Slamon's Tenacity Advances the Field of Breast Cancer Research

Dennis J. Slamon, MD, PhD

The idea that one kind of cancer may include several subtypes, each marked by unique mutations that can be targeted with tailor-made therapies, is taken for granted these days.

Much of today’s research is focused on identifying hallmarks of cancer subtypes and developing medications to target them, and more than 65 targeted therapies for various cancer types are on the market in the United States.

Follow that trend back to its beginning and you’ll find Dennis J. Slamon, MD, PhD, standing on the starting line.

Slamon, now director of Clinical/Translational Research at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles (UCLA), conducted the laboratory work and testing that resulted in trastuzumab (Herceptin), the first molecularly targeted therapy for breast cancer. The monoclonal antibody made by Genentech helps counteract a mutation of the HER2 gene, which is found in about 25% of patients with breast cancer. It reduces recurrence rates by half in specific types of early HER2-positive breast cancer and by one-third in metastatic HER2-positive breast cancer, and increases survival rates by about 35% and 30% in early and metastatic disease, respectively, according to the researcher.

The intravenously administered medication was approved by the FDA in 1998, and within 10 years, it had been used to treat 420,000 women worldwide. Its approval also marks the moment that the area of targeted therapies for cancer really began to take off.

“That’s the area where things are moving the fastest—finding molecular heterogeneity and taking advantage of that to develop novel therapeutic approaches for subtypes, rather than one-size-fits-all approaches,” said Slamon. “That’s where a lot of effort is going on, not just by us, but in a number of labs around the world. Trastuzumab was one of the things that really broke that wide open.”

It’s an accomplishment that made Slamon the subject of both a Lifetime television movie, Living Proof, and a book by Robert Bazell, HER-2: The Making of Herceptin, a Revolutionary Treatment for Breast Cancer. His is a particularly intriguing story because the scientist had to fight for 12 years to get trastuzumab from development through approval, keeping the project alive despite a nearly crippling early lack of funding.

“We followed the data, and if it’s there and it says your approach is right, it doesn’t matter what anyone else’s preconceived notion is,” Slamon said. “We never gave up when people said we were wasting our time.”

Those achievements have been heralded worldwide, and they are certainly appreciated by OncLive. For bringing the world trastuzumab, helping to launch an important new path for cancer research, and developing additional promising anti-breast cancer drugs during a career that has spanned about 40 years, Slamon has been selected as one of OncLive’s Giants in Cancer Care for 2014, in the Breast Cancer category.

“I was honored, as I think were all the honorees, and I felt very good about being named among those peers,” Slamon said upon learning he would receive the award.

Striving For Further Discoveries

These days, Slamon is continuing his fight against cancer through his roles at UCLA. Serving as chief of its Division of Hematology-Oncology and also as a professor of Medicine, the doctor devotes about 30% of his hours to administrative duties, including raising money for research; another 20% to seeing cancer patients; and a small percentage to teaching and giving lectures.

He spends the remainder of his time—nearly half—reviewing data and considering where it might lead.

“The highlight of my day is to meet with mid- and junior-level investigators and see this new stuff,” he said. “With colleagues capable of pushing the agenda in a positive way, we can think about exciting ideas.”

One of the most promising recent developments to come out of Slamon’s lab has been palbociclib, an oral inhibitor of CDK 4/6 that was developed for the treatment of hematopoietic malignancies but was only mildly active in that cancer type. In February, the FDA granted accelerated approval to palbociclib, which Pfizer developed under the trade name Ibrance, in combination with letrozole as a first-line treatment for HER2-negative advanced or metastatic breast cancer in postmenopausal women.

Another project of Slamon’s lab has involved BMN 673, a PARP inhibitor being developed by BioMarin that targets BRCA1/2 mutations in patients with locally advanced or metastatic breast cancer, but that also may have promise for the treatment of triple-negative breast cancer, some breast cancers, and other malignancies, Slamon said. The drug is being tested in a phase III clinical trial.

Not surprisingly, Slamon and his colleagues are also continuing to work with trastuzumab.

In 2010, the drug was approved by the FDA for use in HER2-positive metastatic stomach cancer, in combination with chemotherapy. Now, Slamon’s group is considering potentially better ways to use the drug, such as in combination with other antibodies or other targeted agents.

“We’re looking at what other pathways you might be able to block in combination with HER2 to be more efficacious in any malignancy where the alteration is—breast and gastric, although some ovarian cancers, 8% to 10%, have the alteration, as well,” he said.

Paving The Way To A Meaningful Career

The son of a coal worker and a homemaker, Slamon knew from the age of 5 or 6 that he wanted to be a doctor, inspired by the physician who used to make house calls to treat his family.

“He was very caring, very gentle, and very effective,” Slamon recalled. “I thought it would be great to be able to help people like that and make a family feel so good.”

In high school in New Castle, Pennsylvania, a student teacher fueled Slamon’s interest by infusing his lessons about biology with enormous enthusiasm. Slamon moved on to Washington & Jefferson College, in his home state, excited to learn more.

“I took all but one of the biology courses the school had to offer, because I couldn’t fit any more into my schedule,” he said. “I loved the topic, the diversity of it, and the more I learned, the more I thought about combining my interests in biology and medicine.”

Slamon did exactly that, simultaneously earning his medical degree and doctorate in cell biology in 1975 through a combined MD/PhD program at the Pritzker School of Medicine at the University of Chicago.

It was there that he began the research that paved the way for trastuzumab. In the lab of Winston A. Anderson, PhD, a cell biologist in the Anatomy Department, and under the tutelage of Werner Kirsten, MD, of the Pathology Department, Slamon participated in research on retroviruses that caused cancer in mice.

“They were incredibly potent, more than anything we’d seen—acutely transformative retroviruses that caused cancer 2 to 3 weeks after injection,” Slamon said. “We learned, ultimately, that they were carrying an oncogene,” a gene with cancer-causing potential.

Long Battle, Long Hours On Path To Trastuzumab

That work led to a breakthrough several years later as Slamon completed a fellowship at UCLA’s Division of Hematology-Oncology.

“We realized that what these acutely transformed viruses were carrying that made them so potent were genes stolen from normal cells,” Slamon said. Once stolen, the researcher found, those genes—known as proto-oncogenes—were altered, becoming abnormal and contributing to the growth of cancer.

Slamon built on that knowledge in 1986, when he was asked by a Genentech researcher to look for siblings to the epidermal growth factor receptor, also known as HER1, a protein that sits on the surface of a cell and can cause cancer if mutated. One of the six genes Slamon was asked to investigate was HER2, and the results intrigued him.

“In 25% of breast tumors, we saw an alteration of gene amplification, an overabundance of numbers of the HER2 gene,” Slamon recalled. “Then, we realized that women whose tumors contained the alteration had a much different outcome. They had a more aggressive tumor that recurred more rapidly, and they died more quickly.”

The chilling finding proved something that would help change the face of cancer treatment.

“It told us right away that we were not dealing with one disease in breast cancer,” Slamon said, “even though the dogma at the time was that each disease was a monolith, defined by the tissue where it arose and treated with a one-size-fits-all approach.”

To Slamon, HER2 looked like a perfect target for treatment with an antibody, but not everyone agreed.

“No one was interested in pursuing antibodies because so many had failed,” Slamon said. “I was trying to convince Genentech to stay with the program based on the data, and it took a couple of years of hard sell. The company wasn’t terribly enthused, but there was a core of people there who believed in the data and kept the project alive.”

Lining Up Private Funding

Luckily for Slamon, there were also private funders who felt certain he was on the right track.

One was Lilly Tartikoff (now Lilly Tartikoff Karatz), whose husband, Brandon, then president of NBC’s Entertainment Division, had been treated for cancer by Slamon. The other was Tartikoff’s friend, Ronald O. Perelman, chairman of Revlon, whom Tartikoff approached for support.

Initially, Slamon recalled, Perelman donated $1.8 million to help with his research. In 1995, Perelman gave $7.5 million to establish the Revlon/ UCLA Women’s Cancer Research Program, which Slamon still directs.

Millions more have been raised for Slamon’s research, first through an annual Fire and Ice Ball founded by Tartikoff and Perelman, and now through the yearly Revlon Run/Walk. There’s one Run/Walk in Los Angeles and one in New York, which together largely fund the translation of work from Slamon’s lab into clinical trials, he said.

“Lilly told me what amazing work Denny was doing, and said that if he only had the funding, he could help many people,” recalled Perelman, who also is CEO and chairman of MacAndrews & Forbes Holdings. “After meeting him and seeing the potential in what he was working on, I immediately wanted to get involved. Denny is one of the most brilliant and dedicated researchers in medicine today, and his work has saved many women’s lives. I am so proud to have been able to help him accomplish that.”

A major supporter of Slamon’s preclinical work has been the US Department of Defense’s Breast Cancer Research Program, through its Innovator Award, the doctor added.

With funding still difficult to come by for many scientists, Slamon wants to see every grant and donation used as effectively as possible. That’s why the researcher spent 3 years as part of a Dream Team put together by Stand Up To Cancer, a project of the Entertainment Industry Foundation that utilizes the star power of celebrities to raise funds aimed at slowing the competition between labs and bringing them together to collaborate.

“The idea that one lab will make progress quickly is archaic,” he said. “Putting funds behind the effort to bring labs together is a good experiment.”

While Slamon’s grant through Stand Up To Cancer has been completed, he remains convinced that collaboration between labs is essential.

“That’s still the ideal way to do research, although I’m not sure we’ve yet mastered it,” he said. “There are still improvements we can have on that model, but I think that kind of collaboration, team research, can be conducted and is the best way to approach problems on a given drug.”

Regardless of the format, Slamon is committed to continuing the work that was his childhood dream—and the embodiment of the values he absorbed during those years.

“My parents taught us that doing something productive that could help others was the pinnacle of what you might want to achieve,” he recalled. Accomplishing that through the development of trastuzumab was “enormously gratifying,” he added. “It’s what it’s all about.”

Saluting the “Quintessential Mentor”

Richard Finn, MDAssistant Professor, MedicineGeffen School of Medicine at UCLACo-Director, JCCC Signal Transduction and Therapeutics Program AreaJonsson Comprehensive Cancer CenterLos Angeles, CA

“I have worked with Dr Slamon since I wandered into his laboratory as an undergraduate at UCLA. Dennis has been the quintessential mentor: inspiring, supportive, and constructive. Other than my parents, it’s hard to think of someone who has influenced me so much.

“His seminal observation in linking HER2 amplification to outcomes in breast cancer led to a paradigm shift in our approach to not only breast cancer but all of oncology. He then drove the approval of trastuzumab, the epitome of bench-to-bedside oncology.

“He brings a drive for basic scientific investigation that does not lose sight of the main objective: improving the outcomes of patients. It is no coincidence that his contributions have led to both the approval of not only trastuzumab, but also of palbociclib. I am fortunate to be able call him a friend and colleague.”

“There are few people in the oncology community who have had a greater impact on developing drugs for cancer than Dennis Slamon. The preclinical work and follow-on clinical trials that he has led have led to curative and life-prolonging therapy for breast cancer patients around the world.

“This research pedigree, which has now continued with the development of a new targeted therapy palbociclib, is the gold standard for a translational researcher who has had a direct impact on patients.”

DR SLAMON’S SELECTED PAPERS

• Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study [published online December 16, 2014]. Lancet Oncol. 2015;16(1):25-35.
• Perez EA, Press MF, Dueck AC, et al. Immunohistochemistry and fluorescence in situ hybridization assessment of HER2 in clinical trials of adjuvant therapy for breast cancer (NCCTG N9831, BCIRG 006, and BCIRG 005) [published online February 19, 2013]. Breast Cancer Res Treat. 2013;138(1):99-108.
• Wainberg ZA, Anghel A, Rogers AM, et al. Inhibition of HSP90 with AUY922 induces synergy in HER2-amplified trastuzumab-resistant breast and gastric cancer [published online February 8, 2013]. Mol Cancer Ther. 2013;12(4):509-519.
• Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. New Engl J Med. 2011;365(14):1273-1283.
• Valero V, Forbes J, Pegram MD, et al. Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens [published online November 29, 2010]. J Clin Oncol. 2011;29(2):149-156.
• Hurvitz SA, Allen HJ, Moroose RL, et al. A phase II trial of docetaxel with bevacizumab as first-line therapy for HER2-negative metastatic breast cancer (TORI B01). Clin Breast Cancer. 2010; 10(4):307-312.
• O'Brien NA, Browne BC, Chow L, et al. Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib [published online May 25, 2010]. Mol Cancer Ther. 2010;9(6):1489-1502.
• Slamon DJ, Press MF. Alterations in the TOP2A and HER2 genes: association with adjuvant anthracycline sensitivity in human breast cancers [April 28, 2009]. J Natl Cancer Inst. 2009; 101(9):615-618.
• Jones LW, Haykowsky M, Peddle CJ, et al. Cardiovascular risk profile of patients with HER2/neu-positive breast cancer treated with anthracycline-taxane-containing adjuvant chemotherapy and/or trastuzumab. Cancer Epidemiol Biomarkers Prev. 2007;16(5):1026-1031.
• Mass RD, Press MF, Anderson S, et al. Evaluation of clinical outcomes according to HER2 detection by fluorescence in situ hybridization in women with metastatic breast cancer treated with trastuzumab. Clin Breast Cancer. 2005;6(3):240-246.
• Tripathy D, Slamon DJ, Cobleigh M, et al. Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. J Clin Oncol. 2004;22(6):1063-1070.
• Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2002;20(3): 719-726.