Optimizing Adjuvant Taxanes in Early Breast Cancer
Authors: Miguel Martin, Sara López-Tarruella
Journal: Journal of Clinical Oncology (2015)

The unique design of the ECOG (Eastern Cooperative Oncology Group) E1119 trial confers great clinical relevance to this study. The trial’s main aim was the identification of the best taxane-containing regimen for adjuvant treatment of operable breast cancer. The first planned analysis was published 7 years ago, after a median follow-up of 5.3 years. The study, with a 2 2 design, failed to provide an answer to the primary questions: what is the best taxane (docetaxel v paclitaxel) and the best taxane schedule (once per week v once every 3 weeks) in sequence after four cycles of doxorubicincyclophosphamide (AC 4). A significant interaction between taxane type and schedule was observed, which precluded interpretation of the two factors separately. However, the secondary analysis showed that paclitaxel once per week and docetaxel once every 3 weeks were associated with a significant improvement in disease-free survival (DFS) compared with the control (AC 4 followed by paclitaxel once every 3 weeks). Only AC 4 followed by paclitaxel once per week was associated with a statistically significant increase in overall survival. Updated results of the E1119 trial are presented by Sparano et al in the article that accompanies this editorial, which provides detailed information on the outcome of the patients after a median follow-up of 12.1 years. AC 4 followed by weekly paclitaxel remains associated with a significant improvement in disease-free survival (hazard ratio [HR], 0.84; P .011), although the improvement is less marked when compared with the first analysis (HR, 0.73). The current marginal improvement in overall survival (HR, 0.87) is no longer statistically significant when compared with the control group (AC 4 followed by paclitaxel once every 3 weeks). The first conclusion of the authors of the article is that the initial benefit that was observed with once-perweek paclitaxel was qualitatively similar but quantitatively less pronounced with longer follow-up. The reason for that apparent loss of benefit of once-per-week paclitaxel in the long term is unclear. The annual hazard rate of breast cancer relapse varies over time, with a peak near 3% per year between the second and third years after primary surgery and then a decline to 1% to 2% per year by the sixth through eighth years. In addition, as shown in the article by Sparano et al, the pattern of relapse is different in different breast cancer subtypes: patients with hormone receptor–negative tumors (particularly those with the triple-negative phenotype) relapse mainly in the first 5 years of follow-up, whereas hormone receptor–positive/human epidermal growth factor receptor 2 (HER2) –negative patients receiving adjuvant hormones have a lower and constant risk of relapse over time. This differential pattern of relapse has been reported in other trials as well. In addition, several studies have suggested that improvements with chemotherapy are greater in estrogen receptor (ER)–negative tumors. Given that chemotherapy seems to produce a greater absolute benefit in patients with hormone receptor–negative tumors, and because these patients have a higher relapse rate, particularly during the first 5 years after surgery, we can speculate that the benefits obtained with the best taxane-containing regimens are greater in initial reports compared with reports of long-term results. In addition, the ability of adjuvant hormonal therapy to reduce relapses in the population of patients with hormone receptor–positive breast cancer can obscure the long-term benefits obtained with chemotherapy in this predominant subgroup and in the overall population of patients as well. In support of this hypothesis, a similar loss of benefit over time has been reported in two additional adjuvant taxane trials (North American Intergroup Trial C9741 and the Finnish FinXX [Finland Capecitabine Trial]). The described loss of efficacy over time of adjuvant once-perweek paclitaxel that was observed in the ECOG E1119 trial and in other trials should be accepted with great caution, given that a similar loss of efficacy was not seen in the same ECOG trial with docetaxel administered once every 3 weeks. Three other adjuvant taxane trials that reported results over time (US Oncology 9735, the Grupo Espanol de Investigacion en Cancer de Mama [GEICAM] 9906, and Breast Cancer International Research Group [BCIRG] 001) showed no signs of a loss of benefit obtained with the taxane regimen at 7 to 10 years of follow-up in comparison with early reports. Therefore, it remains unclear whether or not the loss of efficacy of adjuvant taxanecontaining chemotherapy over time in the full spectrum of patients with breast cancer is a real finding. An interesting issue that was addressed by Sparano et al in their interpretation of the E1119 data is the apparent breast cancer subtype specificity of the once-per-week paclitaxel regimen. In an exploratory analysis, they found that this regimen is specifically more active in patients with triple-negative tumors. In the era of personalized medicine, identification of subgroups of patients who benefit from specific regimens is an important goal; therefore, this matter is certainly of the upmost relevance. The HR for relapse with once-per-week paclitaxel versus the control arm in the E1119 trial was 0.69 (95% CI, 0.52 to 0.91) in triple-negative tumors, which translated into an impressive absolute disease-free survival (DFS) improvement of approximately 10% at 10 years in that population of patients. Conversely, in the population of patients with hormone receptor–positive/HER2-negative tumors, the once-per-week paclitaxel schedule offered little or no DFS improvement compared with JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 21 JULY 2