Abstract
Introduction
The current gold standard treatment for breast cancer liver metastases (BCLM) is systemic chemotherapy and/or hormonal therapy. Nonetheless, greater consideration has been given to local therapeutic strategies in recent years. We sought to compare survival outcomes for available systemic and local treatments for BCLM, specifically surgical resection and radiofrequency ablation.
Methods
A review of the PubMed (MEDLINE), Embase and Cochrane Library databases was conducted. Data from included studies were extracted and subjected to time-to-event data synthesis, algorithmically reconstructing individual patient-level data from published Kaplan–Meier survival curves.
Findings
A total of 54 studies were included, comprising data for 5,430 patients (surgery, n=2,063; ablation, n=305; chemotherapy, n=3,062). Analysis of the reconstructed data demonstrated survival rates at 1, 3 and 5 years of 90%, 65.9% and 53%, respectively, for the surgical group, 83%, 49% and 35% for the ablation group and 53%, 24% and 14% for the chemotherapy group (p<0.0001).
Conclusion
Local therapeutic interventions such as liver resection and radiofrequency ablation are effective treatments for BCLM, particularly in patients with metastatic disease localised to the liver. Although the data from this review support surgical resection for BCLM, further prospective studies for managing oligometastatic breast cancer disease are required.
Keywords: Breast cancer, Liver metastases, Hepatic resection, Radiofrequency ablation, Systemic therapy
Introduction
Breast cancer is the most commonly diagnosed cancer in women, with 1.67 million cases and 522,000 deaths estimated in 2012.1 Approximately 25–40% of these cases will eventually develop metastases; the majority of metastases will be multi-site, and include the liver.2 Approximately 5% of patients with metastatic disease will present exclusively with breast cancer liver metastases (BCLM).3 A pathophysiological mechanism of liver metastases has been proposed by Ma et al,4 including consecutive steps as follows: intravasation, circulation, margination, extravasation and colonisation.
Patients with BCLM have reported a median survival of 3–6 months from the diagnosis of metastases if left untreated.5 The current gold standard treatment for BCLM with or without extrahepatic disease is systemic chemotherapy and/or hormonal therapy, depending on tumour hormone receptor status, and is associated with a median survival time ranging from 19 to 26 months.3
In colorectal cancer, local treatment in the form of liver resection, combined with systematic chemotherapy, has produced significant improvement in overall survival (OS) for patients with colorectal cancer liver metastases and is now recognised as the standard of treatment for this cohort of patients.6 Local therapeutic strategies for liver tumours have been available for years, such as liver resection, microwave/radiofrequency ablation, transarterial chemoembolisation, selective internal radiation therapy, stereotactic body radiation therapy and irreversible electroporation. These locoregional therapies have gained increasing consideration in the treatment of BCLM in recent years and many studies conducted in highly selected patients have been published on the matter. Nevertheless, there are no prospective randomised controlled trials comparing all the available local therapies for BCLM7 and, as such, high-level data are scarce.
We sought to compare the outcomes in terms of survival of the available systemic and local treatments for metastatic breast cancer to the liver, reviewing the available literature and pooling the data extracted from each single series. We investigated local resection, radiofrequency ablation and a systemic therapy approach (including chemotherapy and hormonal therapy).
Methods
This review followed PRISM guidelines (Figure 1).8
Figure 1 .
Flow chart of study selection
Research strategy
A systematic literature research was conducted in the PubMed (MEDLINE), Embase and the Cochrane Library databases by two independent researchers (KR and LL). The following search terms were used: (1) breast cancer AND (liver metastasis OR liver metastases) AND (liver resection OR hepatectomy OR partial hepatectomy OR surgical treatment); (2) breast cancer AND (liver metastasis OR liver metastases) AND (microwave frequency ablation OR radiofrequency ablation OR ablation OR locoregional therapy); (3) ((chemotherapy[Title/Abstract] OR hormonal[Title/Abstract]) AND breast cancer[Title/Abstract]) AND ((liver metastasis[Title/Abstract]) OR liver metastases[Title/Abstract]). We also extended the research to the list found on each reviewed paper with inclusion of any relevant studies. Suitable studies published up to 7 July 2020 were included.
Inclusion/exclusion criteria
All articles with published survival (Kaplan–Meier) curves for survival following surgical, chemotherapy/hormonal or radiofrequency ablation treatment for BCLM were included. When studies from the same institution presented accumulating data published multiple times, we selected the most recent and complete reports. To extract patient-level data, studies reporting patient-level data or including Kaplan–Meier curves for survival were included. Abstracts without published manuscripts, case reports, editorials and expert opinions were excluded, as were non-English language articles and studies with fewer than ten patients. When studies compared locoregional treatments for liver metastases from different types of tumour we selected the specific Kaplan–Meier curve for survival for BCLM.
The research and the data extraction were conducted by two independent investigators (KR and LL), data were reviewed and discrepancies were resolved by discussion and consensus.
The outcome of interest of this review was long-term survival at 1, 3 and 5 years. When more than one Kaplan–Meier curve for survival was reported in the study, eg comparing two different chemotherapeutic treatments, we considered the curves individually and we extracted data from both.
Data extraction and statistical analysis
Our review strategy was a time-to-event data synthesis, based on the method described by Guyot et al9 to reconstruct individual patient data from published Kaplan–Meier survival curves, using a newly developed algorithm that assumes constant censoring. We digitised the Kaplan–Meier curves data using the software Plot Digitiser v.2.6.8.0 and we entered the numbers obtained into the algorithm, using R statistical software. We then aggregated the reconstructed individual patient survival data to create a combined survival curve, comparing the long-term outcomes of the three therapeutic strategies analysed, using Stata (v.16; StataCorp).
Statistical analysis of the data is presented in supplementary Tables S1–S3 (including age, median follow-up) and in Tables 1–6 (including presence of single metastases, synchronous metastases, hormone receptors, extrahepatic disease, R0 resection for the surgical group and complete ablation for the ablation group, additional treatment of primary tumour and neoadjuvant treatment in the surgical group). The statistical analysis was conducted only on the studies in which the data were available, therefore the mean values and percentages presented refer only to the studies in which the data were included.
Table 1 .
Breast cancer liver metastases status for surgical group
| Study | Total no. of patients | Single metastases (%) | Synchronous metastases (%) | Mean age at hepatectomy ± sd | Resection margins | Receptor status | Extrahepatic disease (%) | |||
|---|---|---|---|---|---|---|---|---|---|---|
| R0 | R1/2 | ER+ | PR+ | HER+ | ||||||
| Chun10 | 136 | – | 56 (41) | – | – | – | 88 (65) | 51 (38) | 47 (36) | 31 (23) |
| Feng11 | 65 | 42 (65) | – | 51±11 | 62 (95) | 3 (5) | – | – | 32 (49) | 50 (77) |
| He12 | 67 | 43 (64) | 1 (1) | 51±11 | 64 (96) | 3 (4) | – | – | 14 (21) | 14 (21) |
| Lucidi13 | 72 | 33 (46) | 21 (29) | – | – | – | 57(79) | 45(63) | 32(40) | 21 (29) |
| Sundén14 | 29 | 19 (66) | – | 54 | 17 (59) | 6 (21) | 13 (59) | 9 (45) | 9 (45) | – |
| Cheung15 | 21 | – | – | 45 | 21 (100) | – | 11 (52) | 8 (38) | 5 (24) | – |
| Bacalbasa16 | 67 | 33 (49) | 54 (81) | – | 62 (93) | 5 (7) | 31(46) | 30(45) | 1(1) | – |
| Labgaa17 | 59 | 31 (62) | 6 (11) | 58 | 36 (71) | 15 (30) | – | – | – | 24 (41) |
| Ruiz18 | 139 | – | 11 (8) | – | 77 (55) | 51 (37) | 74 (53) | 40 (29) | 35(25) | 67 (48) |
| Ruiz19 | 139 | 56 (41) | – | 49±11 | – | – | 55 (82) | 41 (65) | 17 (34) | – |
| Abbas20 | 23 | 15 (65) | 8 (35) | 54 | 16 (73) | – | 17 (94) | 9 (50) | 5 (28) | 4 (17) |
| Ruiz21 | 139 | 56 (40) | 11 (8) | 51±11 | 77 (55) | 51 (37) | 74 (53) | 39 (28) | 35 (25) | 41 (29) |
| Margonis22 | 131 | – | – | 54±14 | 108 (90) | 11 (10) | 66 (73) | 53 (59) | 54 (54) | 15 (13) |
| Sadot23 | 69 | 44 (64) | 7 (10) | 51±11 | 43 (84) | – | 42 (78) | 32 (59) | 29 (45) | – |
| Bacalbasa24 | 43 | 24 (56) | 4 (9) | 53±11 | 39 (91) | 4 (91) | 22 (82) | 22 (82) | 27 (62) | – |
| Sabol25 | 15 | 9 (60) | 1 (6) | 49±9 | 15 (100) | 0 (0) | 8 (53) | 6 (40) | 4 (26) | 3 (20) |
| Kim26 | 13 | 7 (54) | 2 (15) | 51±9 | – | – | 7 (54) | 7 (54) | 5 (38) | 6 (46) |
| Mariani27 | 100 | 65 (65) | 7 (7) | 50±7 | 82 (82) | 18 (18) | – | – | 12 (12) | 22 (22) |
| Kostov28 | 42 | 22 (52) | – | – | 35 (83) | 7 (17) | 19 (45) | 4 (9) | 9 (21) | 20 (47) |
| Dittmar29 | 34 | 12 (35) | 6 (17) | – | 21 (61) | 13 (39) | – | – | 22 (64) | 12 (35) |
| Polistina30 | 12 | 12 (100) | – | 60±10 | 11 (91) | 1 (9) | 9 (75) | 5 (41) | – | – |
| van Walsum31 | 32 | 22 (68) | 6 (18) | 50±6 | 29 (90) | 3 (10) | 20 (62) | – | 8 (25) | 28 (87) |
| Groeschl32 | 115 | – | 24 (20) | – | 92 (80) | 23 (20) | – | – | – | – |
| Abbott33 | 86 | 53 (62) | 25 (29) | – | 77 (90) | 9 (10) | 59 (69) | 59 (69) | 32 (37) | 24 (27) |
| Duan34 | 16 | – | – | – | – | – | – | – | – | – |
| Rubino35 | 18 | 10 (55) | 1 (5) | 46±7 | 18 (100) | 0 (0) | 12 (66) | 12 (66) | 4 (22) | 0 (0) |
| Hoffmann36 | 41 | 20 (49) | 4 (10) | – | 32 (78) | 9 (22) | 18 (44) | 14 (34) | 11 (26) | 12 (30) |
| Caralt37 | 12 | – | 2 (16) | 57±11 | 9 (75) | 3 (25) | 9 (75) | 9 (75) | – | 1 (8) |
| Lubrano38 | 16 | 12 (75) | 0 (0) | 53±7 | 16 (100) | 0 (0) | 10 (83) | 8 (66) | – | 0 (0) |
| Thelen39 | 39 | 20 (51) | 6 (15) | – | 28 (72) | 11 (28) | 26 (66) | 19 (48) | 14 (35) | 13 (33) |
| Adam40 | 85 | 32 (37) | 9 (11) | 47±8 | 56 (66) | 29 (34) | 44 (51) | 21 (24) | 24 (28) | 27 (31) |
| Sakamoto41 | 34 | 19 (56) | 4 (11) | 51±8 | – | – | 17 (50) | – | – | 9 (26) |
| Vlastos42 | 31 | 20 (64) | 9 (29) | 46±7 | – | – | 18 (53) | 11 (35) | – | 0 (0) |
| Elias43 | 54 | – | 12 (22) | 49±5 | 44 (81) | 10 (19) | 32 (59) | 32 (59) | – | 0 (0) |
| Selzner44 | 17 | 12 (71) | – | 49±12 | 17 (100) | 0 (0) | 3 (17) | – | – | 3 (17) |
| Pocard45 | 52 | 36 (69) | – | 47±9 | 51 (98) | 1 (2) | 19 (67) | – | – | 11 (23) |
Table 6 .
Breast cancer liver metastases additional treatments for chemotherapy group
| Study | Total no. of patients | Adjuvant chemotherapy for breast primary (%) | Adjuvant hormonal therapy for breast primary (%) | Adjuvant targeted therapy for breast primary (%) | Adjuvant radiotherapy for breast primary (%) |
|---|---|---|---|---|---|
| Chun10 | 763 | – | – | – | – |
| Lu54 | 54 | – | – | – | – |
| Sundén14 | 33 | – | – | – | – |
| Aarts55 | 176 | – | – | – | – |
| Ruiz19 | 523 | 281 (54) | 248 (48) | 46 (9) | – |
| Abbas20 | 27 | 14 (61) | 17 (74) | 4 (17) | – |
| Sadot23 | 98 | 39 (60) | 43 (61) | 30 (31) | 37 (53) |
| Er56 | 132 | 34 (26) | 35 (27) | – | 59 (45) |
| Pentheroudakis57 | 500 | 265 (53) | – | – | – |
| Eichbaum58 | 301 | – | – | – | – |
| Li59 | 20 | 20 (100) | – | – | 9 (45) |
| Nabholtz60 | 392 | 74 (19) | 74 (19) | – | – |
| Hoe61 | 44 | – | – | – | – |
BCLM = breast cancer liver metastases
Findings
Included studies
A total of 2,403 papers were identified using this research strategy and 387 abstracts were evaluated. Of these, 241 relevant full-text articles were identified and assessed. After applying all the remaining inclusion and exclusion criteria, 54 papers were selected for final data synthesis (Figure 1). Thirty-six papers were categorised into surgical treatment, 10 papers ablation and 13 chemotherapy/hormonal therapies. Among these papers, one study compared surgical treatment, chemotherapy and ablation therapy and was included in all three categories,20 four studies10,14,19,23 comparing surgical and chemotherapy treatments were included in both categories, as was one study comparing surgical and ablation therapy.30
Surgical group
In the surgical group (n=2,063), the mean (± sd) age of the patients from papers that reported participant age was 50.40±10.40 years. Median follow-up in the included studies was 47.48 months (supplementary Table S1).
Single metastases were presented in 54.13% of the cases and synchronous metastases in 19.30%. Hormone receptors were categorised as: oestrogen receptor (ER; positive in 54.76% of cases), progesterone receptor (PR; positive in 41.17% of cases) and human epidermal growth factor receptor 2 (HER2; positive in 29.60% of cases).
Extrahepatic disease was present in 29.51% of the cases, and a microscopically margin-negative resection (R0 resection) was achieved in 78.10% of cases (Table 1).
Regarding systemic treatment, adjuvant chemotherapy for primary breast cancer was used in 56.30% of the cases, adjuvant hormone therapy in 39.06%, adjuvant targeted therapy in 11.04% and adjuvant radiotherapy in 59.59%. Neoadjuvant chemotherapy for BCLM was used in 67.80% of the cases, neoadjuvant hormone therapy in 53.01% and neoadjuvant targeted therapy in 25.93% (Table 2).
Table 2 .
Breast cancer liver metastases additional treatment for surgical group
| Study | Total no. of patients | Neoadjuvant chemotherapy for BCLM (%) | Neoadjuvant hormonal therapy for BCLM (%) | Neoadjuvant targeted therapy for BCLM (%) | Adjuvant systemic therapy non-specified for breast primary (%) | Adjuvant chemotherapy for breast primary (%) | Adjuvant hormonal therapy for breast primary (%) | Adjuvant targeted therapy for breast primary (%) | Adjuvant radiotherapy for breast primary (%) |
|---|---|---|---|---|---|---|---|---|---|
| Chun10 | 136 | 93 (68) | – | 43 (32) | – | – | – | – | – |
| Feng11 | 65 | – | – | – | – | 54 (88) | 42 (65) | 6 (9) | 40 (62) |
| He12 | 67 | – | – | – | – | – | – | – | – |
| Lucidi13 | 72 | 60 (83) | 63 (88) | 24 (33) | – | – | – | – | – |
| Sundén14 | 29 | – | – | – | 29 (100) | – | – | – | – |
| Cheung15 | 21 | – | – | – | – | – | – | – | – |
| Bacalbasa16 | 67 | – | – | – | – | – | – | – | – |
| Labgaa17 | 59 | – | – | – | – | – | – | – | – |
| Ruiz18 | 139 | 98 (71) | – | – | – | 58 (42) | 47 (34) | – | 94 (68) |
| Ruiz19 | 139 | – | – | – | – | 81 (58) | 47 (34) | 9 (7) | – |
| Abbas20 | 23 | – | – | – | – | 11 (48) | 16 (73) | 6 (27) | – |
| Ruiz21 | 139 | – | – | – | – | 81 (58) | 47 (34) | 9 (6) | 72 (52) |
| Margonis22 | 131 | 39 (75) | 51 (49) | 35 (40) | – | 41 (51) | 43 (47) | 21 (27) | – |
| Sadot23 | 69 | – | – | – | – | 52 (81) | 31 (51) | 11 (16) | 44 (68) |
| Bacalbasa24 | 43 | – | – | – | – | 41 (96) | – | – | – |
| Sabol25 | 15 | 5 (26) | – | – | 15 (100) | – | – | – | – |
| Kim26 | 13 | 2 (15) | – | – | 13 (100) | – | – | – | – |
| Mariani27 | 100 | 79 (79) | 91 (91) | – | – | – | – | – | – |
| Kostov28 | 42 | 42 (100) | 23 (54) | 9 (21) | – | – | – | – | – |
| Dittmar29 | 34 | 19 (38) | – | – | – | – | – | – | – |
| Polistina30 | 12 | 11 (91) | 10 (8) | 9 (75) | – | – | – | – | – |
| van Walsum31 | 32 | 13 (40) | 5 (15) | 2 (6) | – | 19 (59) | 17 (53) | 4 (12) | 22 (68) |
| Groeschl32 | 115 | 100 (86) | – | – | – | – | – | – | – |
| Abbott33 | 86 | 65 (76) | – | 24 (75) | – | – | – | – | – |
| Duan34 | 16 | – | – | – | – | – | – | – | – |
| Rubino35 | 18 | 4 (22) | – | – | – | – | – | – | – |
| Hoffmann36 | 41 | 14 (34) | 2 (4) | – | – | 24 (58) | 12 (29) | – | 17 (41) |
| Caralt37 | 12 | 6 (50) | – | – | 12 (100) | – | – | – | – |
| Lubrano38 | 16 | 16 (100) | 12 (75) | – | – | – | – | – | – |
| Thelen39 | 39 | – | – | – | 39 (100) | – | – | – | – |
| Adam40 | 85 | 71 (83) | – | – | – | – | – | – | – |
| Sakamoto41 | 34 | – | – | – | – | – | – | – | – |
| Vlastos42 | 31 | – | – | – | – | 25 (81) | 14 (52) | – | – |
| Elias43 | 54 | 52 (96) | – | – | – | – | – | – | – |
| Selzner44 | 17 | 10 (59) | – | – | – | – | – | – | – |
| Pocard45 | 52 | 29 (56) | 7 (19) | – | – | – | – | – | – |
BCLM = breast cancer liver metastases
Ablation group
In total 305 cases were included. The mean (± sd) age of the patients from the papers that reported participant age 51.60±10.01 years. Median follow-up in the included studies was 27.71 months (supplementary Table S2)
Single metastases were found in 54.91% of the cases and synchronous metastases in 20.66%. A complete ablation was accomplished in the 93.90% of the metastases. They were found to be ER-positive in 52.82% of cases, PR-positive in 43.08% and HER-positive in 28.32%. Extrahepatic disease was found in 49.44% of cases (Table 3).
Table 3 .
Breast cancer liver metastases status for ablation group
| Study | Total no. of patients | Single metastases (%) | Synchronous metastases (%) | Mean age at hepatectomy ± sd | Total no. of metastases | Complete ablation (on total no. of metastases) | Incomplete ablation (on total no. of metastases) | Receptor status (%) | Extrahepatic disease (%) | ||
|---|---|---|---|---|---|---|---|---|---|---|---|
| ER + | PR + | HER + | |||||||||
| Bai46 | 69 | 35 (51) | 3 (4) | 50.3±10 | 135 | 125 (93) | 10 (7) | 43(62) | 37 (54) | 22 (32) | 32 (46) |
| Onal47 | 22 | 19 (86) | 3 (14) | – | 29 | – | – | 17 (77) | 13 (59) | – | 15 (48) |
| Abbas20 | 11 | 5 (45) | 3 (27) | 54 | – | – | – | 5 (63) | 2 (25) | 1 (14) | 4 (36) |
| Veltri48 | 45 | 27 (60) | 6 (13) | 45±8 | 87 | 78 (90) | 9 (10) | – | – | – | 18 (40) |
| Taşçi49 | 24 | – | – | 50±2 | 57 | – | – | 6 (25) | 4 (16) | 6 (25) | – |
| Polistina30 | 14 | 1 (7) | – | 56±13 | 54 | 51 (94) | 3 (6) | 11 (78) | 8 (57) | 3 (21) | – |
| Carrafiello50 | 13 | 8 (61) | – | 54±13 | 21 | 21 (100) | 0 (0) | – | – | – | 8 (61) |
| Meloni51 | 52 | – | 8 (15) | 55±14 | 87 | 83 (95) | 4 (5) | – | – | – | 27 (52) |
| Jakobs52 | 43 | – | 27 (32) | 57±8 | 111 | 107 (96) | 4 (4) | 18 (42) | 18 (42) | 11 (25) | 18 (42) |
| Sofocleous53 | 12 | – | – | 55±7 | 14 | 13 (92) | 1 (8) | 3 (25) | 2 (16) | 6 (50) | 10 (83) |
Neoadjuvant chemotherapy for BCLM was used in 77.56% of cases and hormonal therapy in 32.67% (Table 4).
Table 4 .
Breast cancer liver metastases additional treatment for ablation group
| Study | Total no. of patients | Neoadjuvant chemotherapy for BCLM (%) | Neoadjuvant hormonal therapy for BCLM (%) | Neoadjuvant targeted therapy for BCLM (%) | Adjuvant chemotherapy for breast primary (%) | Adjuvant hormonal therapy for breast primary (%) | Adjuvant targeted therapy for breast primary (%) | Adjuvant radiotherapy for breast primary (%) |
|---|---|---|---|---|---|---|---|---|
| Bai46 | 69 | – | – | – | – | – | – | – |
| Onal47 | 22 | 19 (86) | 3 (14) | – | – | – | – | – |
| Abbas20 | 11 | – | – | – | 5 (45) | 5 (45) | 1 (9) | – |
| Veltri48 | 45 | – | – | – | – | – | – | – |
| Taşçi49 | 24 | – | – | – | – | – | – | – |
| Polistina30 | 14 | 14 (100) | 13 (92) | – | 9 (64) | 11 (78) | – | 11 (78) |
| Carrafiello50 | 13 | 7 (53) | 7 (53) | – | – | – | – | – |
| Meloni51 | 52 | 40 (77) | 10 (19) | – | – | – | – | – |
| Jakobs52 | 43 | 39 (90) | – | 11 (25) | – | 19 (44) | – | – |
| Sofocleous53 | 12 | 2 (16) | – | – | – | – | – | – |
BCLM = breast cancer liver metastases
Chemotherapy group
In total, 3,062 patients were in this group. Mean age (± sd) from the papers that reported participant age was 51.43±10.20 years. Median follow-up in the included studies was 41.28 months (supplementary Table S3).
Single metastases were found in 12.87% of cases. Hormone receptor status was as follows: ER-positive in 56.90% of cases, PR-positive in 47.45% and HER-positive in 27.57%. Extrahepatic disease was present in 74.03% of the cases (Table 5).
Table 5 .
BCLM status for chemotherapy group
| Study | Total no. of patients | Single metastases (%) | Synchronous metastases (%) | Mean age at hepatectomy ± sd | Receptor status | Extrahepatic disease (%) | ||
|---|---|---|---|---|---|---|---|---|
| ER+ | PR+ | HER+ | ||||||
| Chun10 | 763 | – | 248 (33) | – | 454 (60) | 341 (45) | 242 (32) | – |
| Lu54 | 54 | – | – | – | 115 (62) | 106 (57) | 44 (24) | – |
| Sundén14 | 33 | 23 (70) | – | 54 | 13 (59) | 9 (45) | 9 (45) | – |
| Aarts55 | 176 | – | 32 (18) | – | 135 (80) | 111 (66) | 29 (19) | 129 (73) |
| Ruiz19 | 523 | 13 (13.8) | – | 49±11 | 182 (63) | 122 (43) | 97 (35) | – |
| Abbas20 | 27 | 3 (11) | 4 (15) | 54 | 12 (80) | 4 (27) | 5 (33) | 17 (63) |
| Sadot23 | 98 | 29 (30) | 28 (29) | 47±3 | 55 (59) | 46 (50) | 28 (34) | – |
| Er56 | 132 | – | 13 (10) | 54±8 | 39 (29) | 23 (17) | – | – |
| Pentheroudakis57 | 500 | – | – | 54±9 | 270 (54) | 270 (54) | – | 385 (77) |
| Eichbaum58 | 301 | 56 (16) | – | 50±11 | 204 (68) | 207 (69) | – | 199 (57) |
| Li59 | 20 | 5 (25) | – | 55±12 | – | – | – | – |
| Nabholtz60 | 392 | – | – | – | – | – | – | 305 (78) |
| Hoe61 | 44 | – | – | 58±10 | 14 (70) | 6 (30) | – | 11 (25) |
BCLM = breast cancer liver metastases
Adjuvant chemotherapy was used for primary breast cancer in 42.97% of the cases, hormonal therapy in 35.58% and radiotherapy in 42.00% (Table 6).
Survival outcome
Individual patient survival data were reconstructed using the algorithm published by Guyot et al9 for a total of 2,063 patients in the surgical group, 305 in the ablation group and 3,062 in the chemotherapy group.
In the overall population, pooled data showed a significant improvement in survival with surgery compared with systemic chemotherapy (risk ratio (RR) 0.82; 95% confidence interval (CI) 0.72 to 0.94; p<0.001) (Figure 3). Analysis of the reconstructed data demonstrated survival rates at 1, 3 and 5 years of 90% (95% CI 89.2–92), 65.9% (95% CI 63–67) and 53% (95% CI 51–56), respectively, for the surgical group. This is significantly higher than survival rates for the ablation group of 83% (95% CI 78–87), 49% (95% CI 43–55) and 35% (95% CI 29–41) (p<0.003, log rank test) and higher than for the systemic therapy group which had survival rates of 53% (95% CI 50–55.1), 24% (95% CI 22–26) and 14% (95% CI 12.5–16) (p<0.001, log rank test) (Figures 2 and 3). Overall comparison p<0.001, log rank test.
Figure 3 .
Forest plot comparing outcomes for surgery and chemotherapy in breast cancer liver metastases
Figure 2 .
Combined Kaplan–Meier curve for overall survival at 72 months, comparing surgical, ablation and chemotherapy groups
Restricted mean survival was 51 months (95% CI 48–53) for the surgery group, 36 months for the ablation group (95% CI 29.3–42.1) and 14.3 months for the chemotherapy group (95% CI 13.5–15.5). The risk of publication bias was visually assessed as low (supplementary Figure S1), with no significant bias risk as measured by Egger’s test (p>0.05).
Discussion
Distant metastatic disease affects 25–40% of patients diagnosed with breast cancer, and 15% of them develop liver metastases with or without other sites.2 Whereas patients with metastatic breast cancer were traditionally considered candidates for palliative chemotherapy and/or hormonal therapy only, with very poor survival,62 this meta-analysis suggests that the use of local disease control in the form of surgical resection or tumour ablation may contribute to significantly improved survival outcomes in appropriately selected populations of oligometastatic disease confined to the liver.
The benefits of localised treatment of liver metastases is well established in other populations such as colorectal and neuroendocrine liver metastases. Liver resection is increasingly becoming the standard of care for patients with colorectal liver metastases, reaching 5-year survivals of >40%.63 Retrospective studies have reported a 5-year survival of 60–80% for curative resection of liver metastases from neuroendocrine neoplasms, compared with 30% of patients with unresected metastases.64
Interestingly, since updating our meta-analysis, there continues to be increasing evidence in the literature of satisfactory long-term results after liver resection. Feng et al11 reported a mean OS and 1, 3 and 5-year OS rates of 61.8 months, 92.6%, 54.7% and 54.7%, respectively, for hepatic resection compared with no resection (38.6 months, 79.2%, 45.6% and 21.9%; p<0.007). Lucidi et al also suggest good oncological outcomes with surgical intervention with a median OS of 50 months.13
To date, the role of local therapy in BCLM has been less well accepted, in part due to the presumed pathophysiological mechanism of metastatic spread. Liver involvement in colorectal tumours is thought to occur via the portal circulation, resulting in a majority of patients with metastatic disease that may be limited to the liver. By contrast metastatic involvement of the liver in the setting of breast cancer implies a systemic spread, with reduced survival rates of this population even if undergoing local therapies. As expected, the highest percentage of patients with extrahepatic disease were individuals in the chemotherapy and radiofrequency ablation group, because often patients without isolated liver metastases are offered less-invasive non-surgical treatment. Although little information is included in the radiofrequency ablation studies about the type of extrahepatic disease or how this was treated, it was associated with reduced survival, which may account for some of the differences noted on the OS between groups.13,40 However, radiofrequency ablation can be used successfully in extrahepatic disease as long as stable.45 A worse OS in some of the papers included in the chemotherapy group, when compared with the surgery and radiofrequency ablation groups, may be due to the high percentage of patients included with extrahepatic disease, although other independent baseline predictors may also account for this, such as higher liver tumour burden.49
Local treatments have also been trialled for breast cancer lung metastases; the International Registry of Lung Metastases database reports a median survival of 37 months after complete metastases resection, compared with 25 months after incomplete resection. Advantageous outcomes, considering the reported median survivals are 13 to 25 months after chemotherapy and hormonal therapy of isolated lung metastases in the few cited observational studies.65
In this review, we sought to compare three different strategies available for BCLM. We investigated the surgical approach, ablative approach (radiofrequency and microwave ablation techniques) and systemic therapy approach (including chemotherapy and hormonal therapy). Although other forms of local treatment have also been described, we considered only the most commonly reported modalities for which sufficient data were available.
The primary limitation of our study is the limited quality of data with a lack of comparative data or clear selection criteria for resectability of BCLM. As a result, the included data were highly heterogenous and precluded any adjusted or case-matched analysis. Single metastases were present only in 48% of cases and extrahepatic disease in 25%. As a result, the included data are unable to control for patient or disease factors, and are subject to selection bias with differences between different treatment groups.
In addition, the survival outcomes reported in some retrospective series may reflect patient selection, increasing the possibility of inherent selection bias as opposed to a distinct therapeutic benefit of surgery, which may not have appropriate propensity score matching.10 This may also occur because not all patients will have been eligible candidates for surgical intervention or radiofrequency ablation, thereby introducing further bias.
These results illustrate the potential survival advantage that may be gained by the addition of local tumour control strategies to systemic therapy. Additional effects on survival rates may be ascribed to the advance of chemotherapeutic agents over time. For the purposes of our analysis, treatment with chemotherapy was pooled, regardless of which agents were used, potentially introducing additional heterogeneity.
Another limitation concerns the immunohistochemical profile of tumour subtypes. The hormone receptor profiles of both the primary breast cancer and liver metastases were not analysed in all studies; this may have some bearing on prognostication and stratifying disease management in patients.66,67 This may also affect the outcomes reported due to the introduction, in the past two decades, of her2neu therapy as neoadjuvant treatment for primary disease, due to the wide range of included dates in the inclusion criteria.
In addition, although we have reported receptor status in the subgroups, the lack of consistent data across the studies limits the analysis of any differences in cohorts of receptors, particularly as we know that patients with ER-positive disease and her2neu disease may do well with systemic therapy, where triple-negative outcomes are uniformly worse. However, although studies did report the number of patients receiving neoadjuvant targeted therapy, no sub-analysis is provided to allow for further elucidation on the impact this could have had on OS.
Conclusions
Local therapies such as liver resection and radiofrequency ablation may be considered safe and effective techniques for BCLM treatment in select populations, either in isolation or in conjunction with systemic therapies. Insufficient data are available to directly compare these treatments or clearly define patient selection strategies. Further prospective studies to define the best approach for oligometastatic breast cancer, particularly with reference to BCLM, are required as to date there have been no randomised controlled trials comparing the outcomes between hepatic resection and non-hepatic resection in BCLM patients.
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