BCIRG 006 Update Questions Role of Anthracyclines

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Oncology NEWS InternationalOncology NEWS International Vol 16 No 1
Volume 16
Issue 1

A second interim efficacy analysis of the phase III Breast Cancer International Research Group (BCIRG) 006 study confirmed the benefits reported previously for docetaxel (Taxotere)-plus-trastuzumab (Herceptin) regimens in early HER2-positive breast cancer, and further showed a higher rate of toxicity for anthracycline-based regimens.

SAN ANTONIO—A second interim efficacy analysis of the phase III Breast Cancer International Research Group (BCIRG) 006 study confirmed the benefits reported previously for docetaxel (Taxotere)-plus-trastuzumab (Herceptin) regimens in early HER2-positive breast cancer, and further showed a higher rate of toxicity for anthracycline-based regimens. The updated findings, in fact, raise the provocative question of whether, in some patients, anthracyclines do more harm than good. Dennis Slamon, MD, PhD, co-chair of the study and director of Clinical and Translational Research at UCLA's Jonsson Comprehensive Cancer Center, reported the results at the 29th Annual San Antonio Breast Cancer Symposium (abstract 52).

BCIRG 006 randomized 3,222 women with primary HER2-positive and either node-positive or high-risk node-negative breast cancer to one of three regimens: a control arm of four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC-T); an experimental arm of the AC-T regimen followed by one year of trastuzumab (AC-TH); and an experimental arm of docetaxel, carboplatin, and one year of trastuzumab (TCH).

Median follow-up was 23 months at the first analysis, reported at ASCO 2005, and is now 36 months. The current analysis is based on 462 disease-free survival events (up from 322 in the ASCO 2005 report) and 185 deaths (up from 84).

The number of observed events at the second analysis was significantly greater with AC-T (192) vs AC-TH (128) (P = .000011) or TCH (142) (P = .00028). By contrast, the number of observed events was comparable between AC-TH and TCH (P = .42).

Compared with AC-T, the relative reduction in the risk of relapse was 39% with AC-TH (P < .0001) and 33% with TCH (P = .0003). The absolute difference in disease-free survival (DFS) was similar for the arms containing trastuzumab (6% with AC-TH and 5% with TCH). Notably, node-negative patients (29% of the population) derived this magnitude of benefit as well. Metastatic events were reported for 143 patients with AC-T (13.1%) vs 93 with AC-TH (8.7%) and 98 (9.1%) with TCH.

The relative reduction in risk of death was 41% (

P

< .0041) and 34% (

P

< .017), respectively, for AC-TH and TCH vs the control arm. At 4 years, 92% and 91% of patients were alive in the AC-TH and TCH arms, respectively, vs 86% in the AC-T arm. For all subpopulations, disease-free and overall survival were improved with AC-TH and TCH vs AC-T.

Differences in Safety Profile

The cardiotoxicity of the two experimental arms significantly favored the nonanthracycline TCH regimen. Grade 3-4 cardiac left ventricular failure (congestive heart failure) occurred in only 4 TCH patients vs 20 AC-TH patients (P = .0015). There were 50% fewer cases of patients with greater than 10% relative LVEF decline in the TCH arm (8.5%), compared with AC-TH (18%) (P < .0001).

The TCH arm was superior to AC-TH with regard to sensory and motor neuropathy, nail changes, and myalgia, Dr. Slamon said. Significantly more grade 3-4 neutropenia and leukopenia were seen with AC-TH vs TCH, and more grade 3-4 thrombocytopenia and anemia with TCH than AC-TH. Importantly, leukemia developed in four patients receiving anthracyclines but in no patients on TCH.

"Six cycles of TCH provided similar benefit as eight cycles of AC-TH without increasing cardiotoxicity," Dr. Slamon said. "These data should help influence daily practice, with TCH being considered an option for women with early-stage HER2-positive breast cancer, irrespective of nodal status."

Topo IIα Co-Amplification

Amplification of the topoisomerase II (Topo II-α) gene was shown in the first initial analysis to be associated with better DFS vs non-co-amplified patients, and predictive of an improved response to anthracyclines. The earlier findings "held right on target" in the second analysis, he said. DFS at 4 years was 84% for the co-amplified population vs 78% for the non-co-amplified patients (P < .001). In the co-amplified patients, DFS was numerically but not significantly higher with AC-TH (85%) vs the other regimens (83% each).

"We thought with further follow-up, this might become significant; however, what happened instead is that all the arms now look very similar. You just buy more toxicity with ACT and certainly more with AC-TH," he said. In non-co-amplified patients, disease-free survival was 83% with AC-TH and 81% with TCH vs 71% with AC-T (

P

< .001).

Need to Rethink

"The therapeutic index for the two Herceptin-containing arms shows that only 14 events now separate AC-TH from TCH (128 vs 142 events), fewer than in the last analysis, and we see the same phenomenon for overall survival (49 vs 56 deaths). And only three breast cancer deaths separate the arms (44 vs 47)," he said. "However, the differences in critical adverse events, including grade 3-4 congestive heart failure, are fivefold, with four cases of leukemia in the anthracycline-based arms."

In terms of global safety, Dr. Slamon concluded, "TCH is superior to AC-TH. I think if we are now causing more problems than we are solving with our treatment regimens, we have to rethink what we are doing."

Denying an Effective Treatment

In addition, Dr. Slamon said, "23 patients with bona fide HER2 amplification who were randomized to AC-TH never got Herceptin due to unacceptable declines in LVEF before receiving Herceptin. While this is never scored as a toxicity, I think we need to look at it because you are denying an effective therapy to a patient because of the backbone you've put it on."

Dr. Slamon stated what he considers "the critical question" at this point in light of his findings, and those of Jones et al (J Clin Oncol 234 :5381, 2006) showing significant superiority of TC vs AC with a hazard ratio between 0.50 and 0.60 for all breast cancers: What is the role of anthracyclines in the adjuvant treatment of breast cancer?

Taking It One Step Further

Kent Osborne, MD, of Baylor College of Medicine, commented on Dr. Slamon's statement. "I will take this conclusion one step further," he said. "Now there is a question of whether any kind of chemotherapy offers anything to a truly endocrine-responsive tumor. As your curves with all these chemotherapies come together, one wonders if the chemotherapy is adding nothing, and all we are seeing is the effect of Herceptin."

Dr. Slamon responded, "This question is right on target, and is one that we need to ask and answer. I think it will be a challenge to enroll patients in such a trial, but this is the direction in which we now need to go."

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