Long-term results of the PACS 04 trial evaluating adjuvant epirubicin plus docetaxel in node-positive breast cancer and trastuzumab in the HER2-positive subgroup

Abstract

Background: Long term information on the risk/benefit ratio of currently available therapies remains crucial for treatment decisions. In the PACS04 phase III trial, patients (pts) with node‐positive (N+) breast cancer (BC) were double‐randomized to concomitant taxane‐anthracycline versus standard FEC, as well as 1‐year trastuzumab versus nill in the HER2+ subpopulation. Methods: 3009 pts (20% HER2+, 12% triple negative (TNBC) BC) were randomly assigned to receive 6 cycles of fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 (FEC) or epirubicin 75mg/m2 and docetaxel 75 mg/m2 (ED). Pts with HER2+ tumors were randomized to either trastuzumab (TRA) for one year, or observation (OBS). The primary endpoint was disease‐free survival (DFS). Results: After a median 115‐month follow‐up, DFS was not different in the ED compared to the FEC arm (70% vs 68% respectively, HR=0.88 [95% CI: 0.77‐1.01]; p=0.064), nor was OS: 80% with FEC and 81% with ED (HR=0.97 [95% CI: 0.81‐1.16]; p=0.729). Subgroup analysis suggested better DFS with ED in non‐TNBC pts [HR=0.82 (0.71‐9.96) p=0.02]. In the 528 pts with HER2+BC, there was trend for a higher DFS in the TRA arm (68%; [95% CI: 61‐74]) versus the OBS arm (60%; [95% CI: 54‐66]); HR=0.77 [95% CI:0.57‐1.03]; p=0.079 (intent to treat population). In the per protocol population, DFS, but not OS, was significantly higher in the TRA arm (HR: 0.69 [95%CI: 0.51‐0.94]; p=0.0156). ED led to more neurological and hematological toxicities (31% vs 11% febrile neutropenia) and led to 5 versus 1 treatmentrelated deaths. During follow‐up, 75 pts developed a second non‐breast primary cancer (43 with FEC and 32 with ED); 12 were hematologic malignancies (7 with FEC and 5 with ED). Long term cardiac deaths were rare (3 with FEC and 1 with ED). Conclusions: This study did not show superiority of the concomitant anthracyclinetaxane arm, which was more toxic in high‐risk N+ BC pts. Long‐term results of the HER2+ subpopulation are in line with the other adjuvant TRA trials but less striking probably due to lack of power. Long term cardiac toxicity and second primary cancer rate are similar to what has been reported by others.