1.      Introduction

 Systemic and surgical management of primary Breast Cancer (BC) has continued to evolve over the past four decades, but for patients with metastatic breast cancer, treatment options are limited. Breast cancer most commonly metastasizes to the liver, lung, brain, bone and skin [1,2].The liver is the third most common site for BC metastasis accounting for about 10% of patients, of which only 5-18% present with isolated Breast Cancer Liver Metastasis (BCLM) [1,3-9]. Metastatic BC is considered an incurable disease despite new therapies. Systemic chemotherapy is currently the mainstay for management of BCLM with a median survival of 1-25 months and a 5-year Overall Survival Rates (OSR) ranging from 8.5%-40% [10-14]. However, recent success in Surgical Resection (SR) and Ablation Therapy (AT) reported for colorectal liver metastases have encouraged the development of similar protocols for management of BCLM [15,16]. 

Previous studies evaluating surgical and ablative techniques for management of BC patients with hepatic metastasis have suggested favorable oncologic outcomes with low morbidity. Only a few large-scale studies have evaluated survival, recurrence rates and other measures of oncologic safety for management of BCLM. The purpose of this systematic review is to summarize the totality of evidence that evaluates oncologic outcomes after SR and AT in the setting of breast cancer metastasis to the liver. We performed a systematic literature review to assess Overall Survival (OS), Disease-Free Survival (DFS), Local Recurrence (LR), Mortality Rates (MR), and Complication Rates (CR) among BCLM patients undergoing SR and AT. 

2.      Materials and Methods 

2.4.  Study Selection 

A search was conducted of peer-reviewed articles through the MEDLINE database using PubMed. Our search terms included: "Breast Neoplasms", "Breast Cancer", "Liver Neoplasms", "Hepatectomy", "Resection of Liver", "Neoplasm Metastasis”, or "Ablation Techniques" We filtered all articles from 1950 to 2016. A manual search of bibliographies of relevant articles was performed. All searches were conducted in September 2016. Abstracts were screened to identify studies that measured DFS, OS, OSR at 1, 2, 3 and/or 5 years, LR, MR and/or CR. 

2.5.  Data Extraction 

Two investigators performed the search, independently screened articles pertaining to breast cancer liver metastasisusing Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and extracted data from each study [17]. Discrepancies in coding required agreement between authors to be considered resolved.

2.6.  Definitions of Outcomes of Interest 

Included studies reported at least one of the following outcomes:  

2.6.1.         Disease-Free Survival (DFS): Patients in the study who were alive from the time of surgery to date of last follow-up without the development of local or distant disease recurrence or a new breast tumor. 

2.6.2.         Overall Survival (OS): Patients in the study who were alive from the time of surgery to date of last follow-up. 

2.6.3.         Overall Survival Rate (OSR):at 1, 2, 3 and/or 5 years: Proportion of patients who were alive from the time of surgery to 1, 2, 3 and/or 5 years after surgery, respectively. 

2.6.4.         Complication Rate (CR): Proportion of patients who experienced a complication associated with surgery. 

2.6.5.         Mortality Rate(MR): Proportion of patients who died from time of surgery to date of post-operative follow-up.

2.7.  Inclusion and Exclusion Criteria 

Studies were selected based on the following inclusion criteria:

-               Report on women undergoing SR or AT in the setting of BCLM

-               Report on DFS, OS, OSR, LR, CR and/or MR

Studies were excluded by any one of the following criteria:

-                      Review articles

-               Evaluated methods other than surgical resection or ablative therapy for management of BCLM

-               Studies that included only patients with extrahepatic disease (EHD) from breast cancer or combined treatment modalities

-               Evaluated fewer than 5 patients 

2.8.  Statistical Analysis 

For all studies, we reported one or more of the primary outcomes of interest (DFS, OS, OSR at 1, 2, 3 and/or 5 years, LR, CR and/or MR). We further determined the weighted average of OS, DFS, OSR, LR, CR and/or MR among the SR and AT groups. We determined mean OS, median DFS, OSR, LR, CR and MR according to decade in which the studies ended (1990s versus 2000s versus 2010s for the SR group; 2000s versus 2010s for the AT group). The median age and mean follow-up time were also extracted, in addition to the proportion of people who had EHD. We determined the mean length of OS among patients with and without EHD. 

We performed a one-way analysis of variance test to compare measures of oncologic safety (OS, DFS, OSR, LR, CR and MR) for studies that evaluated patients in the SR group through the 1990s versus 2000s versus 2010s in order to assess if a statistically significant difference exists among these outcomes of interest among patients treated with older versus more recent surgical techniques. We then performed an independent samples t-test to compare the same outcomes of interest among patients in studies continuing through the 2000s versus 2010s in the AT group to assess if a statistically significant difference exists among these outcomes of interest among patients treated with older versus more recent ablative techniques.  We also performed an independent samples t-test among patients who underwent SR to determine if length of OS differed significantly for patients with and without EHD. 

3.      Results 

The literature search yielded 3,028 articles (Figure 1). Sixty-seven studies published from 1988 to 2016 met inclusion and exclusion criteria and were selected for the systematic literature review. Table 1a and 1b provide baseline characteristics of studies selected for the systematic literature review reflecting patients undergoing SR. Table 2 provides baseline characteristics of studies selected for the systematic literature review reflecting patients undergoing AT.

5.1.  Results of Patients Undergoing Surgical Resection

Forty-eight studies evaluated 1,497 patients undergoing SR for BCLM with median age 49.3 years. Mean follow-up time ranged from 12-60 months with a mean of 35.6 months. Twenty-five studies reported on the presence or absence of EHD in 901 patients undergoing SR, with 17.2% of patients with demonstrated evidence of EHD. Weighted-averages for median length of OS and DFS were 43.2 and 22.8 months, respectively, among the SR group. Local recurrence was 51.4%, while CR and MR were 17.7% and 0.37%, respectively. OSR at 1, 2, 3 and 5 years were 86.8%, 70.6%, 58.3% and 36.8%, respectively. Among SR patients, the weighted-average for length of OS among patients with EHD was 43.2 months compared to 37.6 months among patients without EHD (p=0.68). 

For studies evaluating patients undergoing surgical resection through the 1990s, 2000s and 2010s, median length of OS and DFS was 47.2, 36.6 and 47.5 years (p=0.104), and 24.0, 24.6 and 14.0 years (p=0.399), respectively; LR was 53.3%, 52.6%, 53.1% (p=0.959); CR was 14.3%, 13.0% and 15.6% (p=0.370); and MR was 0.3%, 0.17% and 0.0% (p=0.514). OSR for studies ending in the 1990s, 2000s and 2010s was 94.7%, 86.4% and 86.9% at 1 year (p=0.541), 66.7%, 76.0% and 57.0% at 2 years (p=0.362); 54.7%, 59.0%, 74.4% at 3 years (p=0.250); and 31.3%, 37.9% and 42.8%, respectively (p=0.160). 

5.2.  Results of Patients Undergoing Ablative Therapy 

Nineteen studies evaluated 772 patients undergoing AT for BCLM with median age 53.3 years and mean follow-up time 21.7 years (range 10-29.5 months). Fifteen studies reported on the presence or absence of EHD in 648 patients undergoing AT, with 39.5% of patients having evidence of EHD. Weighted-averages for median length of OS and DFS were 40.6 months and 23.4 months among the AT group. Local recurrence was 13.9%, while CR and MR were 8.8% and 0.04%, respectively. OSR at 1, 2, 3 and 5 years were 87.3%, 79.3%, 56.4% and 37.5%.             

For studies evaluating patients undergoing ablative therapy through the 2000s versus 2010s, median length of OS and DFS was 41.9 versus 27.5 months (p=0.233) and 14.2versus 27.5 months (p=0.142), respectively; LR was 16.1% versus 20.8% (p=0.618); CR was 3.87% versus 37.0% (p=0.332); and MR was 0.26% versus 0.0% (p=0.230), respectively. OSR for studies ending in the 2000s versus 2010s was 74.3% versus 82.5% at 1 year (p=0.581); 79.3% versus 63.0% at 2 years (p=0.294); 56.8% versus 46.0% at 3 years (p=0.159), and 34.0% versus 29.0% at 5 years (p=546), respectively.

4.      Discussion

Metastatic BC treatment is usuallypalliative with the goal to improve quality of life and prolong survival. Between 60-95% of BCLM patients have disease progression while on systemic therapy with multiple chemotherapeutic agents[18].Metastatic BC treatment has historically involved5-fluorouracil or anthracycline-based regimens as first-line or adjuvant chemotherapy [19]. Other agents such as taxanes and vinorelbine have been added with significant benefit. Currently taxanes and anthracyclines are used by many as first-line treatment, with response rates up to 40% when used alone and up to 80% when used in combination regimens in selected patient populations[20-22].

A phase III multicenter European Organization for Research and Treatment of Cancer (EORTC) trial previously examined the efficacy of paclitaxel vs doxorubicin, as well as doxorubicin/paclitaxel vs doxorubicin/cyclophosphamide as first-line chemotherapy regimens for management of patients with metastatic BC. The median OS for BCLM patients without EHD ranged from 22.7-27.1 months, while the median OS for BCLM patients with EHD ranged from 14.2-16.8 months from these trials.[18] Another recent study evaluating patients with advanced HER2/neu-negative BCundergoing systemic chemotherapy still found a relatively low median OS of 20 months for BCLM patients[23].

Similarly, the CLEOPATRA trial evaluatedpertuzumab/trastuzumab/docetaxel compared to placebo/trastuzumab/docetaxel in patients with HER2-positive metastatic BC[24].Median progression-free survival was 12.4 months in the placebo group and 18.7 months in the pertuzumab group [24].More recently, the PALOMA-3 trial looking at palbociclib/fulvestran found a significant and consistent improvement in progression-free survival compared with fulvestrant/placebo. The reported median progression-free survival was 9.5 months in the fulvestrant/palbociclib group versus 4.6 months in the fulvestrant/placebo group (p<0·0001)[25].Although occasional high response rates with such chemotherapy regimens have been reported, the duration of response demonstrated in the aforementioned studies has been consistently short-lived, and prognosis remains poor. The outcome for non-responders with BCLM is considered much worse. Previous studies have reported an OS of non-responders as low as three months with no patients surviving longer than eighteen months[26].

Given that BC is the most common malignancy affecting women worldwide and liver metastases develop in up to half of all women with metastatic BC, patients may benefit clinically from a more aggressive multimodality treatment approach. Our review aims to specifically examine the current literature on outcomes data for surgical and ablative management of BCLM.

Among all studies, we found relatively high rates of DFS and OS, including high OSR at 1, 2, 3 and 5 years for both SR and AT. The median OS of 43.2 months and 40.6 months found among patients undergoing SR and AT, respectively, in our systematic review is nearly twice, or more than twice, that of patients going systematic therapy alone in the aforementioned trials. Among 5 studies in the SR group that reported a mean OS greater thanor equal to 5 years, the majority of breast cancer patients had invasive ductal carcinoma, solitary metastasis, size of primary tumor less than or equal to 5 cm, size of the largest metastasis less than 5 cm, time to liver metastases greater than 12 months, and negative liver resection margins. In the one study in the AT group that reported mean OS greater than or equal to 5 years, the majority of patients had invasive ductal carcinoma, size of liver metastases less than 4cm, and time to liver metastases greater than 12 months. In studies with mean OSgreater than or equal to 5 years in both the SR and AT groups, the majority of patients had undergone systemic adjuvant chemotherapy.

Similar to OS, the median DFS, 22.8 and 23.4 months, among patients in our systematic review undergoing SR and AT, respectively, are longer than the progression-free survival times found in the aforementioned studies. Of note, the mean time to the development of liver metastasis among patients undergoing SR was 42.2 months,while mean time to the development of liver metastasis among patients undergoing ATwas 48.5 months. Therefore, we demonstrate SR and AT offer BCLM patients the opportunity for alternative therapies that prolong survival and improve their prognosis longer than available chemotherapy regimens currently offer them.

Complication rates in our systematic review are also lower than in previously reported studies of patients undergoing systemic chemotherapy.In the CLEOPATRA trial, complications were reported in 29% who received placebo versus 36% in the pertuzumab group [24]. The PALOMA-3 trial reported a 73% adverse event rate in the palbociclib/fulvestrant group [25]. In comparison, we report a lower CR of 17.7% and 8.8% for patients undergoing SR and AT, respectively. Complication rates such as bile leak/injury, pleural effusion and bleeding were among the most commonly reported. The mortality rate was also low in both treatment groups. The results of our study suggest that hepatectomy and/or ablation are beneficial and safe in patients with BCLM either alone or as adjuncts to systemic therapy, leading to improved oncologic outcomes, as compared to those who undergo systemic treatments alone.

Our systematic reviewdemonstrates lower LR rates for AT compared to SR. The implications of this difference remain unclear, although it may be attributable to thesignificant number of SR patients in the included studies that did not achieve R0 on resection. However, OSR for SR and AT were ultimately comparable. Regardless, both treatment modalities demonstrated relatively low morbidity and mortality thus encouraging the utility of SR and AT treatment options for BCLM.

Despite advances in management of breast cancer in the last 5 to 10 years, our study did not show a statistically significant difference in any of the measures of oncologic safety studied (OS, DFS, LR, CR, MR) between studies examining patients through the 1990s versus 2000s versus 2010s for the SR or AT groups. This finding could be due to the fact that many of the studies recruited and collectively reported on patients over a 10 to 20-year time period spanning multiple decades from the 1980s to 2010s, and thus we do not have an effective means to compare measures of oncologic safety among patients treated by older versus more recent techniques in this systematic review.

With regard to SR specifically, although some studies included cases without EHD, a significant proportion of the reviewed studies included cases with EHD. The presence of EHD complicates the decision process for whether surgical resection for curative intent is the most appropriate management for BCLM. In the past, the presence of multiple lesions may have been considered a limiting factor to SR. However, many studies selected for our systematic review included patients with multiple lesions, and many required major hepatectomy with resection of greater than three segments. Our analysis, however, did not show a statistically significant difference for OS between those undergoing SR with and without EHD. As a result, the presence of EHD should not be a limiting factor preventing patients from undergoing SR. In addition, the median age of patients undergoing SR in our review was 49.3 years, demonstrating the fairly young age of the studied population in which aggressive surgical treatment for curative purposes should most certainly be offered.

Few studies specified the appropriate candidates for surgical resection and ablative therapy. Among studies that commented on patient selection criteria, appropriate SR candidates were described as patients with good performance status, patients in whom feasibly complete and safe resection of liver tumour could be achieved with most patients. Tumour size was not mentioned as a specific criterion and most studies did not report it. Among studies that did comment on tumour size, the mean size ranged from 1-4cm. Patients who underwent AT were those deemed surgically unresectable either technically or due to impaired patient tolerance for major liver surgery. The mean tumor size for the AT group was not much larger than those in the SR group with a range from 1-4.9cm. AT procedures were performed usually using expandable electrodes that were placed under CT-fluoroscopy guidance, although other methodologies have also been described and are not uniformly performed [27].

There werefew studies that examined the prognostic factors for longer survival for those undergoing surgical and ablative management of breast cancer liver metastases. These factors included the following: hormone-receptor positivity (i.e. estrogen receptor and/or progesterone receptor), complete oncologic resection, longer disease-free interval, solitary liver metastasis, no tumor recurrence, tumor size < 3 cm, negative axillary lymph node status and a period to metastases development ≥ 24 months and the use of adjuvant chemotherapy and/or radiation. While these factors were individually reported to be associated with longer survival in each study, there was no consensus amongst these few studies on these factors except for two variables: estrogen receptor positivebreast cancers and solitary liver metastasis were uniformly reported to be the prognostic factors for longer survival for patients undergoing surgical and/or ablative management of breast cancer liver metastases.

Our study hassome limitations. Many studies had missing data with respect to tumor characteristics and use of adjuvant therapy that may impact the reported oncologic outcomes. The use of observational data also introduces confounding factors, including patient demographics, genetic predisposition, tumor size, specimen weight, nodal status, hormonal status, and neoadjuvant and/or adjuvant therapy, that may bias oncologic outcomes in certain studies, but cannot be accounted for in a systematic review. Finally, the methodology utilized in a systematic review includes many retrospective studies. As a result, our systematic review isnot adequate to determine causality. Large randomized controlled trials are necessary to further evaluate the oncologic safety of SR and AT for patients with BCLM versus standard systemic therapy alone.

Despite the limitations described above, our study has specific strengths. Through a rigorous and transparent literature review, we have identified, synthesized and assessed all available evidence to demonstrate the oncologic safety of SR and AT for breast cancer liver metastasis. As a result, our study is the largest comprehensive literature review on the surgical and ablative management of BCLM to date. The large representative sample of 2,269 patients in 67 studies enhances our study’s external validity. Our results are likely generalizable to women with breast cancer with isolated liver metastasis highlighting the importance of careful patient selection.

5.      Conclusion

Historically, patients with BCLM undergoing systemic therapy have had a poor prognosis with fairly short survival times. Surgical and ablative therapies for BCLM provide alternative modalities to improve prognosis, as demonstrated by the relatively favorable overall and disease-free survival with low morbidity and mortality among the SR and AT groups in our study. The integration of localized surgical and ablative therapies with previously established options for management of BCLM, namely systemic chemotherapy, promises encouraging results in terms of overall and disease-free survival. While a clinical trial would provide a higher level of evidence for support of SR and AT for localized management of BCLM, a clinical trial may not be feasible and surgery and ablative therapy should still be highly considered for select patients with BCLM.

6.      Disclosures: No external funding was secured for this study. The authors have no financial relationships or conflicts of interest relevant to this article to disclose.

7.      Contributor’s Statement:LC conceptualized and designed the project. LC and KYF performed the systematic literature review and data acquisition. SB performed data analysis and interpretation. KYF, SB and RM drafted the initial manuscript. CF, NN, JT, BC and LC assisted in critical revision of the manuscript. All authors reviewed, revised and approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

8.      Synopsis:A systematic literature review reveals both surgical and ablative management of breast cancer liver metastasis yield favorable overall and disease-free survival with low morbidity and mortality.

Figure 1:Flow Chart of the Literature.

Table 1a: Study Characteristics-Surgical Resection.

Table 1b:Study Characteristics (Continued)-Surgical Resection.

Table 2:Study Characteristics-Ablative Therapy.

Data were extracted from the 67 studies that collectively evaluated 2,269 patients with median age 49.6 years (range 45.2-62.5). Follow-up time ranged from 10-62 months with a mean of 32.5 months. Most common tumor histology was invasive ductal carcinoma (74.5%). Extrahepatic disease was present in 32.0% of patients overall. Table 3a and 3b describe the primary outcomes of interest among the SR group, while Table 4 describes the primary outcomes of interest among the AT group.

Table 3a:Oncologic Outcomes-Surgical Resection.

Table 3b:Oncologic Outcomes (Continued)-Surgical Resection.

Table 4:Oncologic Outcomes-Ablative Therapy.

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