Jeong, Jong‐Hyeon

512 Background: The joint efficacy analysis of NCCTG N9831 and NSABP B-31 demonstrated improved outcomes with the addition of trastuzumab (H) to doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) in women with surgically removed HER2- positive breast cancer (NEJM 2005). Following this report, patients randomized to AC→T and less than 6 months from completion of chemotherapy were eligible to receive H. We have updated the initial combined results of these two trials. Methods: Primary and secondary efficacy endpoint were disease free survival (DFS) and overall survival (OS). Cox modeling was performed. Hazard ratios are adjusted for nodal status, tumor size, T schedule, hormone receptor status, and trial (also age for OS). Results: Among the 3,969 women enrolled (ages: 22 to 80yrs), there have been 619 events (H group: 222, non-H: 397). First events were: recurrence (511), contralateral breast disease (18), other second primary cancers (48), and death without recurrence or second primary cancers (42). The median follow-up among the 3,711 women still alive is 2.9 years (range up to 6,4 years). The 4 yr DFS rate and 4 yr OS rate respectively were: 85.9% (95%CI: 84.0–87.8%) and 92.6% (95%CI: 91.2–94.2%) in H group and 73.1% (95%CI: 70.6–75.8%) and 89.4% (95%CI: 87.6–91.2%) in non- H group. Hazard ratio for adjuvant (H/non-H) was 0.49 (P<0.0001; 95%CI: 0.41–0.58) for DFS and 0.63 (P=0.0004; 95%CI: 0.49–0.81) for OS.The rates of a first event per 1,000 women/year during yrs 1–4 were: 26.7, 52.9, 49.6 and 23.2 for H and 42.3, 102.3, 107.6 and 61.5 for non-H. The impact of crossover on clinical outcome will be explored. Conclusions: With an increase in the median follow-up of 11 months and with 225 additional events, the demonstration of substantial improvement in outcomes with the addition of trastuzumab to chemotherapy persist. This improvement continues in spite of some degree of cross-over occurring after the initial results were reported.Updated data regarding crossover outcomes and H duration (as they relate to disease free survival) will be presented. [Table: see text]

Purpose Positive interim analysis findings from four large adjuvant trials evaluating trastuzumab in patients with early-stage human epidermal growth factor receptor 2 (HER2) –positive breast cancer were first reported in 2005. One of these reports, the joint analysis of North Central Cancer Treatment Group NCCTG N9831 (Combination Chemotherapy With or Without Trastuzumab in Treating Women With HER2-Overexpressing Breast Cancer) and the National Surgical Adjuvant Breast and Bowel Project NSABP B-31 (Doxorubicin and Cyclophosphamide Plus Paclitaxel With or Without Trastuzumab in Treating Women With Node-Positive Breast Cancer That Overexpresses HER2), was updated in 2011. We now report the planned definitive overall survival (OS) results from this joint analysis along with updates on the disease-free survival (DFS) end point. Methods In all, 4,046 patients with HER2-positive operable breast cancer were enrolled to receive doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in both trials. The required number of events for the definitive statistical analysis for OS (710 events) was reached in September 2012. Updated analyses of overall DFS and related subgroups were also performed. Results Median time on study was 8.4 years. Adding trastuzumab to chemotherapy led to a 37% relative improvement in OS (hazard ratio [HR], 0.63; 95% CI, 0.54 to 0.73; P < .001) and an increase in 10-year OS rate from 75.2% to 84%. These results were accompanied by an improvement in DFS of 40% (HR, 0.60; 95% CI, 0.53 to 0.68; P < .001) and increase in 10-year DFS rate from 62.2% to 73.7%. All patient subgroups benefited from addition of this targeted anti-HER2 agent. Conclusion The addition of trastuzumab to paclitaxel after doxorubicin and cyclophosphamide in early-stage HER2-positive breast cancer results in a substantial and durable improvement in survival as a result of a sustained marked reduction in cancer recurrence.

Purpose Trastuzumab is a humanized monoclonal antibody against the human epidermal growth factor receptor 2 (HER2). The clinical benefits of adjuvant trastuzumab have been demonstrated in interim analyses of four large trials. Initial data of the combined analysis of the North Central Cancer Treatment Group (NCCTG) N9831 Intergroup trial and National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial were reported in 2005. Long-term follow-up results on disease-free survival (DFS) and overall survival (OS) have been awaited. Patients and Methods Patients with HER2-positive operable breast cancer were randomly assigned to doxorubicin plus cyclophosphamide followed by paclitaxel with or without trastuzumab in the NCCTG N9831 and NSABP B-31 trials. The similar design of both trials allowed data from the control and trastuzumab-containing arms to be combined in a joint analysis. Results At 3.9 years of median follow-up, there continues to be a highly statistically significant reduction in DFS event rate in favor of the trastuzumab-containing arm (P < .001). Similarly, there continues to be a statistically significant 39% reduction in death rate in favor of the trastuzumab-containing arm (P < .001). Conclusion These data demonstrate consistent DFS and OS advantages of adjuvant trastuzumab over time, with the longest follow-up reported to date. The clinical benefits continue to outweigh the risks of adverse effects.