Local Treatment of Breast Cancer Liver Metastasis

Breast cancer represents a leading cause of death worldwide. Despite the advances in systemic therapies, the prognosis for patients with breast cancer liver metastasis (BCLM) remains poor. Especially in case of failure or cessation of systemic treatments, surgical resection for BCLMs has been considered as the treatment standard despite a lack of robust evidence of benefit. However, due to the extent and location of disease and physical condition, the number of patients with BCLM who are eligible for surgery is limited. Palliative locoregional treatments of liver metastases (LM) include transarterial embolization (TAE), transarterial chemoembolization (TACE), and selective internal radiotherapy (SIRT). Percutaneous thermal ablation methods, such as radiofrequency ablation (RFA) and microwave ablation (MWA), are considered potentially curative local treatment options. They are less invasive, less expensive and have fewer contraindications and complication rates than surgery. Because conventional ultrasound- and computed tomography-guided single-probe thermal ablation is limited by tumor size, multi-probe stereotactic radiofrequency ablation (SRFA) with intraoperative image fusion for immediate, reliable judgment has been developed in order to treat large and multiple tumors within one session. This review focuses on the different minimally invasive local and locoregional treatment options for BCLM and attempts to describe their current and future role in the multidisciplinary treatment setting.


Introduction
Breast cancer is a leading cause of mortality worldwide [1]. It is a heterogeneous disease with specific molecular subtypes, which are associated with different prognosis and response to treatment. Approximately 50% of all women diagnosed with breast cancer develop metastatic disease. The common metastatic sites are liver, lung, bone, and brain. Liver metastases develop in approximately 50% of all patients with metastatic breast cancer and 5-12% of patients develop liver metastases as the primary site of breast cancer recurrence [2].
Metastatic liver disease may cause impairment of liver function and endanger the patients' life. If left untreated, liver metastases (LM) are associated with poor survival ranging from 4 to 8 months [3]. Patients with advanced disease are primarily treated by systemic hormone-and/or chemotherapy [4,5]. However, despite an improvement in systemic treatment, median survival of patients with metastatic disease from the time of diagnosis of metastatic breast carcinoma is approximately 18-24 months, and 5-year and 10-year survival rates are still as low as 27% and 13%, respectively [6]. Despite transient response to chemotherapy or endocrine therapy, most patients exhibit progressive disease changes after 1-2 years [7].
Recent studies demonstrated that subgroups of these heterogeneous patients with oligometastatic disease benefit from additional local or locoregional treatment, with improved survival rates after R0

Resection of BCLM
In contrast to the substantial evidence for local treatment of colorectal liver metastases, the data for resection of BCLM are limited. In heterogenous case series the reported median 3-, and 5-year survival rates after metastasectomy of BCLM range between 24-116 months, and 49-94% and 5-78%, respectively [3,10,. In a systematic review Fairhurst et al. [55] analyzed 33 papers dealing with resection of BCLM in a total of 956 patients. The mortality ranged between 0% and 5.9% and the median morbidity rate was 15%. The median overall survival (OS) was 35.1 months, with a median 1-, 2-, 3-, and 5-year survival of 84.6%, 71.4%, 52.9%, and 33% respectively. The median disease-free survival (DFS) was 21.5 months with a 3-and 5-year median DFS of 36% and 18%. In a more recent paper, Ercolani et al. reported a 10-year OS rate of 16% in an updated single center experience in 51 patients [27]. In a case-matched analysis, patients from the Netherlands with BCLM who received systemic treatment only were compared with patients from France who received a combination of systemic treatment with hepatectomy. After matching, the resection group had a median OS of 82 months with a 3-and 5-year OS of 81% and 69%, respectively, compared with a median OS of 31 months in the systemic group with a 3-and 5-year OS of 32% and 24%, respectively [10]. The authors concluded that for patients with BCLM, liver resection combined with systemic treatment results in improved OS compared to systemic treatment alone.
The major drawback of most studies is the poor data quality due to the inclusion of small numbers of patients and multiple confounding variables including tumor biology of the primary tumors, presence of synchronous or metachronous extrahepatic metastases, systemic treatments and time intervals between primary tumor and systemic treatment and the type of local treatment of BCLM. Most patient cohorts in the surgical series are highly selected and it remains unclear whether the resection itself or the favorable tumor biology is responsible for the results.
Despite some promising reports, surgical resection of BCLM is still controversial because of its invasiveness. In addition, many patients develop unpredictable recurrent disease [56]. Liver recurrences and extrahepatic recurrences were diagnosed at a mean interval of 15 months and 22 months after hepatectomy [57].

Prognostic Factors
In order to select the proper patients, it is crucial to find out independent factors that influence the prognosis after BCLM resection. Characteristics of primary breast cancer such as small tumor size, low grade, node negativity, and early stage may be associated with better outcome after liver metastasectomy [39][40][41]58]. Moreover, response to preoperative systemic therapy has been identified as a prognostic factor which is likely related to effective systemic eradication of microscopic metastatic lesions [3,21,30]. In addition, complete macroscopic and microscopic resection (R0) [3,29,30,32,40], liver-limited disease (with the exception of isolated pulmonary and bony metastases) [23,39,59], solitary BCLM [36,41], a long interval (more than 1 year) between breast cancer diagnosis and the detection of BCLM [21,28,29,35,37,57] and patients with PgR-and/or ER-positive BCLM [21][22][23]27,30,34,60] were independent prognostic factors. In conclusion at least a selected group of patients with BCLM benefits from aggressive local curative treatment. Further studies are required to define more specific selection criteria for local treatment of BCLM.

Non-Surgical Local Treatment Options with Palliative Intent
For various reasons the majority of patients are unresectable at the time of diagnosis of BCLM [10,61]. In addition, alternative minimally invasive treatment options that achieve equal local control but with lower morbidity and mortality as compared to surgical resection would be highly desirable.
Transarterial locoregional therapies including transcatheter arterial embolization (TAE), transcatheter arterial chemoembolization (TACE) [53,62,63], and selective internal radiation therapy (SIRT) [46][47][48][49][50][51][52] have been introduced with the primary goal of palliation. They are based on the observation from animal studies that hepatic tumors are mainly supplied from the hepatic artery as opposed to the portal vein. They have been developed to deliver high doses of chemotherapeutic (TACE) or radioactive agents (SIRT) directly to the target tumor and to prolong drug/radiation exposure to the tumor cells while minimizing systemic side effects.

Transarterial Chemoembolization (TACE)
In TACE [64] high doses of chemotherapeutic agents are directly delivered to the target tumor. In addition, the chemotherapeutic effect of TACE on tumor cells is augmented by the embolization induced ischemia. It is well established for the palliative treatment of hepatocellular carcinoma [65]. TACE is a minimally invasive procedure associated with a very short hospital stay and minimal side effects. However, there is only sparse data available on the application of TACE for patients with BCLM.
Li et al. [54] reported the results of TACE and systemic chemotherapy for 46 patients with BCLM. After a median follow-up of 28 months response rates for the TACE group and chemotherapy group, were 35.7% and 7.1%, respectively. The 1-, 2-, and 3-year respective survival rates for the TACE group were 63.0%, 30.4%, and 13.0%, and those for the systemic chemotherapy group were 33.9%, 11.3%, and 0%.
The role of TACE in unresectable BCLM was also evaluated by Cho et al. [62] in a retrospective review of ten patients treated by a median number of four TACE sessions. An increase in median survival was observed for patients who responded to treatment when compared to non-responders (24 vs. 7 months, p = 0.02). In a prospective phase II study, Eichler et al. [53] evaluated the efficacy and tolerability of TACE with gemcitabine in 43 patients with inoperable BCLM. All patients tolerated the treatment well. Follow-up imaging revealed a partial response in three patients, stable disease in 16 patients, and progression in 22 patients, resulting in a progression-free survival of 3.3 months, and an estimated median survival rate of 10.2 months.

Selective Internal Radiation Therapy (SIRT)
SIRT was originally developed as a liver-directed therapy for primary liver cancer and colorectal liver metastases. A randomized multicenter clinical trial showed an improvement in radiological response rate and hepatic progression-free survival in patients with colorectal liver metastases treated with SIRT [66]. SIRT is based on the administration of yttrium-90 (90 Y) microspheres with a diameter of approximately 30 µm via the arterial blood supply of liver tumors. Adverse events include radioembolization-induced liver disease (REILD), postradioembolization syndrome (PRS), biliary complications, radiation pneumonitis, gastroduodenal ulceration, lymphopenia, vascular injury, and portal hypertension [67]. REILD is characterized by jaundice and ascites 1 to 2 months after SIRT without bile duct occlusion or tumor progression, which occurs in up to 20% of cases and seems to be associated with the combined effect of radiation and chemotherapy [68].
PRS typically consists of unspecific symptoms including fatigue, anorexia, and fever and is commonly observed after SIRT but is mild, requiring only symptomatic management. Several retrospective studies have explored the use of SIRT in patients with BCLM refractory to systemic treatment with a median OS of 4-13.6 months [46][47][48][49][50][51][52]. Haug et al. reported a median OS of 11.8 months in 58 women receiving SIRT for BCLM [49]. Gordon et al. achieved a partial response of 35.3% and stable disease in 63.2%, with a median OS of 6.6 months in 75 patients [48]. One systematic review included 198 patients from six retrospective cohort studies. Disease control (complete response, partial response or stable disease) was observed in 78-96% at 2-4 months [69]. The absence of extrahepatic disease [50,51], response to SIRT [49,51,52] and a low liver tumor burden have been associated with good prognosis [48,51,52].

Stereotactic Body Radiation Therapy (SBRT)
The liver parenchyma has low radiation tolerance doses. However, by delivering higher doses to small volumes, organ function can be maintained without causing functional compromise [67]. Due to the delivery of conformal doses and steep dose gradients SBRT allows normal liver tissues to be spared.
Retrospective and prospective studies have demonstrated the feasibility of SBRT for LM from different tumor entities with local control (LC) rates ranging from 60-90% at 2 years after treatment [70,71]. In a recent paper, Onal et al. [43] combined liver SBRT and systemic treatment in a total of 22 patients with 29 BCLM, with a mean size of 2.1 ± 1.2 cm. After a median follow-up time of 16.0 months (range 4.4-59.4 months), 18 patients (82%) had disease recurrence. The 1-and 2-year OS rates were 85% and 57%, and the 1-and 2-year PFS rates were 38% and 8%, respectively. The 1-and 2-year LC rates were 100% and 88%, respectively. The authors concluded that SBRT may be an effective and safe treatment option in selected patients with BCLM. Mahadevan et al. [44] reported the results after SBRT of a total of 427 patients with liver metastases from different origin including 42 patients with BCLM. At a median follow-up of 14 months (1-91 months) the median OS for patients with BCLM was 21 months. In the whole cohort, smaller tumor volumes (<40 cm 3 ) and BED10 ≥ 100 Gy correlated with improved OS ((25 months vs. 15 months, p = 0.0014) and (27 months vs. 15 months p < 0.0001)), respectively. In BCLM the LC rate after 2 years was 24%.
Hypoxia particularly within large lesions may cause local failure [72] and the distance between treated lesions and the surrounding visceral organs at risk should be more than 8 mm [71]. Liver SBRT is technically challenging, requiring daily imaging guidance and insertion of fiducial markers and/or image fusion to localize the target and assess respiration-related organ motion [44]. The patient selection criteria, and optimal dose and fractionation for liver SBRT are still under investigation.

Interstitial Brachytherapy (BT)
BT is a type of radiotherapy where a small amount of radioactive material sealed in catheters, wires, needles, or seeds is directly inserted into the tumor tissue. Wieners et al. [45] introduced a technique of interstitial BT applied with CT guidance and 3D CT dataset for exact dose planning. In 41 consecutive patients with 115 BLCM with a median tumor size of 4.6 cm (1.5-11 cm), the CR, PFS, and OS rates at 12 months were 93.5%, 40%, and 79%, respectively. One postinterventional hemorrhage was the only major complication that was encountered. The authors concluded that CT-guided BT is a safe and effective treatment, however further studies are needed to identify best candidates for BT as long-term data is missing.

Thermal Ablation
Thermal ablation methods are minimally invasive, potentially curative, low-risk procedures for local tumor treatment [73][74][75]. In RFA an alternating current is flowing between the uninsulated probe tip and a dispersive skin electrode (unipolar) or between the different electrodes within one or multiple probes (multipolar). Radiofrequency current is converted into tissue heating by friction of the ions in close vicinity to the uninsulated tip of the RFA electrode [76][77][78]. MWA is based on an electromagnetic field (0.9-2.450 GHz), that radiates from an antenna. Water molecules in the surrounding tissue are forced to continuously realign with the oscillating electric field. The kinetic energy rise of the polar water molecules induces heat in the tissue adjacent to the antenna [79]. In contrast to RFA, microwave probes provide faster tissue heating over a larger volume with a less prominent 'heat sink effect'. With the latest generation microwave antenna, a spherical shaped ablation zone with a short axis diameter of up to 4 cm can be achieved [80]. Cryoablation is based on local tissue destruction based on very low temperatures inducing cellular dehydration, protein denaturation and microcirculatory failure [81].
Thermal ablation is considered the first choice for treatment of unresectable liver malignancies. If similar local recurrence rates can be achieved, minimally invasive thermal ablation may serve as an attractive alternative to resection. In contrast to surgical resection with reported overall mortality rates of 5.8 percent in a total of 110,332 liver procedures [16], thermal ablation is associated with a very low complication rate. In a meta-analysis in 9531 patients the reported mortality and major morbidity rates after RFA of liver tumors were 0.15% and 3.29%, respectively [17].
Unfortunately, the reported local recurrence rates after conventional CT-/US-guided RFA of BCLM range between 14% and 50% [82,83]. Especially in large lesions the results after thermal ablation are still unacceptable independent of tumor etiology. Therefore, in colorectal liver metastases the sole use of thermal ablation is currently only recommended for liver metastases <3 cm [84]. The size of the ablation zone should cover the entire tumor including a safety margin (0.5-1 cm) of unaffected surrounding tissue [74]. For large lesions, multiple overlapping ablation zones are required [77,85]. Complex planning and placement of multiple probes/electrodes/coaxial needles are difficult to achieve with conventional ultrasound and CT guidance techniques only. Therefore, frameless stereotactic navigation systems in combination with neurosurgical aiming devices [86] are applied for sophisticated 3D planning, translation of the virtual plan into the real patients, and intraoperative confirmation of the ablation margins [87,88] In a recent retrospective study, the efficacy of the so-called stereotactic radiofrequency ablation (SRFA) with intraprocedural image fusion was evaluated for treatment of HCC by histopathological examination of explanted livers in 97 patients, who were treated by SRFA before liver transplantation. Complete pathological response in the explanted liver specimen was achieved in 183 of 188 nodules (97.3%), and in 50 of 52 nodules ≥3 cm (96.2%) [89]. In addition, reported local control and survival rates after SRFA of intrahepatic cholangiocellular carcinoma [18], colorectal liver metastases [13], and melanoma liver metastases [15] were at least comparable to the surgical literature. In all studies tumor size was not related to an increase of local recurrence rate or a decrease of the survival rate.
Results after Thermal Ablation of BCLM Veltri et al. [12] reported the results after ultrasound guided RFA of 45 patients with 87 BCLM. After a mean follow-up of 30 months the local recurrence rate was 19.7%, with a time to local progression of 8 months. Local recurrence rate was significantly influenced by the BCLM diameter. OS at 1 and 3 years was 90% and 44%. Carrafiello et al. [90] treated 13 female patients with 21 BCLM by ultrasound guided RFA. No complications were observed. A mean OS of 10.9 months after RFA was achieved. Lawes et al. [14] evaluated the effectiveness of RFA as a cytoreductive strategy in the management of BCLM in 19 patients including 11 patients with additional stable extrahepatic disease. After a median follow-up of 15 months, 13 patients were alive, with a survival rate of 41.6% at 30 months.
Jakobs et al. [91] treated 111 BCLM in 43 patients with conventional percutaneous CT-guided RFA and achieved a local recurrence rate of 13.5% and a median OS of 58.6 months and a median time to progression of 10.5 months from the date of RFA. Hormone receptor status, HER2 overexpression, and presence of isolated bone metastases did not significantly influence survival. However, extrahepatic disease with the exception of skeletal metastases was associated with a shorter survival time. In a similar study in 12 patients Sofocleous et al. [83] reported a median OS of 60 months after a median follow-up of 22.5 months, with 3-and 5-year OS rates after RFA of 70% and 30%, respectively. The median primary local progression-free interval was 12 months.
Meloni et al. [82] treated 52 patients with BCLM with percutaneous US-guided RFA and reported a median OS of 29.9 months and a 5-year OS rate of 27%. Local tumor progression was observed in 25% (13 of 51) of patients. New intrahepatic metastases occurred in 53% of patients. Patients with large tumors (>2.5 cm in diameter) had a worse prognosis as compared to patients with smaller tumors (hazard ratio: 2.1).
Kuemler et al. [92] reported a local recurrence rate of 22% after percutaneous US-guided RFA of BCLM in 32 consecutive patients. The median time to intrahepatic progression was 11 months (range 1.6-184 months) and the median survival after first RFA was 33.5 months, with an OS of 87% and 48%, at 1 and 3 years, respectively.
Zhang et al. [19] treated 17 patients with 39 BCLM with a median tumor size of 3.5 cm (range: 2-5 cm) by cryoablation. They reported no major complications, a LR rate of 15.4% and a 1-year OS of 70.6%. The authors concluded that cryoablation is a safe and effective treatment, however further studies are needed as long-term data is missing.
Our group [93] reported initial experiences with stereotactic radiofrequency ablation (SRFA) for the treatment of 64 drug resistant BCLM in 26 patients. Despite the inclusion of lesions up to 8.5 cm, a complete local response was achieved in 59/64 (92.2%) of the tumors, with no significant differences (p = 0.662) when comparing tumor sizes <3 cm, 3-5 cm and >5 cm. This local control rate is well comparable to the reported R0 rates after surgical resection, which range from 62 to 96%. Estimated median OS and DFS from SRFA treatment were 29.3 and 32 months after a median follow-up of 23 months. In contrast to other studies using conventional image guidance no significant differences (p = 0.891) in survival were observed when comparing tumor sizes <3 cm (48.1 ± 13.5 months, median 15.0) vs. 3-5 cm (37.4 ± 5.7 months, median 51.1) vs. >5 cm (21.2 ± 4.8 months, median 20.9). As described above, the selection of the ideal patients is key to achieve long-term survival. In this group 31% of the patients suffered from extrahepatic disease and 83% from multiple BCLM, respectively.
Reported survival rates for percutaneous RFA in selected patients with BCLM confined to the liver or with stable extrahepatic metastases are comparable to those obtained with resection. Conventional CT-and US-guided RFA and MWA should be used for small lesions and stereotactic RFA and MWA for large lesions. RFA is a safe technique that can be repeated in the case new BCLM appear. When compared with surgical resection, thermal ablation is less invasive, less expensive, has fewer contraindications. and is easier to repeat in case of disease recurrence. Since many patients will develop BCLM after surgical resection, application of the test-of-time approach [91] by applying thermal ablation as initial treatment may avoid unnecessary surgical resections in patients who would develop new metastases. Despite the lack of randomized studies minimally invasive RFA/SRFA may be considered as first line treatment in selected patients with BCLM confined to the liver or with stable extrahepatic disease.

Conclusions
In a selected group of patients with oligometastatic disease, effective local treatment of BCLM achieves a survival advantage over systemic chemotherapy and/or hormonal therapy alone. To maximize survival and minimize unnecessary operative morbidity, multiple criteria reflecting the biology of the disease including response to systemic therapy, hormone receptor status, and extent of the disease have to be carefully considered for the determination of appropriate candidates and the ideal timing for local treatment. Further studies are required to better identify those subgroups of patients for whom a multidisciplinary treatment approach with curative intention might be an option.
Transarterial locoregional treatments including TACE and SIRT may be applied in selected patients with chemo-resistant advanced metastatic liver disease.
Percutaneous thermal ablation methods, such as conventional CT-and US-guided RFA and MWA for small lesions, and stereotactic RFA and MWA for large lesions, seem to be an attractive alternative to surgical resection. They enable a tissue sparing and cost-saving local curative treatment approach paired with a low complication rate. The decision for local curative treatment of BCLM might therefore be easier if treatment options with similar potential for local control but lower morbidity and mortality as compared to surgical resection are available. In addition, ablation procedures allow to access tumors that are surgically not treatable due to their location or patient comorbidities.