It’s been 10 years since the Food and Drug Administration (FDA) approved the drug Herceptin, revolutionizing treatment for the 20 to 30 percent of breast cancer patients with particularly aggressive tumors that make too much of a protein called HER2. The drug, which latches onto diseased cells and marks them for destruction, has extended and in some cases saved lives. It has spurred development of other anti-HER2 drugs—some more powerful than traditional chemotherapy. And it has brought within reach the possibility of vaccines that might one day prevent this type of breast cancer altogether.

These are promising times for women with HER2-positive cancer, and the medical world continues to study the disease in search of fresh insights. “What we’re struggling with right now is how best to convert this knowledge into clinical advances,” says Clifford Hudis, MD, chief of breast cancer medicine service at Memorial Sloan-Kettering Cancer Center in New York. “The gains we make are incremental, but they are really important.”

In this, the first of a series, MAMM looks at the methods doctors use to determine HER2 status, as well as the surprising findings about why some breast cancers become resistant to Herceptin, the first line of offense against HER2, and which drugs may be effective when Herceptin isn’t.

What is HER2?

Oncologists now know that what we call breast cancer is actually a variety of different diseases, each of which has to be treated in its own way. HER2-positive cancer is one of them. We all carry two copies of the HER2 gene in nearly all of our cells. They tell the cells to make a protein called HER2, which regulates cell growth, division and death. But cancerous breast cells contain extra copies of the HER2 gene, which in turn make too much HER2 protein (it’s called “overexpression”). HER2-positive cancers grow quickly and are considered more aggressive than other breast cancers, with a higher risk of recurrence and death. So it’s important for women to have their tumors tested for HER2 overexpression to ensure they get the most effective treatment.

How does HER2 make cancers pack such a strong punch? At the University of California, Davis, investigators recently discovered that HER2 can turn off its own regulator, a gene called LRIG1 that normally keeps HER2 protein production under control. Lead author Colleen Sweeney, MD, an associate professor of biochemistry and molecular medicines, suggested that when scientists know more about how HER2 turns off the gene, they may be able to design treatments aimed at restoring or replacing LRIG1’s function.

Typically women with HER2-positive cancer receive chemotherapy and Herceptin if their tumors are larger than 5 millimeters or if their disease has spread. However, data recently presented at the 2008 San Antonio Breast Cancer Symposium show that women with small HER2-positive tumors who don’t receive adjuvant treatment are nearly three times as likely to have a recurrence as women with HER2-negative cancer. This may change the way oncologists look at and treat small HER2-positive tumors.