The role of local therapies in metastatic breast cancer

INTRODUCTION — Stage IV breast cancer, either de novo at presentation or secondary after a primary diagnosis, is a heterogeneous disease. While patients with metastatic breast cancer are unlikely to be cured of their disease, more effective systemic therapies with chemotherapy and targeted endocrine and biologic therapies have contributed to significantly improved overall survival and progression-free survival in the past decade, particularly among those with hormone receptor-positive and/or human epidermal growth factor receptor 2 (HER2)-positive disease [1-4]. The median survival for patients with stage IV breast cancer is now 18 to 36 months, although the range extends from a few months to many years and may vary widely by patient, tumor, and treatment factors including age, performance status, comorbidities, extent and location of distant disease, biologic subtype, and availability of effective systemic therapy [1-5]. (See "Overview of the approach to metastatic breast cancer" and "Tumor, node, metastasis (TNM) staging classification for breast cancer".)

Although systemic therapy is the mainstay of treatment for metastatic breast cancer, local management of both of the primary breast cancer, as well as metastasis-specific local treatment (ie, metastasectomy, radiation therapy, radiofrequency ablation, cryotherapy, and other image-guided percutaneous interventional procedures) may palliate symptoms and prevent cancer-related complications. Some evidence suggests a potential for prolonging survival, although available data are limited [6]. These approaches and their rationale are discussed here.

Systemic therapy for metastatic breast cancer, consisting of chemotherapy, endocrine therapy and/or biologic therapies, and supportive care, is discussed elsewhere. (See "Overview of the approach to metastatic breast cancer".)

LOCAL MANAGEMENT OF THE PRIMARY IN A PATIENT WITH DE NOVO METASTASES AT THE TIME OF INITIAL DIAGNOSIS

Approach — The primary role of local treatment to the breast and/or regional nodes in patients with stage IV breast cancer is palliation. Patients with metastatic disease should be evaluated for possible management of the primary and/or regional nodes if it may control debilitating symptoms from the cancer (eg, locally advanced breast tumors causing pain, bleeding, ulceration, infection, and poor wound healing; or regional nodal disease causing pain, motor weakness, and sensory deficits from brachial plexus invasion, or lymphedema). It should be noted that systemic therapy can also be helpful in such situations, decreasing the size of the tumor and alleviating symptoms.

However, in general, for patients who are asymptomatic at the site of their locoregional disease, locoregional treatment with surgery and/or radiation therapy is not standard-of-care treatment given lack of clear evidence that this improves survival.

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. We may also do surgery in patients who are not symptomatic, but we are concerned may be symptomatic if they do not respond quickly, such as a primary breast mass that is amenable to resection and close to ulcerating. 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. In these rare cases, the anticipated outcome of the local therapy and its lack of effect on systemic disease should be discussed with the patient.

Evidence — Four prospective randomized trials have been conducted to evaluate the survival effect of surgical resection of the primary lesion. Three of these have not shown a statistically significant difference in overall survival (OS), while a fourth did. In two of these, quality-of-life (QOL) analyses either showed no difference or even worse outcome with primary tumor resection (table 1).

No statistically significant improvement in OS was observed with local management of the primary in the following trials, although locoregional control was typically improved:

●In the multicenter ECOG-ACRIN 2108 (E2108) trial, 256 patients with de novo stage IV breast cancer who had been on systemic therapy for four to eight months without progression were randomly assigned to continued systemic therapy alone or to early local therapy (surgery, with or without adjuvant radiation), with subsequent resumption of systemic therapy [7]. The median OS was 53 months, with no difference in three-year OS rates (68 percent in both groups). The three-year rate of locoregional progression was higher among patients receiving systemic therapy only (40 versus 16 percent), but, despite this, these patients experienced similar or better QOL outcomes at various time points compared with those receiving early local therapy.

●The multicenter phase III NCT01015625 trial from Austria randomly assigned 90 patients with stage IV breast cancer to surgical resection of the primary tumor and axillary dissection followed by systemic therapy versus systemic therapy alone. The trial was designed to enroll 254 subjects but closed prematurely due to poor accrual. At a median follow-up of 37.5 months, median survival was 35 months in the cohort treated with surgery compared with 55 months without surgery. These OS data were not statistically significant (HR 0.69, 95% CI 0.36-1.33). Surgery also did not confer benefits in time to distant metastasis, time to locoregional metastases, or improved QOL [8,9].

●Similar results were observed in a single-institution trial from India, in which 350 women with de novo metastatic breast cancer who had resectable hormone receptor-positive disease or who achieved a partial or complete response to anthracycline-based chemotherapy were randomly assigned to surgery (mastectomy or breast-conserving surgery [BCS] with axillary dissection) and standard postoperative radiation versus no locoregional treatment [10]. At a median follow-up of 23 months, no statistically significant difference in OS was observed between the surgery versus control groups (19.2 versus 20.5 months; HR 1.04, 95% CI 0.81-1.34). Locoregional treatment was associated with improved locoregional progression-free survival (PFS; median not attained versus 18.2 months; HR 0.16, 95% CI 0.10-0.26) but shorter distant PFS (11.3 versus 19.8 months in the control group; HR 1.42, 95% CI 1.08-1.85). In this study, endocrine therapy, taxanes, and HER2-directed therapy were permitted when clinically appropriate; however, most eligible women did not receive these treatments. It is unclear whether locoregional therapy would have improved survival in these women if effective systemic treatments had been administered.

Contrasting results, however, were observed in a trial from Turkey:

●In the Turkish trial, 274 women with de novo metastatic breast cancer were randomly assigned to local management (mastectomy, or BCS with radiation) followed by systemic therapy, versus systemic therapy only [11]. This design differed from some of the previous trials, in which patients were enrolled only if they achieved disease control or response on systemic therapy [10,12]. While there was no difference in three-year survival, patients who received locoregional therapy experienced an improvement in five-year survival (42 versus 24 percent; HR 0.66, 95% CI 0.49-0.88). However, the arms were not balanced according to biologic subtypes and other potential prognostic factors. Patients randomized to locoregional therapy had lower rates of triple-negative disease (7 versus 17 percent), and higher rates of hormone receptor-positive disease (86 versus 72 percent) and solitary bone metastases (34 versus 24 percent), raising the concern that they were in better prognostic categories before the intervention. In a post-hoc subgroup analysis, patients with hormone receptor-positive, HER2-negative disease; age younger than 55 years; and those with solitary bone metastases appeared to derive the greatest benefit from local management.

Several previous retrospective studies have suggested that women with stage IV breast cancer have improved survival with removal of the primary tumor, but interpretation and generalizability of these results are limited by selection bias [13-30]. The randomized trials discussed above are more informative regarding the effect of locoregional therapy to women who present with de novo metastases and new primary breast cancers. As such, we typically suggest against surgery in the majority of patients with stage IV breast cancer unless it is directed towards palliation and symptom management.

A multicenter phase III trial from Japan (JCOG-1017) with similar design as the E2108 trial has completed accrual [31].

LOCAL MANAGEMENT OF METASTASES — The goal of therapy for patients with distant metastases is, in general, palliation. Therefore, the standard of care is, for most patients, systemic therapy with complementary surgery or radiation as indicated for particularly worrisome problems, such as brain or spinal cord metastases or intractable bone pain or fractures.

Selection of patients for local therapy to the metastasis

●Patients who have severe pain at diagnosis of metastatic disease, or who have intractable pain in spite of systemic therapy for metastases, are usually considered candidates for radiation therapy to the affected site.

●Metastases in certain sites are considered medical emergencies and are an indication for surgery and/or radiation. These include spinal cord or cauda equina compression, mass effect due to brain metastases, and impending or present pathologic fracture due to a bony metastasis. The primary objective of these treatments is palliative to control symptoms and to stabilize the patient.

●Metastases to the chest wall are also usually treated with locoregional therapy, principally with the intent of avoiding future symptoms. Local therapy such as excision and radiation may also be helpful in patients with hemorrhagic chest wall lesions.

In patients with prior radiation to such an area, secondary radiation may be considered, although there is a high risk of additional skin complications. Alternatively, hyperthermia has been reported to be of value in previously irradiated areas, although this modality is not widely available. (See "Surgery and radiation for locoregional recurrences of breast cancer", section on 'Hyperthermia plus conventional RT'.)

●Additionally, for patients with a first presentation of apparent metastatic disease, biopsy of an accessible metastatic site should be performed to confirm the diagnosis and re-establish receptor status. In some cases, a surgical approach may be appropriate (eg, wedge resection of a solitary pulmonary nodule or intracranial metastasis) rather than a biopsy by interventional radiology, and might also serve a treatment function. (See "Overview of the approach to metastatic breast cancer", section on 'Biopsy of metastatic lesion'.)

●For other patients, who lack symptoms from their locoregional and distant disease,

•With incidentally discovered asymptomatic central nervous system (CNS) involvement, local therapy is typically suggested (see below). This is unusual, however, given that screening of the CNS in patients without CNS symptoms is not routine in patients with metastatic breast cancer. (See 'Brain' below and "Brain metastases in breast cancer", section on 'Choosing between options'.)

•With metastases in other sites, we suggest systemic treatment alone for most asymptomatic patients and reserve local therapies for symptomatic progression.

Exceptions may be made in rare instances, upon multidisciplinary discussion, for select patients with multiple good prognostic factors (eg, good performance status, fewer than three metastases, long disease-free interval between definitive treatment of the primary and development of distant oligometastasis, and high likelihood of complete resection) [6,32-42]. However, patients with good prognostic factors such as these are likely to have extended periods of survival regardless of whether they are offered surgery or not, and as such, systemic therapy alone remains the standard approach, even in these patients.

As examples of available data, in preliminary results of a randomized trial in 125 patients with ≤4 extracranial metastases from breast cancer, the addition of metastasis directed stereotactic body radiation therapy (SBRT) to standard of care systemic therapy failed to improve median progression-free survival (PFS; 19.5 months with SBRT versus 23 months without SBRT) or overall survival (OS; 36-month OS rates of 69 and 72 percent, respectively) [43]. Similarly, in a randomized trial in patients with oligometastatic non-small cell lung cancer or breast cancer, there was no demonstrated PFS or OS benefit with the addition of SBRT to standard systemic treatments among the 47 patients with breast cancer [36]. Only a single randomized trial in patients with all cancer types (including breast) has suggested a survival benefit to aggressive local treatment of metastases [37]. However, this study is relatively small and only contained very few patients with metastases from breast cancer. Data that are largely observational have suggested a survival benefit for aggressive local therapy in patients with oligometastatic disease [6,22,32-35]. However, selection bias is likely to have played a role in these studies.

Techniques for local management — For patients with metastatic breast cancer undergoing local therapy, surgery, radiation therapy, or both is primarily employed.

Radiation therapy techniques should be individualized with the aim of providing adequate coverage of the disease and minimizing exposure of adjacent normal tissue and organs at risk. Depending on the clinical situation, radiation therapy techniques that may be considered include SBRT for oligometastases, or conventional external-beam radiation therapy (EBRT) with simple one- to two-beam arrangements or more complex multibeam techniques, depending on the clinical situation and therapeutic goals. Radiofrequency ablation (RFA, typically with surgery) is a one-time treatment that has been examined as an alternative to SBRT for select, small hepatic tumors, and is discussed below. Indications for each modality, according to anatomic site, are discussed later in this topic. (See 'Indications by site' below.)

Further discussion of the technique of SBRT is found separately. (See "Radiation therapy techniques in cancer treatment", section on 'Stereotactic radiation therapy techniques'.)

All patients treated with local therapy should also receive appropriate systemic therapy. (See "Systemic therapy for locoregionally recurrent breast cancer".)

Indications by site

Brain — For most patients with brain metastases, a local approach such as surgical resection, stereotactic radiosurgery (SRS), or whole-brain radiotherapy should be employed, irrespective of whether the patient is symptomatic or not, often prior to or in conjunction with systemic therapy. However, an exception may be made in select patients with limited intracranial disease from human epidermal growth factor receptor 2 (HER2)-positive breast cancer, as systemic therapy alone may be a reasonable option in some cases. (See "Brain metastases in breast cancer", section on 'Choosing between options'.)

The approach to systemic therapy in patients with isolated brain metastases and no systemic disease is discussed elsewhere. (See "Brain metastases in breast cancer", section on 'Systemic therapy'.)

Patients with multiple metastatic deposits or extensive leptomeningeal disease are treated with whole-brain radiation therapy. For cases with more limited intracranial disease, when possible, SRS is used instead of whole-brain radiation to reduce toxicity. The risk factors, prognosis, and management of brain metastases in breast cancer are discussed separately. (See "Brain metastases in breast cancer" and "Overview of the treatment of brain metastases" and "Treatment of leptomeningeal disease from solid tumors".)

Ophthalmic structures — The prevalence of metastases involving the eyes in patients with metastatic breast cancer has been variably reported as ranging from 5 percent in asymptomatic patients to 38 percent in patients with visual symptoms [38,39]. The most common site of ophthalmic metastasis from breast cancer is the choroid [40]. Less common sites include the iris, ciliary body, optic nerve, optic disc, orbital bone and soft tissues, extraocular muscles, retina, and vitreous body. While presenting symptoms such as blurred vision, diplopia, floaters, field defect, and eye pain or discomfort may be nonspecific and may be attributed to some systemic therapy drugs or other malignant and nonmalignant causes, prompt referral for ophthalmology assessment is critical as loss of vision is a devastating outcome that may be avoided by timely investigation and treatment.

Local therapy decisions for choroidal metastases should be multidisciplinary, with the goals of preserving visual function, controlling pain, and avoiding tumor progression that may require enucleation. In patients with ophthalmic metastases, brain computed tomography (CT) and magnetic resonance imaging (MRI) should also be performed to rule out concomitant brain metastasis. A prospective study of patients with choroidal metastasis reported that the rate of brain metastasis identified on CT with contrast was 26 percent [41].

●In patients who are asymptomatic, systemic therapy with careful observation is an option [42].

●In patients with symptoms, palliative EBRT sparing the lens and anterior chamber is the most common modality demonstrated to be safe and effective.

•A prospective study from the German Cancer Society reported outcomes in 50 patients with choroidal metastases treated with EBRT 40 Gy in 20 fractions using a single lateral beam for unilateral disease and parallel opposed lateral beams for bilateral disease [44]. Visual function improved in 36 percent and stabilized in 50 percent of cases. On ultrasound follow-up, complete regression was observed in 38 percent and partial regression in 44 percent of cases.

•In the palliative setting, shorter EBRT courses over 5 to 10 fractions may also be considered. In a study of 123 patients with choroidal metastases, 71 percent of whom had breast cancer, the most commonly used regimen was 30 Gy in 10 fractions. Visual improvement was observed in 55 percent of cases after EBRT and 80 percent of cases after chemotherapy plus EBRT [45]. Similarly, in a series of 55 patients with 71 affected eyes treated with EBRT 20 Gy in five fractions, visual acuity was stable or improved in 80 percent, tumor regressed in 91 percent, and complete response was observed in 67 percent of affected eyes [46].

Local treatment alternatives to conventional EBRT include proton therapy, plaque brachytherapy, photodynamic therapy, and intravitreal injection of anti-vascular endothelial growth factor (VEGF) [47]. Proton therapy allows highly focused tumor targeting with preservation of normal adjacent tissues [48,49]. Plaque brachytherapy entails applying a radioactive plaque, most commonly Iodine-125 or Palladium-103, to the sclera to deliver radiation over a short distance to the target while sparing the lens and retina [47]. Proton therapy and plaque brachytherapy, however, are less commonly used in the setting of metastatic breast cancer than EBRT, as they are not as widely available and are generally reserved for more radioresistant tumors such as sarcoma and melanoma. Photodynamic therapy and intravitreal injections of anti-VEGF are less invasive office-based treatments that may be offered by ophthalmologists, but data reporting outcomes specific to the metastatic breast cancer setting are limited to case reports and small case series [47].

Bone

●Indications for local management – Indications for local management of bone disease are spinal cord or cauda equina compression, pathologic fracture or impending fracture, significant pain, or decreased mobility of a joint.

Specific approaches are discussed below.

●Surgery – Pathologic fractures, impending fractures, or epidural spinal cord or nerve compression may require surgical intervention. For asymptomatic patients without evidence of impending fracture, there is no clear role for resection. 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 [50-52]. One UpToDate expert (MS) views a solitary sternal metastasis as a possible exception, given that sternal metastases may remain solitary for a long time and may represent a locoregional recurrence rather than true metastatic disease [53,54]. However, the other UpToDate experts note that sternal resection is associated with morbidity and risk of poor cosmesis and has not been shown to improve survival, and therefore do not favor this approach over less invasive options such as surveillance on systemic therapy or local treatment with radiation therapy. (See 'Selection of patients for local therapy to the metastasis' above.)

●Radiation – In cases with painful bone (spinal and extraspinal) metastases, short-course, local-field external-beam palliative radiotherapy using single or multiple fractions is commonly used, supported by a large body of prospective data demonstrating its safety and palliative efficacy [55,56]. The role of more complex radiation techniques such as SBRT in breast cancer patients with bone metastases, including those with limited-volume disease, remains to be defined by prospective trial data and is discussed separately. (See "Treatment and prognosis of neoplastic epidural spinal cord compression", section on 'Selection of definitive treatment' and "Radiation therapy for the management of painful bone metastases".)

●Minimally invasive, image-guided percutaneous techniques – Interventional radiology and anesthesiology are disciplines that can offer useful adjunctive local procedures to palliate patients with symptomatic bone metastases, including patients who have recurrent or intractable pain despite radiation therapy. Minimally invasive, image-guided percutaneous techniques such as vertebroplasty, kyphoplasty, cementoplasty, thermal ablation, and neurolysis can provide durable pain control and stabilization for both spinal and nonspinal bone metastases and may be considered for carefully selected patients with interdisciplinary review and operator expertise [57-59]. (See "Overview of therapeutic approaches for adult patients with bone metastasis from solid tumors" and "Image-guided ablation of skeletal metastases".)

●Systemic therapy and adjunctive treatments – As in other metastatic sites, systemic therapy can improve symptoms and progression of bone metastases. Bisphosphonates, other osteoclast inhibitors, and radioisotope therapy reduce the morbidity of metastatic bone disease, in particular skeletal-related events, which include fracture, need for surgery or radiation to bone, spinal cord compression, and hypercalcemia of malignancy.

•(See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors".)

•(See "Radiation therapy for the management of painful bone metastases".)

•(See "Treatment and prognosis of neoplastic epidural spinal cord compression".)

Lung — Lung metastases that are asymptomatic generally do not require local intervention, while those that are symptomatic or pose urgent risks to pulmonary function such as intrinsic or extrinsic airway obstruction and superior vena cava obstruction may benefit from prompt local treatments. For some patients, pulmonary resection may be diagnostic as well as palliative, since a significant number of solitary pulmonary nodules in patients with a history of breast cancer are not breast cancer metastases [60-62]. Patients evaluated for lung resection should have a complete pulmonary evaluation. (See "Diagnostic evaluation of the incidental pulmonary nodule" and 'Selection of patients for local therapy to the metastasis' above.)

As discussed above, metastasectomy for therapeutic purposes has been reported to occasionally be associated with long-term survival [6,32,33,63]. It must be noted, however, that patients who experience such apparent benefit have a favorable prognosis, regardless of whether surgery is done; therefore, most UpToDate experts prefer to avoid the morbidity and mortality associated with such procedures, particularly in the absence of randomized data. Case series suggest five-year overall survival (OS) ranging from 30 to 80 percent and median survival duration ranging from 40 to 100 months among select breast cancer patients undergoing resection of pulmonary metastases [32,60,63-65]. A meta-analysis of 16 retrospective studies with almost 2000 patients reported a five-year survival rate of 46 percent after resection of isolated lung metastases [66]. Adverse prognostic features were short DFI <3 years, >1 metastatic lesion, and negative hormone receptor status. (See "Surgical resection of pulmonary metastases: Outcomes by histology".)

Other approaches in the local management of lung metastases include EBRT, typically for lung or mediastinal/hilar masses causing extrinsic airway obstruction, peripheral or pleural disease-causing chest wall pain, or apical masses extending into spinal canal or brachial plexus; endobronchial brachytherapy for intrinsic bronchial obstruction; SBRT; and RFA, although central lesions may be difficult to reach by RFA. The local management of lung metastases, including each of these modalities, is discussed separately.

●(See "Diagnostic evaluation of the incidental pulmonary nodule".)

●(See "Endobronchial brachytherapy".)

●(See "Stereotactic body radiation therapy for lung tumors".)

●(See "Image-guided ablation of lung tumors".)

Liver — Hepatic metastases occur in over one-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 [67-69].

●Indications for local management – Indications for local management of liver metastases include pain, bleeding that is refractory to medical therapy, or biliary obstruction.

Some UpToDate 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. Proponents of this approach identify candidates as those with isolated liver involvement (5 to 12 percent of patients with metastatic breast cancer [67-69]), particularly those with hormone-positive disease, who have normal liver function, good performances status, and have had a long DFI [6,70,71]. However, such patients are likely to have a good prognosis regardless of whether they undergo surgery, so most UpToDate experts prefer to treat with systemic therapy only in the absence of urgent or palliative indication. (See 'Selection of patients for local therapy to the metastasis' above.)

●Approaches for local management – Hepatic resection and SBRT are the most frequently employed methods of ablating liver metastases in carefully selected patients. The selection of SBRT versus surgery depends on which modality will result in the highest probability of preserving liver function. For larger (>5 cm) peripheral lesions, surgery can sometimes preserve more functional liver than SBRT. By contrast, for central lesions, SBRT may be preferred. RFA has been explored as another option for tumors <3 cm that are not close to major vessels, biliary structures, or the diaphragm [72]. While there are only retrospective data reporting outcomes after RFA in patients with metastatic breast cancer, these data suggest local efficacy particularly for solitary hepatic lesions smaller than 3 cm in diameter [72-77].

Although we do not suggest their routine use based on available data, alternative local therapies are being explored to treat liver metastases, including selective internal radiation therapy, percutaneous ethanol injection, cryotherapy, hepatic arterial infusion chemotherapy, transhepatic arterial chemoembolization, and interstitial laser therapy [78,79]. In general, there are fewer data regarding the use of these techniques for metastatic breast cancer than there are for patients with liver metastases from colorectal cancer or with primary hepatocellular cancer. Furthermore, none of these methods has been directly compared with systemic chemotherapy in metastatic breast cancer.

●Outcomes with local therapy – The data to support local therapy for liver metastases were derived from a systematic review of 19 retrospective studies including 535 patients who underwent hepatectomy for metastatic breast cancer [80]. Hepatectomy was undertaken in patients with mostly solitary lesions or with a median of two lesions (range, one to four). The median OS was 40 months (range, 23 to 77 months) with a five-year survival following resection of 40 percent (range, 21 to 80 percent) [80]. Postoperative mortality ranged from 0 to 6 percent, and the complication rate ranged from 0 to 44 percent. Poor prognostic factors following hepatic resection include positive margins and hormone-refractory disease.

In a subsequent case-control retrospective study of 167 patients, 69 of whom received surgery and/or ablation and 98 of whom were treated medically, OS between the two groups was not significantly different (50 versus 45 months in the local treatment versus medical treatment groups, respectively) [81]. Local treatment was associated with a recurrence-free interval of 28.5 months. Those receiving local treatment had lower-risk disease, with a higher frequency of estrogen receptor positivity, lower median number of liver metastases, and a longer interval between breast cancer diagnosis and solitary liver metastasis presentation (53 versus 30 months). These results suggest that among patients with favorable-risk disease, local treatment may provide a significant period of disease-free survival and time off from systemic chemotherapy. (See "Overview of hepatic resection" and "Open hepatic resection techniques".)

However, as noted, it is highly likely that patients who are chosen for local therapies are selected for otherwise favorable prognostic factors, including isolated and usually single metastases, often with hormone receptor-positive disease, and it is unclear if apparent favorable OS is due to, or in spite of, the therapy.

Gastrointestinal tract — Gastrointestinal (GI) tract metastases are infrequently encountered in practice, although autopsy series have reported rates ranging from 8 to 30 percent [82,83]. Invasive lobular cancers have a higher propensity to metastasize to the GI tract compared with other histologies [84-86], as may hormone receptor-positive cancers, irrespective of histology [86]. The most common sites of GI metastases from breast cancer are the stomach and colon, while esophageal and small intestine metastases are possible but less common. Often, these metastases to unusual sites originate from lobular infiltrating cancers of the breast.

As GI metastases can occur many years after an initial breast cancer diagnosis, and given that some can respond to chemotherapy and endocrine therapy depending on biomarkers, patients with unexplained GI symptoms should be referred to gastroenterology for thorough evaluation of the abdomen and GI tract, with biopsy of any suspicious lesions seen on endoscopy to differentiate metastatic breast cancer from other entities such as primary GI cancer, lymphoma, or benign disease and to guide appropriate treatment.

In cases with confirmed GI metastases causing obstruction, bleeding or intractable pain, and in which a targetable lesion can be identified, involved-field palliative EBRT may be considered for symptom control. Other local modalities in symptomatic patients include palliative surgical bypass, percutaneous enterostomy, or endoscopic stenting. The choice of local procedure should be made in a multidisciplinary setting with consideration of the clinical scenario and patient's goals of care.

Ovaries — Although the ovaries are also a rare site for metastases from breast cancer [87,88], limited data suggest ovarian breast cancer metastases can appear many years following the initial diagnosis of breast cancer, often originating from lobular primary cancers [89-92]. Surgical evaluation of an adnexal mass may be required to differentiate metastatic breast cancer from a primary ovarian cancer. Furthermore, for premenopausal patients with hormone receptor-positive breast cancer, oophorectomy can provide a therapeutic effect, regardless of whether metastatic disease to the ovaries is present or not. (See "Approach to the patient with an adnexal mass", section on 'Scope of surgery' and "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Additional considerations for premenopausal women'.)

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 OS after ovarian metastasectomy was 41 months [93]. For the entire series, massive intraoperative ascites, multiple metastases, and locally invasive disease were independent factors for a poorer OS.

INTEGRATING SYSTEMIC THERAPY WITH LOCAL TREATMENT — All patients who undergo local management of metastatic breast cancer should also receive systemic therapy.

Whether or not next-line therapy is chosen depends upon whether the line of treatment the patient was previously receiving was well tolerated, and whether it was controlling disease that was not addressed by local therapy. For example, if a patient with hormone receptor positive, human epidermal growth factor receptor 2 (HER2)-negative disease experienced progression intracranially on a well-tolerated endocrine agent but had stable systemic disease, it would be reasonable to manage the brain lesions with radiation and continue the given line of endocrine therapy. However, if progression occurred systemically as well, or if the present line of therapy was poorly tolerated, next-line systemic therapy should be offered. (See "Overview of the approach to metastatic breast cancer".)

For patients who will receive systemic therapy with endocrine agents or immunotherapy, treatment is usually continued concurrently with radiation. However, chemotherapy and targeted agents such as cyclin-dependent kinase 4/6 inhibitors are typically held for radiation and resumed several days after completion.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Breast cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Treatment of metastatic breast cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Patients with metastatic breast cancer are unlikely to be cured of their disease by any means, and the goal of treatment is principally palliative in nature. (See 'Introduction' above.)

●Although systemic therapy is the mainstay of treatment for metastatic breast cancer, local management of the primary as well as metastasis-specific local treatment may palliate existing symptoms and improve local progression-free survival. Further data are required to clarify the effect on overall survival. (See 'Introduction' above.)

●The primary role of local treatment to the breast in metastatic breast cancer is palliation. In general, for patients who are asymptomatic at the site of their primary with no threat to organ function, we suggest systemic therapy alone rather than local treatment and systemic therapy (Grade 2C), given a lack of clear evidence that it improves survival. However, exceptions may be made in rare instances, upon multidisciplinary discussion. (See 'Local management of the primary in a patient with de novo metastases at the time of initial diagnosis' above.)

●For the first presentation of metastatic disease, biopsy of the metastatic site should be performed to confirm the diagnosis and re-establish receptor status. (See "Overview of the approach to metastatic breast cancer", section on 'Biopsy of metastatic lesion'.)

●Patients who present with symptomatic metastases, eg, intractable pain, bleeding, 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 function and quality of life. (See 'Indications by site' above.)

●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, most UpToDate experts manage asymptomatic metastatic disease with systemic therapy only and reserve local therapies for symptomatic progression, while a few UpToDate experts may offer local management to select patients with multiple good-risk features, although this is not considered standard of care. (See 'Indications by site' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Julia White, MD, and Pauline T Truong, MDCM, who contributed to an earlier version of this topic review.