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