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Key Words

Breast cancer, HER2, trastuzumab (Herceptin®). (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)

Summary

Breast cancer was half as likely to come back in patients who received the drug trastuzumab (Herceptin®) for a year after completing chemotherapy than in patients who received chemotherapy alone, according to results from a large international clinical trial. Taken together with similar results from two U.S. trials, these findings establish a new standard of care for patients with an aggressive form of breast cancer.

Source

New England Journal of Medicine, October 20, 2005 (see the journal abstract).

Background

About 20 percent of breast cancers make too much of (overexpress) a protein called HER2, which is found on their cell surface. Tumors that overexpress HER2 tend to grow faster and are more likely to come back (recur) than tumors that don’t overproduce the protein.

Trastuzumab is a drug that targets tumor cells that overexpress HER2 (called HER2-positive) and slows or stops their growth. Since 1998 it’s been used to treat HER2-positive breast cancers that have spread to other organs. The drug offers no benefit for patients whose tumors don’t make too much HER2.

As a result of trastuzumab's success in treating women with advanced breast cancer that was HER2-positive, several large clinical trials were set up to test its effectiveness in earlier-stage disease as additional (adjuvant) treatment immediately after surgery.

Combined results from two of these trials, which were sponsored by the National Cancer Institute (NCI), were released early in April 2005 (see the NCI press release). An interim analysis (published in the Oct. 20, 2005, issue of the New England Journal of Medicine; see the journal abstract) showed that patients who received trastuzumab in combination with chemotherapy had a 52 percent decrease in the risk of breast cancer recurrence, compared with patients who received chemotherapy alone.

As a result of these findings, these two trials were stopped and patients receiving chemotherapy alone were offered trastuzumab.

What follows is a description of a third international trial that found similar results.

The Study

Called the Herceptin Adjuvant (HERA) trial, this international phase III study involved more than 3,300 women with early-stage breast cancer in 39 countries. They were eligible for the study if their disease had spread to the lymph nodes or if their lymph nodes were cancer-free but their tumor was larger than 1 centimeter (about half an inch) in diameter. All of the patients had tumors that overexpressed HER2.

Some of the women had chemotherapy before surgery to remove their tumors, while others had chemotherapy after surgery. A variety of chemotherapy regimens were used. Patients were also treated with radiation and hormonal therapy ( tamoxifen or an aromatase inhibitor) if appropriate.

After completing all chemotherapy and radiation treatment, the women were assigned at random to one of three groups. One group took trastuzumab for a year. A second group took the drug for two years. A third group did not take the drug and were observed by their doctors.

The research team that conducted the study was led by Martine Piccart-Gebhart, M.D., of the Jules Bordet Institute in Brussels, Belgium.

Results

After a median of one year of follow-up, patients who took trastuzumab for a year had a 46 percent reduction in the risk of breast cancer recurrence compared with patients who did not receive trastuzumab. (Patients assigned to take trastuzumab for two years were not included in this analysis; those results will be reported later.) Trastuzumab appeared to be equally effective in reducing the risk of disease recurrence regardless of the type of chemotherapy that women had received.

Because of the shortness of the follow-up period, it wasn’t possible to tell if there was a statistically significant difference in overall survival between the two groups.

These results were so compelling that patients in the observation-only group were offered the opportunity to begin taking trastuzumab. Follow-up of all patients is to continue for 10 years.

Limitations

Previous studies of trastuzumab have shown that the drug increases the risk of congestive heart failure in some patients. In congestive heart failure, the heart has trouble beating normally because of damage to the heart muscle. Women with risk factors for congestive heart failure were not eligible to enroll in this trial. Nevertheless, more patients in the trastuzumab group than in the observation group suffered congestive heart failure or other heart problems.

Because trastuzumab offers no benefit to patients whose tumors do not overexpress the HER2 protein, careful testing must be done before patients are offered trastuzumab therapy. In this study, testing for overexpression had to be done twice - the second time in a central laboratory - to reduce the number of false positives (patients whose test results incorrectly showed overexpression of HER2).

Trastuzumab therapy should be considered only if the test showing overexpression of HER2 has been done in a laboratory that performs the test routinely and follows careful procedures to ensure correct results, the study authors recommend.

Comments

The results of this study, taken together with the results of the two NCI-sponsored studies that were stopped early in April, “are simply stunning,” writes Gabriel N. Hortobagyi, M.D., of the University of Texas M.D. Anderson Cancer Center in Houston, in an accompanying editorial.

Until now, he writes, no drug except tamoxifen has resulted in a 50 percent reduction in the risk of disease recurrence. (Tamoxifen is given to patients whose tumors are responsive to the hormone estrogen.)

Trastuzumab in addition to chemotherapy should now become standard treatment for all women with HER2-positive breast cancer that has spread to the lymph nodes and for most patients with HER2-positive disease that has not yet spread to the lymph nodes, he recommends.

“These results are dramatic and set a new standard of care for patients with HER2-positive breast cancer,” says Jo Anne Zujewski, M.D., a medical oncologist and breast cancer specialist with the National Cancer Institute’s Cancer Therapy Evaluation Program.

Although the follow-up period reported here was short, the fact that three large studies all have had similar results increases confidence in the findings, she adds. “Longer follow-up will provide more information about trastuzumab’s long-term side effects,” she says.

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