Clinical application of gelatin sponge microparticles combined with pirarubicin for hepatic transcatheter arterial chemoembolization in breast cancer liver metastasis treatment: results of a single-center long-term study

Objective To retrospectively analyze the safety and long-term clinical efficacy of gelatin sponge microparticles combined with the chemotherapy drug pirarubicin for hepatic transcatheter arterial chemoembolization (GSMs-TACE) in order to treat breast cancer liver metastasis (BCLM). Methods Twenty-seven BCLM patients who underwent GSMs-TACE from July 2010 to July 2016 were enrolled. Tumor target blood vessels were slowly and regionally embolized with absorbable gelatin sponge particles and pirarubicin injections. Plain computed tomography (CT) scans and biochemical indexes were re-examined at 4 days after treatment, and enhanced CT scans or magnetic resonance images and biochemical indexes, 1 month later. For patients with stable tumors, the follow-up period was 2 to 3 months, and the tumor response was evaluated using Modified Response Evaluation Criteria in Solid Tumors. Adverse reactions, survival time, and prognostic factors were assessed. Results By October 2019, 27 patients with BCLM had undergone GSMs-TACE, with an average of 2.44 ± 1.58 treatments. The 1-, 3-, and 5-year survival rates were 62.96%, 22.22%, and 14.81%, respectively, and the mOS was 22.0 months. No serious complications, such as acute liver failure and liver abscess, had occurred. There were two cases of acute cholecystitis that recovered after symptomatic treatment. Multivariate analysis of the prognosis showed that the primary tumor size, number of metastatic lymph nodes, estrogen receptor/progesterone receptor (ER/PR) status, and time to postoperative liver metastasis and combination therapy were statistically significant. Conclusions The overall prognosis of BCLM was poor. GSMs-TACE was safe and effective for BCLM treatment and could prolong the median survival time of patients. Therefore, it is worthy of widespread clinical application.

A Nomogram for Predicting Survival in Patients With Breast Cancer Liver Metastasis: A Population-Based Study

ObjectiveThe prognosis of patients with breast cancer liver metastasis (BCLM) was poor. We aimed at constructing a nomogram to predict overall survival (OS) for BCLM patients using the SEER (Surveillance Epidemiology and End Results) database, thus choosing an optimized therapeutic regimen to treat.MethodsWe identified 1173 patients with BCLM from the SEER database and randomly divided them into training (n=824) and testing (n=349) cohorts. The Cox proportional hazards model was applied to identify independent prognostic factors for BCLM, based on which a nomogram was constructed to predict 1-, 2-, and 3-year OS. Its discrimination and calibration were evaluated by the Concordance index (C-index) and calibration plots, while the accuracy and benefits were assessed by comparing it to AJCC-TNM staging system using the decision curve analysis (DCA). Kaplan-Meier survival analyses were applied to test the clinical utility of the risk stratification system.ResultsGrade, marital status, surgery, radiation therapy, chemotherapy, CS tumor size, tumor subtypes, bone metastatic, brain metastatic, and lung metastatic were identified to be independent prognostic factors of OS. In comparison with the AJCC-TNM staging system, an improved C-index was obtained (training group: 0.701 vs. 0.557, validation group: 0.634 vs. 0.557). The calibration curves were consistent between nomogram-predicted survival probability and actual survival probability. Additionally, the DCA curves yielded larger net benefits than the AJCC-TNM staging system. Finally, the risk stratification system can significantly distinguish the ones with different survival risk based on the different molecular subtypes.ConclusionWe have successfully built an effective nomogram and risk stratification system to predict OS in BCLM patients, which can assist clinicians in choosing the appropriate treatment strategies for individual BCLM patients.

Claudin-2 promotes colorectal cancer liver metastasis and is a biomarker of the replacement type growth pattern

Claudin-2 promotes breast cancer liver metastasis by enabling seeding and early cancer cell survival. We now demonstrate that Claudin-2 is functionally required for colorectal cancer liver metastasis and that Claudin-2 expression in primary colorectal cancers is associated with poor overall and liver metastasis-free survival. We have examined the role of Claudin-2, and other claudin family members, as potential prognostic biomarkers of the desmoplastic and replacement histopathological growth pattern associated with colorectal cancer liver metastases. Immunohistochemical analysis revealed higher Claudin-2 levels in replacement type metastases when compared to those with desmoplastic features. In contrast, Claudin-8 was highly expressed in desmoplastic colorectal cancer liver metastases. Similar observations were made following immunohistochemical staining of patient-derived xenografts (PDXs) that we have established, which faithfully retain the histopathology of desmoplastic or replacement type colorectal cancer liver metastases. We provide evidence that Claudin-2 status in patient-derived extracellular vesicles may serve as a relevant prognostic biomarker to predict whether colorectal cancer patients have developed replacement type liver metastases. Such a biomarker will be a valuable tool in designing optimal treatment strategies to better manage patients with colorectal cancer liver metastases.

Immune Milieu Established by Postpartum Liver Involution Promotes Breast Cancer Liver Metastasis

In rodents, we identified a physiologic process within the normal liver that creates a pre-metastatic niche. This physiology is weaning-induced liver involution, characterized by hepatocyte cell death, immune influx, and extracellular matrix remodeling. Here, using weaning-induced liver involution as a model of a physiologically regulated pro-metastatic niche, we investigate how liver involution supports breast cancer metastasis. Liver metastases were induced in BALB/c immune competent hosts by portal vein injection of D2OR (low metastatic) or D2A1 (high metastatic) mouse mammary tumor cells. Tumor incidence and multiplicity increased in involution hosts with no evidence of a proliferation advantage. D2OR tumor cell extravasation, seeding, and early survival were not enhanced in the involuting group compared to the nulliparous group. Rather, the involution metastatic advantage was observed at 14 days post tumor cell injection. This metastatic advantage associated with induction of immune tolerance in the involution host liver, reproductive state dependent intra-tumoral immune composition, and CD8-dependent suppression of metastases in nulliparous hosts. Our findings suggest that the normal postpartum liver is in an immune suppressed state, which can provide a pro-metastatic advantage to circulating breast cancer cells. Potential relevance to women is suggested as a postpartum diagnosis of breast cancer is an independent predictor of liver metastasis.

Hepatectomy, RFA, and Other Liver Directed Therapies for Treatment of Breast Cancer Liver Metastasis: A Systematic Review

BackgroundThe liver is the second most common site of breast cancer metastasis. Liver directed therapies including hepatic resection, radiofrequency ablation (RFA), transarterial chemo- and radioembolization (TACE/TARE), and hepatic arterial infusion (HAI) have been scarcely researched for breast cancer liver metastasis (BCLM). The purpose of this review is to present the known body of literature on these therapies for BCLM.MethodsA systematic review was performed with pre-specified search terms using PubMed, MEDLINE, EMBASE, and Cochrane Review resulting in 9,957 results. After review of abstracts and application of exclusion criteria, 51 studies were included in this review.ResultsHepatic resection afforded the longest median overall survival (mOS) and 5-year survival (45 mo, 41%) across 23 studies. RFA was presented in six studies with pooled mOS and 5-year survival of 38 mo and 11–33%. Disease burden and tumor size was lower amongst hepatic resection and RFA patients. TACE was presented in eight studies with pooled mOS and 1-year survival of 19.6 mo and 32–88.8%. TARE was presented in 10 studies with pooled mOS and 1-year survival of 11.5 mo and 34.5–86%. TACE and TARE populations were selected for chemo-resistant, unresectable disease. Hepatic arterial infusion was presented in five studies with pooled mOS of 11.3 months.ConclusionAlthough further studies are necessary to delineate appropriate usage of liver directed therapies in BCLM, small studies suggest hepatic resection and RFA, in well selected patients, can result in prolonged survival. Longitudinal studies with larger cohorts are warranted to further investigate the effectiveness of each modality.