The drug Herceptin may help battle an aggressive form of breast cancer by righting a cell pathway gone wrong.

A Pittsburgh-based research group has found that Herceptin, which recently has been shown to be highly effective in treating breast cancers linked to the HER2 gene, may allow a potentially cancer-causing gene known as cMYC to return to one of its normal functions and trigger the death of cancer cells.

The finding could become important for treatment of other cancers involving cMYC, said Dr. Soonmyung Paik of the National Surgical Adjuvant Breast and Bowel Project, known as the NSABP. He noted that about 30 percent of human cancers are linked to the cMYC gene. Those cancers tend to have a worse prognosis than cancers without cMYC abnormalities.

At a symposium this month in San Antonio, Dr. Paik, director of the NSABP's Institute of Molecular Pathology, presented findings from an analysis of breast tumor specimens collected from more than 3,000 patients treated in two large clinical trials conducted by the NSABP. The three-year project required screening more than 51,000 test samples.

Herceptin, or trastuzumab, consists of a specially developed antibody that attacks a protein called HER2, which is found on the surfaces of cells. Breast tumors with unusual amounts of the HER2 protein, or with multiple copies of the gene that makes the protein, tend to be unusually aggressive and prone to fatal recurrences.

Dr. Paik had noted in his earlier research that some breast cancers contained multiple copies of both the cMYC and HER2 genes. His team compared the benefit of chemotherapy alone, and chemotherapy combined with Herceptin, in patients with multiple copies of the HER2 gene alone and those with multiples of both HER2 and cMYC. They found that patients with multiples of cMYC who were treated with Herceptin and chemotherapy achieved a 76 percent reduction in cancer recurrence compared to a 37 percent reduction for those who did not have cancer linked to cMYC.

Among 237 patients with HER2 and cMYC amplified cancers who received both Herceptin and chemotherapy, breast cancer recurred in only 5 percent four years after the start of treatment, with death occurring in only 3 percent within four years of diagnosis. The rate of recurrence or death was three to four times higher in patients with HER2 and cMYC amplification who were treated only with chemotherapy.

"Since patients with cMYC amplified tumors start with a worse prognosis, it is remarkable that their fortune is essentially reversed with the addition of Herceptin to chemotherapy," Dr. Paik said.

Dr. Victor Vogel, director of the Magee-Womens Breast Cancer Program, called the drop in cancer recurrence "spectacular." Dr. Vogel, who serves on the board of directors of NSABP but was not an investigator in Dr. Paik's study, noted that a percentage improvement in the single digits is usually considered substantial.

The research also is another step toward individualizing treatment based on the behavior of tumors, Dr. Vogel said.

Most people don't get cancer because genes such as cMYC that promote proliferation of normal cells also prompt programmed cell death to keep the expansion in check. But activation of the HER2 gene can suppress the cMYC pathway that normally leads to cell death, making it possible for an aggressive cancer to develop.

Patients with HER2 amplified breast cancer should be strongly considered for treatment with Herceptin regardless of whether or not they have cMYC amplified tumors. As a result, there is no need for patients to "rush to the doctor to ask that a cMYC test be run on their tumor," said Dr. Charles Geyer Jr., director of breast oncology at Allegheny General Hospital. "Herceptin provides substantial benefits for HER2 amplified patients regardless of cMYC status."

If confirmed by other studies, the latest findings could lead to improved treatment for patients with many types of cancers linked to a combination of cMYC and other cancer-causing genes, said Dr. Geyer, a co-author of the abstract presented in San Antonio and manager of the NSABP's Herceptin trial.

"A very exciting aspect of this study is the potential that this same approach might be used to find effective therapies for patients with other types of cMYC amplified tumors," Dr. Geyer said.

Targeting other genes that are blocking the cell death pathway the same way that HER2 appears to block the pathway in breast cancer patients may restore the ability of cMYC to cause programmed cell death, he said.

The announcement by Dr. Paik's team follows groundbreaking findings on the effectiveness of Herceptin reported in May by the NSABP and the North Central Cancer Treatment Group based in Minnesota. Researchers called a preliminary halt to two federally sponsored trials in patients with HER2 positive early stage breast cancers because they found Herceptin cut by 50 percent the risk of a breast cancer occurring elsewhere in the body.