Patients with metastatic breast cancer are unlikely to be cured of their disease by any means. Complete remissions from systemic chemotherapy are uncommon, and only a fraction of complete responders remain progression free for a prolonged period. The median survival for patients with stage IV breast cancer is 18 to 24 months, although the range extends from only a few months to many years [1-3].

Although systemic therapy is the mainstay of treatment for metastatic breast cancer, local management of the primary as well as metastasis-specific local treatment (ie, metastasectomy, radiofrequency ablation, cryotherapy, and radiation therapy) may palliate symptoms and prevent cancer-related complications. Some evidence suggests a potential for prolonging survival, although data are limited [4].

The primary role of local treatment to the breast in metastatic breast cancer is palliation. Patients with metastatic disease should be evaluated for possible local management of the primary if it may control local complications from the cancer (eg, bleeding, infection, or wound management). However, in general, for patients who are asymptomatic at the site of their primary, we do not offer local treatment given lack of clear evidence that it improves survival. While retrospective evidence suggests a possible benefit, prospective data have shown no overall survival (OS) benefit or only minimal survival benefit, and are limited by methodologic issues. As such, we typically do not offer surgery in such cases.

Deviations to this approach may be rarely made on a case-by-case basis in a multidisciplinary setting, although these instances are exceptional. For example, we have offered local management of the primary to patients with human epidermal growth factor receptor 2 (HER2)-positive disease who have a brisk and dramatic response to systemic therapy, or when systemic disease is well controlled with systemic therapy but the primary site is progressing. However, the decision to proceed with local management in a similar situation should take into account patient preferences and should be made in a multidisciplinary setting.

Patients who present with symptomatic metastases, eg, intractable pain, loss of function, or an oncologic emergency (eg, cord compression, mass effect due to brain metastases, pathologic fracture due to a bony metastasis), are appropriate candidates for urgent local intervention to relieve symptoms and preserve patient ability to function. The objective of this treatment is palliative to relieve symptoms and to stabilize the patient rather than to prolong survival outcomes.

Additionally, for patients with a first presentation of metastatic disease, biopsy of the metastatic site should be performed to confirm the diagnosis and reestablish receptor status.

For patients who lack symptomatic metastases, systemic therapy without surgical intervention is usually the most appropriate treatment. While retrospective data suggest a survival benefit for aggressive local therapy in patients with oligometastatic disease [4-7], selection bias may have played a role in these studies. Prospective data are not available.

In the absence of conclusive data, some experts use systemic treatment alone for asymptomatic patients; others adopt an individualized approach to the asymptomatic patient, offering local management to those with multiple good prognostic factors, although this is not considered standard of care at this time:

●Good performance status –The most important issues in choosing patients for local treatment of metastatic disease are the performance status and an estimation of the relative risks of a planned operation. Asymptomatic patients without imminent risk of significant organ dysfunction with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or worse should not proceed with local management, as they are likely to have high rates of postoperative morbidity and mortality.

● Multivariable analysis of local treatment outcomes suggests that those patients with limited metastatic disease, ie, solitary or few detectable lesions (oligometastatic disease) and limited to a single organ, are more likely to benefit from local therapy than those with multiple metastases [4,5,6,8,9]. One exception is oligometastatic hepatic disease, as a few studies found that the presence or absence of extrahepatic disease (predominantly bone) did not affect long-term outcomes in patients undergoing hepatic resection [10-12].
Many of the studies that report successful surgery for metastatic disease, limited enrollment to patients with single-organ involvement.

●Long disease-free interval –A long disease-free interval (DFI), the period of time between the definitive treatment of the primary breast cancer and the development of distant oligometastasis, may portend an improved prognosis with local therapies [13-15]. The specific cutoff DFI that best discriminates between favorable and unfavorable outcomes is unclear, although an acceptable range is two to five years.

●High likelihood of complete resection – Careful preoperative evaluation is necessary to determine the likelihood that complete resection of the metastatic deposit is feasible. Positive margins are associated with worse outcomes in most but not all series [8, 16-19].

For patients with oligometastatic breast cancer undergoing local therapy, surgery, stereotactic body radiation therapy (SBRT), or both are primarily employed, though radiofrequency ablation (RFA, typically with surgery) is a one-time treatment that may be utilized as an alternative to SBRT for small hepatic tumors (<3 cm) that are not close to major vessels, biliary structures, or the diaphragm [20].

Brain — For most patients with brain metastases, a local approach such as resection, stereotactic radiosurgery (SRS), or whole-brain radiotherapy should be employed, often prior to or in conjunction with systemic therapy. When possible, SRS is used instead of whole-brain radiation to reduce toxicity.

Bone — Indications for local management of bone disease are fracture or impending fracture due to a metastasis, significant pain or decreased mobility of a joint, or spinal cord compression. In such cases, short-course palliative radiotherapy is commonly used. Pathologic fractures, pending fractures, or epidural spinal cord or nerve compression may require surgical intervention.

For asymptomatic patients without evidence of pending fracture, there is a limited role for resection as a means of extending survival. When metastatic breast cancer is confined to the bones, the natural history is usually characterized by an indolent course and good response to systemic therapy [21-23].

Lung — While most lung metastases are asymptomatic and do not require local intervention, those that are symptomatic or pose urgent risks to pulmonary function may benefit from local treatments. For some patients, pulmonary resection may be diagnostic as well as palliative in breast cancer patients, since a significant number of solitary pulmonary nodules in patients with a history of breast cancer are not breast cancer metastases [18,24,25].

Some experts additionally offer local treatment to a select subset of asymptomatic patients with multiple good-risk features, including solitary metastases (which occur in 10 to 25 percent of patients with metastatic breast cancer [9,26]), a DFI greater than 36 months, and hormone receptor-positive disease [4,8]. Some experts prefer to avoid the morbidity and mortality associated with such procedures, particularly in the absence of randomized data.

Liver — Hepatic metastases occur in over half of patients with metastatic breast cancer. They are most commonly a late development, associated with disseminated disease and a poorer prognosis than bone or soft tissue metastases. Only 5 to 12 percent of patients have isolated liver involvement [27-29]. Indications for local management of liver metastases include pain, bleeding that is refractory to medical therapy, or biliary obstruction. Some experts also offer local resection in carefully selected, asymptomatic patients, although there are no prospective data comparing local therapy with the administration of systemic treatment. Appropriate candidates include those with isolated liver involvement (5 to 12 percent of patients with metastatic breast cancer [27-29]), particularly those with hormone-positive disease, who have normal liver function, good performances status, and have had a long DFI [4,10,30].

Ovaries — Although the ovaries are a rare site for metastases from breast cancer [31,32], limited data suggest ovarian breast cancer metastases can appear many years following the initial diagnosis of breast cancer [33-36]. Surgical evaluation of an adnexal mass may be required to discriminate metastatic breast cancer from a primary ovarian cancer. Furthermore, for the premenopausal women with hormone-positive breast cancer, oophorectomy can provide a therapeutic effect, regardless of whether metastatic disease to the ovaries is present or not.

Other indications for local management of ovarian metastases may include pain or bleeding that is refractory to medical therapy, although in practice this presentation is rare.

Data are limited in regards to local management of ovarian metastases from breast cancer. In one series of 147 patients with metastatic disease to the ovary (8 percent of whom had a breast primary), the median overall survival after ovarian metastasectomy was 41 months [37]. For the entire series, massive intraoperative ascites, multiple metastases, and locally invasive disease were independent factors for a poorer overall survival.

Lack of overall survival benefit with local management of the primary tumor in metastatic breast cancer (June 2020)

Previous trials have shown mixed results on whether local treatment of the primary tumor in metastatic breast cancer improves survival. In the ECOG-ACRIN 2108 trial, approximately 250 patients with stage IV breast cancer who had been on systemic therapy for several months without progression were randomly assigned to continued systemic therapy versus local therapy (surgery, with or without radiation), followed by systemic therapy [1]. The three-year overall survival rate was 68 percent in both groups. Although local therapy reduced locoregional recurrence rates, quality of life outcomes were not improved. Given these and earlier results, we suggest systemic therapy without local management of the primary for most patients with metastatic breast cancer.

ΙΝ SUMMARY

Patients with metastatic breast cancer are unlikely to be cured of their disease by any means.

For the first presentation of metastatic disease, biopsy of the metastatic site should be performed to confirm the diagnosis and reestablish receptor status.

Patients who present with symptomatic metastases, eg, intractable pain, loss of organ function, or an oncologic emergency (eg, cord compression, mass effect due to brain metastases, pathologic fracture due to a bony metastasis), are appropriate candidates for urgent local intervention to relieve symptoms and preserve patient ability to function.

For asymptomatic patients, local management may be appropriate in select situations, for example, for the patient with an undiagnosed lung nodule or the patient with one or more brain metastases. Outside of these situations, some experts manage asymptomatic metastatic disease with systemic therapy only, while other experts may offer local management to select patients with multiple good-risk features, although this is not considered standard of care at this time.

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STYLIANOS GIASSAS
MEDICAL ONCOLOGIST
CHIEF OF THE 2nd ONCOLOGY CLINIC
IASO HOSPITAL