Women presenting with newly diagnosed de novo metastatic breast cancer derived no additional survival benefit from surgery and radiotherapy given after systemic treatment, although the practice may reduce locoregional progression of disease, according to the results of the phase III E2108 study presented in the Plenary Session of the ASCO20 Virtual Scientific Program.1
“Based on the results of our study, women who present with a new diagnosis of breast cancer already in stage IV should not be offered surgery and radiation for the primary breast tumor with the expectation of a survival benefit,” said lead investigator Seema A. Khan, MD, Professor of Surgery and the Bluhm Family Professor of Cancer Research at Northwestern University, Chicago. “When making these decisions, it is important to focus energy and resources on proven therapies that can prolong life.”
Seema A. Khan, MD
Study Addressed Conflicting Data
“About 6% of patients with newly diagnosed breast cancer present with stage IV disease and an intact primary tumor. Locoregional treatment for this primary was hypothesized to improve survival, based on retrospective analyses,” Dr. Khan said.
In a combined analysis of more than 15 trials, a reduction in risk of about 30% had been estimated for the addition of surgery and radiotherapy, she noted. “However, these studies were biased in that women receiving surgery were younger and had smaller tumors, more estrogen receptor–positive disease, and a lower metastatic burden,” pointed out Dr. Khan.
Further complicating matters, two randomized clinical trials published in the past 5 years had conflicting results. A study from Tata Memorial Hospital in Mumbai, India, found no survival advantage with early locoregional therapy,2 whereas the Turkish Federation MF07-01 study showed an overall survival improvement of 17% with locoregional treatment,3 Dr. Khan explained. The trial in India had a similar design to E2108, she added.
The phase III E2108 trial was conducted by the ECOG-ACRIN Cancer Research Group. E2108 enrolled 390 women (median age, 55 years) with de novo stage IV breast cancer. Approximately half had hormone receptor–positive HER2-negative tumors, 29% had HER2-positive tumors, and 10% had triple-negative disease. In the enrolled population, metastases in bone alone were observed in 31% of cases; in viscera alone, in 26%; and in both, in 27%. In the randomized population, the bone-plus-viscera percentage rose to 41%. The most frequently used systemic therapy was chemotherapy plus anti-HER2 agents.
Patients were treated with systemic therapy optimized according to patient and disease characteristics. The 256 patients who experienced no progression of distant disease after 4 to 8 months of therapy were then randomly assigned to continued systemic therapy alone (n = 131) or early local therapy (n = 125). In the local therapy arm, of the 125 patients, 109 underwent surgery, 87 achieved free surgical margins and required no additional treatment, and 74 were treated with radiotherapy as well. Patients were followed for 5 years to determine overall survival, the primary endpoint.
No Survival Improvement With Local Therapy
At a median follow-up of 53 months, 121 patients had died. Median overall survival was 54 months, with no differences observed between the arms (hazard ratio [HR] = 1.09; P = .63). “The survival curves overlap…. They are completely superimposable, and there is no hint of an advantage in terms of survival with locoregional treatment to the primary intact tumor,” Dr. Khan reported.
Overall survival by tumor subtype also showed no significant differences for the 79 women in the HER2-positive subset (HR = 1.05) and the 137 women in the hormone receptor–positive HER2-negative subset (HR = 0.94). However, for the 20 women with triple-negative breast cancer, survival was worse with the addition of early local treatment (HR = 3.50), but this was not statistically significant given the small number of patients in this subset.
Locoregional treatment did, however, prevent better locoregional control in the early local therapy arm. Of the 43 locoregional disease progression events, 25.6% occurred in patients treated with systemic therapy alone, compared with 10.2% among patients receiving locoregional treatment as well (HR = 0.37, P = .003).
Unexpected Health-Related Quality-of-Life Outcomes
Health-related quality of life measured by the Functional Assessment of Cancer Therapy–Trial Outcome Index was significantly worse in the locoregional therapy arm than with systemic therapy alone at 18 months post randomization. However, Dr. Khan added, no difference was observed at 6 or 30 months, noting not all patients completed these surveys.
“Although we saw a 2.5-fold higher risk of local disease progression without locoregional therapy, the use of locoregional treatment for the primary site did not lead to improved quality of life,” Dr. Khan said. “This result was a little surprising, since one of the reasons for considering surgery and radiation is the idea that growth of the tumor will impair quality of life. Instead, we found the adverse effects of surgery and radiation appear to balance out the gains in quality of life that were achieved with better control of the primary tumor.”
“When combined with the results of an earlier trial in Mumbai, India,2 these results of E2108 tip the scales against the possibility that local therapy to the breast tumor will help women live longer,” Dr. Khan concluded. Although she and her colleagues maintain that locoregional therapy has little benefit, it should be considered, however, “when systemic disease is well controlled with systemic therapy but the primary site is progressing,” she added.
Results are still pending for the ongoing Japan Clinical Oncology Group study JCOG-1017, which has a similar design as E2108.
DISCLOSURE: Dr. Khan reported no conflicts of interest.
1. Khan SA, Zhao F, Solin LJ, et al: A randomized phase III trial of systemic therapy plus early local therapy versus systemic therapy alone in women with de novo stage IV breast cancer: A trial of the ECOG-ACRIN Research Group (E2108). ASCO20 Virtual Scientific Program. Abstract LBA2. Presented May 31, 2020.
2. Badwe R, Hawaldar R, Nair N, et al: Locoregional treatment versus no treatment of the primary tumour in metastatic breast cancer: An open-label randomised controlled trial. Lancet Oncol 16:1380-1388, 2015.
3. Soran A, Ozmen V, Ozbas S, et al: Randomized trial comparing resection of primary tumor with no surgery in stage IV breast cancer at presentation: Protocol MF07-01. Ann Surg Oncol 25:3141-3149, 2018.