Transarterial Embolotherapy Combined with Chemotherapy Versus Immunotherapy for Breast Cancer Liver Metastasis

Abstract

Purpose

Breast cancer liver metastases (BCLMs) are common and associated with poor prognosis despite systemic treatments. This study compared overall survival (OS) and treatment outcomes of transarterial radioembolization (TARE) and transarterial chemoembolization (TACE) for BCLM, including the impact of their combination with immunotherapy or chemotherapy.

Methods

This retrospective cohort study used a large multicenter database, TriNetX, which aggregates anonymized electronic medical records from 68 health care organizations in the United States, and included patients with BCLM who underwent TARE (n = 334) or TACE (n = 84) between January 2016 and July 2024, after progressing despite one, two, or three lines of systemic therapy. TARE or TACE was performed alone or in combination with chemotherapy or immunotherapy. The primary outcome was OS, and secondary outcomes included liver function changes and adverse events. Kaplan–Meier and propensity score-matched analyses were performed.

Results

Median OS was significantly longer after TARE (36 months) than TACE (25 months; p = 0.04). Immunotherapy/TARE showed the longest OS (38 months), followed by immunotherapy/TACE (36 months; p = 0.03), chemotherapy/TARE (33 months; p = 0.05), and chemotherapy/TACE (30 months; p = 0.04). TACE was associated with higher postprocedural liver enzyme elevations and greater rates of adverse events compared with TARE.

Conclusion

In this large retrospective study, TARE was associated with superior survival and better tolerability compared with TACE in BCLM patients. Combination with immunotherapy further improved outcomes, suggesting potential synergy. These findings highlight the need for prospective studies to evaluate the role of TARE and immunotherapy in BCLM treatment.

Keywords

breast cancer liver metastasis - radioembolization - chemoembolization

Introduction

Half of patients with breast cancer develop metastatic disease, with two-thirds of these cases involving the liver. Breast cancer liver metastasis (BCLM) is associated with particularly poor outcomes and is the likely cause of death in at least 20% of breast cancer–related deaths.[1] There is an urgent need to develop better strategies to address BCLM. Liver-directed locoregional therapies may be options for patients either in combination with systemic therapies or when systemic treatments are infeasible. Hepatic embolotherapies, including transarterial radioembolization (TARE) with radioactive microspheres and transarterial chemoembolization (TACE) with chemotherapy and embolic agents, selectively deliver treatments to hepatic tumors via cannulation of their supplying vessels and have been used for BCLM. Several retrospective studies suggest that TARE results in better local control than TACE (78 vs. 59%).[2] Minimally invasive locoregional therapies, including TACE and TARE, are increasingly considered for select patients with metastatic breast cancer, particularly those with hepatic oligo-progression or intolerance to systemic therapy, but optimal modality and patient selection remain undetermined and require further prospective study.[3] [4]

There is only one retrospective study directly comparing TACE and TARE at a single institution, suggesting better tolerability and longer survival after TARE, though sample sizes were small.[5] A more recent systematic review and meta-analysis included 26 studies, and found pooled response rates of 49% for TARE and 34% for TACE by Response Evaluation Criteria in Solid Tumors criteria, but did not allow for direct comparison of overall survival (OS) due to heterogeneity and missing time-point data.[6] Given the need to develop more effective treatments for BCLM, studies comparing available embolotherapies are needed. Compared with hepatocellular and colorectal cancer, there is a paucity of data regarding locoregional treatment of BCLM. The present study used a large anonymous database compiling data from several institutions to evaluate survival outcomes of BCLM patients undergoing embolotherapy combined with immunotherapy or chemotherapy.

Methods

This retrospective study was reviewed and approved by our institution's institutional review board, with a waiver of informed consent due to the use of de-identified data. The analysis was conducted using the TriNetX database, a global research network aggregating anonymized clinical data from electronic medical records at predominantly academic health care institutions. All data were fully de-identified and compliant with HIPAA regulations. No clinical trial registration was required. For this study, data were extracted from 68 organizations in the United States (January 2016–July 2024), using CPT (Current Procedural Terminology) and ICD-10 (International Classification of Diseases, 10th Revision) codes to identify patients with metastatic breast cancer who underwent TACE or TARE. The TriNetX browser-based analytics network with real-time analytics features was used for analysis.

In total, 418 patients were included, with TARE in 334 and TACE in 84 ([Table 1]). TARE and TACE patients were similar in age and estrogen receptor status; however, TARE patients were less likely to be progesterone receptor-positive (3 vs. 12%; p = 0.001) and human epidermal growth factor receptor 2-positive (2 vs. 12%; p = 0.001), or to have undergone prior liver resection or ablation. Pre-embolotherapy total bilirubin and alanine aminotransferase levels were slightly higher for TACE patients, though the mean values were within normal range. Eastern Cooperative Oncology Group performance status was not available in over 80% of patients, so the data are not included. TARE and TACE patients received systemic therapies at similar rates before transarterial therapy. Embolotherapy administration was assessed as following first-, second-, or third-line systemic therapy regimens, and as a combination with either chemotherapy or immunotherapy ([Table 1]). OS probabilities were assessed by Kaplan–Meier analysis. Propensity score matching (PSM) analysis accounting for hormone receptor status and line of therapy was used to compare a matched cohort of patients who received immunotherapy/TARE to patients who received chemotherapy/TARE, immunotherapy/TACE, and chemotherapy/TACE on survival.

Table 1 Baseline characteristics

Characteristic			TARE	TACE	p-Value
n			334	84
Demographics
	Age (y)		70 ± 13	71 ± 11	0.29
	Female gender (n)		334 (100%)	84 (100%)	1.00
	Number of white patients		261 (78%)	58 (69%)	0.10
	Number of black patients		30 (9%)	10 (12%)	0.53
	Number of Hispanic patients		20 (6%)	10 (12%)	0.09
Histology
	BRCA/BRCA2, % (n)		10 (3%)	0 (0%)	1.00
	ER		131 (39%)	31 (36%)	0.70
	PR		10 (3%)	10 (12%)	<0.01
	HER2-neu		10 (2%)	10 (12%)	<0.01
Preprocedure laboratory values
	Creatinine (mg/dL)		1.15 ± 1.5	1.15 ± 0.91	1.00
	Platelet count (× 109/L)		40.8 ± 31.2	69.4 ± 110	0.02
	Alanine aminotransferase (U/L)		30.9 ± 20.6	47.5 ± 72.8	<0.01
	Aspartate aminotransferase (U/L)		45.4 ± 61.7	66.7 ± 12.2	<0.01
	Bilirubin (mg/dL)		0.7 ± 0.5	1.0 ± 1.4	<0.01
Prior liver-directed therapy
	Prior liver resection		20 (6%)	10 (12%)	0.04
	Prior liver ablation		10 (3%)	10 (12%)	0.06
	Prior liver radiation		33 (10%)	10 (12%)	0.65
Treatment regimen
	After first-line systemic therapy
		Combined with chemotherapy	150	38
		Combined with immunotherapy	33	5
	After second-line systemic therapy
		Combined with chemotherapy	84	21
		Combined with immunotherapy	27	3
	After third-line systemic therapy
		Combined with chemotherapy	20	5
		Combined with immunotherapy	9	3

Abbreviations: ER, estrogen receptor; PR, progesterone receptor; TACE, transarterial chemoembolization; TARE, transarterial radioembolization.

Results

Median OS for the entire study population was 34 months. Survival after TARE was 36 months and after TACE was 25 months (hazard ratio [HR]: 1.42, 95% confidence interval [CI]: 1.01–1.98, p = 0.04). After accounting for hormone receptor status and line of therapy, the median OS for TARE was 38 months and for TACE was 30 months (HR: 1.53, 95% CI: 1.18–1.98, p = 0.03). Alanine aminotransferase and aspartate aminotransferase levels were higher after TACE than TARE (p < 0.01), though mean values were within normal limits. There was no significant difference in the mean creatinine, bilirubin, or platelet counts after TACE compared with TARE ([Table 2]). Grade 3 and higher elevations in liver function tests, biliary complications, and emergency room visits were observed more frequently after TACE than TARE, while adverse events, including gastrointestinal ulcers, cholecystitis, pancreatitis, and liver abscess, were more common after TARE ([Table 2]).

Table 2 Laboratory values and adverse events after embolotherapy

Characteristic		TARE	TACE	p-Value
n		334	84
Mean laboratory value within 90 days
	Highest creatinine (mg/dL)	1.24 ± 1.0	1.2 ± 0.8	0.68
	Lowest platelet count (× 109/L)	44.2 ± 31.1	47.3 ± 11.4	0.66
	Highest alanine aminotransferase (U/L)	30.2 ± 20.0	40.4 ± 42.3	<0.01
	Highest aspartate aminotransferase (U/L)	28.8 ± 19.2	46.0 ± 47.2	<0.01
	Highest bilirubin (mg/dL)	1.2 ± 0.8	1.6 ± 0.3	0.27
Grade 3 or greater elevation in laboratory value within 90 days
	Alanine aminotransferase	102 (31%)	47 (56%)	0.02
	Aspartate aminotransferase	93 (28%)	51 (61%)	0.03
	Bilirubin	18 (5%)	26 (31%)	0.01
Other adverse event within 60 days
	GI ulcer, cholecystitis, pancreatitis, or liver abscess	9 (2.7%)	0 (0%)	0.01
	Biliary complication	10 (2.9%)	22 (26%)	<0.01
Emergency room visit within 30 days		28 (8%)	22 (26%)	0.05

Abbreviations: GI, gastrointestinal; TARE, transarterial radioembolization; TACE, transarterial chemoembolization.

Note: Continuous variables are presented as mean ± standard deviation. Adverse events and emergency room visits were assessed using Current Procedural Terminology and International Classification of Diseases, 10th Revision codes.

Of the 418 patients, embolotherapy was administered in combination with systemic chemotherapy or immunotherapy in 398 patients, with 254 receiving chemotherapy/TARE, 64 chemotherapy/TACE, 69 immunotherapy/TARE, and 11 immunotherapy/TACE. Among the 80 patients who received immunotherapy, the most common agents were pembrolizumab (n = 29, 36%), atezolizumab (n = 20, 25%), nivolumab (n = 20, 25%), and durvalumab (n = 10, 13%). Other agents included trastuzumab (n = 10, 13%), ado-trastuzumab emtansine (T-DM1; n = 10, 13%), rituximab (n = 10, 13%), interferon (n = 10, 13%), and obinutuzumab (n = 3, 4%). Embolotherapy was administered after first- (n = 226), second- (n = 135), and third-line (n = 37) therapy ([Table 2]) with no difference in the distribution of first-, second-, and third-line administration between TARE and TACE groups (p = 0.25). Median OS, adjusted by PSM analysis accounting for hormone receptor status and line of therapy, was significantly longer in patients who received immunotherapy/TARE (38 months), compared with immunotherapy/TACE (36 months; p = 0.03), chemotherapy/TARE (33 months; p = 0.05), and chemotherapy/TACE (30 months; p = 0.04) ([Fig. 1]). Three-year survival was highest after immunotherapy/TARE (52%), followed by immunotherapy/TACE (48%), chemotherapy/TARE (45%), and chemotherapy/TACE (40%) (p = 0.04).

Fig. 1 Survival after TARE or TACE. TACE, transarterial chemoembolization; TARE, transarterial radioembolization.

Discussion

The liver is a common site of metastasis in breast cancer, with BCLM associated with higher rates of treatment failure and fatality. In this study, TARE and TACE were evaluated as locoregional therapies for managing liver metastasis in a large database of patients to enable comparisons. Data suggest that in patients who were progressing despite a systemic regimen, those who underwent TARE or received immunotherapy for BCLM had better survival compared with patients who underwent TACE or received chemotherapy. These results are concordant with studies that suggest superior disease control outcomes with TARE compared with TACE in similar settings,[2] but extend prior research by suggesting potential synergy with immunotherapy. Large registry data further support the role of TARE in noncolorectal liver metastases, showing particularly favorable outcomes in breast cancer patients.[7]

In this study, combining embolotherapy with immunotherapy provided better results than its combination with chemotherapy. Immunotherapy aims to boost antitumor immunity, and in combination with locoregional therapy may induce an abscopal effect, a distant tumoricidal response to local therapy.[8] Locoregional therapies are one strategy being used to produce tumor antigens that can induce abscopal effects and are currently being explored in combination with immunotherapy.[9] The finding that TARE combined with immunotherapy yielded the longest survival may reflect observed and theorized differences in immune modulation by embolotherapies, with TACE inducing a short-lived inflammatory surge and immune-suppressive signals, while TARE promotes delayed but sustained immune activation with robust recruitment of effector T cells and tumor-infiltrating lymphocytes—features more favorable for synergy with checkpoint blockade.[10]

This study has several limitations. Despite obtaining data from a large national database, the number of TACE cases was lower than TARE cases, reflecting the uncommon use of locoregional therapy for BCLM and creating an imbalance in cohort sizes. The subgroup of patients receiving both immunotherapy and TACE was very small (n = 11), limiting the strength of conclusions. Though PSM analysis was used to adjust for differences, residual selection bias remains likely. Performance status was missing in most patients, which could also introduce significant bias in how particular treatments were chosen. TACE patients had higher rates of HER2 positivity, progesterone receptor positivity, and more prior local therapies, which are clinically meaningful differences that could confound survival outcomes. TriNetX does not provide details regarding the size and number of hepatic tumors, further limiting the ability to assess tumor burden. The higher prevalence of prior ablation or resection in TACE patients suggests that these patients may have had lower tumor burden. Alternatively, exposure to multiple different modalities of liver-directed therapy may confound OS. Reliance on billing codes to identify adverse events introduces the potential for misclassification or underreporting. Taken together, these factors underscore the exploratory nature of the dataset. Findings should therefore be interpreted with caution and considered hypothesis-generating, highlighting the need for prospective studies to clarify the role of TARE—particularly in combination with immunotherapy—for patients with BCLM.

Conclusion

Findings indicate that TARE, especially when combined with immunotherapy, may offer benefit; however, prospective studies are needed to further evaluate these observations. Combination strategies may offer novel insights and opportunities for improving outcomes in this challenging population.

Conflict of Interest

None declared.

Acknowledgments

Dr. Deipolyi and Dr. Bryce are consultants for Boston Scientific, Inc. The other authors have no disclosures.

Declaration of Generative AI and AI-Assisted Technologies in the Writing Process

During the preparation of this work, the authors did not use generative AI or AI-assisted technologies. All content was generated and reviewed solely by the authors, who take full responsibility for the final work.

Compliance with Ethical Standards

This research adheres to the principles of the Helsinki Declaration and institutional guidelines. All data were de-identified and fully compliant with HIPAA regulations.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by our institution's institutional review board, with a waiver of informed consent due to the retrospective nature of the study and use of de-identified data.

Informed Consent

Informed consent was waived by the institutional review board due to the use of anonymized, de-identified data collected for research purposes.

This work was carried out at Charleston Area Medical Center.

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Publication History

Article published online:
10 November 2025