Inetetamab combined with pyrotinib and chemotherapy in the treatment of breast cancer brain metastasis: A case report

BACKGROUND Breast cancer brain metastasis(BCBM)is an advanced breast disease that is difficult to treat and is associated with a high risk of death.Patient prognosis is usually poor,with reduced quality of life.In this context,we report the case of a patient with HER-2-positive BCBM treated with a macromolecular mAb(ine-tetamab)combined with a small molecule tyrosine kinase inhibitor(TKI).CASE SUMMARY The patient was a 58-year-old woman with a 12-year history of type 2 diabetes.She was compliant with regular insulin treatment and had good blood glucose control.The patient was diagnosed with invasive carcinoma of the right breast(T3N1M0 stage IIIa,HER2-positive type)through aspiration biopsy of the ipsilateral breast due to the discovery of a breast tumor in February 2019.Immunohistochemistry showed ER(-),PR(-),HER-2(3+),and Ki-67(55-60%+).Preoperative neoadjuvant chemotherapy,i.e.,the AC-TH regimen(epirubicin,cyclophosphamide,docetaxel-paclitaxel,and trastuzumab),was administered for 8 cycles.She underwent modified radical mastectomy of the right breast in November 2019 and received tocilizumab targeted therapy for 1 year.Brain metastasis was found 9 mo after surgery.She underwent brain metastasectomy in August 2020.Immunohistochemistry showed ER(-)and PR.(-),HER-2(3+),and Ki-67(10-20%+).In November 2020,the patient experienced headache symptoms.After an examination,tumor recurrence in the original surgical region of the brain was observed,and the patient was treated with inetetamab,pyrotinib,and capecitabine.Whole-brain radiotherapy was recommended.The patient and her family refused radiotherapy for personal reasons.In September 2021,a routine examination revealed that the brain tumor was considerably larger.The original systemic treatment was continued and combined with intensity-modulated radiation therapy for brain metastases,followed by regular hospitalization and routine examinations.The patient’s condition is generally stable,and she has a relatively high quality of life.This case report demonstrates that in patients with BCBM and resistance to trastuzumab,inetetamab combined with pyrotinib and chemotherapy can prolong survival.CONCLUSION Inetetamab combined with small molecule TKI drugs,chemotherapy and radiation may be an effective regimen for maintaining stable disease in patients with BCBM.

Apigenin is an anoikis sensitizer with strong anti-metastatic properties in experimental breast cancer

Loss of susceptibility to anoikis signals is a crucial step in metastasis.Anoikis resistance therefore represents a promising adjuvant therapeutic target for cancer management.In this study,we have conducted a rationalized screening to search for novel leading anoikis sensitizer from daily foods.Among 19 tested dietary phytochemicals,the best results were obtained with apigenin,a natural component of celery.Phenotypically,apigenin sensitized breast cancer cells to anoikis,lowered the number of circulating tumor cells,and protected against breast cancer metastasis to lung in mice.Mechanistically,we demonstrated that the thromboxane A_(2)(TXA_(2))-TXA_(2)receptor(TP)axis has a critical role in acquired anoikis resistance by activating PI3K-Akt signaling pathway.Blockage of TXA_(2)signaling up-regulated p53 as well as its target gene p21,caused a G1 phase arrest,and finally led to apoptosis in breast cancer cells.TXA_(2)level was positively correlated with breast cancer cell anoikis rate,and apigenin significantly inhibited TXA_(2)biosynthesis in vitro and in vivo.Collectively,we identified apigenin as a potent anoikis sensitizer with anti-metastatic properties in a mouse model of breast cancer,and these findings might provide a rationale for introducing apigenin supplementation to breast cancer patients.

Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival.The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect.To improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually decorated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone metastases.Doxorubicin(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size distribution.The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release.The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells.Rapid binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model.In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity.In conclusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

Breast metastasis from lung cancer：a report of two cases and literature review

Breast metastasis from extra-mammary malignancy is rare. An incidence of 0.4% to 1.3% has been reported in literature. The primary malignancies that most commonly metastasize to the breast are leukemia, lymphoma, and malignant melanoma. In this report, two cases of pulmonary metastasis to the breast were presented. A 40-year-old female manifested a right breast mass of 2-month duration. After physical examination was performed, a poorly defined mass was noted in the upper outer quadrant of the right breast. Another 49-year-old female manifested right breast mass of 5-day duration. A poorly defined mass was noted in the lower inner quadrant of the right breast. Mammography results also revealed breast cancer. The patients underwent local excision. After histological and immunohistochemical analyses were conducted, a primary lung carcinoma that metastasized to the breast was diagnosed. An accurate differentiation of metastasis to the breast from primary breast cancer is very important because the treatment and prognosis of the two differ significantly.

Ononin inhibits triple-negative breast cancer lung metastasis by targeting the EGFR-mediated PI3K/Akt/mTOR pathway

The spreading of cancer cells from the primary tumor site to other parts of the body,known as metastasis,is the leading cause of cancer recurrence and mortality in patients with triple-negative breast cancer(TNBC).Overexpression of epidermal growth factor receptor(EGFR)is observed in approximately 70%of TNBC patients.EGFR is crucial for promoting tumor metastasis and associated with poor prognosis.Therefore,it is vital to identify effective therapeutic strategies targeting EGFR inhibition.Ononin,an isoflavonoid found in various plants,such as clover and soybeans,has been shown to have anticancer properties in several cancers.In the present study,we aimed to investigate the effects of ononin on TNBC lung metastasis and the associated molecular pathways.We used various assays,including cell viability,colony formation,Transwell,wound healing,ELISA,Western blotting,and staining techniques,to achieve this objective.The results demonstrated that ononin effectively suppressed cellular proliferation and induced apoptosis,as evidenced by the cell viability assay,colony formation assay,and expression of apoptosis markers,and reduced the metastatic capabilities of TNBC cells.These effects were achieved through the direct suppression of cell adhesion,invasiveness and motility.Furthermore,in TNBC xenograft lung metastatic models,ononin treatment significantly reduced tumor growth and lung metastasis.Additionally,ononin reversed the epithelial-mesenchymal transition(EMT)by downregulating the expression of EMT markers and matrix metalloproteinases,as confirmed by Western blot analysis.Furthermore,ononin treatment reduced EGFR phosphorylation and suppressed the PI3K,Akt,and m TOR signaling pathways,which was further confirmed using EGFR agonists or inhibitors.Importantly,ononin treatment did not exert any toxic effects on liver or kidney function.In conclusion,our findings suggest that ononin is a safe and potentially therapeutic treatment for TNBC metastasis that targets the EGFRmediated PI3K/Akt/m TOR pathway.Further studies are warranted to validate its efficacy and explore its potential clinical applications.

A nanoagent for concurrent therapy of breast cancer bone metastasis and cancer-induced bone pain through SLC7A11 interruption and photodynamic therapy

Bone metastasis,a life-threatening complication of advanced breast cancer,is often accompanied by debilitating pain(cancer-induced bone pain,CIBP)that severely impairs life quality and survival.The concurrent treatment of bone metastases and CIBP remains a clinical challenge because the therapeutic options are limited.In this study,we construct a near-infrared light-activated nano-therapeutic system to meet this conundrum.In detail,sorafenib(SRF)and photosensitizer(chlorin e6,Ce6)are encapsulated into mesoporous hydroxyapatite nanoparticles(HANPs),which are further functionalized with hyaluronic acid(HA)to obtain HA-SRF/Ce6@HANPs system.The designed nanoplatform destroys tumor cells in vitro and in vivo via the synergism of SRF(interrupting the exchange of cystine/glutamate by inhibiting SLC7A11)and photodynamic therapy(PDT,inducing reactive oxygen species generation).The decrease in tumor burden and reduction of extracellular glutamate significantly attenuate CIBP in mice model with developing bone cancer.Moreover,the combination of HA-SRF/Ce6@HANPs and PDT inhibit osteoclasts activation,promote osteoblast differentiation and accelerate bone repair.Overall,the nanoagent with good biocompatibility may provide an effective therapy method for the concurrent treatment of breast cancer bone metastasis and CIBP.

Enterolactone modulates the ERK/NF-κB/Snail signaling pathway in triple-negative breast cancer cell line MDA-MB-231 to revert the TGF-β-induced epithelial–mesenchymal transition

Objective:Triple-negative breast cancer(TNBC)is highly metastatic,and there is an urgent unmet need to develop novel therapeutic strategies leading to the new drug discoveries against metastasis.The transforming growth factor-β(TGF-β)is known to promote the invasive and migratory potential of breast cancer cells through induction of epithelial–mesenchymal transition(EMT)via the ERK/NF-κB/Snail signaling pathway,leading to breast cancer metastasis.Targeting this pathway to revert the EMT would be an attractive,novel therapeutic strategy to halt breast cancer metastasis.Methods:Effects of enterolactone(EL)on the cell cycle and apoptosis were investigated using flow cytometry and a cleaved caspase-3 enzyme-linked immunosorbent assay(ELISA),respectively.Effects of TGF-βinduction and EL treatment on the functional malignancy of MDA-MB-231 breast cancer cells were investigated using migration and chemo-invasion assays.The effects of EL on EMT markers and the ERK/NF-κB/Snail signaling pathway after TGF-βinduction were studied using confocal microscopy,quantitative reverse transcription polymerase chain reaction(q RT-PCR),Western blot,and flow cytometry.Results:Herein,we report that EL exhibits a significant antimetastatic effect on MDA-MB-231 cells by almost reverting the TGF-β-induced EMT in vitro.EL downregulates the mesenchymal markers N-cadherin and vimentin,and upregulates the epithelial markers E-cadherin and occludin.It represses actin stress fiber formation via inhibition of mitogen-activated protein kinase p-38(MAPK-p38)and cluster of differentiation 44(CD44).EL also suppresses ERK-1/2,NF-κB,and Snail at the m RNA and protein levels.Conclusions:Briefly,EL was found to inhibit TGF-β-induced EMT by blocking the ERK/NF-κB/Snail signaling pathway,which is a promising target for breast cancer metastasis therapy.

Adipocyte-derived SFRP5 inhibits breast cancer cells migration and invasion through Wnt and epithelial-mesenchymal transition signaling pathways

Objective:Obesity is closely associated with metastasis in breast cancer patients.Secreted frizzled-related protein 5(SFRP5),one of the novel adipokines with anti-inflammatory properties,is associated with obesity.This study aims to study the role of SFRP5 in the crosstalk between obesity and breast cancer metastasis and identify the underlying mechanism.Methods:3T3-L1 pre-adipocytes were differentiated to mature adipocytes and a hypertrophic adipocyte model was induced with palmitic acid(PA).Cell motility was measured in MDA-MB-231 and MCF-7 breast cancer cells co-cultured with adipocytes conditioned medium(CM)with or without SFRP5 protein.Wnt and epithelialmesenchymal transition(EMT)signal pathways were investigated by western blot.Circulating SFRP5 level in 218 breast cancer patients and the association with clinicopathologic characteristics of breast cancer were further determined.Online databases ENCORI and PREDICT Plus were used to exam the link between SFRP5 and prognosis.Results:Reduced SFRP5 level was detected in the hypertrophic adipocyte model.Recombinant SFRP5 protein inhibited MDA-MB-231 and MCF-7 cells invasion and migration induced by PA-treated adipocyte CM,and SFRP5 inhibition by specific antibody reversed the effect of SFRP5.Furthermore,SFRP5 significantly inhibited Wnt and downstream EMT in breast cancer cells.Low circulating SFRP5 level correlated with body mass index(BMI),lymph node(LN)metastasis,TNM stage and high Ki67 expression in breast cancer patients.Increased SFRP5 level was associated with favorable predicted survival.Kaplan-Meier curves showed high SFRP5 level in tumor tissue was associated with better outcome of breast cancer patients.Conclusions:Our findings demonstrated SFRP5 is a vital adipokine that mediates the crosslink between obesity and the metastatic potential of breast cancer.Promotion of SFRP5 expression in the adipose microenvironment may represent a novel approach for preventing breast cancer metastasis.

Predicting survival and prognosis of postoperative breast cancer brain metastasis:a population-based retrospective analysis

Background:Breast cancer is one of the most common cancer in women and a proportion of patients experiences brain metastases with poor prognosis.The study aimed to construct a novel predictive clinical model to evaluate the overall survival(OS)of patients with postoperative brain metastasis of breast cancer(BCBM)and validate its effectiveness.Methods:From 2010 to 2020,a total of 310 female patients with BCBM were diagnosed in The Affiliated Cancer Hospital of Xinjiang Medical University,and they were randomly assigned to the training cohort and the validation cohort.Data of another 173 BCBM patients were collected from the Surveillance,Epidemiology,and End Results Program(SEER)database as an external validation cohort.In the training cohort,the least absolute shrinkage and selection operator(LASSO)Cox regression model was used to determine the fundamental clinical predictive indicators and the nomogram was constructed to predict OS.The model capability was assessed using receiver operating characteristic,C-index,and calibration curves.Kaplan-Meier survival analysis was performed to evaluate clinical effectiveness of the risk stratification system in the model.The accuracy and prediction capability of the model were verified using the validation and SEER cohorts.Results:LASSO Cox regression analysis revealed that lymph node metastasis,molecular subtype,tumor size,chemotherapy,radiotherapy,and lung metastasis were statistically significantly correlated with BCBM.The C-indexes of the survival nomogram in the training,validation,and SEER cohorts were 0.714,0.710,and 0.670,respectively,which showed good prediction capability.The calibration curves demonstrated that the nomogram had great forecast precision,and a dynamic diagram was drawn to increase the maneuverability of the results.The Risk Stratification System showed that the OS of lowrisk patients was considerably better than that of high-risk patients(P<0.001).Conclusion:The nomogram prediction model constructed in this study has a good predictive value,which can effectively evaluate the survival rate of patients with postoperative BCBM.

All-stage targeted therapy for the brain metastasis from triple-negative breast cancer

Brain metastasis is a common and serious complication of breast cancer,which is commonly associated with poor survival and prognosis.In particular,the treatment of brain metastasis from triplenegative breast cancer(BM-TNBC)has to face the distinct therapeutic challenges from tumor heterogeneity,circulating tumor cells(CTCs),blood-brain barrier(BBB)and blood-tumor barrier(BTB),which is in unmet clinical needs.Herein,combining with the advantages of synthetic and natural targeting moieties,we develop a“Y-shaped”peptide pVAP-decorated platelet-hybrid liposome drug delivery system to address the all-stage targeted drug delivery for the whole progression of BM-TNBC.Inherited from the activated platelet,the hybrid liposomes still retain the native affinity toward CTCs.Further,the peptide-mediated targeting to breast cancer cells and transport across BBB/BTB are demonstrated in vitro and in vivo.The resultant delivery platform significantly improves the drug accumulation both in orthotopic breast tumors and brain metastatic lesions,and eventually exhibits an outperformance in the inhibition of BM-TNBC compared with the free drug.Overall,this work provides a promising prospect for the comprehensive treatment of BMTNBC,which could be generalized to other cell types or used in imaging platforms in the future.

HBXIP blocks myosin-ⅡA assembly by phosphorylating and interacting with NMHC-ⅡA in breast cancer metastasis

Tumor metastasis depends on the dynamic balance of the actomyosin cytoskeleton.As a key component of actomyosin filaments,non-muscle myosin-ⅡA disassembly contributes to tumor cell spreading and migration.However,its regulatory mechanism in tumor migration and invasion is poorly understood.Here,we found that oncoprotein hepatitis B X-interacting protein(HBXIP) blocked the myosin-ⅡA assemble state promoting breast cancer cell migration.Mechanistically,mass spectrometry analysis,co-immunoprecipitation assay and GST-pull down assay proved that HBXIP directly interacted with the assembly-competent domain(ACD) of non-muscle heavy chain myosin-ⅡA(NMHC-ⅡA).The interaction was enhanced by NMHC-ⅡA S1916 phosphorylation via HBXIP-recruited protein kinase PKCβⅡ.Moreover,HBXIP induced the transcription of PRKCB,encoding PKCβⅡ,by coactivating Sp1,and triggered PKCβⅡ kinase activity.Interestingly,RNA sequencing and mouse metastasis model indicated that the anti-hyperlipidemic drug bezafibrate(BZF) suppressed breast cancer metastasis via inhibiting PKCβⅡ-mediated NMHC-ⅡA phosphorylation in vitro and in vivo.We reveal a novel mechanism by which HBXIP promotes myosin-ⅡA disassembly via interacting and phosphorylating NMHC-ⅡA,and BZF can serve as an effective anti-metastatic drug in breast cancer.

CSF2 upregulates CXCL3 expression in adipocytes to promote metastasis of breast cancer via the FAK signaling pathway

Recent studies have demonstrated that cancer-associated adipocytes (CAAs) in the tumor microenvironment are involved in the malignant progression of breast cancer. However, the underlying mechanism of CAA formation and its effects on the development of breast cancer are still unknown. Here, we show that CSF2 is highly expressed in both CAAs and breast cancer cells. CSF2 promotes inflammatory phenotypic changes of adipocytes through the Stat3 signaling pathway, leading to the secretion of multiple cytokines and proteases, particularly C–X–C motif chemokine ligand 3 (CXCL3). Adipocyte-derived CXCL3 binds to its specific receptor CXCR2 on breast cancer cells and activates the FAK pathway, enhancing the mesenchymal phenotype, migration, and invasion of breast cancer cells. In addition, a combination treatment targeting CSF2 and CXCR2 shows a synergistic inhibitory effect on adipocyte-induced lung metastasis of mouse 4T1 cells in vivo. These findings elucidate a novel mechanism of breast cancer metastasis and provide a potential therapeutic strategy for breast cancer metastasis.

Radiofrequency ablation versus hepatic resection for breast cancer liver metastasis: a systematic review and meta-analysis

Objective： To evaluate the comparative therapeutic efficacy of radiofrequency ablation （RFA） and hepatic resection （HR） for breast cancer liver metastases （BCLMs）. Methods： Studies that had examined the outcomes for both RFA and HR for BCLM were identified by searching the electronic databases PubMed, EMBASE, and the Cochrane Library. Pooled analyzes of the overall survival （OS）, disease-free survival （DFS）, and short-term outcomes of BCLM were performed. Results： Patients with BCLM gained many more survival benefits from HR than from RFA with regard to the 3-year OS rate （combined odds ratio （OR） 0.41, 95% confidence interval （CI） 0.29-0.59, P〈0.001）, 5-year OS rate （combined OR 0.38, 95% CI 0.32-0.46, P〈0.001）, 3-year DFS （combined OR 0.36, 95% CI 0.27-0.49, P〈0.001）, and 5-year DFS （combined OR 0.51, 95% CI 0.40-0.66, P〈0.001）. RFA had fewer postoperative compli- cations （combined OR 0.30, 95% CI 0.20-0.44, P〈0.001） and shorter hospital stays （combined OR -9.01, 95% CI -13.49-4.54, P〈0.001） than HR. Conclusions： HR takes precedence over RFA in the treatment of patients with BCLM, considering the better survival rate. RFA gives rise to fewer complications and can be carried out with a shorter hos- pital stay, compared to HR. RFA should be reserved for patients who are not optimum candidates for resection.

Inhibition of furin by bone targeting superparamagnetic iron oxide nanoparticles alleviated breast cancer bone metastasis

Breast cancer bone metastasis poses significant challenge for therapeutic strategies.Inside the metastatic environment,osteoclasts and tumor cells interact synergistically to promote cancer progression.In this study,the proprotein convertase furin is targeted due to its critical roles in both tumor cell invasion and osteoclast function.Importantly,the furin inhibitor is specifically delivered by bone targeting superparamagnetic iron oxide(SPIO)nanoparticles.Our in vitro and in vivo data demonstrate that this system can effectively inhibit both osteoclastic bone resorption and breast cancer invastion,leading to alleviated osteolysis.Therefore,the bone targeting&furin inhibition nanoparticle system is a promising therapeutic and diagnostic strategy for breast cancer bone metastasis.

Brucine Inhibits Bone Metastasis of Breast Cancer Cells by Suppressing Jagged1/Notch1 Signaling Pathways

Objective： To examine the effects of brucine on the invasion, migration and bone resorption of receptor activator of nuclear factor-kappa B ligand（RANKL）-induced osteoclastogenesis. Methods： The osteoclastogenesis model was builded by co-culturing human breast tumor MDA-MB-231 and mouse RAW264.7 macrophages cells. RANKL（50 ng/m L） and macrophage-colony stimulating factor（50 ng/m L） were added to this system, followed by treatment with brucine（0.02, 0.04 and 0.08 mmol/L）, or 10 μmol/L zoledronic acid as positive control. The migration and bone resorption were measured by transwell assay and in vitro bone resorption assay. The protein expressions of Jagged1 and Notch1 were investigated by Western blot. The expressions of transforming growth factor-β1（TGF-β1）, nuclear factor-kappa B（NF-κB） and Hes1 were determined by enzyme-linked immunosorbent assay. Results： Compared with the model group, brucine led to a dose-dependent decrease on migration of MDA-MB-231 cells, inhibited RANKL-induced osteoclastogenesis and bone resorption of RAW264.7 cells（P 〈0.01）. Furthermore, brucine decreased the protein levels of Jagged1 and Notch1 in MDA-MB-231 cells and RAW264.7 cells co-cultured system as well as the expressions of TGF-β1, NF-κB and Hes1（P〈0.05 or P〈0.01）. Conclusion： Brucine may inhibit osteoclastogenesis by suppressing Jagged1/Notch1 signaling pathways.

DKK1 determines organotropism of breast cancer metastasis by regulating microenvironments

Supported by the National Natural Science Foundation of China,a collaborative study by the laboratories of Dr.Hu Guohong(胡国宏)from Shanghai Institutes for Biological Sciences,Chinese Academy of Sciences and Dr.Yang Qifeng(杨其峰)from Shangdong University demonstrates that Dickkopf1(DKK1)

Effective nanotherapeutic approach for metastatic breast cancer treatment by supplemental oxygenation and imaging-guided phototherapy

Metastasis remains the primary cause for mortality of breast cancer.Despite advances in current therapeutic agents,patients with metastatic breast cancer still have poor prognoses.Tumor hypoxia,a key microenvironment factor,is emerging as an attractive target to prevent metastasis and is also involved with resistance to phototherapy.Here,we show an effective nanotherapeutic approach based on manganese dioxide-coated polydopamine nanocarriers to trigger robust anti-tumor and anti-metastasis responses against metastatic breast cancer by supplemental oxygenation and multimodal imaging-guided phototherapies.In cancer cells,the produced oxygen by the developed nanoplatform decreases the expression of hypoxia-inducible factors 1 a to inhibit tumor metastasis,and enhances the efficacy of photodynamic therapy.This nanotherapeutic approach enables the combined photodynamic/photothermal treatments with great inhibition on cell migration and invasion in vitro.Moreover,the nanotherapeutics effectively suppresses primary tumor progress and inhibits lung metastasis in v ivo in a breast cancer mouse model with satisfying biosafety.This study suggests that the tumor hypoxia-targeting nanotherapeutics have great potential for preventing and treating metastatic cancers.

Role of surgical resection for non-colorectal non-neuroendocrine liver metastases

It is widely accepted that the indications for hepatectomy in colorectal cancer liver metastases and liver metastases of neuro-endocrine tumors result in relatively better prognoses, whereas, the indications and prognoses of hepatectomy for non-colorectal non-neuroendocrine liver metastases(NCNNLM) remain controversial owing to the limited number of cases and the heterogeneity of the primary diseases. There have been many publications on NCNNLM; however, its background heterogeneity makes it difficult to reach a specific conclusion. This heterogeneous disease group should be discussed in the order from its general to specific aspect. The present review paper describes the general prognosis and risk factors associated with NCNNLM while specifically focusing on the liver metastases of each primary disease. A multidisciplinary approach that takes into consideration appropriate timing for hepatectomy combined with chemotherapy may prolong survival and/or contribute to the improvement of the quality of life while giving respite from systemic chemotherapy.