In the field of HER2 research, there is overwhelming consensus on at least one point that HER2 is a clinically important molecule. Peter M. Ravdin, M.D., Ph.D., of the University of Texas Health Science Center at San Antonio, opened up a National Cancer Institute conference on HER2 last October by saying that he feels that HER2 and the estrogen receptor are the two central molecules driving breast cancer therapy.
"Within the last couple of years, I think HER2 has emerged as a macromolecule that many of us now will be using for treatment planning," said Ravdin. "Both [HER2 and the estrogen receptor] are relevant to the growth of neoplasia. Both have prognostic implications. Both have been implicated in responsiveness to therapy, and both are targets for therapeutics," he said.
But agreement on the importance of HER2 is easier than agreement on how HER2 status should be used to guide therapy. That HER2 is a predictor of poorer outcome and shortened survival in breast cancer patients whose tumors overexpress HER2 protein is by now fairly firmly established, although Ravdin and others pointed out that there are still data showing overexpression of the protein is not prognostic. Central to the HER2 debate today is whether HER2 status can predict responsiveness to therapies other than Herceptin, such as tamoxifen, taxanes, and doxorubicin.
HER2 Research
HER2 (human epidermal growth factor receptor-2 also known as c-erbB-2) protein overexpression occurs in 25% to 30% of breast tumors, which have higher proliferation rates than normal cells. Herceptin, a humanized version of a mouse monoclonal antibody that targets the receptor for therapy, was approved by the U.S. Food and Drug Administration in 1998 for treatment in combination with chemotherapy of women with HER2-overexpressing metastatic breast cancer. However, there is still debate about the best method to test for HER2 expression in tumor cells (see News, Feb. 16, 2000).
Presenters at the NCI conference highlighted recent research on HER2 status and cancer therapy. Hyman Muss, M.D., at the University of Vermont, Burlington, pointed out several reports showing that HER2-positive patients are less responsive to endocrine therapy, such as tamoxifen or other SERMs (selective estrogen receptor modifiers). However, in a collaborative study using breast tissue from a completed NCI cooperative group trial (Cancer and Leukemia Group B, protocol 8541) looking at the effect of tamoxifen treatment in ER-positive patients who had been followed for an average of 10 years, Muss and his collaborators found something different.
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Furthermore, the results were the same no matter how they tested for HER2. Because the HER2 gene is amplified in about 90% of breast tumors that overexpress HER2, investigators can either look for the amplified HER2 gene or for the receptor itself to detect the level of HER2 expression. In this case, the investigators used three different methods: immunohistochemistry, which uses antibodies to detect protein; and polymerase chain reaction and fluorescent in situ hybridization, which detect amplified gene copies.
Soonmyung Paik, M.D., of Allegheny University of the Health Sciences, Pittsburgh, looked at similar data from the National Surgical Adjuvant Breast and Bowel Project-B14 trial, a randomized trial of about 2,800 women who had node-negative, ER-positive breast cancer and were randomly treated with either tamoxifen or placebo. He also found that the survival rates of women receiving tamoxifen were the same irrespective of their HER2 status.
Another speaker, Mitch Dowsett, Ph.D., from the Royal Marsden Hospital, London, measured HER2 levels in 813 tumors from two breast cancer trials, and concluded that HER2-negative patients benefitted from tamoxifen irrespective of ER status.
Should HER2 status be used in the clinic to decided whether women who are ER-positive patients with early stage breast cancer be treated with tamoxifen? "I think from the best data available, the answer is no," said Ravdin. "At this point it is not appropriate to use HER2 to define whether to use tamoxifen therapy."
The data from the taxanespaclitaxel (Taxol) and docetaxel (Taxotere) at this point seem to be more consistent. Andrew D. Seidman, M.D., of Memorial Sloan-Kettering Cancer Center, New York, showed data from a 1997 study involving 122 patients treated with either Taxol or Taxotere for metastatic breast cancer over a 5-year period; HER2 status was measured with the mouse monoclonal antibody 4D5.
"We found a statistically significant higher response for those women whose tumors tested positive for HER2 compared to those with normal levels of the protein," said Seidman.
He and his colleagues are now in the process of going back and looking at the blocks from 450 metastatic patients enrolled in the completed CALGB 9342 trials who were given Taxol. HER2 status will be tested by several methods.
Seidman is also involved in two trials looking at HER2 status and responsiveness to a combination of Taxol and Herceptin. In the pivotal trials leading to approval of Herceptin in 1998, the combination resulted in improved survival benefit compared with Taxol alone.
Seidman reported the preliminary results from a trial involving 100 women showing that a weekly versus every-3-week regimen of Taxol (used in the 1998 trial) in combination with Herceptin may be more effective. Women overexpressing HER2 also showed a greater sensitivity to the combined therapy than normal expressors. A large multi-center trial, CALGB 9840, will test both these hypotheses.
By far the most compelling data were those showing an association between HER2 overexpression and responsiveness to doxorubicin-containing regimens, commonly CAF (cyclophosphamide, doxorubicin [Adriamycin], and 5-fluorouracil). Retrospective analyses from three large multicenter trials, CALGB, NSABP, and SWOG (Southwest Oncology Group) showed a greater responsiveness of HER2 overexpressors to doxorubicin-containing treatment. Responsiveness to CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) tended to be greater in the underexpressors, although the results were less consistent.
Donald A. Berry, Ph.D., professor and chairman of biostatistics at The University of Texas M. D. Anderson Cancer Center in Houston, reviewed several key studies and concluded that doxorubicin could increase the survival in HER2-positive patients.
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He added that his own attitude "is that if a woman is HER2 positive she should get Adriamycin. If she is HER2 negative, I think its important not to give Adriamycin."
Seidman agreed. "Based on the analyses from the three trials, I have a bias toward using Adriamycin when one would consider CMF or [Adriamycin and cyclophosphamide] in node-negative breast cancers that are HER2 overexpressing. I think there is a consensus building very strongly in that direction."
Antonio Wolff, M.D., at Johns Hopkins Oncology Center in Baltimore, was less emphatic. "I tell HER2-positive patients that they may benefit more if they get anthracyclines than if they are negative. But that is just one additional piece in a puzzle. If I have someone who is strongly positive and also young and node positive, I may use that as an additional element in making a decision about therapy."
Future Studies
Other opportunities to collect more data are in process. The effectiveness of Herceptin in HER2-positive patients with no sign of clinical metastases will be looked at in three large intergroup trials. Seidman expects his trial treating patients with metastatic disease who are high or normal expressors with Herceptin and two regimens of Taxol to begin in early spring. The trial will test the two Taxol regimens as well as the role of Herceptin in normal expressors. Berry is planing to test about 2,500 patients from an already completed intergroup CALGB study that were treated with Adriamycin plus or minus Taxol for HER2 status.
Though it is not clear how HER2 status should guide certain therapies, many of the conference participants think it is important for physicians to test breast cancer patients routinely for HER2 status. Those with metastatic disease need to know if they are candidates for Herceptin and those with earlier stage disease can consider entering a clinical trial.
A summary of the meeting is expected to be available soon on the Internet at http://ctep.info.nih.gov.
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