Does Topoisomerase II–Alpha Gene Amplification Provide Useful Information for Treatment Selection in Patients With Breast Carcinoma?

TO THE EDITOR: Press et al 1 concluded that “TOP2A coamplification, not HER2 amplification, is the clinically useful predictive marker of an incremental response to anthracycline-based chemotherapy.” I do not believe that this conclusion is justified on the basis of the data they examined. To evaluate whether a marker is predictive for benefit from a drug, one should compare (either prospectively or by using archived specimens from a previous trial) outcomes for patients who were randomly assigned to receive a regimen containing the drug or the same regimen not containing the drug, and one should examine how this treatment effect (ie, hazard ratio) depends on marker status. 2 The studies Press et al 1 examined did not permit such an evaluation. The closest one could come to a direct analysis of whether TOP2A amplification is a predictive marker of anthracycline effectiveness was an analysis that Press et al did not comment on. In trial BCIRG-006 of the Breast Cancer International Research Group, patients with HER2amplified tumors were randomized to receive ACT (doxorubicin, cyclophosphamide, docetaxel), ACTH (ACT plus trastuzumab), or TCH (docetaxel, carboplatin, trastuzumab). A comparison of the ACTH regimen with the TCH regimen isolates the value of the anthracycline relative to carboplatin with both in the presence of trastuzumab. In Figure 3 of the article by Press et al, 1 outcomes for these two regimens seem equivalent both forTOP2A-amplified and forTOP2Aunamplified tumors. In the patients with amplified tumors, there were 35 events on treatment with ACTH compared with 42 events on treatment with TCH; in the patients with unamplified tumors, there were 87 events on ACTH compared with 92 on TCH. Consequently, on the basis of the only relevant direct randomized comparison of anthracycline use available in the authors’ data, there is no evidence that the efficacy of the anthracycline depends on TOP2A status. The authors base their conclusions on indirect evidence. In both the BCIRG-006 adjuvant study and the H0648g, the original trastuzumab metastatic disease licensing study, the investigators compared an anthracycline regimen not containing trastuzumab with the same anthracycline regimen administered with trastuzumab. They noted that trastuzumab did not seem to improve outcome in the small subset of patients with amplifiedTOP2A but that it did improve outcome for patients without TOP2A amplifications. The significant interaction in Table 3 is for the incremental effect of trastuzumab, not as stated for the incremental effect of anthracycline. They interpret this variation in trastuzumab treatment effect as indicating that the anthracycline is more effective in patients withTOP2A amplifications. The fact that trastuzumab is ineffective in patients with TOP2A amplifications receiving an anthracycline-based regimen does not necessarily mean that the anthracyclines are effective in that subset. Patients with large amplifications not focused on the HER2 gene may have tumors driven by genes other than HER2 and thus be less responsive to HER2 inhibition. The conclusion is also based on a limited number of events involved. This type of indirect analysis does not provide a strong level of evidence according to the scale introduced by Simon et al 2 for evaluating the medical utility of predictive biomarkers. The pragmatic question of importance is which patients should be considered good candidates for anthracycline-based regimens. Previous studies have indicated that patients without HER2-amplified tumors are unlikely to benefit from such regimens. 3,4 The data for BCIRG-006 indicates that, for patients with HER2-amplified tumors who will receive trastuzumab, the docetaxel/carboplatin regimen seems as effective as the ACT regimen, regardless of TOP2A status. This leaves little room for the use of anthracyclines and no reason for the measurement of TOP2A amplification status. The data for BCIRG-006 suggests that patients with amplified HER2 and TOP2A might do as well on ACT as on ACTH—ie, they might not benefit from trastuzumab in the presence of ACT. This conclusion of therapeutic equivalence requires independent confirmation in a larger study, however, as it is based on only 42 disease-free survival events on ACT compared with 35 on ACTH.