Herceptin: An Entirely New Weapon Against Cancer

June 24, 1998 -- 

A new drug to fight breast cancer is pointing the way toward the development of an entirely new type of weapon against cancers of all types. Results of a trial of Herceptin™ (known generically as trastuzumab) that were presented recently at the American Society of Clinical Oncology annual meeting show it can dramatically improve the effectiveness of chemotherapy against some advanced breast cancers. Genentech, Inc. has asked the US Food and Drug Administration for "fast-track" consideration of Herceptin, while researchers continue studies. 

Former nurse Virginia Empey's breast cancer had spread to her liver. Multiple rounds of chemotherapy, including Taxol, were unable to stop it, when she began receiving Herceptin as part of an early study of the new drug. That was almost three years ago. 

"After three months, the tumors shrank significantly, which is a volume of 25 percent or greater," says Empey. "And since that time, they have continued to slowly, slowly decrease, until now there are only tiny lesions left in my liver." 

Empey says she's able to carry on her life now, even though some cancer remains. "I feel really great. I have not completely recovered my energy, but gradually, and I've had plateaus. Like after that first three months, when we really knew the drug was working, I had a big breakthrough. And then since then I've had a couple more." Empey still gets Herceptin treatment. 

Although researchers say Virginia Empey's long-lasting response is unusual, recently-released study results show what Herceptin may add to standard chemotherapy. The first large-scale trial of Herceptin and chemotherapy involved 469 women with advanced metastatic breast tumors. All the women had a type of tumor that appears susceptible to Herceptin treatment. While not holding out any expectation of curing these advanced cancers, researchers reported that tumors disappeared, at least temporarily, in 8 percent of the women receiving combination therapy. Tumors shrank in another 41 percent of the women.

The researchers were gratified to see that women who received Herceptin in addition to standard chemotherapy often fared better than those who got chemotherapy alone. As Dr. Dennis Slamon of UCLA said, "The addition of Herceptin made a significant increase in all of the parameters that we were looking at. There was a significant increase in the response rate of 50 percent. There was a significant increase in the duration of that response, by 57 percent." Dr. Slamon said that on average, women who received Herceptin gained three months of time before their cancer progressed, from an average of 4.6 months to about 7.6 months, an increase of 67 percent. 

Some experts say the significance of the Herceptin trial goes far beyond this temporary delay in the progression of metastatic breast cancers; that it heralds a new, and more effective method, for finding new treatments to slow, stop, or prevent cancers of all types by understanding what makes tumor cells appear and then grow. Dr. Craig Henderson of UCSF says, "I think this is the first step into the future, going from poisons, which are going to be around for a long time -- this is not the end of chemotherapy by any means -- but I think we've taken a huge step forward, and this is the first payoff in a very common disease." 

Most current chemotherapy agents were discovered by a process that relied largely on trial-and-error testing. Using cancer cell cultures in the laboratory, thousands of potential drugs might be tested in order to find one worthy of further investigation. In many cases, it was only after a drug showed some effectiveness that researchers would figure out how it worked. 

Herceptin reverses the process, by starting with a discovery about the basic genetics of cancer, and then designing a drug to counteract the abnormality. The key in this case is a gene called HER-2/neu. The gene carries instructions for a protein that sits on the surface of a cell and receives signals from "growth factor" molecules. Thus the HER-2/neu gene and protein play a key role in the fundamental threat of cancer: tumor cells that grow out of control. 

Normal cells carry two copies of HER-2/neu, and have a small number of the HER-2/neu protein receptors on their surfaces. But researchers found that some cancers have extra copies of the gene and an overabundance of cell surface receptors. The abnormality is not inherited; rather, it is an error acquired during the lives of some people. 

Researchers estimate that 20 to 30 percent of women with breast cancer have extra HER-2/neu genes in their tumors, amounting to as many as 60-thousand cases a year in the United States. UCLA researchers say women with cancers that "overexpress" HER-2/neu are more likely to suffer relapses after treatment and do not survive as long as women with normal amounts of the gene. Researchers then set out to find a way to block the HER-2/neu receptors, and thus dampen the signals telling the tumor cells to keep growing. They developed a molecule called a monoclonal antibody that is in essence a mirror-image of the HER-2/neu receptor. Researchers think that when the antibody (now named Herceptin) attaches to the receptor, like a key fitting a lock, it prevents growth factor molecules from attaching. 

The promising results of clinical trials suggest that when the growth signals are turned down on these cancers, chemotherapy drugs have a better chance of defeating the tumors. UCLA's Dr. Slamon says, "In addition to the excitement about the results... I think it proves the paradigm. That if we understand what is fundamentally broken in the malignant cell, we might be able to target it effectively." 

Supplies of Herceptin are extremely limited, though Genentech expects to have new facilities ready to produce the drug by the time FDA officials are ready to act on the application for clinical use in metastatic breast cancer. That regulatory action could come before the end of 1998, according to Genentech officials. 

Meanwhile, researchers are continuing to study the drug to see if it can improve the prognosis of women with earlier stage breast cancers. HER-2/neu over-expression is also present in the tumors of about one in five ovarian cancer patients; so the drug will be tested in these women as well.