately, results from Phase II trials, presented at that very same ASCO meeting, showed the drug did little to slow the growth of other types of cancers.³¹ Sliwkowski, who had worked on both projects, says the dichotomy was emotionally confusing. Herceptin was at its highest point, but their hopes for this new medicine had been dashed.

Little did they know at that moment that it wasn’t completely over for the drug that would eventually become known as PerjetaⓇ (pertuzumab). [Important Safety Information] Despite mounting evidence against it, the Roche development team decided to push forward with additional research and explore one final possibility: What if they tried combining Perjeta with Herceptin in HER2-positive breast cancer? What if the two medicines could work together, in complementary ways, to slow these cancers more effectively than either medicine alone?

According to Max Hasmann, a Roche scientist who was working on the project in Penzberg, Germany: “It wasn’t easy because in the beginning everyone would ask: ‘Why do you need two antibodies targeting the same target?’ After all, they had already developed Herceptin for HER2-positive breast cancer. Did they really need another medicine for the same thing?”

“It was scientifically plausible. Not standard, but still plausible,” says Sliwkowski. The approach was in stark contrast to how second-generation medicines are normally designed – with the objective of the second outperforming the first. But if the success of Herceptin had proved anything, it was that they didn’t always have to follow the standard way of doing things, they just had to follow their science.

And sticking with it turned out to be the right decision. The combination was a success, proven by results from a Phase III trial, dubbed CLEOPATRA. Adding Perjeta and Herceptin to docetaxel chemotherapy prolonged the time people with previously untreated HER2-positive metastatic breast cancer lived without their disease getting worse and helped them live longer overall.^32,33  [Important Safety Information]

On average, the Perjeta combination extended the lives of those who received it by almost 16 months compared to Herceptin and chemotherapy alone.^33,34 They lived a median of almost five years – the longest ever observed in people with this aggressive type of advanced breast cancer (56.5 months vs. 40.8 months).^33,34 It’s a significant result for a combination of medicines that almost never came to be.

Like Herceptin, Perjeta is associated with serious side effects and may cause heart problems. It carries a boxed warning because of these serious cardiac risks, and doctors must monitor patients’ heart function closely. Perjeta also has a boxed warning for the potential to harm an unborn baby.

Lisa discusses her decision to pursue treatment

In June 2012, the FDA approved Perjeta in combination with Herceptin and docetaxel chemotherapy for the first-line treatment of people with HER2-positive metastatic breast cancer.  [Important Safety Information]

Lisa is just one of the patients who has benefited since then, although not everyone has or will have the same experience as her. Looking back on her diagnosis, when she was so sure that her life had come to an end, Lisa says she didn’t have high hopes but was determined to try it for her boys. She’s so happy that she did and is grateful for the time with them. “My children are everything to me,” she says.

Though the advent of new cancer medicines has helped some people live longer, balancing the benefits with the potential side effects remains a challenge to this day. While their sole objective is to kill the cancer, the fact that they are delivered all throughout the body means that they can also affect healthy cells. Chemotherapy, for example, is designed to help kill rapidly dividing cancer cells but they’re not the only cells in the body that behave that way – healthy cells in places including the bone marrow, stomach, bowel and hair follicles replicate quickly too. It’s part of the reason why patients undergoing these treatments often experience side effects like infections, nausea, diarrhea and hair loss. But chemotherapy continues to play a fundamental role in treating many cancers.^35,36

Soon after the first approval of Herceptin, the team at Genentech wondered if they could harness the benefits of targeted medicine to somehow help reduce this collateral damage on healthy cells. The concept, called an “antibody-drug conjugate,” was another one of these ideas that scientists had been considering for decades but very few had been able to pull off.^37,38

The thinking was this: You can build an antibody to target a specific receptor on a cell. What if you could attach a chemotherapy drug to that antibody and deliver it directly inside the cancer cell?

Fred Jacobson, staff scientist, Genentech

“It was a research idea that had been around for at least 20 years by the time we started working on it. There were a number of companies that had been trying to take the idea and turn it into medicines. Very few of them had been successful,” says Fred Jacobson, a staff scientist at Genentech.

One of the main challenges was how to connect the chemotherapy to the Herceptin antibody. The molecular attachment, also referred to as the linker, turned out to be an important part of this new concept because it had a major impact on whether the medicine would be safe and effective. ^39,40,41 If the linkage holding the chemo molecule to the antibody wasn’t stable enough and was broken on the way to its target, then the powerful and highly toxic chemotherapy drug would be generally released into the body.^39,40

Genentech scientists spent several years working to find a linker and chemo combination that would remain intact and then break apart only once it entered the cell.⁴¹ To everyone’s surprise, the most successful version ended up being very different from what the team had originally envisioned: It was an unbreakable linker that worked best.

“It was sort of an ‘Ah Ha!’ moment,” says Jacobson. It turned out that, in some forms of cancer, even if the linker didn’t break, the antibody itself was broken down enough so that the chemotherapy was still capable of killing the cell.⁴¹

Following that discovery, in collaboration with Massachusetts-based ImmunoGen, the medicine that would become KadcylaⓇ (ado-trastuzumab emtansine) was born.  [Important Safety Information] Results of the Phase III EMILIA trial that led to its FDA approval in 2013 showed that it helped give certain people with HER2-positive metastatic breast cancer more time before their cancer got worse and extended their lives by almost six months compared to a standard treatment, at the time of the trial.^42-44

People receiving Kadcyla in the trial still experienced severe side effects, including nerve problems, low levels of red blood cells, tiredness, liver problems, pain, bleeding and constipation. Kadcyla also has boxed warnings for potential heart and liver damage, can also harm an unborn baby and must not be substituted for Herceptin. [Important Safety Information]

Much like Herceptin and Perjeta before, even after its FDA approval, scientists continued to study other ways Kadcyla might be able to help patients. As part of this effort, they conducted a large trial looking at a different combination involving Kadcyla, hoping it could help people with HER2-positive advanced breast cancer live even longer. But despite their belief in the science, they were disappointed to see that the combination didn’t work as they had hoped.

After many successes in the HER2 journey, it reminded the team that medicine development is rife with challenges and often you don’t get the result you want. “However,” says Ellie Guardino, M.D., Ph.D., oncologist and senior group medical director at Genentech, “You learn. This is science. If you get one answer, it leads to 10 more questions. And 10 more questions are what we’re after. All the incremental benefits that you get, in the end if you look from start to finish, are tremendous.”

When you ask the researchers, scientists and physicians what their takeaway is from these past 30 years, they’ll all agree that relentlessly pursuing the science wherever it leads is what has ultimately helped patients. Even when you have something that is proven to work, you don’t just pack up and move on. If you have failures in the development process, you learn from them, answer the new questions they create, believe in your data, and keep moving forward.

Mark Sliwkowski, distinguished staff scientist, Genentech

“Let’s understand the biology, let’s understand the target,” says Dietmar Berger, global head of oncology at Genentech. “If the target is important, work as long as you need in order to find a mechanism to effectively address it.” The approach, he says, was entirely new with the advent of medicines like Herceptin. After a time, it “turned the entire industry upside down.”

Before Herceptin, there were no targeted treatments for solid cancer tumors. In fact, there were also no “personalized” medicines tailored to individual patients paired with companion diagnostic tests.⁴⁵ When Herceptin was introduced, there also had to be a sea-change in the way cancer itself was diagnosed. To determine if the medicine would be appropriate, doctors would first have to test their patient's tumor to see if it was HER2-positive. It’s a common practice now that was unheard of two decades ago.²⁶ Today, the field of personalized medicine is widely regarded as one of the most important areas of drug development.

HER2-positive breast cancer is a particularly aggressive disease that once had a very poor prognosis. But today, on average, people who are diagnosed with it have better survival rates than those with HER2-negative cancer.⁴⁶ It’s a landmark shift in patient care.

And, in the end, helping people is what this is all about. The reason the scientists kept jumping into new and untested areas of research and the reason they persisted in saving projects that looked doomed to fail is because they believed in their data. And when the data give you hope that someday someone’s life might be saved, you don’t ever stop.

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The information in this story represents a specific point in time when this article was published. The story is not being updated and no representation should be made concerning Lisa's current condition. The story should not be used as a substitute for professional medical advice.