Abstract ES9-1: Local therapy of the primary tumor in de novo Stage IV breast cancer
Authors: Khan S 
Published: March 2022

Abstract
Background: Distant metastases are present in 6% or more of newly diagnosed breast cancer patients, worldwide. In this context, locoregional therapy for the intact primary tumor has been hypothesized to improve overall survival and local control, based on multiple retrospective studies, but clinical trials have reported conflicting results. Methods: All four completed trials included women presenting with metastatic breast cancer and an intact primary tumor. The trial design mandated initial systemic therapy prior to randomization in two trials (EA2108 and Tata Memorial) with subsequent randomization to locoregional therapy (LRT) or not, if there was no progression. In two other trials (MF 07-01 and POSYTIVE) randomization occurred upfront. LRT consisted of surgery and radiotherapy per standards applied to patients with non-metastatic disease, with minor differences between trials. The primary endpoint was two or three year overall survival in all four trials, with locoregional control and quality of life as secondary endpoints. Progression-free survival was also examined. The randomized sample size ranged from 93 to 350 across the trials (the POSYTIVE trial did not reach full accrual). Tumor characteristics were balanced between arms, except MF 07-01, which favored the LRT arm. Prospectively measured quality of life (QoL) outcomes have been reported for POSYTIVE and EA2108, assessed using standard instruments. Results. The design, accrual, and main results of the four completed trials, and one still in follow-up (Shien, JCOG 1017) are shown in the Table. Median follow-up duration at the time of reporting ranges from 23 to 53 months in these trials. The overall survival in three of four trials shows no advantage with the use of LRT. MF 07-01 is an outlier, with improved 5-year OS in the LRT arm. Of note, survival rates vary across the trials, depending on the resource environment; in the Tata (India) trial this was 20 months at 2 years, and in EA2108 (USA and Canada) it was 53.1 months (95% CI: 47.9,-) in the systemic therapy arm and 54.9 months (95% CI: 46.7,-) in the locoregional therapy arm. Locoregional progression rates were significantly lower in those randomized to primary site LRT, with locoregional progression occurring in less than 20% of patients treated with LRT with systemic therapy. However, in the systemic therapy alone arms, a minority of patients (under 20%) required palliative LRT, demonstrating the efficacy of contemporary systemic therapy in avoiding symptomatic locoregional progression. Despite the improved local control however, quality of life measures were largely similar between arms in the two trials where prospective, preplanned evaluation of these parameters has been reported (POSYTIVE and EA2108). Conclusions: The preponderance of current evidence does not support use of early locoregional therapy for the primary site as a means to improve survival in patients presenting with metastatic breast cancer. However, LRT was associated with improved locoregional disease control, albeit with no overall impact on quality of life. Questions remain regarding the survival value of primary site LRT in the oligometastatic setting, since this aspect has not been prospectively examined in any existing trial.
Phase III trials testing primary site local therapy in de novo Stage IV breast cancersystemic therapy firstAccrual period.Randomized NOverall survival HR (95% CI)Locoregional progression-free survivalBadwe (India)Yes2005-123501.04 (0.84, 1.34)0.16 (0.10, 0.26)Khan (USA & Canada)Yes2011-152561.11 (0.82, 1.52)0.35 (0.21, 0.57)Shien (JapanYes2011-16407Not reportedNot reportedSoran (Turkey)No2008-122740.66 (0.49, 0.88)1% vs. 11%Fitzal (Austria)No2010-19930.69 (0.36, 1.33)8.9% vs. 17.8%
Citation Format: S Khan. Local therapy of the primary tumor in de novo Stage IV breast cancer. [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES9-1.