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Local treatment of a primary tumor did not improve survival for women with de novo metastatic breast cancer, results of a randomized trial showed.

After a median follow-up of 53 months, median survival for all 256 randomized patients was 54 months and did not differ between the patients who received systemic therapy only and those who received systemic therapy and local treatment (surgery with or without radiation therapy) of the primary tumor. Progression-free survival (PFS) also did not differ, as 89 patients in each arm died or had progressive disease.

Locoregional progression occurred more often in patients who had systemic therapy only. Quality of life was significantly worse at 18 months in patients who had local treatment but otherwise was similar to patients who did not have surgery or radiation therapy, as reported during the .

"Early local therapy does not improve survival in patients with de novo metastatic breast cancer and an intact primary tumor," Seema Khan, MD, of Northwestern University Feinberg School of Medicine in Chicago, said in a recorded presentation. "Based on the available data, locoregional therapy for the primary tumor should not be offered to women with stage IV breast cancer with the expectation of a survival benefit. When systemic disease is well controlled with systemic therapy but the primary site is progressing, locoregional therapy may be considered."

A larger Japanese study with a similar design is ongoing, and results of a survival analysis are expected in 2022, she added.

Rationale for Primary Surgery

About 6% of patients with breast cancer have stage IV disease (metastatic) at diagnosis and an intact primary tumor. Locoregional treatment of the primary tumor has been hypothesized to improve survival on the basis of retrospective analyses. In general, however, the studies had multiple biases in patient selection that could have accounted for the observed benefit of locoregional treatment of the primary tumor, said Khan.

The only two completed randomized trials of local therapy to date yielded conflicting data. A showed no survival advantage with early locoregional therapy, whereas a showed superior 5-year overall survival (OS) with treatment of the intact primary tumor.

Khan reported findings from the randomized trial, which began patient accrual in 2011 and ended in 2015. Although total accrual was originally planned for 368 patients, slow enrollment led to design modifications and a reduction in accrual to 258 patients. The trial had statistical power to detect a 19% difference in 3-year survival (30% with systemic therapy alone to 49.3% with locoregional therapy).

Following diagnosis of de novo metastatic breast cancer, all patients received optimized systemic therapy. Those who had no disease progression after 4 to 8 months of systemic therapy were randomized to continue systemic treatment or to complete surgical resection of the primary tumor with clear margins, with or without radiotherapy per standard of care.

The randomized patients had a median age of 55-56, more than 80% were white, a majority had metastatic involvement of a single organ, and a majority (57-59%) had hormone receptor (HR)-positive/HER2-negative breast cancer, followed by HER2-positive breast cancer (33%).

Of the 125 patients randomized to surgery, 109 actually underwent surgery, 87 had clear surgical margins, and 74 received locoregional radiotherapy. Of the 131 women randomized to systemic therapy, 25 subsequently had surgery.

No Survival Benefit

The OS analysis showed no difference between groups. Comparison of continued systemic therapy and surgery with or without radiotherapy produced a hazard ratio of 1.09 (90% CI 0.80-1.49). Similarly, PFS curves were overlapping (P=0.40). Analysis of OS by tumor subtype suggested worse survival with locoregional therapy (HR 3.50) for patients with triple-negative breast cancer, but the subgroup included only 20 patients, too few to make a definitive conclusion, said Khan.

Continuation of systemic therapy was associated with a significantly higher rate of locoregional recurrence or progression (25.6% vs 10.2%, HR 0.37, 95% CI 0.19-0.73). Investigators defined locoregional progression in the systemic therapy group as development of symptoms leading to a decision for local therapy. In the group randomized to surgery, locoregional progression was defined as regional nodal progression, chest-wall disease, or invasive in-breast recurrence.

Health-related quality of life was similar between the two arms during follow-up, with the exception of the 18-month mark, when patients assigned to continue systemic therapy had a significantly better composite score (P=0.001).

The results, combined with those of previous trials, clearly showed that every patient with metastatic breast cancer and an intact primary tumor should not have surgery, but also did not rule out the possibility of a benefit for selected patients, said invited discussant Julia White, MD, of Ohio State University in Columbus.

"Should the answer be 'sometimes'? I think consistently based on these trials, the answer to that is 'yes,'" White said. "The rationale for that is patients have locoregional symptoms or progressions that occur and are going to need surgical approaches for palliation. As a result, 'never' is the incorrect answer."

Another subgroup of patients might also benefit from local therapy and is the subject of an ongoing clinical investigation: those with de novo oligometastatic breast cancer -- defined as operable tumors with no more than four distant metastases. The hypothesis came from the Turkish study, which showed a survival benefit with local therapy in patients with solitary bone metastases.

"We know that adjunctive systemic therapy prolongs survival by eliminating subclinical disease," said White. "We've just seen that surgery in the setting of metastatic breast cancer can achieve local control. Things like stereotactic body radiotherapy ablation or resection of all metastases can eliminate [disease at the] site, prolonging median survival. This raises the question that might it be possible to render these patients who have de novo oligometastatic breast cancer [free of disease], indeed, long term or short?"

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