Prospective WSG phase III PlanB trial: Final analysis of adjuvant 4xEC→4x doc vs. 6x docetaxel/cyclophosphamide in patients with high clinical risk and intermediate-to-high genomic risk HER2-negative, early breast cancer.
Authors: Harbeck Nadia , Gluz Oleg , Clemens Michael R. , Malter Wolfram , Reimer Toralf , Nuding Benno , Aktas Bahriye , Stefek Andrea , Pollmanns Anke , Lorenz-Salehi Fatemeh , Uleer Christoph , Krabisch Petra , Kummel Sherko , Liedtke Cornelia , Shak Steven , Wuerstlein Rachel , Christgen Matthias , Kates Ronald , Kreipe Hans Heinrich , Nitz Ulrike ,   West German Study Group
Published: September 2018

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Background: Optimal chemotherapy in HER2-negative, particularly HR-positive, early breast cancer (EBC), especially the survival impact of anthracyclines, is still a matter of debate. Retrospective analyses saw most benefit of 6xCEF vs. 6xCMF in HER2+ EBC. Prospective trials have shown conflicting results; no predictive molecular factors have been validated so far, particularly for HR+ EBC. The WSG PlanB trial is the first trial that randomized only patients with high clinical risk or with Recurrence Score >11 in the HR+/HER2- subgroup (pN0-1). Patients with RS<11 (pN0-1) had an excellent prognosis (five-year DFS of 94%) with endocrine therapy alone (Gluz et al. ASCO 2016). Methods: The WSG PlanB trial was originally planned as a non-inferiority study for comparison of 6 cycles of anthracycline-free TC (Arm A) vs. standard anthracycline-taxane based chemotherapy (4xEC→4xDoc) (Arm B) in patients with high-risk pN0 (T2-4, G2-3, <35 years, or high uPA/PAI-1) or pN+ HER2- EBC. Following an early amendment, Oncotype DX was performed in all HR+ tumors, and omission of chemotherapy (CT) was recommended in RS≤11 HR+ pN0-1 disease. Primary endpoint was DFS, defined as time to any recurrence, secondary cancer or death. Final analysis for the CT randomization was planned after completed 5-year follow-up in all patients. Results: From 2009 to 2011, PlanB enrolled 3198 patients (n=3073 with central pathology review). In 348 patients (15.3%), CT was omitted based on RS≤11. 2449 patients were randomized to 6xTC (n=1222) and 4xEC→4xDoc (n=1227). Within this cohort, 41% were pN+, 42% had G3 tumors and 18% HR-negative tumors by central pathology. After median follow-up of 61 months, very similar five-year DFS of 89.9% [88.1%-91.7%] vs. 90.2% [88.4%-92.0%] and five-year OS of 94.7% [93.4%-96.1%] vs. 94.6% [93.2%-96.0%] were observed in Arms A vs. B. Five treatment-related deaths were observed in Arm A (TC) vs. one in Arm B (EC-Doc) (0.4% vs. 0.1%), despite a trend to more SAE’s in Arm B vs. Arm A (n=397 vs. 358). Although recurrence score is a strong prognostic factor, it was not predictive for anthracycline efficacy; no efficacy differences between the study arms were observed in (locally) triple-negative patients or in those with >4 involved lymph nodes, despite the prognostic impact of these factors. Conclusion: In the WSG PlanB trial, patients with early HER2-negative BC seem to be sufficiently treated by six cycles of docetaxel/cyclophosphamide compared to four cycles of EC followed by four cycles of docetaxel -- no efficacy differences are evident in high-risk subgroups defined by triple-negative status, nodal status, or high Recurrence Score. Further prospective studies are urgently needed before final conclusions for impact of anthracyclines in HER2-negative BC can be drawn. Clinical trial information: NCT01049425.