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ACS Cancer Research Program

To Operate or Not in De Novo Stage IV Breast Cancer: Is That Still a Question?

Preeti D. Subhedar, MS, MD, FACS, Sarah Blair, MD, FACS, and Judy C. Boughey, MD, FACS

June 1, 2022

Approximately 6% of newly diagnosed breast cancer cases are de novo stage IV with an intact primary at presentation.1 Survival outcomes for this group of patients have been studied with both retrospective and randomized clinical trials (RCTs), but conflicting results have led to confusion about optimal therapy. The decision to offer locoregional therapy (surgery +/- radiation) to the breast primary in addition to systemic therapy is still hotly debated.

Studies using several large databases and registries—such as the Surveillance, Epidemiology, and End Results (SEER) Program and the National Cancer Database (NCDB)— have been published on this topic. Some studies have shown an improvement in overall survival with resection of the intact primary breast cancer, whereas others have not.2-4 Additional studies have hinted at a benefit from locoregional therapy in young patients, those with favorable receptor subtypes, or with oligometastatic disease.5-7 While these large datasets allow for the study of a question that would otherwise take several years to answer in a randomized fashion, there are inherent issues with data capture and selection bias that cannot be completely controlled and should be taken into account when using retrospective data to make clinical decisions.

Conflicting Clinical Trials

Fortunately RCTs have studied outcomes in de novo stage IV breast cancer; unfortunately, the results from these trials also have been conflicting. The RCT from India’s Tata Memorial Cancer Centre and the ABCSG-28 POSYTIVE trials failed to show a benefit to adding locoregional therapy over optimal systemic therapy alone.8,9 The Turkish MF07-01 trial has been the only RCT to show that the risk of death was lower in patients who received locoregional therapy to the primary breast tumor.10 This discrepancy has made it difficult to arrive at the optimal recommendations for treatment of patients with this presentation of breast cancer.

The ECOG-ACRIN 2108 trial, led by Seema Khan, MD, FACS, was designed to evaluate the role of locoregional therapy in de novo stage IV breast cancer patients with an intact primary breast tumor.11 This latest RCT study adds further evidence that locoregional therapy does not appear to provide a benefit in overall survival.

This 2011−2015 prospective randomized phase III clinical trial was published in the Journal of Clinical Oncology in 2022. Patients received 4−8 months of systemic therapy, and those who did not have progression of distant disease were randomized into receiving additional locoregional therapy versus continuing with systemic therapy alone.

In all, 256 patients were eligible to be randomized; 131 were randomized into the systemic therapy-alone arm and 125 were randomized to receive locoregional therapy. The study found a higher proportion of patients with locoregional progression in the systemic therapy-alone group versus the locoregional therapy group, 39.8% versus 16.3%, respectively (HR = 0.34, p <0.001). However, at a median follow-up of 53 months, no significant difference was seen in survival between the groups, with 53.1-month survival in the systemic therapy group versus 54.9 months in the locoregional therapy group (HR = 1.11, p <0.57).

Table 1. RCTs of Locoregional Therapy in De Novo Stage IV Breast Cancer

Study Year

Sample Size

Result hazard ration (95% confidence interval)

Studies showing no difference in survival between systemic therapy alone versus locoregional therapy

Indian Tata Memorial Cancer Centre trial 2015


Locoregional arm: 19.2 months
Systemic therapy arm: 20.5 months
HR 1.04 (0.81–1.34, p = 0.79)

ABCSG-28 POSYTIVE trial 2019


Locoregional arm: 34.6 months
Systemic therapy arm: 54.8 months
HR 0.691 (0.358–1.333, p = 0.267)

ECOG-ACRIN 2108 trial 2022


Locoregional arm: 54.9 months
Systemic therapy arm: 53.1 months
HR 1.11 (0.82–1.52, p = 0.57)

Study showing improved survival with locoregional therapy versus systemic therapy alone

Turkish MF07-01 trial 2018


5-year overall survival:
Locoregional arm: 41.6%
Systemic therapy arm: 24.4%

Hazard of death 34% lower in locoregional arm:
HR 0.66 (0.49–0.88, p = 0.005)

Rationale for Locoregional Therapy

Although no survival advantage was seen in the ECOG-ACRIN 2108, Tata Memorial, or ABCSG-28 trials, proponents of locoregional therapy cite reasons such as the ability to provide symptomatic relief, disease progression prevention, and patient preference as factors that should be considered when deciding whether to offer locoregional therapy in this cohort. To address these questions, Dr. Khan also included a health-related quality-of-life questionnaire that measured depression, anxiety, and well-being. Although patients who did not receive locoregional therapy experienced a higher rate of disease progression, quality of life at 30 months was similar for patients receiving systemic therapy alone and individuals undergoing locoregional therapy. In addition, both groups had similar patient-reported scores with regard to symptoms, worry, and functionality due to disease progression, contradicting theories that disease progression is a psychological burden for patients who do not receive locoregional therapy.

The variety in metastatic presentation has led clinicians to postulate that locoregional therapy may benefit patients with limited oligometastatic disease. Although the ECOG-ACRIN 2108 was not designed to answer this specific question, 16% of patients did have oligometastatic disease, and again, no survival difference was seen between the two groups in patients with limited metastatic disease.

The ECOG-ACRIN 2108 trial is the latest RCT to add to previous data that show a lack of benefit to locoregional therapy in patients who have responded to systemic therapy. Neither a survival advantage nor an improvement in quality-of-life measures was seen in this trial. It is imperative that clinicians explain this lack of benefit to patients when discussing optimal management of the breast primary in the setting of stage IV disease. 


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