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Key Words

Breast cancer, HER2, anthracycline, doxorubicin ³ (Adriamycin®), epirubicin ⁴ (Ellence®). (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary ⁵.)

Summary

Combined data from eight randomized clinical trials shows that chemotherapy with an anthracycline drug such as doxorubicin or epirubicin extends survival for women with HER2-positive, but not HER2-negative, breast cancer. These results suggest that women with HER2-negative breast cancer may be spared these drugs, which carry a rare risk of potentially severe side effects including heart damage.

Source

Journal of the National Cancer Institute, Jan. 2, 2008 (see the journal abstract ⁶).
(J Natl Cancer Inst. 2008 Jan 2;100(1):14-20. Epub 2007 Dec 25)

Background

Women with early-stage invasive breast cancer often receive chemotherapy in addition to surgery and radiation therapy. Several randomized clinical trials have shown that chemotherapy for breast cancer with a class of drugs called anthracyclines extends survival compared with non-anthracycline-based chemotherapy. However, the absolute increase in survival is not large and anthracycline chemotherapy can have severe side effects in some women, including heart damage and secondary leukemia.

Recent studies have suggested that women whose tumors produce too much of a protein called HER2 (called HER2-positive) may be the only ones who actually benefit from anthracycline chemotherapy. HER2-positive tumors are tumors that have HER-2 gene amplification (too many copies of the HER2 gene) or protein over-expression ( extra HER2 protein).

However, studies so far have not consistently shown a link between HER2 status (positive or negative) and the effectiveness of anthracycline chemotherapy. Many studies may have been too small to show a difference. In addition, studies have used different techniques to collect breast tissue samples and measure HER2 status, and used different chemotherapy regimens, making it difficult to compare results between them.

Knowing more certainly whether HER2 status influences the effectiveness of anthracycline chemotherapy would help physicians better personalize treatment for individual patients.

The Study

Investigators from the National Cancer Research Institute of Italy combined data (called a meta-analysis) from eight randomized clinical trials of chemotherapy for breast cancer. They found these eight trials by comprehensively searching databases of the medical literature and conference proceedings for published and unpublished clinical trials in English. All trials included in the meta-analysis had to meet three criteria:

• All patients included in the trial were randomly assigned to treatment
• The trial tested anthracycline-based chemotherapy against non-anthracycline-based chemotherapy after surgery for breast cancer
• The trial reported disease-free and overall survival rates based on HER2 status, or these rates could be calculated from the available data

The investigators then compared whether disease-free and overall survival differed for women receiving anthracycline-based chemotherapy depending on whether or not their tumors produced extra HER2.

Results

Out of 6,564 patients randomly assigned in one of the eight trials, 5,354 (82 percent) had their tumors tested for HER2 status. Of these, 1,536 (29 percent) had tumors that had extra HER2 protein or extra copies of the HER2 gene – that is, they were HER2 positive.

Six of the trials had data on disease-free survival. Seven trials had data on overall survival. When the meta-analysis was complete, the data showed that treatment with anthracycline-based chemotherapy significantly reduced the risk of relapse and reduced the risk of death from any cause compared with non-anthracycline-based chemotherapy.

However, when the results were broken into two groups by HER2 status, only women with HER2-positive tumors actually had a significantly reduced risk of relapse and death after anthracycline-based chemotherapy.

Limitations

The authors acknowledge several limitations to their study. They had to rely on results summarized by the other studies, and did not have access to the actual patient data. Therefore, they could not confirm the initial conclusions or perform additional statistical tests.

Also, the eight studies included in the meta-analysis did not all use the same methods for measuring HER2 status. However, this did not seem to influence the measured effectiveness of anthracycline-based chemotherapy when tested by the investigators.

Finally, there might have been unpublished clinical trials not found by the authors that failed to find a link between HER2 status and the success of anthracycline treatment. Not including these studies in the meta-analysis could cause a false-positive result (called publication bias). However, the authors did perform statistical tests designed to detect publication bias, and did not find any indication of such bias.

Comments

“Our results confirm that the added benefit of adjuvant chemotherapy with anthracyclines is confined to women who have breast tumors in which HER2 is overexpressed or amplified,” concluded the authors. “The absence, in our study, of any effect of anthracyclines observed in patients with HER2-negative disease suggests that this group of patients could be spared unnecessary toxic effects related to the use of this class of agents.”

Jo Anne Zujewski, M.D., a breast cancer specialist with the National Cancer Institute’s Division of Cancer Treatment and Diagnosis, agreed, saying “Women with estrogen-receptor-positive, HER2-negative breast cancer should ask their doctors about avoiding anthracycline-containing chemotherapy….The evidence is pretty consistent now that the benefit of anthracycline chemotherapy is seen in the HER2-positive cases but not in others.”

Further clinical trials are needed, she explained, to determine what type of chemotherapy is best for women with so-called “triple-negative” breast cancer, which is HER2 negative, estrogen-receptor-negative, and progesterone-receptor negative. Some women with triple-negative disease may still derive a benefit from treatment with anthracyclines.

Glossary Terms

Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back. Adjuvant therapy may include chemotherapy, radiation therapy, hormone therapy, targeted therapy, or biological therapy.

A type of antibiotic that comes from certain types of Streptomyces bacteria. Anthracyclines are used to treat many types of cancer. Anthracyclines damage the DNA in cancer cells, causing them to die. Daunorubicin, doxorubicin, and epirubicin are anthracyclines.

The length of time after treatment for a specific disease during which a patient survives with no sign of the disease. Disease-free survival may be used in a clinical study or trial to help measure how well a new treatment works. Also called DFS and disease-free survival time.

Describes cells that do not have a protein to which the hormone estrogen will bind. Cancer cells that are estrogen receptor negative do not need estrogen to grow, and usually do not stop growing when treated with hormones that block estrogen from binding. Also called ER-.

The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein.

A protein involved in normal cell growth. It is found on some types of cancer cells, including breast and ovarian. Cancer cells removed from the body may be tested for the presence of HER2/neu to help decide the best type of treatment. HER2/neu is a type of receptor tyrosine kinase. Also called c-erbB-2, human EGF receptor 2, and human epidermal growth factor receptor 2.

Cancer that has spread beyond the layer of tissue in which it developed and is growing into surrounding, healthy tissues. Also called infiltrating cancer.

Describes cells that do not have a protein to which the hormone progesterone will bind. Cancer cells that are progesterone receptor negative do not need progesterone to grow, and usually do not stop growing when treated with hormones that block progesterone from binding. Also called PR-.

A molecule made up of amino acids that are needed for the body to function properly. Proteins are the basis of body structures such as skin and hair and of substances such as enzymes, cytokines, and antibodies.

A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial.

The extent of a cancer in the body. Staging is usually based on the size of the tumor, whether lymph nodes contain cancer, and whether the cancer has spread from the original site to other parts of the body.