For the past 5 years, evidence has been mounting that breast tumors with high levels of the protein HER2 respond better to the widely used drug doxorubicin (Adriamycin) than tumors that are HER2 negative. Last month in San Antonio, that pile of data seemed to have reached a critical level, filling much of an afternoon session and spilling into other presentations and poster sessions at the annual Breast Cancer Symposium hosted by the San Antonio Cancer Institute.
With strong data supporting the idea that HER2 levels do correlate with response to doxorubicin and other anthracyclines, the critical question is now the one asked by San Antonio's Peter Ravdin, M.D.: "Are these results ready for clinical application?" For many at the meeting the answer was a cautious yes, tempered mainly the lack of a standardized way to determine HER2 status.
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For example, Ravdin said in an interview, HER2 positivity might now sway a physician toward use of doxorubicin and cyclophosphamide in a situation where he or she wouldn't normally feel comfortable with it because of doxorubicin's potential toxicities.
New Data, Old Trials
The newest data on HER2, also widely known as erbB-2, have come from major breast cancer trials of the past two decades multicenter, randomized trials already completed by Clinical Trials Cooperative Groups. These consortiums, including the Cancer and Leukemia Group B, the Southwestern Oncology Group, and the National Surgical Adjuvant Breast and Bowel Project, are now going back to banked tumor specimens from earlier trials and analyzing them for HER2 levels.
One of the completed CALGB trials, for example, had originally tested doxorubicin, in combination with cyclophosphamide and 5-fluorouracil, at high, medium, and low doses. The high-dose arm had done better in terms of survival. Now the retrospective data on HER2 status in this trial shows that it was actually the patients with high HER2 levels who derived the most benefit from the higher-dose regimens. Women with low HER2 levels benefitted equally regardless of the dose.
It was an earlier analysis of these CALGB tumor specimens that first alerted oncologists to the possibilities of HER2 as a predictive biomarker. Published in the New England Journal of Medicine by Hyman Muss, M.D., University of Vermont, Burlington, and colleagues in 1994, this analysis set the stage for more correlative studies.
"A whole new dimension became available," said Norman Wolmark, M.D., Allegheny University of the Health Sciences, Pittsburgh, and chair of the NSABP. Wolmark said that after the 1994 article, NSABP turned to its own banked tumor specimens to do similar kinds of analyses.
In one of the NSABP trials, patients had been randomized to receive a specific chemotherapy regimen either with or without doxorubicin. Those on the doxorubicin arm had a statistically significant survival benefit. But when NSABP's Soonmyung Paik, M.D., also from Allegheny, analyzed the tumor samples for HER2, he found that most of the difference in the two arms was accounted for by HER2 status. That is, among tumors that were HER2 negative, there was no statistically significant difference in disease-free or overall survival. In the HER2-positive tumors, there was a difference in disease-free survival.
The NSABP study, along with an update of the earlier CALGB data, began to change minds about HER2 when they were published last September (see Journal, Sept. 16, 1998), according to experts in San Antonio. And with the new data presented at the meeting, the pendulum seemed definitely to be swinging toward acceptance of the protein as a useful clinical tool.
Larry Norton, M.D., head of the Division of Solid Tumor Oncology at Memorial Sloan-Kettering Cancer Center in New York City, said he used to be doubtful but now was convinced that HER2 status should play a role in clinical decisionmaking. "I am going to use it," he said.
Another expert who said he thought that clinical practice would be changing was Robert Carlson M.D., Stanford University Medical Center, Palo Alto, Calif., who chairs the breast cancer committee of the National Comprehensive Cancer Network. Like Norton, he pointed to the two recently published studies as a turning point in physicians' acceptance of HER2.
Despite the growing data, however, some doubts remain. For one thing, the findings are not so clearcut that physicians will be able to use HER2 to decide for or against doxorubicin with the same confidence that many now have in using the estrogen receptor to decide for or against hormone therapy with tamoxifen. Wolmark, in particular, emphasized that "HER2 is not an ER."
One reason it is not an ER is that in the studies published and presented so far, not all the survival advantage for doxorubicin has been in the HER2-positive group; some patients who did not overexpress HER2 still benefitted from the drug. So, while HER2-positive patients may benefit from doxorubicin-based therapy, some investigators, Ravdin included, are reluctant to conclude at this point that the converse is necessarily true that any patient who is HER2 negative can safely forego doxorubicin.
Nevertheless, the evidence is pointing that way and may influence clinical practice, say others. "We may see a decrease in the use of anthracycline containing regimens in the HER2-negative tumors while we see an increase in the use of anthracycline containing regimens in the HER2-overexpressing tumors," Carlson said.
Lack of Standards
Another factor that could limit the clinical usefulness of HER2 as a biomarker is the lack of a standardized method to define HER2 positivity. Most of the studies done so far have used different antibodies and different scoring systems. Moreover, there is no consensus that using antibodies (immunohistochemistry) to detect overexpression of the HER2 protein is preferable to methods that detect amplification of the HER2 gene, such as fluorescent in situ hybridization (FISH).
Gary Clark, M.D., San Antonio Cancer Institute, pointed out in a recent editorial (Journal, Sept. 16, 1998), that the proof of principle that response to doxorubicin depends on HER2 status had been achieved. "But," he added, "before we begin to routinely select adjuvant chemotherapy for patient with breast cancer on the basis of erbB-2 status, we need a consensus about the most reliable, most reproducible, and most predictive method to determine erbB-2 status."
"This is now recognized as a major issue," said Ravdin. "People should know that there is the possibility of making a bad decision based on a bad test."
To address this problem, Ravdin said that SWOG intends to repeat its analysis of HER2 levels in tumor samples from one of the large doxorubicin trials. This time, investigators will use one of the assays recently approved by the Food and Drug Administration (see sidebar) and will prospectively define cutoff points for high and low HER2 levels.
Once the results of this study are in, Ravdin said, he will have no reservations about the clinical use of HER2 to help decide on therapy. "The only reason I'm cautious," he said, "is that I'd like to see results using one of the approved methodologies."
In the meantime, HER2 is also under scrutiny as a biomarker for other kinds of treatment. There have been some indications that it may predict for resistance to tamoxifen and cyclophosphamide, sensitivity to radiotherapy, and sensitivity or resistance to taxol and other taxanes. More retrospective analyses of tumor specimens, many of them already under way, are expected to throw light on these possible links.
"These questions are still very much on the table," said Hayes. "We hope they will be answered in the next 18 months."
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