Herceptin Plus Chemotherapy After Surgery Improves Survival of Women with Early-Stage, HER2-Positive Breast Cancer

Reviewed study: "Herceptin Plus Chemotherapy After Surgery Improves Survival of Women with Early-Stage, HER2-Positive Breast Cancer" by E. Perez et al., American Society of Clinical Oncology Annual Meeting, May 2005, late-breaking session

Is this for me? If you have had surgery and have HER2-positive breast cancer that is not advanced but involves lymph nodes, you might want to read this article.

Background and importance of the study: Herceptin (chemical name: trastuzumab) works on breast cancers that make too much of the HER2/neu, or HER2, protein. These "HER2-positive" cancers tend to grow faster and are more likely to come back than breast cancers that are HER2-negative. About one out of every four breast cancers is HER2-positive.

Herceptin is approved by the U.S. Food and Drug Administration (FDA) for women with metastatic (advanced) HER2-positive breast cancer. The drug slows down or even stops the cancer's growth.

Herceptin can be given alone. And Herceptin may work even better when it is combined with chemotherapy.

Since Herceptin plus chemotherapy does a good job of treating advanced HER2-positive breast cancer, researchers wondered if the combination would also help women with early-stage, HER2-positive breast cancer. Here, they wanted to know if using Herceptin with chemotherapy after surgery would improve survival. (Herceptin and chemotherapy BEFORE surgery is already known to have benefits.)

In the studies reviewed here, researchers compared Herceptin plus chemotherapy to chemotherapy alone after surgery in women with early-stage, lymph node–positive (cancer cells in the lymph nodes), HER2-positive breast cancer. They wanted to see whether the combined therapy worked better than chemotherapy alone at increasing disease-free survival (the length of time before the cancer came back) and overall survival (how long women lived, with or without the cancer returning).

The researchers also wanted to see whether adding Herceptin to chemotherapy resulted in more cardiac side effects. Herceptin may cause heart problems, especially when given at the same time as anthracycline-type chemotherapy drugs, such as Adriamycin (chemical name: doxorubicin). Adriamycin chemotherapy was used in the studies reported here.

Study design: The National Cancer Institute sponsored two studies on Herceptin between 2000 and 2005:

• NSABP-B-31, a study by the National Surgical Adjuvant Breast and Bowel Project of 2,085 women, and
• NCCTG-N9831, a study by the North Central Cancer Treatment Group of 3,406 women.

This research also was funded by The Breast Cancer Research Foundation.

The two studies had similar designs. All of the women:

• were HER2-positive, and
• had early-stage breast cancer that was
  • any size, if the women had positive lymph nodes^*, OR
  • larger than 2 centimeters, regardless of the women's lymph node status, OR
  • larger than 1 centimeter, if the women were hormone-receptor negative (regardless of the women's lymph node status).
    
    ^*In the beginning, only the first group of women—with positive lymph nodes—was included. So the longest follow-up is available on them, and they are the focus of this report. In later reports, we should learn more about the role of Herceptin in the other women, including those with cancers that are either larger than 2 centimeters and do not involve the lymph nodes or larger than 1 centimeter and hormone-receptor-positive.

• had breast removal (mastectomy), or breast-conserving surgery (lumpectomy) with surgery to remove lymph nodes from the armpit (axillary lymph node dissection),
• had had no previous chemotherapy, radiation, or hormonal therapy, and
• had good heart function.

Most of the women were lymph node-positive. About half the women were estrogen-receptor-positive and about 40% were progesterone-receptor-positive.

In both studies, the women were randomly assigned to receive either:

• Adriamycin and Cytoxan (chemical name: cyclophosphamide) followed by Taxol (chemical name: paclitaxel) alone, or
• Adriamycin and Cytoxan followed by Taxol and Herceptin.

The researchers used Adriamycin in this study because it is especially effective in treating HER2-positive breast cancer. However, Adriamycin was given BEFORE (not at the same time as) Herceptin, in order to avoid significant side effects to the heart.

Women who had lumpectomy had radiation after chemotherapy. Women who were hormone-receptor-positive were given tamoxifen or an aromatase inhibitor for five years.

In NCCTG-N9831, the researchers followed the women every three months for the first year and every six months for the next four years. They plan to follow them once a year for the next 15 years.

In NSABP-B-31, the women had checkups every six months for five years and then once a year from then on.

The researchers compared the groups for:

• disease-free survival (how long women live without return of the cancer),
• overall survival, and
• cardiac side effects.

Results: Because the two studies were so similar (with the exception of one treatment group from NCCTG-N9831, which was not included in this evaluation of the results), the researchers looked together at results from both studies, before they were scheduled to end, for a total of 3,351 women. These early results were reported after an average of about two years of follow-up. However, enough women participated in the study for four years or more to allow the researchers to make conclusions about the effect of four years of treatment.

At three years, compared to women who had only chemotherapy, women with early-stage, lymph node–positive, HER2-positive breast cancer who received chemotherapy plus Herceptin had a 52% lower rate of recurrence (the cancer coming back). This difference is statistically significant, meaning that the difference was likely due to Herceptin and not just to chance.

Looked at another way, after three years of treatment, 87% of the women who received chemotherapy plus Herceptin did not have their cancer come back, compared to 75% of the women who received chemotherapy alone. That's an absolute risk reduction of 12%. And after four years, 85% of the women who took chemotherapy plus Herceptin did not have their cancer come back, compared to 67% of the women who received chemotherapy alone. That's an absolute risk reduction of 18%.

Overall survival improved by 53% at three years for women who received chemotherapy plus Herceptin compared to those who received chemotherapy alone. This difference was also statistically significant.

Researchers believe that not having distant recurrence—a return of the cancer to another part of the body—is a predictor of overall survival. After three years of treatment, 90% of the women who received chemotherapy plus Herceptin had no distant recurrence, compared to 81% of the women who received chemotherapy alone. That's an absolute risk reduction of 9%. And after four years, 90% of the women who took chemotherapy plus Herceptin had no distant recurrence, compared to 74% of the women who received chemotherapy alone. That's an absolute risk reduction of 16%.

Because all of these results are so promising, the committee monitoring the studies recommended that the benefits of adding Herceptin to chemotherapy be announced to the public.

The researchers also found that women who received chemotherapy and Herceptin had a 3-4% increase in risk for congestive heart failure (weakening of the heart muscle). This increase is also statistically significant.

Conclusions: The researchers concluded that giving chemotherapy PLUS Herceptin to women with early-stage, lymph node–positive, HER2-positive breast cancer improved disease-free survival (length of life without the cancer coming back) and overall survival. These medical therapies were given after surgery with or without radiation, and before hormonal therapy.

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