AGEs induce MMP-9 promoter demethylation through the GADD45α-mediated BER pathway to promote breast cancer metastasis in patients with diabetes.

Scientific evidence has linked diabetes to a higher incidence and increased aggressiveness of breast cancer; however, mechanistic studies of the numerous regulators involved in this process are insufficiently thorough. Advanced glycation end products (AGEs) play an important role in the chronic complications of diabetes, but the mechanisms of AGEs in breast cancer are largely unexplored. In this study, we first demonstrate that high AGE levels in breast cancer tissues are associated with the diabetic state and poor patient outcomes. Furthermore, AGEs interact with the receptor for AGEs (RAGE) to promote breast cancer cell migration and invasion. Mechanistically, based on RNA sequencing (RNA-seq) analysis, we reveal that growth arrest and DNA damage gene 45α (GADD45α) is a vital protein upregulated by AGEs through a P53-dependent pathway. Next, GADD45α recruits thymine DNA glycosylase for base excision repair to form the demethylation complex at the promoter region of MMP-9 and enhance MMP-9 transactivation through DNA demethylation. Overall, our results indicate a critical regulatory role of AGEs in patients with breast cancer and diabetes and reveal a novel mechanism of epigenetic modification in promoting breast cancer metastasis.

Serum HER2 Level Predicts Therapeutic Efficacy and Prognosis in Advanced Breast Cancer Patients.

Background: The purpose of this study was to investigate the therapeutic efficacy and prognosis of serum HER2 (sHER2) in patients with advanced breast cancer. Methods: We analyzed the sHER2 levels of 200 patients with advanced breast cancer receiving first or second line treatment, the tissue HER2 (tHER2) level was also analyzed. Indicators of therapeutic efficacy and prognosis were objective response rate (ORR), disease control rate (DCR), and time to progression (TTP). Results: The baseline sHER2 level was high in 132 patients and low in 68 patients. The high level of sHER2 is correlated with molecular subtype (p=0.016), visceral metastasis (p<0.001), liver metastasis (p<0.001), tissue HER-2 (tHER2) (p=0.001), and, among tHER2-low tumors (59 patients), the baseline sHER2 high level was associated with a higher proportion of brain metastasis. The ORR of patients with baseline sHER2 high level is higher than those with baseline sHER2 low level (p=0.026). The TTP of patients with baseline sHER2 low level is longer than the patients with baseline sHER2 high level (p=0.024). For patients with baseline sHER2 high level, a significant decrease in sHER2 after two cycles of treatment indicates higher ORR, DCR, and an extension of TTP. After multiple cycles of treatment, for patients with tHER-2 positive and baseline sHER2 high level, the DCR in the sHER2 decrease in the negative group was higher than that in the continuous positive group (p=0.037). Patients with a rapid decline type of sHER2 dynamic change curve had higher ORR and prolonged TTP compared with patients with other types of sHER2 dynamic change curve. There is no correlation between OS and sHER2 levels. Conclusion: Our study showed that patients with advanced breast cancer had a high level of sHER2 at recurrence, regardless of whether they are tHER2 positive or negative. Dynamic detection of sHER2 can help predict therapeutic efficacy and prognosis, regardless of whether tHER-2 is positive or negative.

Bioinformatics analysis of human kallikrein 5 (KLK5) expression in metaplastic triple-negative breast cancer.

Background: Metaplastic breast carcinoma (MBC) is a rare breast cancer subtype; most cases are triple-negative breast cancers (TNBCs) and are poorly responsive to conventional systemic therapy. Few potential diagnostic and prognostic markers for distinguishing between metaplastic TNBC and nonmetaplastic TNBC have been discovered. We performed bioinformatic analysis to explore the underlying mechanism by which metaplastic TNBC differs from nonmetaplastic TNBC and provides potential pathogenic genes of metaplastic TNBC. Methods: Differentially expressed genes (DEGs) in metaplastic tumors and nonmetaplastic tumors from TNBC patients were screened using GSE165407. The GSE76275 data set and The Cancer Genome Atlas (TCGA) database were used to screen DEGs in TNBC and non-TNBC. Metascape and DAVID were used for the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and Gene Ontology (GO) analysis of DEGs. Online databases, including UALCAN, GEPIA, HPA, Breast Cancer Gene-Expression Miner, and quantitative PCR and western blot, were used to examine KLK5 messenger RNA and protein expression in breast cancer. Analysis of KLK5­associated genes was performed with TCGA data, and the LinkedOmics database was used to detect the genes co-expressed with KLK5. STRING (Search Tool for the Retrieval of Interacting Genes) and Cytoscape were used to screen for hub genes. Kaplan­Meier plotter was used for survival analysis. Results: KLK5 was identified among the DEGs in nonmetaplastic TNBC and metaplastic TNBC. The KLK5 gene was overexpressed in nonmetaplastic TNBC but downregulated in metaplastic TNBC. KEGG and GO analyses revealed that epithelial-to-mesenchymal transition was a pathogenic mechanism in metaplastic TNBC and an important pathway by which KLK5 and its associated genes DSG1 and DSG3 influence metaplastic TNBC progression. Prognosis analysis showed that only low expression of KLK5 in metaplastic TNBC had clinical significance. Conclusion: Our research indicated that KLK5 may be a pivotal molecule with a key role in the mechanism of tumorigenesis in metaplastic TNBC.

Pharmacokinetics, pharmacodynamics and efficacy of pemigatinib (a selective inhibitor of fibroblast growth factor receptor 1-3) monotherapy in Chinese patients with advanced solid tumors: a phase i clinical trial.

Pemigatinib is a selective fibroblast growth factor receptor (FGFR)1-3 inhibitor and has demonstrated acceptable tolerability and clinical activity in advanced solid tumors in Western population. This phase I trial evaluated pharmacokinetics/pharmacodynamics (PK/PD) characteristics, preliminary safety and efficacy of pemigatinib in Chinese patients with advanced, solid tumors. Patients with unresectable advanced or metastatic solid tumors bearing FGF/FGFR1-3 alterations received oral pemigatinib at 13.5 mg once daily (QD) on a 2-weeks-on/1-week-off schedule. The primary endpoint was PK/PD characteristics; secondary endpoints were safety and efficacy. Twelve patients were enrolled (median age: 61 years, 58.3% males). PK data demonstrated pemigatinib (13.5 mg QD) was rapidly absorbed with a geometric mean elimination half-life of 11.3 h. The geometric mean values of maximum serum concentration and area under the plasma concentration-time curve from 0 to 24 h at steady state were 215.1 nmol/L and 2636.9 h·nmol/L, respectively. The mean clearance adjusted by bioavailability at steady state was low (11.8 L/h), and the apparent oral volume of distribution was moderate (170.5 L). The PD marker, serum phosphate level, increased on days 8 and 15 of cycle 1 (mean: 2.25 mg/dL, CV% [percent coefficient of variation]: 31.3%) and decreased to baseline post 1 week off. Three (25.0%) patients experienced grade ≥ 3 treatment-emergent adverse events. Partial response was confirmed in one patient with FGFR1-mutant esophageal carcinoma and one with FGFR2-mutant cholagiocarcinoma. Pemigatinib had similar PK/PD characteristics to Western population and demonstrated an acceptable safety profile and potential anti-cancer benefit in Chinese patients with FGF/FGFR1-3 altered, advanced, solid tumor. (ClinicalTrials.gov: NCT04258527 [prospectively registered February 6, 2020]).

The mixed subtype has a worse prognosis than other histological subtypes: a retrospective analysis of 217 patients with metaplastic breast cancer.

OBJECTIVE: Metaplastic breast cancer (MpBC) is an aggressive subtype of all breast cancer. We aimed to investigate the clinicopathological features, treatments and prognoses of MpBC patients. METHODS: We collected the data from MpBC patients diagnosed at Tianjin Medical University Cancer Hospital from 2010 to 2017. Kaplan Meier curves and Cox regression model were used to evaluating clinical outcomes and prognostic factors. After removing baseline differences by propensity score matching (PSM), we analyzed the prognosis between MpBC patients and invasive ductal carcinomas of no special type (IDC-NST) patients. RESULTS: A total of 217 MpBC patients were subsumed. Of all histological subtypes, 45.1% were mixed subtypes, followed by with mesenchymal differentiation (27.2%), pure squamous (15.2%) and pure spindle (12.4%) subtypes. 69.6% of MpBC were triple-negative, 25.3% and 6.5% were HR-positive and HER2-positive. MpBC patients had worse survival compared to IDC-NST patients, with 5-year RFS of 73.8 and 83.6% (HR = 1.177 95%CI (1.171-2.676) P = 0.0068), and 5-year BCSS of 79.0% and 89.7% (HR = 2.187 95%CI (1.357-3.523) P = 0.0013). In the multivariate COX model, AJCC stage, mixed subtype and chemotherapy were independent prognostic factors. Mixed MpBC is more aggressive than pure and with heterologous mesenchymal differentiation subtypes. And whether squamous or spindle MpBC, mixed forms have shorter outcomes than pure forms. CONCLUSIONS: MpBCs are associated with poorer prognoses than IDC-NSTs. They are heterogeneous with different clinicopathological features and clinical outcomes between histological subtypes. Pure and with heterologous mesenchymal differentiation subtypes have more survival benefits than the mixed subtype.

HDAC6-dependent deacetylation of AKAP12 dictates its ubiquitination and promotes colon cancer metastasis.

Aberrant expression of histone deacetylase 6 (HDAC6) is greatly involved in neoplasm metastasis, which is a leading cause of colon cancer related death. Thus, deep understanding of the regulatory mechanisms of HDAC6 in the metastasis of colon cancer is warranted. In this study, we firstly found that HDAC6 expression was highly expressed in metastatic colon cancer tissues and inhibition or knockdown of HDAC6 suppressed colon cancer metastasis. Next, based on proteomic analysis we uncovered A-kinase anchoring protein 12 (AKAP12) was a novel substrate of HDAC6. HDAC6 interacted with AKAP12 and deacetylated the K526/K531 residues of AKAP12. Moreover, deacetylation of AKAP12 at K531 by HDAC6 increased its ubiquitination level, which facilitated AKAP12 proteasome-dependent degradation. Importantly, we observed an inverse correlation between AKAP12 and HDAC6 protein levels with human colon cancer specimens. Further deletion of AKAP12 in HDAC6 knockdown cells restored the cell motility defects and reactivated the protein kinase C isoforms, repression of which were responsible for the inhibition of cancer metastasis of AKAP12. Our study identified AKAP12 was a new interactor and substrate of HDAC6 and uncovered a novel mechanism through which HDAC6-dependent AKAP12 deacetylation led to its ubiquitination mediated degradation and promoted colon cancer metastasis.

A multicenter randomized trials to compare the bioequivalence and safety of a generic doxorubicin hydrochloride liposome injection with Caelyx ® in advanced breast cancer.

Purpose: To compare the pharmacokinetic (PK) bioequivalence (BE) and safety of a generic pegylated liposomal doxorubicin (PLD) formulation with the reference product Caelyx®. Methods: A multicenter, single-dose, open-label, randomized, two-way crossover study was conducted in patients with breast cancer. For each period, the patients were administered with the test or the reference PLD intravenously at a dose of 50 mg/m2. Cmax, AUC0-t and AUC0-∞ for free, and encapsulated doxorubicin (doxorubicin) and partial AUC (AUC0-48h, AUC48h-t) for encapsulated doxorubicin were evaluated in 17 blood samples taken predose, and increasing time intervals over the following 14 days in each period. A washout period of 28-35 days was observed before crossing over. Results: 48 patients were enrolled and randomised, of which 44 were included and analysed in bioequivalence set (BES). The 90% confidence intervals (CIs) of the geometric mean ratio (GMR) of Cmax, AUC0-t and AUC0-∞ for free doxorubicin and encapsulated doxorubicin all fall within the bioequivalent range of 80% to 125%. The 90% CIs of GMR of partial AUC (AUC0-48h, AUC48h-t) for encapsulated doxorubicin also fall within the bioequivalent range. 48 patients were all included in the safety set (SS). The incidence of treatment-emergent adverse events (TEAEs) related to T and R was 95.8% (46/48) and 97.8% (45/46) respectively. The highest incidence of TEAEs was various laboratory abnormalities. 2 patients withdrew due to T-drug-related AEs. Only one patient experienced serious adverse events and no death occurred in this study. There were no significant differences between the safety profiles of the generic formulation and Caelyx®. Conclusions: Bioequivalence between the test and the reference products was established for free and encapsulated doxorubicin. Clinical trial registration: http://www.chinadrugtrials.org.cn, identifier [CTR20210375].

CACA Guidelines for Holistic Integrative Management of Breast Cancer.

Purpose: Breast cancer is now the most common malignant tumor worldwide. About one-fourth of female cancer patients all over the world suffer from breast cancer. And about one in six female cancer deaths worldwide is caused by breast cancer. In terms of absolute numbers of cases and deaths, China ranks first in the world. The CACA Guidelines for Holistic Integrative Management of Breast Cancer were edited to help improve the diagnosis and comprehensive treatment in China. Methods: The Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to classify evidence and consensus. Results: The CACA Guidelines for Holistic Integrative Management of Breast Cancer include the epidemiology of breast cancer, breast cancer screening, breast cancer diagnosis, early breast cancer treatment, advanced breast cancer treatment, follow-up, rehabilitation, and traditional Chinese medicine treatment of breast cancer patients. Conclusion: We to standardize the diagnosis and treatment of breast cancer in China through the formulation of the CACA Guidelines.

Tolerance and Pharmacokinetics of Recombinant Human Endostatin Administered as Single-Dose or Multiple-Dose Infusions in Patients With Advanced Solid Tumors: A Phase I Clinical Trial.

Objective: This study aimed to investigate the tolerance and pharmacokinetic characteristics of recombinant human endostatin (rh-endostatin) administered as single-dose or multiple-dose infusions in patients with advanced solid tumors. Methods: This phase I trial was designed as a single-center, single-arm, nonrandomized, open-label, dose-escalation study. The trial consisted of 2 parts: a single-dose part and a multiple-dose part, each with 3 dose comparison groups. Rh-endostatin was administered as an intravenous injection only once at a dose of 5 mg/m2, 7.5 mg/m2, or 10 mg/m2 in the single-dose part and as a daily intravenous injection for 14 days at the same doses in the multiple-dose part. The serum pharmacokinetics, toxicity and immunogenicity of rh-endostatin were evaluated. Results: Dose-limiting toxicity (DLT) was not observed in any group. A few patients developed cardiotoxicity, such as QT prolongation or narrow arrhythmia. Other adverse events were slight coagulation abnormalities and haematological abnormalities. For rh-endostatin doses of 5 mg/m2, 7.5 mg/m2, and 10 mg/m2, the mean Cmax values in the single-dose part were 344 ± 38.7 ng/mL, 524 ± 157 ng/mL, and 800 ± 201 ng/mL, respectively, and the average AUC0-t values were 3290 ± 3790 ng•h/mL, 4940 ± 4380 ng•h/mL, and 5050 ± 3980 ng•h/mL, respectively. The Cmax ss values of the 3 doses in the multiple-dose part were 575 ± 270 ng/mL, 531 ± 106 ng/mL, and 864 ± 166 ng/mL, respectively, and the AUC0-τ values were 3610 ± 1040 ng•h/mL, 3290 ± 1090 ng•h/mL, and 5180 ± 1210 ng•h/mL, respectively. The Cmax of a single-dose regimen showed linear kinetic characteristics. The patients in the single-dose group were negative for serum antibodies against rh-endostatin, while one patient in the multiple-dose group was positive. Conclusions: Rh-endostatin as a daily intravenous injection for 14 days in patients with advanced solid tumors is safe and well tolerated, without DLT, at doses of 5 mg/m2, 7.5 mg/m2, and 10 mg/m2. Serum antibodies against rh-endostatin were very low after multiple infusions. For phase II trials, the recommended rh-endostatin dose is 10 mg/m2 as a daily intravenous injection for 14 days.

Successful Use of Nivolumab in a Patient with Head and Neck Cancer After Allogeneic Bone Marrow Transplantation.

Recently, programmed cell death 1(PD-1) inhibitors have shown a significant curative effect in the treatment of most solid cancers and some hematological malignancies. The effects of PD-1 inhibitors in recurrent head and neck squamous cell carcinoma (HNSCC) have also been confirmed. However, there is a lack of reliable clinical evidence to confirm the safety and efficacy of PD-1 inhibitors in patients after allogeneic hematopoietic stem cell transplantation, especially when the patient has a second primary cancer. Generally, graft-versus-host disease (GVHD) is unpredictable among these patients. Here we report the case of a patient who successfully used nivolumab without any GVHD or other immune-related adverse events for HNSCC after allogeneic bone marrow transplantation because of the Philadelphia chromosome-positive T cell acute lymphoblastic leukemia.

Romidepsin (FK228) regulates the expression of the immune checkpoint ligand PD-L1 and suppresses cellular immune functions in colon cancer.

Romidepsin (FK228), a histone deacetylase inhibitor (HDACi), has anti-tumor effects against several types of solid tumors. Studies have suggested that HDACi could upregulate PD-L1 expression in tumor cells and change the state of anti-tumor immune responses in vivo. However, the influence of enhanced PD-L1 expression in tumor cells induced by romidepsin on anti-tumor immune responses is still under debate. So, the purpose of this study was to explore the anti-tumor effects and influence on immune responses of romidepsin in colon cancer. The results indicated that romidepsin inhibited proliferation, induced G0/G1 cell cycle arrest and increased apoptosis in CT26 and MC38 cells. Romidepsin treatment increased PD-L1 expression in vivo and in vitro via increasing the acetylation levels of histones H3 and H4 and regulating the transcription factor BRD4. In subcutaneous transplant tumor mice and colitis-associated cancer (CAC) mice, romidepsin increased the percentage of FOXP3+ regulatory T cells (Tregs), decreased the ratio of Th1/Th2 cells and the percentage of IFN-γ+ CD8+ T cells in the peripheral blood and the tumor microenvironment. Upon combination with an anti-PD-1 antibody, the anti-tumor effects of romidepsin were enhanced and the influence on CD4+ and CD8+ T cells was partially reversed. Therefore, the combination of romidepsin and anti-PD-1 immunotherapy provides a more potential treatment for colon cancer.

Phase I dose-escalation and expansion study of PARP inhibitor, fluzoparib (SHR3162), in patients with advanced solid tumors.

OBJECTIVE: Fluzoparib (SHR3162) is a novel, potent poly(ADP-ribose) polymerases (PARP)1, 2 inhibitor that showed anti-tumor activity in xenograft models. We conducted a phase I, first-in-human, dose-escalation and expansion (D-Esc and D-Ex) trial in patients with advanced solid cancer. METHODS: This was a 3+3 phase I D-Esc trial with a 3-level D-Ex at 5 hospitals in China. Eligible patients for D-Esc had advanced solid tumors refractory to standard therapies, and D-Ex enrolled patients with ovarian cancer (OC). Fluzoparib was administered orally once or twice daily (bid) at 11 dose levels from 10 to 400 mg/d. Endpoints included dose-finding, safety, pharmacokinetics, and antitumor activity. RESULTS: Seventy-nine patients were enrolled from March, 2015 to January, 2018 [OC (47, 59.5%); breast cancer (BC) (16, 20.3%); colorectal cancer (8, 10.1%), other tumors (8, 10.1%)]; 48 patients were treated in the D-Esc arm and 31 in the D-Ex arm. The maximum tolerated dose (MTD) was 150 mg bid, with a half-life of 9.14 h. Grade 3/4 adverse events included anemia (7.6%) and neutropenia (5.1%). The objective response rate (ORR) was 30% (3/10) in patients with platinum-sensitive OC and 7.7% (1/13) in patients with BC. Among patients treated with fluzoparib ≥120 mg/d, median progression-free survival (mPFS) was 7.2 [95% confidence interval (95% CI), 1.8-9.3] months in OC, 9.3 (95% CI, 7.2-9.3) months in platinum-sensitive OC, and 3.5 (range, 2.0-28.0) months in BC. In patients with germline BC susceptibility gene mutation (gBRCA Mut) (11/43 OC; 2/16 BC), mPFS was 8.9 months for OC (range, 1.0-23.2; 95% CI, 1.0-16.8) and 14 and 28 months for BC (those two patients both also had somaticBRCA Mut). CONCLUSIONS: The MTD of fluzoparib was 150 mg bid in advanced solid malignancies. Fluzoparib demonstrated single-agent antitumor activity in BC and OC, particularly in BRCA Mut and platinum-sensitive OC.

Pharmacokinetic and bioequivalence study of new S-1 capsule in Chinese cancer patients.

S-1 is a multicomponent capsule containing tegafur, gimeracil, and oteracil potassium that has shown anticancer activity against numerous tumor types. However, S-1 capsules from different manufacturing companies have shown variations in pharmacokinetics and safety. Therefore, this multicenter, single-dose, randomized-sequence, open-label, two-way, self-crossover study was conducted to evaluate the bioequivalence of a newly developed generic S-1 (New Times Pharmaceutical Co., Ltd., Shandong, China) and the original brand-name S-1 capsule (Taiho Pharmaceutical Co., Ltd., Japan). Furthermore, the safety profiles of both products were compared. A total of 70 patients with 18 types cancer including breast, lung, gastric, and colorectal recruited at 5 hospitals who were randomly and alternatively administered 50 mg of the reference and test S-1 with a 7-day interval. Plasma concentrations of tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), oteracil potassium, and 5-fluorouracil were detected using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters, including maximum drug concentration (Cmax), time to achieve Cmax (Tmax), half-life (t1/2, area under the concentration-time curve from 0-time t (AUC0-t), and AUC from 0-infinity (AUC0-∞) were determined using non-compartmental analysis with DAS2.0 software. Bioequivalence of the reference and test S-1 was evaluated according to 90% confidence intervals (CIs) for ratios of AUC and Cmax of S-1. Adverse events were evaluated by monitoring symptoms, physical and laboratory examinations, electrocardiogram, and subject interviews. No significant difference was observed in plasma concentrations and pharmacokinetic profiles of tegafur, CDHP, oteracil potassium, or 5-fluorouracil (p > 0.05) among cancer patients treated with the reference or test S-1 formulation. The 90% CIs of Cmax, AUC0-t, and AUC0-∞ ratios were within the 80%-125% limit. The generic S-1 caused eight mild adverse events including liver dysfunction, diarrhea, nausea, fatigue, abnormal blood electrolytes, hyperglycemia, and dermal toxicity. Similarly, 18 mild adverse events were observed including dysarteriotony, diarrhea, nausea, fatigue, fever, hematotoxicity, abnormal blood electrolytes, hyperglycemia, dermal toxicity, and joint pain. There were no differences in the adverse event incidence between the two formulations. In conclusion, the newly developed generic S-1 showed similar pharmacokinetics to those of an original brand-name S-1 in cancer patients, thereby indicating bioequivalence. Furthermore, both treatments were well tolerated, suggesting that the cost-effective generic S-1 should be considered as a feasible option when treating patients.

Construction of differentially expressed Her-2 related lncRNA-mRNA-miRNA ceRNA network in Her-2 positive breast cancer.

BACKGROUND: Her-2 positive subtype breast cancer is characterized as Her-2 gene amplification with poor survival and increased invasiveness accounting for 20-30% of invasive infiltrated breast cancer. A lncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) network is constructed to detect Her-2 specific RNAs in the development and progression of HER-2 positive breast cancer which may overcoming the anti-HER-2 therapy resistance of breast cancer cells. METHODS: One thousand one hundred and nine breast cancer samples obtained from The Cancer Genome Atlas (TCGA) database were classified into two cohorts including ER+/PR+ (n=461) and ER-/PR- breast cancer (n=152). Differently expressed mRNAs, lncRNAs and miRNAs were screened in ER+/PR+ and ER-/PR- breast cancer cohorts, respectively. lncRNA-miRNA interactions were preformed to predicted and verified by miRcode. miRNA-mRNA interactions were selected to predict targeted mRNAs of miRNAs by miRanda, Targetscan and miRTarBase. RESULTS: lncRNA-miRNA-mRNA ceRNA network was constructed by retained lncRNAs, miRNAs and mRNAs. Fifteen DEmiRNAs, 129 DElncRNAs and 269 DEmRNAs were retained in ER+/PR+ cohort after intersection with DEmiRNAs, DElncRNAs and DEmRNAs between breast cancer and normal tissues. Six hundred and ninety-three DEmRNAs, 25 DEmiRNAs and 364 DElncRNAs were retained in ER-/PR- cohort. ceRNA network in ER+/PR+ breast cancer cohort was constructed of the interactions of 4 DElncRNA-DEmiRNA pairs and 2 DEmiRNA-DEmRNA pairs included 4 DElncRNAs, 1 DEmiRNAs, and 2 DEmRNAs. ceRNA network in ER-/PR- breast cancer cohort was constructed of the interactions of 24 DElncRNA-DEmiRNA pairs and 1 DEmiRNA-DEmRNA pairs included 19 DElncRNAs, 4 DEmiRNAs, and 1 DEmRNA. MIR7-3HG- hsa-mir-204-NTRK2 axis was identified in both ER+/PR+ and ER-/PR- cohort in our study. CONCLUSIONS: Based on the ceRNA hypothesis, a potential Her-2 related regulatory ceRNA networks are constructed which may provide novel insights into the mechanism underlying the biological processes of Her-2 positive breast cancer.

Efficacy and safety of the VEGFR2 inhibitor Apatinib for metastatic soft tissue sarcoma: Chinese cohort data from NCT03121846.

BACKGROUND: There is no standard treatment for stage IV soft tissue sarcoma (STS) after the failure of Adriamycin-based chemotherapy. This phase II study (NCT03121846) assessed the efficacy and safety of apatinib (YN968D1), a new tyrosine kinase inhibitor that targets VEGFR-2, for patients with stage IV STS after chemotherapy failure. METHODS: Forty-two subjects with stage IV STSs who had failed chemotherapy and who received Apatinib were recruited between September 2015 and February 2018. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were the PFS rate (PFR), objective response rate (ORR), and disease control rate (DCR) at week 12. Treatment-related adverse effects (AEs) were evaluated. RESULTS: Forty-two subjects were evaluated for AEs and 38 subjects were evaluated for efficacy. At 12 weeks, the PFR, ORR, and DCR were 70%, 26.32% (10/38), and 86.84% (33/38), respectively. Regarding overall responses, the ORR and DCR were 23.68% (9/38) and 57.89% (22/38), respectively. The median PFS was 7.87 months, and the median overall survival (OS) was 17.55 months. The most common AEs included hypertension (n = 18, 42.86%), hand-foot-skin reaction (n = 15, 35.71%), apositia (n = 13, 30.95%), and proteinuria (n = 11, 26.19%). No subjects had grade 4 AEs and 11 subjects (26.19%) experienced grade 3 AEs, mainly hypertension, hand-foot-skin reaction, proteinuria, apositia, fatigue, pain, and dysgeusia. Notably, the subjects who experienced hypertension, hand-foot-skin reaction, or proteinuria had significantly longer OS than those without these AEs (P = 0.0003). CONCLUSION: With the largest Chinese STS cohort to date, we report that apatinib show good efficacy in advanced STS subjects with significant higher ORR and some adverse events may predict prognosis.

Integrated Analysis of mRNA-miRNA-lncRNA ceRNA Network in Human HR+/Her-2- Breast Cancer and Triple Negative Breast Cancer.

Breast cancer is a heterogeneous disease highly diverse in different subtypes, including hormone receptor positive and hormone receptor negative subtypes with variable malignancy, therapy regimen, and different prognosis. In this study, we develop a hormone receptor-specific mRNA-miRNA-lncRNA ceRNA network to identify whether several RNAs play fundamental roles in development and metastasis of breast cancer. To understand the association of ceRNA expression profiles in different breast cancer subgroups, the expression profiles and clinical information of 428 HR+/Her-2- breast cancer samples and 113 triple negative breast cancer samples were downloaded from The Cancer Genome Atlas database (TCGA). We comprehensively integrated and compared expression profiles of mRNAs, miRNAs, and lncRNAs between the two subgroups mentioned. Aberrantly expressed hormone receptor specific RNAs were identified, whereas lncRNA-miRNA interactions predicted by miRcode and miRNA-targeted mRNA interactions were validated by miRTarBase, Targetscan, and miRDB database. In this study, mRNA-miRNA-lncRNA ceRNA network was constructed that consisted of 44 miRNA-lncRNA interaction pairs and 2 miRNA-mRNA interaction pairs, and visualized by Cytoscape software. Prognostic markers of HR-specific subtype of breast cancer associated with overall survival were identified by Kaplan-Meier survival analysis. Finally, SFRP1, AC006449.1, and MUC2 were novel clinical predictors that may also provide a new therapeutic target in the future.

Correction to: Efficacy and Safety of Supportive Care Biosimilars Among Cancer Patients: A Systematic Review and Meta­Analysis.

The authors unintentionally included in the meta-analysis both the initial abstract and the final paper of the study by Puertolas et al. [45, 48]. In order to remove this duplication, the following corrections are required.

Efficacy and Safety of Anti-cancer Biosimilars Compared to Reference Biologics in Oncology: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Many biosimilars of monoclonal antibodies (mAbs) are becoming increasingly available as anticancer therapies, such as the rituximab, bevacizumab, and trastuzumab biosimilars. However, no comprehensive summary of their efficacy and safety is available. OBJECTIVE: This study synthesized current evidence on the efficacy and safety of mAb biosimilars relative to their reference biologics among cancer patients. METHODS: We searched PubMed, Embase, the Cochrane library, ClinicalTrials.gov, the ISI Web of Science, and several Chinese databases from their inception dates to December 31, 2018, for randomized controlled trials (RCTs) or comparative observational studies that compared the efficacy and safety of biosimilars with reference biologics used in oncology. The binary outcomes were pooled using risk ratio (RR) with 95% confidence intervals (CIs), continuous outcomes using weighted mean difference (WMD) with 95% CIs, and time-to-event outcomes using hazard ratios (HRs). Subgroup and sensitivity analyses were conducted following this. We used the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach to rate the quality of the evidence. RESULTS: We did not find any comparative observational studies that fit the criteria. Twenty-three RCTs were identified for biosimilars of three mAbs, of which eight RCTs examined rituximab biosimilars (total N = 1534), six RCTs were for bevacizumab biosimilars (total N = 1897), and nine were for trastuzumab biosimilars (total N = 4953), respectively. The quality of the GRADE evidence for efficacy and safety outcomes was moderate or low. The findings were robust for all pre-specified subgroup and sensitivity analyses. CONCLUSION: The existing evidence suggests highly comparable efficacy and safety profiles between mAb biosimilars and their reference biologics in oncological drugs.