Cancer Liver Metastases Research Articles

The Increasing Role of CT-Guided Cryoablation for the Treatment of Liver Cancer: A Single-Center Report.

Simple SummaryImage-guided percutaneous ablation of primary and metastatic liver tumors has been gaining importance in patients who are not suitable for hepatic resection or liver transplantation. The aim of our retrospective study was to assess the effectiveness of CT-guided cryoablation in 49 patients with hepatocellular carcinoma or liver metastases. Our results highlighted that cryoablation is an effective and safe method for the treatment of liver cancers that are not amenable to surgical resection. Furthermore, cryoablation has important advantages when compared to other ablation techniques such as radiofrequency or microwave ablation; therefore, this method should be included in the armamentarium of treatment options in centers dedicated to the multidisciplinary treatment of liver cancer.Purpose: Cryoablation (CrA) is a minimally invasive treatment that can be used in primary and metastatic liver cancer. The purpose of this study was to assess the effectiveness of CrA in patients with hepatocellular carcinoma (HCC) and liver metastases. Methods: We retrospectively evaluated the patients who had CrA for HCC or liver metastases between 2015 and 2020. Technical success, complete ablation, CrA-related complications, local tumor progression, local recurrences, and distant metastases were evaluated in the study population. In patients with HCC, the median survival was also estimated. Results: Sixty-four liver tumors in 49 patients were treated with CrA (50 metastases and 14 HCC). The mean tumor diameter was 2.15 cm. The mean follow-up was 19.8 months. Technical success was achieved in the whole study population. Complete tumor ablation was observed after one month in 92% of lesions treated with CrA (79% and 96% in the HCC Group and metastases Group, respectively, p < 0.001). Local tumor progression occurred in 12.5 of lesions, with no difference between the study groups (p = 0.105). Sixteen patients (33%) developed local recurrence (45% and 29% in the HCC Group and metastases Group, respectively, p = 0.477). Seven patients (14%) developed distant metastases in the follow-up period. Ten patients (20.8%) underwent redo CrA for local recurrence or incomplete tumor ablation. Minor complications were observed in 14% of patients. In patients with HCC, the median survival was 22 months. Conclusions: CrA can be safely used for treatment of HCC and liver metastases not amenable of surgical resection. Further studies are necessary to better define the role of CrA in the multidisciplinary treatment of liver malignancies.

Effect of pharmaceutical care on the treatment of neuropathic pain induced by bone metastasis of liver cancer: case report

Effect of pharmaceutical care on the treatment of neuropathic pain induced by bone metastasis of liver cancer: case report

Circulating tumour cell gene expression and chemosensitivity analyses: predictive accuracy for response to multidisciplinary treatment of patients with unresectable refractory recurrent rectal cancer or unresectable refractory colorectal cancer liver metastases

BackgroundPatients with unresectable recurrent rectal cancer (RRC) or colorectal cancer (CRC) with liver metastases, refractory to at least two lines of traditional systemic therapy, may receive third line intraarterial chemotherapy (IC) and targeted therapy (TT) using drugs selected by chemosensitivity and tumor gene expression analyses of liquid biopsy-derived circulating tumor cells (CTCs).MethodsIn this retrospective study, 36 patients with refractory unresectable RRC or refractory unresectable CRC liver metastases were submitted for IC and TT with agents selected by precision oncotherapy chemosensitivity assays performed on liquid biopsy-derived CTCs, transiently cultured in vitro, and by tumor gene expression in the same CTC population, as a ratio to tumor gene expression in peripheral mononuclear blood cells (PMBCs) from the same individual. The endpoint was to evaluate the predictive accuracy of a specific liquid biopsy precision oncotherapy CTC purification and in vitro culture methodology for a positive RECIST 1.1 response to the therapy selected.ResultsOur analyses resulted in evaluations of 94.12% (95% CI 0.71–0.99) for sensitivity, 5.26% (95% CI 0.01–0.26) for specificity, a predictive value of 47.06% (95% CI 0.29–0.65) for a positive response, a predictive value of 50% (95% CI 0.01–0.98) for a negative response, with an overall calculated predictive accuracy of 47.22% (95% CI 0.30–0.64).ConclusionsThis is the first reported estimation of predictive accuracy derived from combining chemosensitivity and tumor gene expression analyses on liquid biopsy-derived CTCs, transiently cultured in vitro which, despite limitations, represents a baseline and benchmark which we envisage will be improve upon by methodological and technological advances and future clinical trials.

Abstract 1007: Spatial, temporal and heterogeneous changes in transport phenotype in liver metastasis of breast cancer

Abstract Various heterogeneities in response of metastatic tumors to systemic anti-cancer therapy are major source of therapeutic resistance. Cancer cells from bulk tumors and cancer cell lines are not clonal. A highly heterogeneous tumor microenvironment is known to develop by subclones. Furthermore, metastasis can evolve during the disease progression as well as in response to systemic therapies. These spatial and temporal variations of heterogeneity in tumors can affect blood perfusion and vascular permeability which can determine the level of mass/anti-cancer drugs transport to tumors (we refer to as “transport phenotype”). Insufficient drug transport to tumor in vivo can generate transport-based therapeutic resistance even for agents with proven efficacy against the target cancer cell lines in vitro. Our goal is to understand spatial and temporal heterogeneity in transport of mass/anti-cancer drugs to metastatic tumors to overcome the therapeutic resistance. The study of bulk tumors will provide a mixture of different functions from heterogeneous sets of various clones. We sought to establish single cell-derived clones from a 4T1 parental murine breast cancer cell line in order to dissect and simplify the heterogeneity in polyclonal cell populations in tumors. First, we found heterogeneous accumulation of systemically injected PEGylated liposomal doxorubicin (PLD) among multiple, experimental liver metastases of 4T1 parental (polyclonal) breast cancer in mouse. Intravital Microscopy imaging of liver metastases through a window chamber over time revealed different transport phenotypes, in terms of circulation and diffusion of systemically injected fluorescent tracers around/inside parental (polyclonal) tumors. Furthermore, transport phenotype can be modulated from one to another after PLD therapy, creating possible mechanisms of transport based on drug resistance. When single cell clone-derived metastases were established, a clone dependent difference in transport phenotype was found. Interestingly transport phenotype even in clonal tumors was temporally evolved and increased its heterogeneity. These data suggest that transport phenotype cannot be determined solely by genotype of tumor and can be evolved and more heterogeneous as a function of tumor growth and systemic chemotherapy. Clinical implication of our findings is that transport of therapeutics to tumor and its efficacy may not be predicted by DNA-based assay for clinical decision-making and transport-based therapeutics resistance will eventually occur in every tumor types. Citation Format: Aygul Sadigova, Megumi Kai, Yan Ting Liu, Thao Nguyen, Chihiro Hashimoto, Kenji Yokoi. Spatial, temporal and heterogeneous changes in transport phenotype in liver metastasis of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1007.

Abstract 6116: Tumor immune environment in liver metastasis of colorectal cancer and its correlation with recurrence free survival

Abstract Introduction: The liver is a common site of metastases of colorectal cancer. Tumor infiltrating lymphocytes (TILs) play an important role in the process of colorectal cancer liver metastasis (CRCLM). A comprehensive investigation into TILs will provide more prognostic information for patients with colorectal liver metastases after liver resection. Methods: 15 CRC patients with liver metastases from our hospital were enrolled in the study. The density and percentage of the TILs [CD8+, CD3+, CD4+, CD20+, tumor associated macrophages (TAMs), dim CD56+NK, bright CD56+NK, PD-1+etc.] in the liver metastasis samples from operation were analyzed by multiplex immunofluorescence technique (3DMedcines Inc.). The level of the density and percentage of immune cells were determined by dichotomy method. The correlation between recurrence free survival (RFS) and immune cells were analyzed using the Kaplan-Meier curve and Log-rank test. Results: The existence of dim CD56+ NK cells in the stroma was associated with significant improvement in RFS (p=0.0461). The median RFS was 26.1 months (95% CI, 14.9 to 33.5) with the existence of dim CD56+ NK cells in the stroma versus 1.7 months (95% CI, -18.0 to 32.4) without dim CD56+ NK cells in the stroma. Nevertheless, dim CD56+ NK cells in the tumor-enriched segments was not significantly associated with improved outcome. The existence of bright CD56+ NK cells in the stroma was associated with significant improvement in RFS (p=0.0307) but not in the tumor-enriched segments. The median RFS was 34.6 months (95% CI, 15.0 to 35.2) with the existence of bright CD56+ NK cells in the stroma versus 7.9 months (95% CI, -5.3 to 23.1) without bright CD56+ NK cells in the stroma. However, low FoxP3+ cells in the tumor-enriched segments (p=0.0037) was significantly associated with improved outcome but not in the stroma. The median RFS was 36.5 months (95% CI, 23.1 to 40.1) with low FoxP3+ cells versus 8.2 months (95% CI, 0.5 to 21.8) with high FoxP3+ cells in the tumor-enriched segments. Low CD3+CD4+FoxP3+ cells (p=0.074) and the existence of PD-L1+CD68+ cells (p=0.0524) in the tumor-enriched segments showed a trend towards better RFS. No significant correlation was achieved for CD8+, CD3+, CD3+CD4+, CD20+, CD68+CD163+, CD68+CD163-, PD-1, PD-1+CD8+ cells either in the tumor-enriched segments nor in the stroma. Conclusion: We identified that CD56+ NK cells in stroma are associated with improved outcome in CRCLM. Nevertheless, FoxP3+ cells are associated with poor prognosis in CRCLM. Citation Format: Jiamin Zhou, Weiqi Xu, Miao Wang, Siqi Zhang, Ding Zhang. Tumor immune environment in liver metastasis of colorectal cancer and its correlation with recurrence free survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6116.

Liver biopsy technique in the era of genomic cancer therapies: a single-center retrospective analysis.

With the evolution of personalized medicine in the field of oncology, which includes optimal treatment selection using next-generation sequencing-based companion diagnostic systems and tumor-agnostic treatments according to common biomarkers, a liver tumor biopsy technique that can obtain a sufficient specimen volume must be established. The current study aimed to evaluate the safety and availability of a liver tumor biopsy technique with multiple puncture sites made using a coaxial introducer needle and embolization with gelatin sponge particles. Patients with primary or metastatic liver cancer who underwent liver tumor biopsies with puncture tract embolization using gelatin sponge (Spongel®) from October 2019 to September 2020 were included in the study. The complication and diagnostic rates were evaluated, and whether the specimen volume was sufficient for Foundation® CDx was investigated. In total, 96 patients were enrolled in this analysis. The median total number of puncture times per patient was 3 (range 1-8). The pathological diagnostic rate was 79.2%. Using the FoundationOne® CDx, specimens with a sufficient volume required for genomic medicine were collected in 84.9% of patients. The incidence rate of bleeding was 4.2% (n = 4), and only one patient presented with major bleeding requiring transfusion. Liver biopsy with puncture tract embolization using a gelatin sponge may be safe and effective for collecting specimens with a volume sufficient for modern cancer treatments.

Abstract 5633: Beta-Glucan treatment restricts liver metastasis in pancreatic cancer

Abstract Introduction: For most patients with pancreatic ductal adenocarcinoma (PDAC), metastatic disease is the main cause of mortality with the liver being the most common site of metastasis. In the liver, macrophages are the most abundant immune cell subset, yet their role in regulating liver metastasis remains poorly understood. Two distinct macrophage populations exist in the liver: liver-resident Clec4f+F4/80+ Kupffer cells (KCs) and Clec4fnegF4/80+ bone marrow derived macrophages (BMDMs). Here, we sought to understand the impact of these macrophage subsets on liver metastasis and the ability of a myeloid agonist, a β-glucan (BG), to skew macrophages towards an anti-metastatic phenotype. Methods: C57BL/6 mice were given an intraportal (iPo) injection of an LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre;LSL-Rosa26-Yfp (KPCY) cell line to model liver metastasis. Mice were necropsied 2 days later to measure metastatic seeding of cancer cells or 12-14 days later to assess metastatic lesion outgrowth. Liver metastatic burden and immune cell populations were analyzed by flow cytometry and immunohistochemistry. In macrophage depletion experiments, liver macrophages were depleted using clodronate encapsulated liposomes (CEL) delivered intraperitoneally. In studies involving BG treatment, weekly intravenous administration of BG began 2 days prior to iPo injection of cancer cells. Results: Liver macrophage depletion did not influence metastatic seeding in the liver; but, did inhibit the outgrowth of established metastatic colonies. Histological analysis showed that Clec4f+ KCs were excluded from metastatic lesions, whereas BMDMs actively infiltrated. BMDM infiltration into lesions was also largely unaffected by CEL treatment. To stimulate macrophages with anti-metastatic activity, BG was administered systemically and found to bind to &amp;gt;95% of KCs but only 30% of BMDMs and 20-35% of other immune cell populations. BG treatment attenuated liver metastasis when given during both the seeding and outgrowth phases of metastasis (mean metastatic burden as % live cells in liver: 1%, BG vs 6.5%, control, p&amp;lt;0.0001). Analysis of metastatic lesions in BG treated mice by histology showed smaller lesions (mean size: 0.9mm2, BG vs 1.5mm2, control, p=0.09), decreased proliferating cancer cells (mean # of proliferating cancer cells per unit metastatic area: 480, BG vs 810, control, p&amp;lt;0.0001), and increased numbers of CD3+ T cells at the periphery of lesions compared to lesions from control mice (mean # of T cells per mm2 metastatic area: 300, BG vs 135, control, p&amp;lt;0.0001). The efficacy of BG to restrict liver metastasis was dependent on liver macrophages. Conclusions: Taken together, these findings suggest that, while liver macrophages can be coopted to support metastatic outgrowth, treatment with a β-glucan, as a myeloid agonist is a novel strategy to engender liver macrophages with anti-metastatic activity. Citation Format: Stacy K. Thomas, Shaanti Choi-Bose, Heather Coho, Christopher Casella, Meredith L. Stone, Max M. Wattenberg, Gregory L. Beatty. Beta-Glucan treatment restricts liver metastasis in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5633.

Abstract 5983: Gene profile analysis of breast cancer lung metastasis, liver metastasis, brain metastasis and primary tumor

Abstract Background: The incidence of male breast cancer (MBC) is lower than female breast cancer (FBC), representing 1% of all breast cancer worldwide. The difference with FBC may affect the treatment strategy of MBC, but the necessary precondition is that we should know more about the difference between FBC and MBC. However, Because of its low incidence that the relevant data about MBC is relatively scarce. Here we report some data about gene mutation of MBC, and compared it with FBC. Methods: Blood or tumor Tissue samples of breast cancer were collected and subjected to NGS in a College of American Pathologists (CAP)-certified and Clinical Laboratory Improvement Amendments (CLIA)-accredited lab for gene mutation analysis (3D Medicines Inc.,Shanghai, China). Statistical analysis was performed using GraphPad Prism (version 7.01) and SPSS version 21.0 (SPSS,Inc.). Results: Approximately 182 samples were analyzed, among which, exist 82 samples were from primary tissue, 66 samples were breast cancer liver metastases, 20 were lung metastases and 14 were brain metastases. High genomic heterogeneity was found among primary breast cancer tissue, breast cancer liver metastases, lung metastases, brain metastases, that is at least 20 gene mutations were found in these BC samples, while different gene mutations were showed among primary and different metastases tissues. The top five mutated gene in primary tumor tissue were TP53(80.49%), PIK3CA(53.66%), FGF19(30.49%), ERBB2(26.83%), MYC(23.17%); in liver metastases tissues were TP53(54.55%), FGF19(39.39%), PIK3CA(37.88%), ERBB2(21.21%), CCND1(19.70%); in lung metastases tissues were TP53(70.00%), PIK3CA(55.00%), ERBB2,MCL1(25.00%), CDKN2A/2B(20.00%), CCND1, NF1, CDK12(15.00%), CCND2, MYC, PTEN, GNAS, FGF19, PTK2, FGFR1(10.00%); in brain metastases tissues were TP53(42.86%), PIK3CA(28.57%), ZNF703, PREX2, JAK3, MYC, FGFR1(14.29%). Besides, levels of TMB were also different among primary tissue, liver, lung and brain metastases tissues. Higher TMB level were showed in liver and brain metastases tissue than primary and lung metastases tissues (p&amp;lt;0.001). Conclusions: Different metastases of breast cancer were different in gene mutation landscape, this imply these patients should be managed differently. Citation Format: Yanman Fang, Hushan Zhang, Jiali Zou, Fulin Zhou, Xuejie Tang, Yi Yang, Li Luo, Yu Ding. Gene profile analysis of breast cancer lung metastasis, liver metastasis, brain metastasis and primary tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5983.

Abstract 2544: Preoperative exercise inhibits hepatic metastasis by suppressing PMN-MDSC formation of NETs

Abstract Introduction: Under surgical trauma, the pathological amplification and activation of neutrophils with potent immunosuppressive functions, also known as polymorphonuclear myeloid-derived suppressive cells (PMN-MDSCs), can promote metastasis by forming neutrophil extracellular traps (NETs) that are web-like structures consisting of nuclear DNA, histones, and granule proteins. Preoperative exercise (PEx) reduces postoperative complications with improved clinical outcomes in cancer patients undergoing surgeries. are. Our preliminary data show that PEx suppresses liver ischemia/reperfusion (I/R)-induced colorectal cancer (CRC) liver metastasis. Our recent studies have shown I/R-induced NETs promote liver CRC metastasis by capturing tumor cells and preventing infiltration and cytotoxicity of CD8+ T cells in tumor microenvironment (TME). We hypothesize that PEx remodels the TME by suppressing PMN-MDSCs formation of NETs. Methods: Male mice were subjected to exercise for 4 weeks, before MC38 colorectal cancer cells were injected through portal vein, and then subjected to 70% partial liver warm I/R as surgical stress. The single-cell RNA sequencing (scRNA-seq) was performed on CD45+leukocytes from TME 3 weeks after surgery. Immunofluorescence staining and Western Blot were used to determine NETs formation in the TME. Flow cytometry was used to determine the infiltration of PMN-MDSCs and CD8+ T lymphocytes in the tumors. Results: Our scRNA-seq data reveal that PEx leads to a remarkable transcriptomic shift in most immune cells types, such as PMN-MDSCs, M-MDSCs, T cells, Kupffer cells, B cells, NK and NKT cells, in the TME. PEx decreases the percentages of PMN-MDSCs in the TME and inhibits theNETs formation by PMN-MDSCs. scRNA-seq shows a significant increase of the chemokines CXCL10 in PEx-trained PMN-MDSCs obtained 3 weeks after I/R-induced hepatic metastasis, compared with sedentary controls. In addition, PEx increases the number of CD8+ T lymphocytes infiltrating the TME. Summary: Our study shows that PEx downregulates NETs formation and increases the CXCL10 expression in PMN-MDSCs, thus promoting the recruitment more cytotoxic CD8 T lymphocytes to suppress tumor metastasis. Citation Format: Xiang Cheng, Hongji Zhang, Allan Tsung, Hai Huang. Preoperative exercise inhibits hepatic metastasis by suppressing PMN-MDSC formation of NETs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2544.

Abstract 2515: Estrogen regulates the immune microenvironment of colorectal cancer liver metastases

Abstract Liver metastases (LM) remain a major cause of cancer-related death and many cancers preferably metastasize to the liver due to its unique anatomical location, rich blood supply and immune-tolerant microenvironment. Up to 50% of colorectal carcinoma patients develop LM during their disease and this is associated with a poor prognosis. Our laboratory previously identified a sexual dimorphism in the regulation of the immune microenvironment (IME) of LM and showed that estrogen could promote the accumulation of myeloid-derived suppressor cells (MDSCs) and Tregs in the liver in response to invading cancer cells. The objective of this study was to elucidate the role of estrogen in the recruitment and polarization of monocytes/macrophages and in the accumulation and phenotype of natural killer (NK) cells in the IME of colorectal carcinoma LM (CRCLM). Moreover, we sought to determine the therapeutic potential of Selective Estrogen Receptor Degrader (SERD) therapy in tumor bearing female mice. In estrogen-competent female mice bearing CRCLM, we found increased gene and protein expression of the immunosuppressive cytokine TGF-β, and inversely a decrease in the pro-inflammatory cytokine TNF-alpha. Furthermore, we identified a significant increase of newly recruited, immunosuppressive CD68+F4/80+CD163+ M2 macrophages, as compared to estrogen-depleted (ovariectomized) mice. The recruitment of pro-inflammatory CD68+F4/80+TNF-alpha+ M1 macrophages, and the accumulation of the highly cytotoxic NK1.1+ CD49a+ liver NK cells were increased in estrogen-depleted female mice and could be restored upon estrogen supplementation. Moreover, treatment of female mice with the SERD Fulvestrant, markedly reduced the number of CRCLM compared to vehicle-treated mice, and significantly reduced the cell frequencies and counts of recruited myeloid cells and M2 macrophages in the liver. Taken together, our results identify estrogen as a critical regulator of an immunosuppressive tumor ME in the liver and a potential therapeutic target. Funding by the Canadian Institute of Health Research is gratefully acknowledged. Citation Format: Yasmine Benslimane, Sarah Lapin, Julien Chambon, Matthew Leibovitch, Stéphanie Perrino, Pnina Brodt. Estrogen regulates the immune microenvironment of colorectal cancer liver metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2515.

Abstract 6154: Distinct immunosuppressive environments elicited in vessel co-opting and angiogenic colorectal cancer liver metastases and changes following treatment

Abstract Colorectal cancer (CRC) is the third most common cancer worldwide and 50% of CRC patients develop liver metastases. Colorectal cancer liver metastases (CRCLM) present as two major histological growth patterns (HGP) that predict response to treatment/survival: 1. angiogenic tumors characterized by a desmoplastic stroma separating CRC cells from the liver parenchyma and are highly angiogenic and 2. co-opting tumors where tumor cells infiltrate the parenchymal cells in the liver and grow by co-opting the sinusoidal blood vessels between the liver cell plates without sprouting angiogenesis. Angiogenic tumors receiving neoadjuvant anti-angiogenics (anti-VEGF) and chemotherapy have more than double the 5-year overall survival compared to patients with co-opting tumors who have received the same neoadjuvant regimen. In addition, our clinical data revealed that anti-angiogenics could negatively affect outcomes in patients with co-opting lesions. The goal of our study is to understand how the immune system affects the development of the two distinct CRCLM tumors. We used both Nanostring GeoMX spatial protein profiling platform, immunohistochemistry and immunofluorescence, to identify the immune landscapes in chemonaïve and treated human CRCLM tumors. We observed that angiogenic tumors were rich in both CD4 and CD8 T cells with a near absence of neutrophils and macrophages. These adaptive immune cells were also FOXP3 positive indicating an immunosuppressive phenotype. Interestingly, we observed that vessel co-opting tumors have far fewer infiltrating lymphocytes than angiogenic tumors, but interestingly have greater numbers of innate cells - mostly neutrophils and macrophages. The macrophages were further characterized as being M2, tumor promoting, leading to an immunosuppressive environment. We then went on to analyze treated tumors. For those patients treated with chemotherapy alone we observed a larger infiltration of T cells in the angiogenic tumors and the appearance of T cells infiltrating the co-opting tumors. Surprisingly, in patients treated with chemotherapy and anti-angiogenic drugs (ie. anti-VEGF), which is part of the standard of care, the co-opting tumors no longer demonstrated the presence of T cell infiltration and had a similar profile to the chemonaïve tumors. This could explain why chemotherapy in co-opting tumors had a higher overall survival compared to those treated with chemotherapy and anti-VEGF. These results suggest developing treatments aimed at reshaping the different immune landscape in angiogenic and co-opting CRCLM to yield beneficial results for patient overall survival. Furthermore, the identification of immune cells or immune mediators facilitating the development of these two tumor would identify immune cell targets for immunotherapies. Citation Format: Diane H. Kim, Thomas Z. Mayer, Stephanie K. Petrillo, Anthoula Lazaris, Peter Metrakos. Distinct immunosuppressive environments elicited in vessel co-opting and angiogenic colorectal cancer liver metastases and changes following treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6154.

Abstract 1580: Cancer cells promote phenotypic alterations in adjacent hepatocytes to facilitate vessel co-option in colorectal cancer liver metastasis

Abstract Vessel co-option is associated with resistance against anti-angiogenic therapy in colorectal cancer liver metastases (CRCLM). Vessel co-opted lesions are characterized by highly motile cancer cells that move toward and along the pre-existing vessels in the surrounding non-malignant tissue and hijack them to gain access to nutrient. In order to access the sinusoidal vessels, the cancer cells must displace the hepatocytes and occupy their space. However, the mechanisms underlying this displacement are unknown. Herein, we examined the involvement of apoptosis, motility, epithelial-mesenchymal transition (EMT) and autophagy pathways in hepatocyte’s displacement by cancer cells. We demonstrated that cancer cells induce the expression of the proteins that associated with upregulation of apoptosis, motility and EMT in adjacent hepatocytes in vitro and in vivo. Accordingly, we observed upregulation of cleaved caspase-3, cleaved poly (ADP-ribose) polymerase-1 (PARP-1) and Actin Related Protein 2/3 (ARP2/3) in adjacent hepatocytes to cancer cells, while we noticed lower expression levels of E-cadherin. Importantly, Runt-related transcription factor 1 (RUNX1) knockdown in the cancer cells has impaired their function towards adjacent hepatocytes in vitro and in vivo. Altogether, our data indicating that cancer cells may exploit various mechanisms to displace the hepatocytes and access to the sinusoidal vessels to establish vessel co-option. Citation Format: Miran Rada, Anthoula Lazaris, Peter Metrakos. Cancer cells promote phenotypic alterations in adjacent hepatocytes to facilitate vessel co-option in colorectal cancer liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1580.

Liver Metastatic Breast Cancer: Epidemiology, Dietary Interventions, and Related Metabolism.

The median overall survival of patients with metastatic breast cancer is only 2–3 years, and for patients with untreated liver metastasis, it is as short as 4–8 months. Improving the survival of women with breast cancer requires more effective anti-cancer strategies, especially for metastatic disease. Nutrients can influence tumor microenvironments, and cancer metabolism can be manipulated via a dietary modification to enhance anti-cancer strategies. Yet, there are no standard evidence-based recommendations for diet therapies before or during cancer treatment, and few studies provide definitive data that certain diets can mediate tumor progression or therapeutic effectiveness in human cancer. This review focuses on metastatic breast cancer, in particular liver metastatic forms, and recent studies on the impact of diets on disease progression and treatment.

Histopathological growth patterns of liver metastasis: updated consensus guidelines for pattern scoring, perspectives and recent mechanistic insights.

The first consensus guidelines for scoring the histopathological growth patterns (HGPs) of liver metastases were established in 2017. Since then, numerous studies have applied these guidelines, have further substantiated the potential clinical value of the HGPs in patients with liver metastases from various tumour types and are starting to shed light on the biology of the distinct HGPs. In the present guidelines, we give an overview of these studies, discuss novel strategies for predicting the HGPs of liver metastases, such as deep-learning algorithms for whole-slide histopathology images and medical imaging, and highlight liver metastasis animal models that exhibit features of the different HGPs. Based on a pooled analysis of large cohorts of patients with liver-metastatic colorectal cancer, we propose a new cut-off to categorise patients according to the HGPs. An up-to-date standard method for HGP assessment within liver metastases is also presented with the aim of incorporating HGPs into the decision-making processes surrounding the treatment of patients with liver-metastatic cancer. Finally, we propose hypotheses on the cellular and molecular mechanisms that drive the biology of the different HGPs, opening some exciting preclinical and clinical research perspectives.

Shedding light on liver metastasis in pancreatic cancer

Shedding light on liver metastasis in pancreatic cancer

Automated detection and segmentation of small cell lung cancer liver metastases on CT.

e13555 Background: Small cell lung cancer (SCLC) is a highly malignant cancer that commonly metastasizes throughout the body (mSCLC) and is molecularly classified based on expression of four transcription regulators (NAPY): NeuroD1, ASCL1. POU2F3, and YAP1. Medical imaging is used for treatment monitoring and patient management. Due to the relatively rare occurrence of this disease, large cohorts of data are not available for training. The purpose of this work is to develop a model for automated detection and segmentation of mSCLC liver metastases by leveraging publicly available data and characterize its output against NAPY subtyping. Methods: Two datasets were used: (1) the Liver Tumor Segmentation Challenge (LiTS), a public dataset containing 130 CT scans and (2) 23 patients with mSCLC imaged at our institution with biopsy-confirmed SCLC metastasis to the liver and available NAPY subtyping. N = 12 mSCLC scans underwent ground truth lesion segmentation by an experienced radiologist (&gt; 10yrs) using ITK-Snap. The LiTS dataset was split to 80/12/8 for training/validation/testing. The mSCLC data was reserved for testing. CT scans were resampled to uniform z-spacing of 1mm and Hounsfield range. A liver organ segmentation model based on 2D UNet and liver lesion segmentation model based on DeepLabV3+ were trained using Fast.ai library. Random flipping, rotation, erasing, and variable CT windowing were applied in each batch. Hyperparameters included cross-entropy loss, Adam optimization, batch size 32, input size [512,512], 1e-4 learning rate, 100 epochs, pre-trained weights from ImageNet. The final liver volume was selected as largest 3D-connected component of output and was used as input to lesion segmentation. Segmentation performance was evaluated by Dice Similar Coefficient (DSC). AI-based lesion segmentations were used to extract 106 shape and texture features (PyRadiomics) for association to NAPY subtypes using logistic regression analysis accounting for the clustered nature of lesion data on the patient-level. Results: The liver model achieved median DSC 0.952 (range (0.926-0.964) and 0.958 (range 0.933-0.969) in the LiTs validation and testing sets, respectively. Lesion segmentation results in validation and testing sets achieved median DSC 0.639 (0-0.848) and 0.523 (0-0.878), respectively. This model demonstrated acceptable generalizabilty in the mSCLC patients from our institution with median Dice coefficient 0.696 (0.102-0.882). Overall, the model achieved 62.1% sensitivity and 88.2% PPV with median 1 FP/image (range 0-4) from 53 ground-truth lesions. Sensitivity analysis showed lesions &gt; 2mm3 had excellent detection performance. AI-based Maximum 2D Diameter and GLCM Difference Entropy were significantly associated with NA vs. PY subtypes across 29 lesions with available outcomes. Conclusions: AI-based models have potential for CT-based disease characterization of liver metastases in mSCLC.

Is cure possible for breast cancer metastatic to the liver?

1099 Background: Metastatic breast cancer (MBC) is a lethal disease and is generally only amenable to systemic treatment. Although increasingly recommended on selected patients, local treatments, and particularly surgery, are seldom used in the therapeutic armamentarium for MBC and their long-term survival benefit is unknown. We hypothesized that combining surgery to systemic treatment for selected patients with breast cancer liver metastases could lead to long-term survival or even an option of cure. Methods: A retrospective study of prospectively gathered data from a surgical series of liver resections for MBC was conducted. Patients with no or limited and stable extra-hepatic disease were offered surgery after multidisciplinary discussion, if the liver metastases were responding to systemic treatment and were amenable to complete macroscopic resection. Five- and ten-year actual survivors were identified and their characteristics were explored. Results: From 1984 to 2020, 207 female patients underwent liver resections for MBC in our institution. There was no postoperative mortality. Postoperative complication rate was 23.3% and liver-specific complication rate was 19.0%. There was a total of 48 repeat hepatectomies. Median disease-free interval between initial breast cancer and liver metastasis was 36 ± 90.1 months. There was a median of 2 ± 1.8 liver metastases at diagnosis with a median size of 33.0 ± 18.3 mm and 73.1% of patients had radiological response before resection. Five- and ten-year overall survivals (OS) as well as 5- and 10-year disease-free survivals (DFS) were 39.6% and 12.7% as well as 14.2% and 6.4%, respectively. Median OS was 44.0 ± 47.2 months in the whole series. Focusing on the 5- and 10-year survivors, median OS were 89.5 ± 44.7 months and 144.0 ±42.6 months, respectively. In the 10-year survivors’ group, median DFS was 98 ±62.3 months. Observed survivals in this study underestimate true actual survivals owing to censoring of patients lost to follow-up. Conclusions: Long-term survival (≥ 5 years) as well as a curative perspective (≥ 10 years survival) are achievable for selected patients with breast cancer liver metastases by combining surgery to systemic treatment. Considering the recent improvements in the results of systemic treatments, introducing surgical resection in the treatment sequences of MBC could play an even more beneficial role.

Nanocomplex therapy for metastatic liver cancer

Nanocomplex therapy for metastatic liver cancer

Simple systemic index associated with oxaliplatin-induced liver damage can be a novel biomarker to predict prognosis after resection of colorectal liver metastasis.

Oxaliplatin, an anticancer drug for advanced colorectal cancer, causes liver sinusoidal damage, sometimes with portal hypertension. We conducted a retrospective comparative study of the relationship of liver sinusoidal disorders and liver function with the prognosis in patients who underwent hepatectomy for colorectal liver metastasis (CRLM). In total, 158 patients who underwent hepatectomy for CRLM were included in the study, and the effect of chemotherapy-associated liver damage on the prognosis was examined. Preoperative oxaliplatin was used in 75 of 158 patients; of these 75 patients, 26 had intraoperative blue liver (BL). In a comparison of the BL group (n=26) and non-BL group (n=132), patients in the BL group had a significantly lower serum albumin concentration and a significantly higher indocyanine green test result, aspartate aminotransferase-to-platelet ratio index (APRI), and FIB-4 score. Operative morbidities were not significantly different between the two groups. The overall survival rate after hepatectomy was significantly worse in the BL group than in the non-BL group. In the univariate analysis, the serum albumin concentration, indocyanine green test, a high tumor burden score (TBS), and the APRI were statistically significant poor prognostic factors. In the multivariate analysis, the APRI and a high TBS were independent poor prognostic factors. The APRI and TBS in patients with CRLM are prognostic predictors after hepatectomy for metastatic liver cancer. This study indicated that liver damage in patients treated with preoperative oxaliplatin has an effect on the prognosis.

Quantitative Proteomics of Hepatic Drug-Metabolizing Enzymes and Transporters in Patients With Colorectal Cancer Metastasis.

The impact of liver cancer metastasis on protein abundance of 22 drug‐metabolizing enzymes (DMEs) and 25 transporters was investigated using liquid chromatography‐tandem accurate mass spectrometry targeted proteomics. Microsomes were prepared from liver tissue taken from 15 healthy individuals and 18 patients with cancer (2 primary and 16 metastatic). Patient samples included tumors and matching histologically normal tissue. The levels of cytochrome P450 (CYPs 2B6, 2D6, 2E1, 3A4, and 3A5) and uridine 5′‐diphospho‐glucuronosyltransferases (UGTs 1A1, 1A6, 1A9, 2B15, 2B4, and 2B7) were lower in histologically normal tissue from patients relative to healthy controls (up to 6.6‐fold) and decreased further in tumors (up to 21‐fold for CYPs and 58‐fold for UGTs). BSEP and MRPs were also suppressed in histologically normal (up to 3.1‐fold) and tumorous tissue (up to 6.3‐fold) relative to healthy individuals. Abundance of OCT3, OAT2, OAT7, and OATPs followed similar trends (up to 2.9‐fold lower in histologically normal tissue and up to 16‐fold lower in tumors). Abundance of NTCP and OCT1 was also lower (up to 9‐fold). Interestingly, monocarboxylate transporter MCT1 was more abundant (3.3‐fold) in tumors, the only protein target to show this pattern. These perturbations could be attributed to inflammation. Interindividual variability was substantially higher in patients with cancer. Proteomics‐informed physiologically‐based pharmacokinetic (PBPK) models of 50 drugs with different attributes and hepatic extraction ratios (Simcyp) showed substantially lower drug clearance with cancer‐specific parameters compared with default parameters. In conclusion, this study provides values for decreased abundance of DMEs and transporters in liver cancer, which enables using population‐specific abundance for these patients in PBPK modeling.