Journal of the National Cancer Institute Advance Access originally published online on March 25, 2008
JNCI Journal of the National Cancer Institute 2008 100(7):459-461; doi:10.1093/jnci/djn092
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© Oxford University Press 2008.
NEWS |
Anthracycline Therapy May Be Avoidable in Early Breast Cancer, New Studies Suggest
Several meta-analyses have shown that the overall outlook for women diagnosed with early breast cancer has improved in recent decades, with better overall survival and fewer relapses. Anthracycline-based therapy, the backbone of early breast cancer treatment, has undoubtedly been a major driving force in those improvements. Yet the drugs also cause long-term heart problems and secondary leukemia in some patients. Researchers are therefore trying to identify equally effective regimens that lack those side effects.
Nonanthracycline regimens that have less long-term toxicity may provide equal clinical benefit in terms of prolonged progression-free and overall survival, according to data presented at the San Antonio Breast Cancer Symposium in December 2007. Given those results and a recently published meta-analysis, some experts are calling for a change in the standard of care: leaving aside anthracyclines. Other breast cancer specialists warn that more trials are needed before the field makes such a major change in care.
"Many women could be treated without anthracyclines," said Stephen Jones, M.D., director of the breast cancer research center at Baylor Charles A. Sammons Cancer Center and medical director at U.S. Oncology Research in Houston. "The data from the two studies really suggest this is correct," he said, referring to the data presented in San Antonio.
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Anthracycline Alternative?
With that goal in mind, Jones and other researchers with U.S. Oncology have run a prospective randomized trial to compare the current anthracycline-based standard of care—four cycles of doxorubicin plus cyclophosphamide (AC)—with a nonanthracycline regimen of four cycles of docetaxel plus cyclophosphamide (TC) in women with early breast cancer. The group first reported 5-year results at the 2005 San Antonio meeting, and at the time they saw no difference in overall survival between the trial arms. Now, with a median follow-up of 7 years, the team found that the nonanthracycline regimen was better than AC for both disease-free and overall survival.
Specifically, the 506 women treated with TC had a statistically significant improvement in disease-free survival relative to the 510 women treated with AC (81% versus 75%, respectively). Overall survival for patients in the TC arm was 87%, compared with 82% for the women treated with AC, which was a statistically significant difference. In the terms of evidence-based medicine, these data provide high-level evidence. "I think now this trial meets level one evidence that there is a survival difference with TC versus AC," Jones said.
The trial was relatively small, though, which concerns some physicians. "The study from Jones is very provocative," said Edith Perez, M.D., director of the breast cancer program at the Mayo Clinic in Jacksonville, Fla. But "it is one study with 1,016 patients. So although provocative, we very seldom change standards of care in the management of breast cancer on the basis of a 1,000-patient randomized trial."
Knowing that one small trial was unlikely to drive a major change, the U.S. Oncology group launched a second trial in May 2007, comparing six cycles of TC with six cycles of docetaxel–doxorubicin–cyclophosphamide (TAC). That trial will include approximately 2,000 women with early breast cancer whose tumors do not overexpress the HER2 gene. The initial study was launched before the U.S. Food and Drug Administration's approval of trastuzumab for the treatment of women with HER2-positive tumors. Therefore, that trial included women with both HER2-positive and -negative tumors, and Jones’ subset analyses suggest that both groups appeared to benefit from the nonanthracycline regimen. Because the current standard of care requires that women with HER2-positive tumors receive trastuzumab, they are not included in the TC–TAC trial.
Anthracycline Benefit Restricted to Subset of HER2
Anthracycline-based therapy became the standard of care after several trials showed an improvement over older regimens, such as cyclophosphamide–methotrexate–5-fluorouracil. More recently, however, several studies, including a meta-analysis by Alessandra Gennari and colleagues published in JNCI (J Natl Cancer Inst 2008;100:14–20) indicated that the benefit in those trials was restricted to patients whose tumors were HER2 positive.
"When you do a meta-analysis, putting all breast cancer together, it appears that the anthracycline regimens are favored in terms of overall survival," said Dennis Slamon, M.D., Ph.D., director of clinical and translational research at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles. "But, in fact, there is a dramatic effect in the HER2-positive group that is dragging the whole group over to give the appearance that anthracyclines are benefiting everyone." The HER2-negative patients derive little or no additional benefit from anthracyclines, according to the meta-analysis.
The benefit that HER2-positive patients derive from anthracyclines appears to be due not to HER2 itself but to a neighboring gene, Topo II. The Topo II gene, which encodes an enzyme required for DNA replication and RNA transcription, is coamplified in approximately one-third of patients with HER2-positive cancers. In vitro studies indicate that Topo II coamplification causes cancer cell lines to be sensitive to anthracyclines. By contrast, when these same cell lines carry an amplification of only HER2, they are not particularly sensitive to anthracycline treatment, Slamon said.
When Slamon's group retrospectively compared patient outcomes and Topo II amplification status in two trials, they found that the patients who had a coamplified Topo II gene were the ones who benefited from anthracycline-based therapy. For example, the team analyzed the outcomes in the Breast Cancer International Research Group trial, which compared two anthracycline arms (one with and one without trastuzumab) with a nonanthracycline arm that included trastuzumab. After 4 years, patients in the trastuzumab-containing arms had greater disease-free survival rates than the nontrastuzumab anthracycline arm (83% and 82% versus 77%). When the team considered only those patients who lacked Topo II coamplification, the disease-free survival dropped substantially in the nontrastuzumab anthracycline arm (71%) but remained relatively constant in the trastuzumab arms (83% and 81%). That difference disappeared, however, when the researchers looked at just those patients who had a coamplification of Topo II. Then all three arms appeared equally effective, with disease-free survival ranging between 83% and 85%. Therefore, Slamon concluded that anthracycline really benefits only the patients with Topo-II coamplification.
Given that the Topo II coamplification occurs in only about one-third of the HER2-positive breast cancers, which themselves account for about 25% of breast cancers, Slamon estimates that only 8% of the women who have breast cancer derive substantial benefit from anthracyclines over less toxic treatments. And those patients can be treated with drugs that target HER2 itself, such as trastuzumab or lapatinib. "So the question is what role, if any, do anthracyclines play in adjuvant care in breast cancer," he said.
In fact, the UCLA breast cancer group, including Slamon, has voted to avoid anthracycline-based treatment because of the data that Slamon and Jones presented. The physicians now use docetaxel–carboplatin plus trastuzumab in HER2-positive patients and TC for women with HER2-negative tumors.
Perez, however, remains hesitant. "There is a lot of retrospective information looking at the potential of Topo II analysis to help predict the patients who might benefit [from anthracycline therapy], but I think this may be oversimplifying the situation," she said. "There are 25,000 genes in the cell, and to think that only one gene or one marker may be predictive of benefit to anthracyclines may not be telling the whole story.
"We need to be cautious with these decisions," Perez said. "To think we can eliminate anthracyclines may be a bit premature."
Jones is more optimistic. "This is potentially the end of anthracyclines for the majority of women with early breast cancer." He predicts that the ongoing trial comparing TAC with TC will show little difference between the two arms because only HER2-negative patients are eligible for the trial. "You are going to keep hearing about this for the next couple of years," he said. "We’re still 3–5 years from having interim results" from that trial. "But I think, right now, you could pick most patients and treat them safely with TC."
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