Authors: Seema Ahsan Khan, Fengmin Zhao, Lawrence J. Solin, Lori J. Goldstein, David Cella, Mark Basik, Mehra Golshan, Thomas B. Julian, Barbara A. Pockaj, Christine A Lee, Wajeeha Razaq, Joseph A. Sparano, Gildy V Babiera, Irene Ang Dy, Sarika Jain, Paula Silverman, Carla Fisher, Amye Juliet Tevaarwerk, Lynne I. Wagner, George W. Sledge; Northwestern Memorial Hospital, Chicago, IL; Dana–Farber Cancer Institute, Malden, MA; Albert Einstein Medical Center, Philadelphia, PA; Fox Chase Cancer Center, Philadelphia, PA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL; McGill University, Jewish General Hospital Segal Cancer Centre, Montréal, QC, Canada; Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston, MA; NRG Oncology, and The Allegheny Health Network Cancer Institute, Pittsburgh, PA; Mayo Clinic, Phoenix, AZ; Swedish Medical Center, Seattle, WA; NSABP Foundation and Peggy and Charles Stephenson Oklahoma Cancer Center, Oklahoma City, OK; Montefiore Medical Center/Albert Einstein College of Medicine/Albert Einstein Cancer Center, Bronx, NY; University of Texas MD Anderson Cancer Center, Houston, TX; St. Luke’s-Roosevelt Hospital, Effingham, IL; Northwestern University Division of Hematology/Oncology, Chicago, IL; University Hospitals Case Medical Center, Cleveland, OH; Indiana University School of Medicine, Indianapolis, IN; University of Wisconsin Carbone Cancer Center, Madison, WI; Wake Forest University Health Sciences, Winston Salem, NC; Stanford University School of Medicine, Stanford, CA
Research Funding: Eastern Cooperative Oncology Group
Background:About 6% of newly diagnosed breast cancer patients present with Stage IV disease and an intact primary tumor (IPT). Locoregional treatment (LRT) for the IPT is hypothesized to improve survival based on retrospective analyses, but randomized trials have provided conflicting data. We now report the results of E2108, a Phase 3 trial that examined the worth of LRT for the IPT following initial systemic therapy.
Methods:Stage IV patients with IPT were registered, treated with optimal systemic therapy (OST) based on patient and tumor characteristics; those who did not progress during 4-8 months of OST were randomized to LRT for the IPT, or no LRT. The primary endpoint was overall survival (OS), with locoregional disease control as a secondary endpoint. Stratified log rank test and Cox proportional hazard model were used to compare OS between treatment groups. Cumulative incidence of locoregional recurrence/progression was estimated and Gray test was used for treatment group comparisons. The trial was designed to detect an improvement in 3 year OS rate from 30% with OST alone to 49.3% for OST+LRT (power 95%, 1-sided alpha 0.05) with full information expected after 152 deaths; the data monitoring committee recommended data release after 80% of full information.
Results:390 patients were enrolled between 2/8/11 and 7/23/15, and received OST. Of these, 256 eligible patients were randomized to either continued OST alone (N = 131) or OST+LRT (N = 125).There were 121 deaths and 43 locoregional progression events after a median follow up 59 months (range: 0-91). There was no significant difference in OS (3-year OS rate 68.4% in OST+LRT vs. 67.9% OST alone arm, stratified log-rank p = 0.63, HR = 1.09, 90% CI: 0.80, 1.49) or in progression-free survival (p = 0.40). The locoregional recurrence/progression was significantly higher in the OST alone arm (3-year rate 25.6% vs 10.2%, Gray test p = 0.003). Health-related quality of life (HRQOL) measured by FACT-B Trial Outcome Index was significantly worse in the OST+LRT arm than OST alone arm at 18 months post randomization (60% completion, Wilcoxon rank sum test p = 0.01), but no difference was observed at time points 6 months (74% completion) or 30 months (56% completion).
Conclusions:Early local therapy does not improve survival in patients with de novo metastatic breast cancer and an IPT. Although there was a 2.5-fold higher risk of local disease progression without LRT, LRT of the IPT did not lead to improved HRQOL. Clinical trial information: NCT01242800.