A ferroptosis amplifier based on triple-enhanced lipid peroxides accumulation strategy for effective pancreatic cancer therapy.

As an iron dependent regulatory cell death process driven by excessive lipid peroxides (LPO), ferroptosis is recognized as a powerful weapon for pancreatic cancer (PC) therapy. However, the tumor microenvironment (TME) with hypoxia and elevated glutathione (GSH) expression not only inhibits LPO production, but also induces glutathione peroxidase 4 (GPX4) mediated LPO clearance, which greatly compromise the therapeutic outcomes of ferroptosis. To address these issues, herein, a novel triple-enhanced ferroptosis amplifier (denoted as Zal@HM-PTBC) is rationally designed. After intravenous injection, the overexpressed H2O2/GSH in TME induces the collapse of Zal@HM-PTBC and triggers the production of oxygen and reactive oxygen species (ROS), which synergistically amplify the degree of lipid peroxidation (broaden sources). Concurrently, GSH consumption because of the degradation of the hollow manganese dioxide (HM) significantly weakens the activity of GPX4, resulting in a decrease in LPO clearance (reduce expenditure). Moreover, the loading and site-directed release of zalcitabine further promotes autophagy-dependent LPO accumulation (enhance effectiveness). Both in vitro and in vivo results validated that the ferroptosis amplifier demonstrated superior specificity and favorable therapeutic responses. Overall, this triple-enhanced LPO accumulation strategy demonstrates the ability to facilitate the efficacy of ferroptosis, injecting vigorous vitality into the treatment of PC.

Correlation Between miR-497-5p Expression With Clinicopathological Characteristics and Prognosis in Patients With Breast Cancer.

Breast cancer (BC) comprises multiple biological and histologic properties. MicroRNAs show key functions in cancer prognosis. This paper explored the relationship between miR-497-5p with clinicopathological characteristics and prognosis in BC. Cancer tissues and normal adjacent tissues (NATs) were collected from 140 included patients with BC. The clinical baseline data, including age, tumor size, pathologic grade, clinical stage, modified Scraff-Bloom-Richardson grade, and lymph node metastasis, were recorded. miR-497-5p expression in cancer tissues and NAT was determined by reverse transcription-quantitative polymerase chain reaction. Patients with BC were followed up for 5 years to record their survival. Patients were divided into the miR-497-5p low expression and high expression groups to assess the correlation between miR-497-5p expression with clinicopathological characteristics and overall survival of patients. The role of miR-497-5p as an independent risk factor for death was further analyzed by a multivariate Cox regression model. miR-497-5p was downregulated in BC tissues than NAT. Tumor size, clinical stage, and lymph node metastasis showed significant differences among patients with high and low miR-497-5p expression levels. Patients with BC with low miR-497-5p expression presented decreased survival. Lowly-expressed miR-497-5p was an independent risk factor for death in patients. Collectively, cancer tissue miR-497-5p low expression increases the risk of death and serves as an independent risk factor for death in patients with BC.

Mucin1 as a potential molecule for cancer immunotherapy and targeted therapy.

Mucin1 is a highly glycosylated type 1 transmembrane mucin that ranks second among 75 tumor-related antigens published by the National Cancer Institute, and has been identified as a possible therapeutic target over the past 30 years. MUC1 plays an important role in malignant transformation and disease evolution, including cell proliferation, survival, self-renewal, and metastatic invasion. MUC1 has been shown to interact with diverse effectors such as ß-catenin, receptor tyrosine kinases, and cellular-abelsongene, which are of importance in the pathogenesis of various malignant tumors. Targeting MUC1 has been shown to be an effective way to induce tumor cell death in vivo and in vitro models. In recent years, a number of therapeutic strategies targeting MUC1 have been developed and their value for tumor therapy have been demonstrated experimentally. This review summarizes recent findings on the structure of MUC1, its expression in different tumors and its involved mechanism pathways, with emphasis on new progress in cancer therapy which related MUC1 in the past decade and evaluates their therapeutic effect.

CuS Nanoparticles-Loaded and Cisplatin Prodrug Conjugated Fe(III)-MOFs for MRI-Guided Combination of Chemotherapy and NIR-II Photothermal Therapy.

Ovarian cancer has become an urgent threat to global female healthcare. Cisplatin, as the traditional chemotherapeutic agent against ovarian cancer, retains several limitations, such as drug resistance and dose-limiting toxicity. In order to solve the above problems and promote the therapeutic effect of chemotherapy, combining chemotherapy and phototherapy has aroused wide interest. In this study, we constructed a versatile cisplatin prodrug-conjugated therapeutic platform based on ultrasmall CuS-modified Fe(III)-metal-organic frameworks (MIL-88) (named M-Pt/PEG-CuS) for tumor-specific enhanced synergistic chemo-/phototherapy. After intravenous injection, M-Pt/PEG-CuS presented obvious accumulation in tumor and Fe(III)-MOFs possessed magnetic resonance imaging (MRI) to guide synergy therapy. Both in vitro and in vivo experimental results showed that M-Pt/PEG-CuS could not only successfully inhibit tumor growth by combining chemotherapy and NIR-II PTT but also avoid the generation of liver damage by the direct treatment of cisplatin(II). Our work presented the development of the nanoplatform as a novel NIR-II photothermal agent, as well as gave a unique combined chemo-photothermal therapy strategy, which might provide new ways of ovarian cancer therapy for clinical translation.

Carbonic anhydrase IX-targeted H-APBC nanosystem combined with phototherapy facilitates the efficacy of PI3K/mTOR inhibitor and resists HIF-1α-dependent tumor hypoxia adaptation.

BACKGROUND: Non-redundant properties such as hypoxia and acidosis promote tumor metabolic adaptation and limit anti-cancer therapies. The key to the adaptation of tumor cells to hypoxia is the transcriptional and stable expression of hypoxia-inducible factor-1 alpha (HIF-1α). The phosphorylation-activated tumorigenic signal PI3K/AKT/mTOR advances the production of downstream HIF-1α to adapt to tumor hypoxia. Studies have elucidated that acid favors inhibition of mTOR signal. Nonetheless, carbonic anhydrase IX (CAIX), overexpressed on membranes of hypoxia tumor cells with pH-regulatory effects, attenuates intracellular acidity, which is unfavorable for mTOR inhibition. Herein, a drug delivery nanoplatform equipped with dual PI3K/mTOR inhibitor Dactolisib (NVP-BEZ235, BEZ235) and CAIX inhibitor 4-(2-aminoethyl) benzene sulfonamide (ABS) was designed to mitigate hypoxic adaptation and improve breast cancer treatment. RESULTS: ABS and PEG-NH2 were successfully modified on the surface of hollow polydopamine (HPDA), while BEZ235 and Chlorin e6 (Ce6) were effectively loaded with the interior of HPDA to form HPDA-ABS/PEG-BEZ235/Ce6 (H-APBC) nanoparticles. The release of BEZ235 from H-APBC in acid microenvironment could mitigate PI3K/mTOR signal and resist HIF-1α-dependent tumor hypoxia adaptation. More importantly, ABS modified on the surface of H-APBC could augment intracellular acids and enhances the mTOR inhibition. The nanoplatform combined with phototherapy inhibited orthotopic breast cancer growth while reducing spontaneous lung metastasis, angiogenesis, based on altering the microenvironment adapted to hypoxia and extracellular acidosis. CONCLUSION: Taken together, compared with free BEZ235 and ABS, the nanoplatform exhibited remarkable anti-tumor efficiency, reduced hypoxia adaptation, mitigated off-tumor toxicity of BEZ235 and solved the limited bioavailability of BEZ235 caused by weak solubility.

Prognostic implications of combined high expression of CD47 and MCT1 in breast cancer: a retrospective study during a 10-year period.

Background: Clinical outcome after surgery of breast cancer needs more prognostic markers to predict currently. Cluster of differentiation 47 (CD47), due to its overexpression in various tumors and ability to inhibit phagocytosis, has been identified as a new immune checkpoint. Monocarboxylate transporter 1 (MCT1) is a protein involved in the immunomodulatory activities of the tumor microenvironment (TME) by maintaining the pH through aerobic glycolysis. Methods: We explored the expression of CD47 and MCT1 in breast invasive ductal carcinoma specimens to determine their association with prognosis. A total of 137 breast invasive ductal carcinoma tissues were collected for CD47 and MCT1 immunohistochemical staining. Results: Statistically analyzed, our study first indicated that in both univariate and multivariate analyses, the coexpression of CD47 and MCT1 was an independent prognostic factor for a poor 10-year overall survival rate (10-OS) and 10-year progression-free survival rate (10-DFS) (P<0.05). In addition, the combined high expression of these two markers also led to worse OS and PFS rates in the TNM (II + III), histologic grade (I + II), HER2 overexpression and basal-like subgroups. High expression of CD47 and MCT1 and combined high expression of CD47 and MCT1 were associated with clinicopathological parameters, such as histological grade, TNM stage, death status, and recurrence status in breast cancer patients. However, in the multivariate survival analysis, high expression of CD47 alone was not an independent prognostic factor for the 10-OS or the 10-DFS (P=0.104; P=0.153), and high expression of MCT1 alone was not an independent predictor for a poor 10-DFS (P=0.177) either. Conclusions: The coexpression of CD47 and MCT1 can serve as a prognostic biomarker leading to poor survival and an increased risk for recurrence, and this novel information could help guide the development of adjuvant therapy for breast cancer.

Immune Myocarditis Overlapping With Myasthenia Gravis Due to Anti-PD-1 Treatment for a Chordoma Patient: A Case Report and Literature Review.

Immunotherapy begins to be widely used due to the increasing exploration and gratifying effects in multiple cancers. Chordoma, as a rare bone malignant tumor, often recurs and metastasizes after undergoing surgery and radiotherapy. Therefore, immunotherapy can be explored as an emerging, potentially effective treatment to improve the survival rate and clinical benefit of patients. However, a variety of immune-related adverse events (irAEs) cannot be avoided completely. And the immunotherapy-induced myocarditis, as a rare but fatal irAE, has been increasingly reported. Understanding the mechanism involved in irAEs can inform best practices for side effects management. Here, we firstly reported a case of immune myocarditis and subsequent myasthenia gravis (MG) following anti-PD-1 treatment for chordoma.

Corrigendum: Programmable Ce6 Delivery via Cyclopamine Based Tumor Microenvironment Modulating Nano-System for Enhanced Photodynamic Therapy in Breast Cancer.

[This corrects the article DOI: 10.3389/fchem.2019.00853.].

Cytokine-induced killer cells-assisted tumor-targeting delivery of Her-2 monoclonal antibody-conjugated gold nanostars with NIR photosensitizer for enhanced therapy of cancer.

Maximizing the accumulation of anticancer medicine in the tumor is the priority to achieve minimal invasive cancer therapy, which raises high demands on tumor-targeting ability of drug delivery systems. Herein, we adopted an emerging "cell-drug" strategy via the nanoplatform construction to achieve high aggregation and intratumoral distribution. We fabricated gold nanostars (GNSs) with HER-2 monoclonal antibody (trastuzumab) and near-infrared region (NIR) photosensitizer indocyanine green (ICG) to obtain GNS@ICG-Ab, which combined the photothermal therapy with photodynamic therapy (PTT/PDT) that rely on enhanced photothermal conversion efficiency of GNS and 1O2 generator ICG under the exposure of a NIR laser. Tumor-tropism CIK cells loaded with GNS@ICG-Ab were able to migrate into tumors and make a difference in efficient accumulation and uniform distribution of the GNS@ICG-Ab-CIK nanoplatform inside tumors based on fluorescence, photoacoustic (PA), and computed tomography (CT) imaging observations. Encouraged by the improvements in tumor targeting and retention presented by real-time imaging, we employed the novel nanoplatform to synergistically inhibit the progression of tumors in SK-BR-3 tumor-bearing mice via PTT/PDT and immunotherapy-implemented by CIK cells for activating the immune response, and with the specific linkage between trastuzumab and SK-BR-3 tumor cells, our platform could exert a precise strike of PDT/PTT. Taken together, the integrating tri-modal imaging with tri-modal therapy endows CIK-GNS@ICG-Ab with promising potential in cancer theranostics and lays a solid foundation for the development of immune cell application in nanomedicine delivery.

CDK12: A Potent Target and Biomarker for Human Cancer Therapy.

Cyclin-dependent kinases (CDKs) are a group of serine/threonine protein kinases and play crucial roles in various cellular processes by regulating cell cycle and gene transcription. Cyclin-dependent kinase 12 (CDK12) is an important transcription-associated CDK. It shows versatile roles in regulating gene transcription, RNA splicing, translation, DNA damage response (DDR), cell cycle progression and cell proliferation. Recently, increasing evidence demonstrates the important role of CDK12 in various human cancers, illustrating it as both a biomarker of cancer and a potential target for cancer therapy. Here, we summarize the current knowledge of CDK12, and review the research advances of CDK12's biological functions, especially its role in human cancers and as a potential target and biomarker for cancer therapy.

Senile Osteoporosis: The Involvement of Differentiation and Senescence of Bone Marrow Stromal Cells.

Senile osteoporosis has become a worldwide bone disease with the aging of the world population. It increases the risk of bone fracture and seriously affects human health. Unlike postmenopausal osteoporosis which is linked to menopause in women, senile osteoporosis is due to aging, hence, affecting both men and women. It is commonly found in people with more than their 70s. Evidence has shown that with age increase, bone marrow stromal cells (BMSCs) differentiate into more adipocytes rather than osteoblasts and undergo senescence, which leads to decreased bone formation and contributes to senile osteoporosis. Therefore, it is necessary to uncover the molecular mechanisms underlying the functional changes of BMSCs. It will benefit not only for understanding the senile osteoporosis development, but also for finding new therapies to treat senile osteoporosis. Here, we review the recent advances of the functional alterations of BMSCs and the related mechanisms during senile osteoporosis development. Moreover, the treatment of senile osteoporosis by aiming at BMSCs is introduced.

Post-synthesis strategy to integrate porphyrinic metal-organic frameworks with CuS NPs for synergistic enhanced photo-therapy.

Multifunctional nanotheranostic systems with both therapeutic and imaging functions are highly desired for the development of more effective and less toxic anti-tumor drugs. Herein, a simple but effective method is reported to fabricate a novel PCN-CuS-FA-ICG-based nanoplatform for dual-modal imaging-guided synergistic photothermal/photodynamic therapy. Porphyrinic metal-organic frameworks with CuS NPs are obtained in aqueous solution via a simple post-synthesis strategy. Furthermore, to obtain a more effective therapy, indocyanine green (ICG) was incorporated into the multifunctional theranostic platform to promote the photothermal therapeutic effect. The as-prepared PCN-CuS-FA-ICG not only exhibits an excellent 1O2 generation efficiency under 650 nm irradiation to achieve remarkable photodynamic cell killing, but also presents outstanding photothermal conversion under 808 nm irradiation to destroy tumor tissues by hyperthermia. In particular, the nanotherapeutic agent realized fluorescence and thermal imaging dual-modal imaging-guided cancer treatment. Meanwhile, in vivo experiments confirmed the evident accumulation of nanoparticles (NPs) at local tumors, and tumor growth was inhibited obviously via synergistic photothermal/photodynamic therapy with negligible side effects.

Programmable Ce6 Delivery via Cyclopamine Based Tumor Microenvironment Modulating Nano-System for Enhanced Photodynamic Therapy in Breast Cancer.

Photodynamic therapy (PDT) has shown great promise in breast cancer treatment. However, simplex target ligand modification or stimuli release cannot meet the requirement of effective drug delivery to solid tumor tissue. To overcome continuous bio-barriers existing in the tumor microenvironment, multi-stage response drug delivery was desirable. Herein, we developed a unique tumor microenvironment tailored nanoplatform for chlorin e6 (Ce6) delivery. We chose bovine serum albumin (BSA) as "mother ships" material for effective tumor periphery resident, cyclopamine (CYC) as extracellular matrix (ECM) inhibitor and synergistic anti-tumor agent, and diselenide containing amphiphilic hyaluronic acid-chlorin e6 polymers (HA-SeSe-Ce6) synthesized as "small bombs" for internal tissue destruction. The above three distinct function compositions were integrated into an independent CYC and HA-SeSe-Ce6 co-delivery albumin nano-system (ABN@HA-SeSe-Ce6/CYC). The obtained nano-system presents good biocompatible, long circulation and effective tumor accumulation. After entering tumor microenvironment, CYC gradually releases to disrupt the ECM barrier to open the way for further penetration of HA-SeSe-Ce6. Subsequently, targeted tumor cell internalization and intracellular redox response release of Ce6 would achieve. Moreover, CYC could also make up the deficiency of Ce6 in hypoxia area, owing to its anti-tumor effect. Improved therapeutic efficacy was verified in a breast cancer cell line and tumor-bearing mice model.

Tumor-Targeted Drug and CpG Delivery System for Phototherapy and Docetaxel-Enhanced Immunotherapy with Polarization toward M1-Type Macrophages on Triple Negative Breast Cancers.

Cancer immunotherapy has achieved promising clinical responses in recent years owing to the potential of controlling metastatic disease. However, there is a limited research to prove the superior therapeutic efficacy of immunotherapy on breast cancer compared with melanoma and non-small-cell lung cancer because of its limited expression of PD-L1, low infiltration of cytotoxic T lymphocytes (CTLs), and high level of myeloid-derived suppressor cells (MDSCs). Herein, a multifunctional nanoplatform (FA-CuS/DTX@PEI-PpIX-CpG nanocomposites, denoted as FA-CD@PP-CpG) for synergistic phototherapy (photodynamic therapy (PDT), photothermal therapy (PTT) included) and docetaxel (DTX)-enhanced immunotherapy is successfully developed. The nanocomposites exhibit excellent PDT efficacy and photothermal conversion capability under 650 and 808 nm irradiation, respectively. More significantly, FA-CD@PP-CpG with no obvious side effects can remarkably inhibit the tumor growth in vivo based on a 4T1-tumor-bearing mice modal. A low dosage of loaded DTX in FA-CD@PP-CpG can promote infiltration of CTLs to improve efficacy of anti-PD-L1 antibody (aPD-L1), suppress MDSCs, and effectively polarize MDSCs toward M1 phenotype to reduce tumor burden, further to enhance the antitumor efficacy. Taken together, FA-CD@PP-CpG nanocomposites offer an efficient synergistic therapeutic modality in docetaxel-enhanced immunotherapy for clinical application of breast cancer.

LINC01133 inhibits breast cancer invasion and metastasis by negatively regulating SOX4 expression through EZH2.

Mounting evidence highlights long non-coding RNAs (lncRNAs) as crucial regulators in multiple types of biological processes and contributing to tumourigenesis. LINC01133, located in chromosome 1q23.2, was a recently identified novel lncRNA with a length of 1154nt. It was involved in the development of colorectal cancer and non-small cell lung cancer. However, its clinical relevance, biological functions and potential molecular mechanism in breast cancer are still unclear. In this study, we found that the LINC01133 expression was significantly down-regulated in breast cancer samples and was associated with progression and poor prognosis of breast cancer. Further experiments demonstrated that overexpression of LINC01133 inhibited invasion and metastasis in breast cancer both in vitro and in vivo. Mechanistic investigations revealed that LINC01133 repressed SOX4 expression by recruiting EZH2 to SOX4 promoter. Moreover, rescue experiments further confirmed that LINC01133 functional acted as an anti-oncogene, at least partly, via repressing SOX4 in breast cancer. Taken together, these findings imply that LINC01133 could serve as a novel prognostic biomarker and potential therapeutic target for breast cancer.

Co-delivery of Cyclopamine and Doxorubicin Mediated by Bovine Serum Albumin Nanoparticles Reverses Doxorubicin Resistance in Breast Cancer by Down-regulating P-glycoprotein Expression.

Combination chemotherapy is considered to be one of the most effective treatments for breast cancer by reducing the emergence of drug resistance. In this study, a novel drug delivery system based on bovine serum albumin nanoparticles (BSA NPs) was successfully developed. Doxorubicin (DOX) and cyclopamine (CYC), a potential anti-cancer agent that inhibits the hedgehog signaling pathway were entrapped into BSA NPs through electrostatic interactions and hydrophobic interactions, respectively. Rather than simple combination of two different chemotherapeutics, the CYC also increased the intracellular DOX accumulation by decreasing the expression of P-glycoprotein (P-gp), which could thus reverse the DOX resistance. Tumor-targeting property of nanoparticles was the prerequisite for its further application. Interestingly, retention of fluorescently-labeled particles in vivo indicated that the dual-drug-loaded BSA NPs could not only target the primary tumors, but also target the metastatic lymph nodes, which would simultaneously inhibit the tumor growth and distant metastasis. Taken together, this study provides a promising strategy for co-delivery of drugs, tumor and metastatic lymph node targeting, and DOX resistance reversing in breast cancer chemotherapy.

Targeted Delivery of Chlorin e6 via Redox Sensitive Diselenide-Containing Micelles for Improved Photodynamic Therapy in Cluster of Differentiation 44-Overexpressing Breast Cancer.

The off-target activation of photosensitizers is one of the most well-known obstacles to effective photodynamic therapy (PDT). The selected activation of photosensitizers in cancer cells is highly desired to overcome this problem. We developed a strategy that enabled diselenide bonds to link hyaluronic acid (HA) and photosensitizer chlorin e6 (Ce6) to assemble the micelles (HA-sese-Ce6 NPs) that can target cancer and achieve a redox responsive release of drugs to enhance the PDT efficiency in breast cancer. The HA was used to form a hydrophilic shell that can target cluster of differentiation 44 (CD44) on the cancer cells. The selenium-containing core is easily dissembled in a redox environment to release Ce6. The triggered release of Ce6 in a redox condition and the positive feedback release by activated Ce6 were observed in vitro. In cytotoxicity assays and in vitro cellular uptake assays, the increased PDT efficiency and targeted internalization of HA-sese-Ce6 NPs in the cells were verified, compared to a free Ce6 treated group. Similar results were showed in the therapeutic study and in vivo fluorescence imaging in an orthotopic mammary fat pad tumor model. In addition, a significant inhibition of metastasis was found after the HA-sese-Ce6 NPs treatment. In general, this study promises an ingenious and easy strategy for improved PDT efficiency.

MT1JP inhibits tumorigenesis and enhances cisplatin sensitivity of breast cancer cells through competitively binding to miR-24-3p.

Accumulating evidence indicates that long non-coding RNAs (lncRNAs) play a key role in the development of many human cancers. MT1JP is a lncRNA that is reportedly involved in gastric cancer development, but a biological role and mechanism for MT1JP in breast cancer is unknown. Here, we found that MT1JP expression was significantly down-regulated in breast cancer tissues and cell lines, and that decreased MT1JP expression was associated with breast cancer progression and poor survival of breast cancer patients. Additionally, we found that overexpression of MT1JP in breast cancer cells significantly inhibited cell proliferation and invasion, and also enhanced the cisplatin sensitivity of breast cancer cells. We then investigated a possible mechanism for these results, finding that MT1JP binds to and negatively regulates miR-24-3p, which is known to be an oncogene in some human cancers. Our rescue experiments showed that the tumor suppressive and cisplatin-sensitizing functions of MT1JP were mediated by negative regulation of miR-24-3p. Finally, western blot results showed that MT1JP inhibited the Wnt/ß-catenin signaling pathway. Collectively, our data indicate that MT1JP functions as an anti-tumor lncRNA, enhances cisplatin sensitivity in breast cancer, and may serve as a novel diagnostic and therapeutic marker of breast cancer.

Metastatic gastric cancer from breast carcinoma: A report of 78 cases.

The metastatic spread of breast carcinoma to the stomach is rare. There are a small number of previous studies that report metastases from the breast to the stomach and these provide limited information regarding this infrequent event. Consequently, the clinicopathological features, clinical outcomes and the optimal treatment for these patients remain to be elucidated. In the present study, 78 cases of gastric metastases from breast cancer, including the current case, were identified from previous studies between 1960 and 2015. The clinicopathological features of primary breast tumors and metastatic gastric lesions, including initial stage, tumor size, hormone receptor status, treatment modalities and overall survival (OS) rate, were analyzed. The patients were all female and the median age at the time of gastric metastasis diagnosis was 59 years old (range, 38-86 years). The majority of the patients initially presented with stage II breast cancer (35.9%) and abdominal pain was the most common symptom of gastric metastases (75.6%). A total of 51/78 patients (65.4%) were identified to have a history of invasive lobular breast carcinoma and the majority of gastric tumors were positive for hormonal receptors and human epidermal growth factor receptor 2 (HER-2) negative (estrogen receptor, 94.0%; progesterone receptor, 68.3%; HER-2, 5.9%). Furthermore, in the univariate analysis, multiple organs involved prior to or at the time of gastric metastases were diagnosed and multiple gastric lesions and peritoneal carcinomatosis were significantly correlated with OS. Additionally, salvage hormonal therapy, but not surgery or chemotherapy, significantly extended OS. However, in the multivariate analysis, metastasis prior to stomach involvement was the only independent indicator of poor OS. In conclusion, physicians must be vigilant when patients with breast cancer history present with gastrointestinal symptoms, despite gastric metastasis from breast cancer being rare. An appropriate systemic therapeutic strategy that includes hormonal therapy may be beneficial for this group of patients.

A meta-analysis of combination therapy versus single-agent therapy in anthracycline- and taxane-pretreated metastatic breast cancer: results from nine randomized Phase III trials.

Nowadays, the philosophy of treating metastatic breast cancer (MBC) is slowly evolving. Especially for the anthracycline- and taxane-pretreated MBC patients, no standard therapy exists in this setting. Whether to choose doublet agents or single agent as salvage treatment remains fiercely debated. Thus, we conducted a meta-analysis to resolve this problem. Databases including PubMed, EMBASE, and Cochrane library were searched for Phase III randomized clinical trials (published before August 2015) comparing the efficacy and adverse effects between the combination therapy and single-agent therapy in anthracycline- and taxane-pretreated MBC patients. The primary end point was the overall survival (OS), and the secondary end points were the progression-free survival (PFS), overall response rate (ORR), and grade 3 or 4 toxicities. The pooled hazard ratio (HR) and pooled risk ratio (RR) were used to evaluate the efficacy. Analyses were also performed to estimate the side effects and safety of both groups. In all, nine eligible randomized clinical trials were included in this meta-analysis. Improvements were proven in the doublet agents group on OS (HR 0.90, 95% confidence interval [CI] 0.84-0.96, P=0.002), PFS (HR 0.81, 95% CI 0.76-0.88, P<0.001), and ORR (RR 1.72, 95% CI 1.34-2.21, P<0.001). Notably, subgroup analysis failed to favor the targeted agent-based combination in terms of OS (HR 1.08, 95% CI 0.89-1.31, P=0.365), PFS (HR 1.09, 95% CI 0.88-1.35, P=0.433), and ORR (RR 1.60, 95% CI 0.69-3.71, P=0.278) compared with single agent. In addition, although more hematological and gastrointestinal toxicities were observed in the doublet agents group, they were acceptable and manageable. Taken together, when compared with single-agent therapy, doublet agents should be considered a treatment option because of the superior efficacy and the manageable safety profile for the prior anthracycline- and taxane-treated MBC patients.