Local therapy for stage IV breast cancer has not been proven to increase overall survival, yet there are some cases where local therapy could be considered outside a clinical trial. For patients with intact asymptomatic primary tumors, local therapy could be offered if distant disease is well controlled with systemic therapy and the primary tumor is progressing. For patients with multiple metastases, ablation of these lesions can be considered if the lesions are few and small, complete ablation appears feasible, and toxicity is low.
Another important point from these data is that women who responded did similarly regardless of whether they had surgery or not.— Seema A. Khan, MD
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Seema A. Khan, MD, outlined the evidence for local therapy of limited disease in stage IV breast cancer at the 2019 Lynn Sage Breast Cancer Symposium,1 hosted by the Robert H. Lurie Comprehensive Cancer Center at Northwestern University, Chicago. Dr. Khan is Professor of Surgery, Bluhm Family Professor of Cancer Research, Lynn Sage Breast Center and Department of Surgery, Northwestern University.
Intact Primary
About 6% of new breast cancer diagnoses in this country are stage IV, associated with a median 3-year survival of around 40%. For patients diagnosed with stage IV breast cancer, the intact primary tumor aids diagnosis, and its biologic subtype influences the selection of systemic therapy, but the tumor can cause symptoms and affect quality of life.
Previous studies have shown a survival benefit for women who had partial or total mastectomy, particularly those who had primary site surgery with negative margins. But these studies showed a consistent bias, Dr. Khan noted. Compared to study participants who did not undergo surgery, the women who did have surgery were younger and had smaller tumors, more estrogen receptor–positive disease, and lower metastatic burdens.
Randomized Trials
Several other randomized trials in the United States, Canada, Europe, and Asia addressing the impact of primary site local therapy are ongoing or have been published in the past few years. In a study at Tata Memorial Centre, Mumbai, India, among 350 women aged 65 years or younger presenting with de novo metastatic breast cancer, those randomly assigned to locoregional treatment had a 2-year overall survival rate of 41.9% vs 43.0% for patients having no locoregional treatment.2
The Turkish Federation MF07-01 trial randomly assigning 274 patients with treatment-naive stage IV breast cancer to locoregional treatment followed by systemic therapy or to systemic therapy alone found no improvement in 3-year survival, the primary endpoint of the study, for those receiving locoregional treatment. There was, however, an improvement in survival at 5 years for patients undergoing surgery.3 That said, Dr. Khan pointed out that the randomization was unbalanced, with the locoregional treatment group having more patients with estrogen receptor (ER)/progesterone receptor–positive tumors, bone-only disease, and solitary bone metastases, and fewer patients with triple-negative tumors and visceral disease. She also noted that unplanned subset analyses showed an advantage for younger women and those with ER-positive and HER2-negative disease.
In the ECOG 2018 study, women with intact primary tumors and metastatic disease at any site except sites with a very poor prognosis and who responded to or had stable disease following systemic therapy were randomly assigned to receive early local therapy or delayed local therapy only if disease progressed. “We hope to have results in the next year,” Dr. Khan said.
Prospective Registry Study
TBCRC 013 (Translational Research Breast Cancer Consortium) a prospective registry study followed 112 patients with de novo stage IV breast cancer for 34 to 78 months, with a median follow-up 54 months.4 Women who responded to first-line therapy “had a distinctly better survival than the nonresponders,” Dr. Khan said, with 78% of the responders vs 24% of nonresponders attaining 30-month survival. “The median survival is markedly improved compared to other studies in this area,” she added, and could be due to changes in disease management.
“Another important point from these data is that women who responded did similarly regardless of whether they had surgery or not,” Dr. Khan stated. Median survival for women responding to systemic therapy was 71 months for those opting for surgery and 65 months for those who did not have surgery. The 30-month survival rate was 77% with surgery vs 76% without. Dr. Khan cautioned, “this is a registry study, and the numbers are small.”
Specific Recommendations
Taking these studies into account, local therapy could be offered to patients with intact asymptomatic primary tumors, if distant disease is well controlled with systemic therapy and the primary is progressing, albeit “with a clear explanation that survival benefit is not proven,” Dr. Khan noted. “Local control benefit appears likely, but few women need palliative surgery when response to systemic therapy is good,” she pointed out. “Breast conservation should be performed preferentially if feasible. Contralateral prophylactic surgery is to be strongly discouraged. Ongoing trials need to be completed.”
In response to a question about breast reconstruction, Dr. Khan noted, “for women who are having primary site surgery in the setting of metastatic disease, the reconstruction decision is often driven by the patient, but I would try to steer patients away from implant-based reconstruction” due to potential complications with systemic chemotherapy.
She advised symposium participants to “work hard to persuade women with stage IV disease not to have contralateral mastectomies. The desire is often based on misconceptions that we could work to correct.”
Oligometastatic Disease
A growing proportion of patients with newly diagnosed stage IV breast cancer have oligometastases, Dr. Khan reported. Characteristics of oligometastatic disease include a limited number of metastatic tumors involving single or few organs and biologic properties that make them amenable to locoregional therapy. “Clinical data suggest that patients with oligometastases are potentially curable,” Dr. Khan said, but questions remain about considering surgical resection, radiation, or other means of ablation outside of a clinical trial.
A review of studies looking at hepatic resection for liver metastases among patients with primary breast tumors found median survivals ranging from 32 to 58 months and 5-year survival rates from 27% to 48%. “Factors associated with poor survival include a disease-free interval of less than 4 years, hormone receptor–negative disease, poor response to chemotherapy, and positive resection margins,” Dr. Khan reported.
Metastasectomy rates are rising, and the rate of increase is greater in high-volume centers.— Seema A. Khan, MD
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“All across the country, metastasectomy rates are rising, and the rate of increase is greater in high-volume centers,” Dr. Khan noted. The rapid adoption of local therapy approaches to oligometastases has occurred in the absence of strong supporting clinical data, and a lack of randomized data are available to support the presumption that ablative treatments can improve overall survival.
“The consensus at the moment,” she said, “seems to be that it could be considered” for patients who have long disease-free intervals or primary breast tumors with one to three metastatic lesions of small size, and if complete ablation is possible through resection with free margins, stereotactic body radiotherapy (SBRT), or other means.
Stereotactic Body Radiotherapy
A prospective analysis of the use of SBRT to treat oligometastases among 121 patients, including 39 with primary breast tumors, found local control was achieved in 87% of patients with breast cancer, and overall survival was 46% at 6 years.5 Dr. Khan called these data “encouraging, although highly selective.”
Another important development in this area was the COMET trial, she added. Patients with controlled primary tumors and one to five oligometastases had a 13-month improvement in overall survival and doubling of progression-free survival with SBRT vs standard care, but had an increased risk of toxicity and a 4.5% risk of treatment-related death.6
Multisite SBRT followed by pembrolizumab is also being tested and has been shown to be well tolerated with acceptable toxicity.
Will Paradigm Shift?
NRG-BR002 is a phase IIR/III trial of standard care systemic therapy with or without local therapy for newly oligometastatic breast cancer. All patients have at least one and no more than two pathologically confirmed metastases and locoregional disease treated more than 3 months prior to trial registration with no known residual disease. Ablation of metastases will be by SBRT or surgery.
“If the addition of ablative therapy of all metastases improves overall survival, then the paradigm shifts to multidisciplinary treatment, rather than just systemic treatment of metastatic disease,” Dr. Khan noted. If overall survival is not improved, “then off-protocol use of SBRT stops,” avoiding toxicity and reducing costs.
For patients today, ablation of oligometastases outside of a clinical trial can be considered if lesions are few and small, the disease-free interval is long, complete ablation appears feasible, and toxicity is low. “Appropriate systemic therapy options should be used in combination,” Dr. Khan advised, and ongoing trials need to be completed. ■
DISCLOSURE: Dr. Khan reported no conflicts of interest.
REFERENCES
1. Khan SA: Local therapy of limited disease in stage IV breast cancer: What is the evidence? 2019 Lynn Sage Breast Cancer Symposium. Presented October 5, 2019.
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.
4. King TA, Lyman J, Gonen M, et al: A prospective analysis of surgery and survival in stage IV breast cancer (TBCRC 013). J Clin Oncol. May 11, 2017 (early release online).
5. Milano RT, Katz AW, Zhang H, et al: Oligometastases treated with stereotactic body radiotherapy: Long-term follow-up of prospective study. Int J Radiat Oncol Biol Phys 83:878-886, 2012.
6. Palma DA, Olson R, Harrow S, et al: Stereotactic ablative radiotherapy for the comprehensive treatment of 4–10 oligometastatic tumors (SABR-COMET-10): Study protocol for a randomized phase III trial. BMC Cancer 19:816, 2019.
