The Culprit Is Cancer

Editor’s note: This is an article from the Fall 1998 issue of UCLA Magazine.

On the morning of May 17, early, the streets of downtown Los Angeles were deserted. Bright sunlight spilled over the gray buildings and empty parking lots around Figueroa and 9th. But inside the sprawling Los Angeles Convention Center, the scene was anything but quiet. Men and women wearing suits and name tags rushed about looking for meeting rooms. Media from Germany and France, as well as from People magazine and CNN, roamed the hallways, looking for a sexy story. All told, some 19,000 physicians and scientists and hundreds of members of the press had converged on the annual meeting of the American Society of Clinical Oncology.

On this day of presentations by the nation’s most esteemed cancer researchers, there was one scientist in particular many were eager to hear. Dr. Slamon had attended countless conferences in his 20 years as a scientist and faced many audiences. As director of the Revlon/UCLA Women’s Cancer Research Program, the 49-year-old researcher had even become something of a celebrity, mingling with Hollywood stars at gala fundraisers and Bel-Air dinner parties. But in all of Slamon’s career, no conference was more critical than this one. Today, at a 9 a.m. press conference, he would announce the final trial results of a new breast cancer drug called Herceptin. This would be the culmination, in essence, of his life’s work.

In a room of the convention center down the hall from where Slamon would meet the press, a small, cheerful woman with blonde curls was waiting to tell her story. Ginger Empey had driven 110 miles from her home in Bakersfield to attend the prestigious scientific gathering, paying the $250 fee out of her own pocket. “I’m carrying this message to a lot of other women,” she explained. “Everybody needs a success story.”

Three years ago, a doctor advised Empey to put her affairs in order. She had tumors in her liver and had already undergone a mastectomy. She couldn’t tolerate any more chemotherapy. “There’s no point subjecting yourself to that kind of trauma,” her doctor told her gently. But Empey fought her way to Slamon at UCLA’s Jonsson Comprehensive Cancer Center and entered the Phase III clinical trials of Herceptin. She was the very first of 469 women admitted to the main trial. “I beat on the door with a telephone,” she laughed.

Though she was still weak and might have to remain on Herceptin for the rest of her life, Empey’s tumors were all but gone. “I feel great,” she said.

A reporter asked Empey, “By being so optimistic about your experience, making of yourself an example, aren’t you concerned about raising false hopes?” Wasn’t it true that Herceptin had not worked for everyone? Hadn’t some of the women in the study died? Weren’t some women dying still?

The 53-year-old grandmother thought for a moment. Then she said, “I’m the sickest person I’ve ever known and I’m recovering. I think that should be encouraging for a lot of women.”

To fully appreciate the excitement Slamon’s news would generate, one has to recall the sensational headlines that ran a few weeks earlier and acknowledge the potent dread that surrounds the subject of cancer. In early May, a front-page story in The New York Times sparked a media frenzy by quoting Nobel Laureate Dr. James Watson as saying that Dr. Judah Folkman, a respected Harvard cancer researcher, would “cure” the disease in two years. Almost immediately, glowing stories appeared in a number of publications about Folkman, whose focus is anti-angiogenesis — killing or shrinking tumors by cutting off their blood supply. Folkman’s office and The National Institutes of Health (NIH) were besieged with calls from desperate patients wanting to know when this therapy would be available. The problem was, however, this marvelous new treatment had so far only been tested in mice.

“To dance around a stockpile of gasoline, lighting matches … You could predict what was going to happen,” says Slamon one afternoon in late May of the incendiary effect of the Times story. “Cancer is a disease that connotes particular things to people. There are other diseases every bit as deadly — heart disease, for example. But we don’t think about them in the same way. It’s what cancer does to you as it progresses, what you have to go through to be treated for it.”

Slamon is a big, gentle man with soulful brown eyes and a thick, brown mustache threaded with gray. Today, sitting in his barely used office in the Gordon and Virginia MacDonald Research Laboratories building on campus, he’s wearing khaki slacks and a pale-blue oxford shirt. He sips a Diet 7-Up as we talk. On top of his rather consuming job, he’s busier than ever with media interviews — Newsweek, Nightline, New York Magazine. But he’ll take as much time as you need to explain the wonders of molecular biology, the mystifying nature of cancer cells. He is notably down-to-earth, accessible. The patients in his study, some of whom feel they have come back from the dead, admire him openly. One 54-year-old corporate lawyer, whose cancer had metastasized to her liver but who has now returned to work, calls him “truly inspirational.”

He is deeply appreciative of the women as well, humbled by their courage. “There’s no way to learn how to use a drug in humans without testing on humans,” he says emphatically. “So these are really the heroines of the story. We explained the risks. To a person, not one said no. ‘I understand it may not help me,’ they said, ‘but it may help somebody down the line.’ It was extraordinary to hear that kind of response.”

Fresh out of the University of Chicago, where he earned his M.D. and Ph.D., Slamon came to UCLA in 1979 to pursue a fellowship in oncology. At the time, researchers were beginning to explore the role genetic defects might play in cancer. Slamon was taken with this area of study and, with a small grant from UCLA’s Jonsson Cancer Center, began screening genes in the lab. The work, involving cell lines and animal models, was tedious and slow.

Slamon wondered if there wasn’t a better way. What if his team looked at cells in human tumors instead? It was a logical idea, but not without risk. “Had I been as sophisticated scientifically as some of my colleagues,” he says, “we probably wouldn’t have approached the problem that way. In human tissue you don’t have 100-percent cancer tissue. You have cancer tissue and many normal cells. So you have to be very careful interpreting your results.”

In 1982, Slamon submitted to NIH a grant proposal for funding to build a human tumor bank using discarded tissue from breast, prostate, colon and lung cancers and then screen the tissue for specific genetic alterations. “The application essentially came back with a laugh track,” he recalls. Undeterred, Slamon and his team secured support from the Jonsson Cancer Center Foundation and UCLA and forged ahead with the human tumor bank plan.

In the meantime, academic and commercial labs across the country were isolating new genes. In 1986, a scientist at MIT discovered an important gene involved in regulating cell growth. It was HER-2/neu — Human Epidermal Growth Receptor No. 2.

Slamon was by now convinced of the logic of his approach, but many of his peers remained dubious. “‘Oh, this lab is on a fishing expedition,’” Slamon recalls his critics saying. “Well, we were fishing for alterations that we might identify. But we felt that once we identified one, we had the capacity to do the harder work of pulling out the gene and introducing it into breast cancer cells to see if it really had an association with a bad outcome. That was the most exciting science of all. As soon as we had valid models, we could start testing.”

Using breast cancer tissue, Slamon and his team began extracting DNA and asking questions: Was the HER-2/neu gene changed? Was its structure somehow rearranged? Was its expression present in some altered way?

Indeed it was. Instead of the single copy of HER-2 normally present in a cell, Slamon found multiple copies in approximately 30 percent of breast cancer samples. “This gene makes something called a growth factor receptor,” he explains. “It’s a protein that sits like an antenna on the membrane of the cell and receives signals from the outside telling the cell to grow.”

Slamon then looked at women who had the genetic alteration to see if tumors they developed were in any way unusual compared to tumors of women without HER-2. Sure enough, women with the alteration had far more aggressive disease: They failed standard therapy, their disease metastasized more quickly, they died sooner.

Slamon was hopeful, but he hadn’t yet proved that HER-2 was causing the cancerous cells to multiply out of control. The alteration might only be a marker, what scientists call an epiphenomenon, that develops along with the real culprit driving the cancer.

It was 1989. Slamon was getting closer to understanding HER-2. But in order to accelerate and expand his work, he needed money — lots of it. Funding for research even this seemingly promising can be difficult to obtain and very slow in coming. Slamon was stalled at a critical crossroad.

Enter Lilly Tartikoff.

“He’s Frankenstein and I’m the monster,” jokes Tartikoff. “Together, there’s no stopping us.”

Tartikoff and Slamon have a close, unusual relationship. He provides the marvelous science. She’s got the connections and resolve to raise millions for research. When she asks him to, Slamon speaks to Fortune 500 CEOs or Hollywood studio executives so they’ll understand the work, feel invested in the cause. Tartikoff is mastermind of the glamorous Fire & Ice Ball, which she co-chairs with Revlon’s Ronald O. Perelman, and she founded the Revlon Run/Walk with Lisa Paulson and the Entertainment Industry Foundation. Tartikoff and Perelman have together raised more than $17 million for Slamon, the Revlon/UCLA Women’s Cancer Research Program and other women’s health research programs at UCLA.

When Slamon learned of the success of the Phase III clinical trials late last year, Lilly Tartikoff was one of the first people he called. The timing was especially poignant: Her husband, Brandon, had died in August of a recurrence of Hodgkin’s disease. “It was bittersweet because it hit so close to home,” Tartikoff recalls. “While I was thrilled, it was impossible for me to feel peaceful and joyous beyond belief. But I celebrate for all women. And I celebrate for Dr. Slamon. He’s a born visionary.”

Sixteen years earlier, Slamon had saved Brandon Tartikoff’s life. Tartikoff had been ill with Hodgkin’s but was assured by a prominent physician that he was now healthy. Slamon found Tartikoff still had active Hodgkin’s and put him on a promising new therapy. When he recovered, a grateful Lilly pledged to raise money for Slamon’s science.

But Slamon’s research on genes was only beginning. It would be years before he availed himself of Lilly Tartikoff’s offer.

“I waited a long time,” Tartikoff confirms.

Slamon needed support in 1989, and Tartikoff had a plan. She had worked as a consultant to the cosmetics and beauty industry and thought, “Why not approach a big-name company like Revlon, that prides itself on appealing to ordinary American women, to help battle a disease that affects thousands of women each year?”

Tartikoff didn’t know Ronald O. Perelman, the New York financier and Revlon’s CEO. But she wrote him, introducing herself and lobbying on Slamon’s behalf. Her initial efforts went nowhere. Then she happened to bump into Perelman at Spago. The determined Tartikoff spoke of Slamon’s important work, and Perelman agreed to dispatch someone from Revlon to UCLA.

That summer, Jim Conroy, Revlon’s special counsel, met with Slamon and Dr. John Glaspy M.P.H., M.D. ’79, a Jonsson Cancer Center scientist engaged in bone marrow transplantation research and nutrition studies pertaining to breast cancer. Slamon told Conroy about his HER-2 findings. The genetic alteration probably played a significant role in breast cancer, Slamon said, but he needed further research to prove it. And, suspecting the gene and its protein of playing roles, he wanted to start testing antibodies directed against HER-2.

Bottom line, the scientist said, this is how it stands: If they relied solely on federal grants, their progress could be delayed by perhaps three years. In that brief period of time, 120,000 more women might succumb to the disease.

Glaspy put it to the Revlon executive more bluntly: “We’ll have a Rose Bowl full of dead women.”

Perelman not only came through for Slamon, but he made an astonishing offer: $800,000 a year for three years, a total of $2.4 million. As support from an American corporation to a single scientific group, the gift was virtually unprecedented. Just as amazing, the research funding was unrestricted. Slamon could use the money however he saw fit.

“It would have taken four concurrent National Cancer Institute grants to build the equivalent of the program Revlon funded with just the stroke of a pen,” Slamon says intently. “And there was no writing a grant, submitting it, waiting eight to 12 months to hear. This gift allowed us to follow our leads almost instantaneously, and made a huge difference in this whole story.”

In 1990, Slamon set out to answer the next critical question about HER-2: Was the defective gene causing the deadly tumors, or was there something else? To find out, the researchers injected normal human breast cells with HER-2. “Sure enough,” says Slamon, “the cells grew more rapidly and they behaved in a more malignant fashion.” The experiment was repeated using mice; the results were identical. Slamon had proved the link between HER-2 and breast cancer.

There was one last piece of the puzzle to solve: Could the researchers find a way to target HER-2 and mediate its apparently destructive effect? Slamon developed antibodies, called in others from academic and commercial pharmaceutical labs and began methodically testing them on tumor cells. After a dozen or so attempts, he tried Herceptin, an antibody manufactured by Genentech. It worked.

“Not only did it work on the HER-2 cells,” Slamon says, “but when we tried the antibody on cells that didn’t have the alteration, it had no effect. That was great news: The antibody was specific, unlikely to affect cells without this alteration. And in mice, exactly the same thing happened. Herceptin stopped the growth of the tumors.” Now that the antibody had been proven effective in the laboratory, Slamon and Genentech went to the FDA and received permission to begin testing the drug in women with advanced breast cancer.

The odds against Slamon succeeding were still huge. As the UCLA researchers entered Phase I of the Herceptin clinical trials, there were plenty of scientists, many at Genentech even, who remained skeptical. Never before had an antibody been shown successful in cancer treatment.

But Slamon’s instinct triumphed again: The early studies proved Herceptin to be relatively safe. In the summer of 1995, the critical Phase III trials began. Eventually, 940 very sick, very hopeful women participated in the breakthrough study at more than 120 institutions around the world.

“Dr. Slamon is so incredibly wonderful to talk to,” Lori Rinde says, as she sits in a big, comfortable chair in UCLA’s Bowyer Oncology Center, Herceptin dripping from an IV into her body. “The fact I was able to get in on this study — I’m so thrilled.”

Rinde is 41. She has freckles across her nose and clear, blue eyes. On a Wednesday afternoon in early June, she is wearing faded jeans, a dark gray sweater and blue Birkenstocks. Her inch-high, spiky blonde hair, which has yet to grow back after she had chemotherapy, is tucked under a navy-blue baseball cap. As Rinde receives her weekly, half-hour infusion of Herceptin, her son Corey, a towheaded boy of 3, plays quietly near her feet. Rinde also has two daughters, Chelsea, 13, and Kate, 10. “They’re a huge part of my recovery,” Rinde says. “They keep me uplifted.”

Rinde was diagnosed with breast cancer in 1990, at age 33, three months after discovering a pea-sized lump in her right breast. The disease was so aggressive she had a modified radical mastectomy and six months of chemotherapy.

For more than four years Rinde had been in remission when she got a shock: She was pregnant. She discussed her medical history with her OB-GYN and a cancer specialist, considered the danger a pregnancy might pose to her health. But Lori and her husband, Paul, decided to have the baby. It was a decision, it seemed, that was meant to be. Rinde had her healthiest pregnancy, and when Corey was born, it was her easiest birth.

“Corey was nine months old when I found another lump,” Rinde recalls. In April 1996, she had a lumpectomy on her left breast and a month later began chemotherapy in an effort to contain the tumor. She also had a CT scan done of her liver and pelvis.

Not long after, she went in to see her doctor. She vividly remembers the look on his face. “He was completely white,” she says. “He had to tell me there were several lesions in my spine, liver and femur.”

This time Rinde’s cancer was even more virulent than before. After rejecting a proposed bone marrow transplant, she and her family began to search for alternatives. Her sister-in-law had recently read about the HER-2 studies under way at UCLA. Tissue samples of Rinde’s tumors were tested and proved positive for the specific genetic alteration Slamon was investigating.

On July 31, 1996, Rinde entered the Phase III trial and was randomized to the group of women who received Herceptin only. (Other groups received Herceptin and conventional chemotherapy or conventional chemotherapy alone.)

A CT scan in March 1997 showed possible spots on her liver; her bone cancer was progressing, too. For a while everyone worried. But since then Rinde’s liver has been clear, and her bone cancer has regressed considerably. “I had great expectations from the beginning,” she says.

Rinde is sitting outside on a bench now, in the pretty courtyard behind the clinic. A huge spray of red begonias is in bloom. It’s a beautiful Los Angeles spring day. The sky is deep blue, the air is bracing, clear. As his mother watches him, Corey toddles along a low wall, babbling in a strange language.

When the child gets near the fountain, Rinde reaches into her wallet and pulls out some coins. Then she reaches her palm out to her third child, the one she unselfconsciously calls “God’s gift.”

“Make a wish,” Lori Rinde says.

Last year, on the day before Thanksgiving, Slamon was at home when he got an unexpected phone call. It was Dr. Steve Shak, the study coordinator at Genentech. He wanted, he said rather mysteriously, to meet with Slamon right away.

“Would you mind telling me what this is about?” Slamon asked.

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

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

The caller insisted that he must see Slamon sooner.

On Friday, Slamon met Shak in the cocktail lounge of the Burbank Airport. Shak carried a briefcase full of papers and graphs, the long-awaited results from the Phase III clinical trials. The news was breathtaking. In the pivotal trial, 234 women with advanced breast cancer who were given the best available chemotherapy were compared with 235 women who received chemotherapy plus Herceptin. The addition of Herceptin boosted the effects of chemotherapy dramatically: In the group that received the experimental drug, nearly 50 percent of the women saw their cancer disappear or their tumors shrink by at least half. What’s more, their cancer didn’t return as quickly as might have been expected.

The study also confirmed the deadliness of the HER-2 tumors. When the chemotherapy drug Taxol, considered one of the best treatments available for breast cancer, was used alone, only 16 percent of the women saw their cancer improve. Typically, 65 percent would be expected to respond positively to the aggressive chemotherapy.

“I wasn’t sure if I should laugh or cry when I saw these dramatic results,” says Slamon. “I didn’t anticipate the antibody would work as well as it did. I was very happy, and Steve and I had several cocktails to celebrate.”

At the American Society of Clinical Oncology’s (ASCO) annual meeting in May, Slamon publicly announced the results of his study. Seated with four other cancer experts at a long table in a room packed with TV cameras and reporters, Slamon had dressed for the occasion in a handsome, dark-brown, double-breasted suit. He was the last scheduled to speak. As he waited, the gray-haired scientist occasionally glanced at his notes, his long fingers clutching a bottle of mineral water.

Finally, his 6-foot-2-inch frame rising slowly out of the chair, Slamon walked to the podium. With cameras clicking away, he began to tell in a steady, understated voice the story of HER-2 and Herceptin. One patient who’d taken the drug only 18 weeks had survived close to six years. Another, still taking the antibody, had lived five years. In others, the therapy slowed the spread of the disease by three months. Considering that women with this virulent form of breast cancer typically die in 18 months, sometimes less than a year, the results Slamon offered were striking.

Then there was this: Though chemotherapy for breast cancer often has numerous hideous side effects, Herceptin has relatively few and comparatively mild ones. “We’re fairly certain there are going to be better ways to use this drug,” Slamon told the attentive crowd. An FDA ruling on Herceptin is expected by the end of the year.

Slamon only hinted at it, but the larger significance of his work with Herceptin escaped no one. Never before had anyone achieved success attacking a genetic alteration in cancer. The tenacious UCLA scientist had achieved precisely that. He had pioneered a new frontier in treating cancer.

Since his appearance at the ASCO conference, interest in Herceptin has exploded and Slamon has been inundated with calls from all over. “Most troubling,” he says, “are the patients who want to know, ‘When can I get it? Why can’t I have it right now?’ This thing is moving as fast as it possibly can. But that’s hard to explain to women who have metastatic breast cancer or are dying.”

Once Herceptin receives FDA approval, Slamon expects it will be used to treat women even earlier in their disease than the patients in the UCLA trials. “There is absolutely no reason to think it will work any differently,” he says confidently. “The biology should be the same in early breast cancer as in late breast cancer.”

There remain the women in the study for whom the drug did not work. The Big Question is: Why not? “What’s going on with those women?” Slamon asks rhetorically. “Are there other alterations occurring alongside HER-2 that play a role? Are other alterations necessary to see the response? These questions are unanswered, but we’re pursuing them very actively.”

Slamon is still hopeful. Other therapies like Herceptin are in early-stage trials for the treatment of lung, prostate and other cancers. There are many genetic alterations that might one day be targetable.

And the Revlon money brokered for Slamon by Lilly Tartikoff may enable additional groundbreaking research. Ronald O. Perelman’s largesse is currently funding nutrition studies of breast cancer patients; enhancing the success of bone marrow transplants; and financing laboratory studies of a gene known as P53, which is mutated in 50 to 60 percent of women with ovarian cancer.

Slamon is also using these resources to educate women about the crucial value to patients and to medical research of human trials. He’s founded a network of outreach programs in community clinics throughout Southern California.

“I really don’t believe what made the difference is that we were so much smarter than anybody else,” he says modestly of his team’s success. “But we believed something before anybody else believed it; we believed that screening tumors for genetic alterations to develop new therapies was a worthwhile endeavor. A number of my colleagues thought it wasn’t a terribly useful thing to do. But it paid off.

“I’d like to tell you I had all these great insights,” says Dennis Slamon, the man who won a big round in the fight against breast cancer. “But the science was straightforward, and I just believed it would work.”