Dennis Slamon's research has led to new breakthroughs in the treatment of breast cancer

If future historians look for a "turning point" in the research and treatment of cancer, they will invariably land on the work of Dr. Dennis Slamon and his UCLA and Genentech, Inc., colleagues, whose work led to the discovery and development of the monoclonal antibody Herceptin, which targets a genetic mutation found in 25-30 percent of breast and ovarian cancers.

Last April, at the 90th annual meeting of the American Association for Cancer Research, Slamon, the director of the Revlon/UCLA Women's Cancer Research Program at the UCLA School of Medicine, presented the latest survival results from a two-year trial of Herceptin. The drug, made by the South San Francisco-based biotech company Genentech, Inc., had just been approved by the FDA for the treatment of metastatic breast cancer the previous fall. On the basis of a one-year clinical trial, the study showed that, compared to the best-available standard chemotherapy, Herceptin improved the response rate (tumor shrinkage by 50 percent or more) by 53 percent, lengthened response duration 58 percent and delayed progression to the next stage of cancer 65 percent.

The relative risk of death among patients treated with Herceptin was reduced by 22.5 percent, with no significant side effects - the largest survival impact ever for a drug used in treating metastatic breast cancer. The number would have likely been even higher, Slamon notes, but, for ethical reasons, women in the trial's control arm were given the option of switching to the experimental drug if they had a recurrence in cancer with standard chemotherapy. Two-thirds opted for the switch.

The Herceptin data already reported are remarkable, and the drug will have an even greater impact on breast-cancer survival if it's shown to be effective in earlier-stage breast-cancer patients. Slamon, who is gearing up for a multinational trial of Herceptin in such patients, is certain that it will. "The biology is exactly the same," he says. "The same alteration is present in the early stages of the disease. The question is just how efficacious it will be in that setting."

But in the history books, the specific data on Herceptin will take a back seat to its larger significance: Herceptin is the first approved cancer drug directed against a specific molecular alteration with a direct role in causing a malignancy."I'm really excited about the breast-cancer patients we're helping," says Slamon, "but at least as big a part of the story is that it proves that the basic science work all of us have been doing in the molecular biology of cancer can pay off. If we can identify what's broken, we can develop targeted therapeutics, as opposed to the nonspecific toxins we use, hoping to kill more bad than good cells. We've theorized for all these years that if we could do that, we would have more effective and less toxic therapy, and that's exactly what Herceptin has proven."

Herceptin has origins in the early 1970s, when molecular biologists identified the existence of oncogenes - genes that control cellular growth and, if damaged, can trigger the malignancy process. Arriving at UCLA in 1979 after earning his M.D. and Ph.D. degrees at the University of Chicago, Slamon was interested in collecting data on the genetic mutations. His first step, in 1982, was to found a human- tumor bank at UCLA, which enabled his group to launch what he calls a "fishing expedition" to see whether the tumors showed patterns of alterations in known oncogenes.

It wasn't long before Slamon and his colleagues discovered that more than one-fourth of breast- and ovarian-cancer samples had extra copies of the HER-2/neu oncogene, causing overproduction of the protein receptor on the surface of breast and ovarian cells. Pursuing that lead, they found that the more copies of the gene in the tumor, the more aggressive the disease and the worse the prognosis. To determine whether HER-2/neu amplification was a cause or merely a marker for the malignancy, Slamon inserted multiple copies of the gene in human-tissue cultures and animal models. The result was faster cell growth and more rapid tumor formation and metastasis. Reasoning that an attack on HER-2/neu might produce therapeutic benefits, Slamon took aim at the proteins the gene creates on the outside of the cell. Working with a genetically engineered antibody called Herceptin, produced by Genentech, he successfully locked onto the protein and interfered with its function, inhibiting the growth of tumor cells in the lab. By 1991, Slamon had begun clinical trials to test the antibody in humans and within years had revolutionized the work in molecular treatment.

Currently, Slamon is also pursuing other potential therapies directed at molecular changes in breast, ovarian, colorectal, prostate and lung cancers.

"We'll continue to use our traditional forms of treatment," says Slamon, "but these targeted therapies, both alone and in combination with traditional therapies, are going to significantly change the effectiveness of cancer treatment. This is the future."

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