December 22, 2008 — The search for biomarkers that would predict a response to anthracycline therapy in breast cancer has homed in on a new promising target, while discarding 2 previous contenders. There is considerable interest in such a biomarker, as it would allow identification of patients who are unlikely to respond to anthracyclines and who could then be offered alternative treatments. This would prevent such patients from being exposed to anthracycline toxicity, which can include long-term cardiovascular damage.
The new biomarker is chromosome 17 polysomy, and data presented by John Bartlett, PhD, from the University of Edinburgh, in Scotland, at the 31st Annual San Antonio Breast Cancer Symposium show that it can effectively predict response to epirubicin.
The study also showed, as did another presentation at the meeting, that 2 biomarkers that had been studied in the past as potential predictors of response to anthracyclines — HER2 and topoisomerase II (TOP2A) — were not strongly predictive. However, both of these appear on chromosome 17, and so they may be acting as surrogates for polysomy 17, which would explain previous mixed results, Dr. Bartlett suggested.
These new data suggest that HER2 and TOP2A are "less useful than we had previously thought," while chromosome 17 polysomy may be "more useful," commented Powell Brown, MD, PhD, from Baylor College of Medicine, in Houston, Texas, who moderated a press conference during the meeting. He told Medscape Oncology that he did not consider the research on chromosome 17 polysomy to be practice changing — at least, not yet. "This is a first report, and the finding needs to be confirmed," he said.
Only One-Third of Patients Respond
The data for chromosome 17 polysomy come from a new analysis of the National Epirubicin Adjuvant Trial (NEAT), which was 1 of the studies that established anthracyclines as a mainstay of treatment for breast cancer. The trial involved more than 2400 women with early breast cancer and showed that adding epirubicin to standard chemotherapy (cyclophosphamide, methotrexate, and fluorouracil [CMF]) significantly improved both relapse-free survival and overall survival, by about 30% compared with that seen with CMF (Poole CJ et al. N Engl J Med 2006;355:1851-1862).
For the current analysis, Dr. Bartlett and colleagues examined tumor samples from 1646 patients for HER2/TOP2A gene alterations and chromosome 17 polysomy.
The former were strongly prognostic for poor survival but showed no treatment interaction with anthracyclines. Chromosome 17 polysomy, in contrast, was not prognostic but showed a significant interaction with anthracyclines.
Patients who had chromosome 17 polysomy tumors had a significantly greater benefit from anthracyclines than those who did not, Dr. Bartlett told the meeting. Patients with chromosome 17 polysomy tumors showed a 35% to 40% reduction in risk for relapse when treated with the anthracycline, while patients without this polysomy derived no significant benefit from anthracycline treatment, he told Medscape Oncology.
Dr. Bartlett noted that this effect was confirmed in data from 2 other trials, the UK BR9601 study and the Canadian MA.5 trial, in work that was described by his group in a separate poster presentation during the meeting
Polysomy was detected in about 30% of all the patients in the trial, commented NEAT lead investigator Christopher Poole, FRCP, from the Cancer Research UK Clinical Trials Unit, Institute for Cancer Studies, at the University of Birmingham
This would suggest that about one-third of patients respond well to anthracyclines, while for the remaining patients another treatment option may be preferable — for example, taxanes, he told Medscape Oncology.
Testing for chromosome 17 polysomy is already available, as it is detected by fluorescence in situ hybridization (FISH), and results can be obtained from most — although not all — commercially available HER2+ FISH tests, Dr. Bartlett said. All women should be tested for HER2+ status, and when the results are equivocal they are tested with HER2+ FISH technology, he explained. The answer for polysomy can be obtained from this test, although some additional training may be required, he added.
"We are close to being able to use this new marker in the clinic to select appropriate therapies in early breast cancer," Dr. Poole commented in a statement.
The NEAT study was funded by Cancer Research UK.
31st Annual San Antonio Breast Cancer Symposium (SABCS): Abstracts 45 and 6059. Presented December 12, 2008 and December 14, 2008.
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