Dr. Henderson provides a thoughtful perspective on an important question that many clinicians often consider: can we ditch anthracyclines in favor of other, more effective and/or less toxic chemotherapeutic agents? Toxicities associated with anthracyclines that are of particular concern include heart failure, which occurs in 1% or more of patients, depending on age and cardiac risk factors (or in about 3% when these agents are followed by adjuvant trastuzumab(Drug information on trastuzumab) [Herceptin]),[1-3] and acute leukemia, which is a rare but almost uniformly lethal late effect.[4] Two pivotal studies have provided some evidence supporting non-anthracycline regimens, including studies demonstrating the effectiveness of docetaxel (Taxotere), carboplatin(Drug information on carboplatin), and trastuzumab in HER2/neu-positive disease, [5] and of docetaxel(Drug information on docetaxel) plus cyclophosphamide(Drug information on cyclophosphamide) in HER2/neu-negative disease.[6] Dr. Henderson points out the limitations of each of these studies, as well as the limitations of molecular markers (eg, topoisomerase 2α [TOP2A] gene alterations) for the selection of subjects most likely to benefit from anthracyclines. He concludes that we should “treat the most aggressive breast cancer with the most effective chemotherapies…and consider no chemotherapy for the rest.” He also states that “four cycles of AC [doxorubicin and cyclophosphamide] is clearly not the most effective regimen in common use for the treatment of early breast cancer. It is likely inferior to other anthracycline regimens and has been proven inferior to taxane combinations”—and he says that “future studies should compare a non-anthracycline, taxane-containing regimen with a combination containing both an anthracycline and a taxane for a minimum of 6 months…..Until a non-anthracycline regimen has been shown to be significantly superior in such a trial (or equivalent in a properly powered non-inferiority trial), anthracyclines should not be dropped from adjuvant chemotherapy regimens.” This conclusion is consistent with a review authored by several other key opinion leaders, which expressed the view that “there is no validated test that can determine whether anthracyclines can be of greater benefit than other agents for individual patients” and that “anthracyclines have been extensively tested in clinical trials spanning several decades; currently, there are insufficient data to recommend replacing them in the adjuvant treatment of breast cancer.”[7]
It is well recognized that only a subset of patients derive benefit from adjuvant chemotherapy, of whom only a still smaller subset benefits specifically from anthracycline therapy. We believe that this is a critical issue that will define the role of anthracyclines, taxanes, and other agents in the future. As Dr. Henderson notes in his review, evidence suggests that HER2/neu overexpressing disease may derive particular benefit from anthrayclines,[8-10] an effect that has been attributed to coamplification of the TOP2A gene on the same amplicon as HER2/neu.[11] The TOP2A gene encodes an enzyme involved in DNA replication and repair, and this is a known therapeutic target for anthracyclines.[12] Although TOP2A gene alterations occur in 40% of HER2/neu overexpressing tumors,[13] they are present in less than 10% of hormone receptor (HR)-positive, HER2/neu non-overexpressing tumors,[9] suggesting that this test may not be useful for selecting for anthracycline therapy among patients with the most common breast cancer subtype, which accounts for about 60% of all breast cancers.
Although there currently appears to be no clinical utility in evaluating TOP2A gene alterations to help with the selection of type of therapy in breast cancer, three recent reports have shown that measuringTOP2A RNA expression may provide useful prognostic information; in addition, such measurement offers promise as an assay for predicting anthracycline benefit. First, Rody et al[14] reported an analysis of Affymetrix microarray data from 1,681 breast cancers which showed that higher TOP2A expression was significantly associated with poorer survival in ER-positive, HER2/neu non-overexpressing disease (P = .001)—but not in ER-negative disease. The association between TOP2A gene expression and recurrence was independent of adjuvant chemotherapy use, and was the single most important prognostic factor in a multivariate model (hazard ratio [HR], 2.40; 95% confidence interval [CI], 1.68 to 3.43; P < .001).
Second, Sparano et al[15] reported that TOP2A RNA expression as measured by quantitative real-time polymerase chain reaction (RT-PCR) was strongly associated with recurrence in patients with HR-positive, HER2/neu non-overexpressing disease with 0 to 3 positive axillary nodes who were treated with adjuvant doxorubicin(Drug information on doxorubicin)-containing chemotherapy. TOP2A expression exhibited the strongest association with recurrence (Korn’s adjusted P value = .01) and was a significant predictor of recurrence in a multivariate analysis adjusted for clinicopathological features (P = .008). Elevated TOP2A expression (using the median level as the cutpoint) also provided information that was complementary to the Oncotype DX Recurrence Score (RS); there was a 2.6-fold increase (95% CI, 1.3 to 5.2; P = .008) in risk of recurrence for high TOP2A expression if there was a low RS (less than 18), and a 2.0-fold increase (95% CI, 1.2 to 3.2; P = .003) if there was an intermediate RS (18 to 30). Furthermore, although there was no difference in recurrence rate between the doxorubicin-cyclophosphamide (AC) treatment arm and the doxorubicin-docetaxel (AT) treatment arm in the overall study population,[16] nor in the subgroup included in the analysis, there was a trend toward high TOP2A expression being associated with better outcomes with AT. This suggests that high TOP2A expression may identify a group of patients whose tumors are resistant to anthracyclines and sensitive to taxanes.
Third, Brase et al[17] evaluated TOP2A DNA amplification and RNA expression in 782 patients with node-negative breast cancer who did not receive systemic therapy, and in 80 patients treated with neoadjuvant epirubicin(Drug information on epirubicin) and cyclophosphamide. High TOP2A RNA levels were significantly associated with inferior metastasis-free survival in node-negative tumors that were ER-positive (HR, 1.59; 95% CI, 1.40 to 1.80; P < .001) or HER2/neu-negative (HR, 1.56; 95% CI, 1.37 to 1.77; P < .001), but not in tumors that were HER2/neu-positive or triple negative. However, TOP2A RNA levels were significantly higher and ESR1 (estrogen receptor alpha) RNA levels were lower in complete responders after neoadjuvant therapy, indicating that the information provided by TOP2A may differ by breast cancer subtype and therapeutic setting.
Taken together, these studies provide consistent evidence that in patients with ER-positive disease, TOP2A RNA expression provides prognostic information whether in the presence or absence of adjuvant anthracycline therapy, and that high levels of TOP2A expression are associated with resistance to adjuvant anthracycline therapy. The potential implication of this work is that TOP2A RNA expression may serve as a useful predictive marker for distinguishing between those patients who would be best treated with a taxane-containing regimen without anthracyclines, and those who would do best treated with an anthracycline-containing regimen used either with or without a taxane. Additional studies in a patient population randomized to receive an anthracycline or no anthracycline will be required in order to properly validate this hypothesis.
What do we recommend to our patients while we await the availability of validated predictive markers—and the results of clinical trials addressing this conundrum? Dr. Henderson suggests that if chemotherapy is given, it should be the best available regimen containing an anthracycline and a taxane, irrespective of recurrence risk, or it should not be given at all. In the era of shared decision making, however, neither all patients nor all clinicians find the benefit:risk ratio of the most aggressive regimens acceptable, especially for those patients at lower risk for recurrence. As Dr. Henderson states, several regimens have been shown to be more effective than 4 cycles of AC chemotherapy, including sequential or concurrent anthracycline-taxane regimens, and docetaxel-cyclophosphamide, although most of these alternative regimens have not been directly compared to each other. Some regimens (eg, sequential AC followed by weekly paclitaxel(Drug information on paclitaxel)) require as many as 16 treatments given over 20 to 24 weeks, whereas others (eg, concurrent docetaxel-cyclophosphamide) may be given in 4 treatments over 12 weeks. Therefore, we suggest that for clinicians and/or patients who are concerned about the cardiac or leukemogenic risks associated with anthracyclines, or about the burdens imposed by some regimens, a course of docetaxel-cyclophosphamide represents a reasonable choice for some patients who have a high enough recurrence risk to warrant chemotherapy, but not sufficiently high to render the risks of anthracyclines acceptable.
