A real-world study of second or later-line osimertinib in patients with EGFR T790M-positive NSCLC: the final ASTRIS data.

Aim: Report the final analysis from ASTRIS, the largest real-world study of second-/later-line osimertinib in advanced/metastatic EGFR T790M non-small-cell lung cancer (NSCLC). Methods: Patients with advanced/metastatic EGFR T790M NSCLC and prior EGFR-TKI treatment, received once-daily osimertinib 80 mg. Primary end point: overall survival (OS); secondary end points: progression-free survival (PFS), time-to-treatment discontinuation (TTD) and response rate. Safety was also recorded. Results: In 3014 patients, median OS: 22.8 months (21.6-23.8), median PFS: 11.1 months (11.0-12.0), median TTD: 13.5 months (12.6-13.9), and response rate: 57.3% (55.5-59.2). All end points reported with 95% CIs. Numerically longer median OS was observed in patients with baseline WHO performance status <2 versus 2 (24.0 vs 11.1 months) and those without versus with brain/leptomeningeal metastases (25.4 vs 18.0 months). No new safety signals were identified. Conclusion: Second-/later-line osimertinib demonstrated real-world clinical benefit and safety in advanced/metastatic EGFR T790M NSCLC. Clinical Trial Registration: NCT02474355 (ClinicalTrials.gov).

Osimertinib is a drug that blocks the activity of a protein called EGFR on cancer cells, reducing their growth and spread. ASTRIS is the largest real-world study that evaluated the outcomes with osimertinib treatment for patients with advanced non-small-cell lung cancer (NSCLC), and the EGFR T790M mutation, who had received previous treatment for their cancer. There were 3014 patients included in this study. The main aim of this study was to measure the time at which half of the patients were still alive after starting osimertinib treatment, this was 22.8 months. The study also measured the time at which half of the patients had experienced worsening (progression) of their cancer (11.1 months) and the time when half of the patients had stopped receiving osimertinib treatment (13.5 months). None of the patients experienced any unexpected side effects of the treatment. These data are consistent with those observed in comparable clinical trials with osimertinib, supporting the use of osimertinib treatment for patients with advanced NSCLC and the EGFR T790M mutation after their initial cancer treatment has stopped working.

Efficacy and safety of recombinant human lymphotoxin-α derivative with cisplatin and fluorouracil in patients with metastatic esophageal squamous cell carcinoma: A randomized, multicenter, open-label, controlled, phase 2b trial.

BACKGROUND: Recombinant human lymphotoxin-α derivative (rhLTα-Da) is a lymphotoxin-α derivative that is missing 27 N-terminal amino acid residues. Previous studies indicated a benefit from the addition of rhLTα-Da to cisplatin-based treatment in patients with metastatic esophageal squamous cell carcinoma. The current study was conducted to evaluate the efficacy and safety of rhLTα-Da plus cisplatin and fluorouracil (PF) in patients with mESCC. METHODS: Patients from 15 centers in China were randomly assigned (1:1:1) to 3 arms (arm A, PF plus 10 µg/m2 daily rhLTα-Da; arm B, PF plus 20 µg/m2 daily rhLTα-Da; arm C, PF alone). The primary endpoints included progression-free survival (PFS) and the confirmed overall response rate (ORR). An exploratory analysis was performed to evaluate the role of serum tumor necrosis factor receptor II (TNFR II) in predicting the efficacy of rhLTα-Da. RESULTS: Between September 2010 and May 2013, 150 patients were enrolled. No significant differences in either PFS or ORR were observed between the 3 arms. However, in a small subset of patients who had low serum TNFR II levels, the median PFS was significantly longer for those in arm B than for these in other 2 arms (7.2 months [95% confidence interval, 5.1-8.6 months] for arm B vs 3.5 months [95% confidence interval, 1.7-5.5 months] for arm A [P = .022] and 4.0 months [95% confidence interval, 3.2-6.3 months] for arm C [P = .027]). The addition of rhLTα-Da significantly increased the incidence of chills (P < .001). CONCLUSIONS: rhLTα-Da combined with the PF regimen failed to improve PFS and ORR in patients with mESCC, except in a small subset that had low serum TNFR II concentrations. Cancer 2017;123:3986-94. © 2017 American Cancer Society.

Basigin-2 upregulated by receptor activator of NF-κB ligand enhances lung cancer-induced osteolytic lesions.

BACKGROUND: Lung cancer bone metastasis causes poor prognosis. Basigin-2, a novel cancer-associated biomarker, is upregulated in lung cancer and has been linked with tumor progression. But little is known about the role of basigin-2 in lung cancer bone metastasis and osteolytic lesion. METHODS: Basigin-2 expression was evaluated in biopsy tissue specimens of 20 lung cancer patients with bone metastases via immunohistochemistry. Invasion assay and MTT proliferation assay were performed to test the invasion and proliferation of lung cancer cell after modulated basigin-2 expression. The osteoclastic activity of basigin-2 was detected in tibia cancer model by injected of lung cancer cells. The regulation role of receptor activator of NF-κB ligand (RANKL) on basigin-2 and its downstream molecules were measured by real-time quantitative RT-PCR, gelatin zymography and western blot analysis. RESULTS: We found that basigin-2 was highly expressed in lung cancer bone metastases. Then, we demonstrated that basigin-2 could promote lung cancer cells invasion, metastasis and proliferation through upregulating metalloproteinases-2 (MMP-2), MMP-9 and vascular endothelial growth factor (VEGF) expression. The lung cancer cells overexpressing basigin-2 strongly induced the osteolytic lesions in immunodeficient mice, which were reduced by treatment with basigin-2 blocking antibody. Furthermore, we explored the enhanced basigin-2 molecular mechanism in lung cancer bone metastasis. Our results indicated the RANKL, pivotal for the control of bone resorption, could increase basigin-2 and its downstream molecules MMP-2, MMP-9 and VEGF expression in vitro. CONCLUSIONS: Basigin-2 upregulated by RANKL induces MMPs and VEGF, which may increase lung cancer cell metastasis ability and support osteoclastic activity. Thus, our data suggest important roles for basigin-2 in lung cancer-induced osteolytic lesion and implicate this protein potential application as a target for lung cancer bone metastasis therapy.

miR-10b is overexpressed in hepatocellular carcinoma and promotes cell proliferation, migration and invasion through RhoC, uPAR and MMPs.

BACKGROUND: Recently, miR-10b is identified as a miRNA highly expressed in many human cancers, promoting cell migration and invasion. However, the specific function of miR-10b in hepatocellular carcinoma (HCC) is unclear at this point. METHODS: The miR-10b expression levels in 60 paired different TNM Stage HCC tumor tissues compared with adjacent non-tumor (ANT) tissues, normal tissue control (8 benign tumor and 7 normal liver tissues), 3 normal liver and 7 HCC cell lines were measured by real-time quantitative RT-PCR and to evaluate their association with HCC clinicopathologic features. Invasion assay, MTT proliferation assay and wound-healing assay were performed to test the invasion and proliferation of HCC cell after transfection. The effect of miR-10b on HCC in vivo was validated by murine xenograft model. RESULTS: We found that miR-10b expression was increased in human HCC tissues and cell lines compared with normal control, respectively. The expression of miR-10b was correlated with HCC metastatic ability. Overexpression of miR-10b in MHCC-97L cells increased cell motility and invasiveness, whereas inhibition of miR-10b in MHCC-97H cells reduced cell motility and invasiveness in vitro and in vivo. We also showed that HOXD10 was negatively regulated by miR-10b at the posttranscriptional level, via a specific target site within the 3'UTR by luciferase reporter assay. Furthermore, we found that miR-10b induced HCC cell invasion and migration by modulating the HOXD10 target gene RhoC, uPAR, MMP-2 and MMP-9 expression. CONCLUSIONS: Our results suggested that miR-10b was overexpressed in HCC and promoted HCC cell migration and invasion through the HOXD10/ RhoC/ uPAR/ MMPs pathway which may provide a novel bio-target for HCC therapy.

Polymorphism of 8q24 rsl3281615 and breast cancer risk : a meta-analysis.

Several genome-wide association studies on breast cancer have reported similar findings of a new cancer susceptibility locus, 8q24 rsl3281615. Subsequent case-control studies have rapidly investigated the association between the single nucleotide polymorphism of rsl3281615 at chromosome 8q24 and breast cancer risk, but the effect of 8q24 rsl3281615 polymorphism on breast cancer is still unclear due to the inconsistence among those studies. Given the contradictory findings, a meta-analysis was performed to determine the association between 8q24 rsl3281615 polymorphism and breast cancer risk. 12 eligible case-control studies with a total of 42,508 cases and 53,928 controls were finally included into this meta-analysis by searching the PubMed, Embase, and China Biology Medicine (CBM) databases. We estimated the summary odds ratio (OR) with its corresponding 95 % confidence interval (95 % CI) to assess this association. Meta-analyses of total 12 studies showed 8q24 rsl3281615 polymorphism was significantly associated with an increased risk of breast cancer in all contrast models (OR(G vs. A) = 1.10, 95 % CI 1.05-1.14, P (OR) < 0.001; OR(GG vs. AA) = 1.20, 95 % CI 1.11-1.29, P (OR) < 0.001; OR(AG vs. AA) = 1.08, 95 % CI 1.05-1.12, P (OR) < 0.001; OR(GG vs. AA +AG) = 1.13, 95 % CI 1.07-1.19, P (OR) < 0.001; OR(GG+AG vs. AA) = 1.13, 95 % CI 1.07-1.19, P (OR) < 0.001). Meta-analyses of studies with high quality showed that 8q24 rsl3281615 polymorphism was still significantly associated with an increased risk of breast cancer under the five genetic contrast models. Sensitivity analyses by sequential omission of any individual studies and subgroup analyses by ethnicity further identified the significant association between 8q24 rsl3281615 polymorphism and breast cancer risk. Conclusively, this meta-analysis shows a significant association between 8q24 rsl3281615 polymorphism and breast cancer risk.

A bioequivalence study of trifluridine/tipiracil tablets in Chinese metastatic colorectal cancer patients under fed conditions.

PURPOSE: Colorectal cancer (CRC) is the second most common cause of cancer death worldwide. Trifluridine (FTD) remained at higher concentrations longer when administered along with tipiracil (TPI) compared with FTD alone. Lonsurf® is a combination formulation consisting of FTD and TPI. This study aimed to investigate the bioequivalence of FTD/TPI formulations in Chinese metastatic colorectal cancer (mCRC) patients. METHODS: In this phase I, randomized, open-label, single-dose, two-sequence, four-cycle crossover study in mCRC patients, the bioequivalence of 60 mg (20 mg tablet, 3 tablets) of the test formulation and the reference formulation (Lonsurf®) was evaluated. Due to its high variability, the method of reference-scaled average bioequivalence (RSABE) was used to investigate the bioequivalence of the test and reference formulations. RESULTS: Thirty-two patients were enrolled. 78.1% of the subjects were male, and the mean (standard deviation) age was 53.9 (SD = ± 9.0) years old. The time to reach the maximum plasma concentration (Tmax) was almost 2.0 h post-dose. The geometric least-squares mean ratios (GMRs) (test/reference) of Cmax and AUC0-t for FTD were 95.3% and 102.9%, respectively, with 90% confidence intervals (CIs) for the natural log-transformed ratios of Cmax and AUC0-t of 90.0-100.9% and 99.9-105.9%, while the GMRs of Cmax and AUC0-t for TPI were 95.7% and 100.7%, respectively, with 90% CIs of 90.5-101.2% and 97.0-104.7%. In addition, the GMRs of Cmax and AUC0-t for FTD's major metabolite, trifluorothymine (FTY), were 94.8 (90% CI 90.3-99.5%) and 99.33 (90% CI 96.9-101.9%), respectively. These were in accord with the FDA bioequivalence definition interval of 80-125%. CONCLUSION: The test and reference FTD/TPI formulations were bioequivalent in Chinese mCRC patients under fed conditions.

Amelioration of ligamentum flavum hypertrophy using umbilical cord mesenchymal stromal cell-derived extracellular vesicles.

Ligamentum flavum (LF) hypertrophy (LFH) has been recognised as one of the key contributors to lumbar spinal stenosis. Currently, no effective methods are available to ameliorate this hypertrophy. In this study, human umbilical cord mesenchymal stromal cell-derived extracellular vesicles (hUCMSC-EVs) were introduced for the first time as promising vehicles for drug delivery to treat LFH. The downregulation of miR-146a-5p and miR-221-3p expressions in human LF tissues negatively correlated with increased LF thickness. The hUCMSC-EVs enriched with these two miRNAs significantly suppressed LFH in vivo and notably ameliorated the progression of transforming growth factor ß1(TGF-ß1)-induced fibrosis in vitro after delivering these two miRNAs to mouse LF cells. The results further demonstrated that miR-146a-5p and miR-221-3p directly bonded to the 3'-UTR regions of SMAD4 mRNA, thereby inhibiting the TGF-ß/SMAD4 signalling pathway. Therefore, this translational study determined the effectiveness of a hUCMSC-EVs-based approach for the treatment of LFH and revealed the critical target of miR-146a-5p and miR-221-3p. Our findings provide new insights into promising therapeutics using a hUCMSC-EVs-based delivery system for patients with lumbar spinal stenosis.

Real-world evidence of osimertinib in Chinese patients with EGFR T790M-positive non-small cell lung cancer: a subgroup analysis from ASTRIS study.

PURPOSE: ASTRIS study aimed the largest to evaluate the effectiveness and safety of second- or higher-line osimertinib in patients with advanced/metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) in the real-world setting. Here we report the results of Chinese patients in ASTRIS study. METHODS: Adults with EGFR T790M-positive advanced NSCLC pretreated with EGFR-tyrosine kinase inhibitor (EGFR-TKI), having a WHO performance status score of 0-2 and asymptomatic, stable central nervous system (CNS) metastases were included. All patients received once-daily osimertinib 80 mg orally. The outcomes included investigator-assessed clinical response, progression-free survival (PFS), time-to-treatment discontinuation (TTD), and safety. RESULTS: A total of 1350 patients were included. Response rate was 55.7% (95% confidence interval [CI] 0.53-0.58). The median PFS and the median TTD were 11.7 months (95% CI 11.1-12.5) and 13.9 months (95% CI 13.1-15.2), respectively. Overall, 389 patients (28.8%) had at least one protocol-specified adverse event (AE); AEs of interstitial lung diseases/pneumonitis-like events and QT prolongation were reported in 3 (0.2%) and 59 (4.4%) patients, respectively. CONCLUSION: Osimertinib was effective in Chinese patients with T790M-positive NSCLC who had progressed after first- or second-generation EGFR-TKI in real-word setting and the results were consistent with ASTRIS study overall population and AURA studies. No new safety signals or events were identified. CLINICAL TRIAL NUMBER: NCT02474355.

Down-regulation of ß3-integrin inhibits bone metastasis of small cell lung cancer.

Bone is one of the most frequent targets of small cell lung cancer (SCLC) metastasis, but the molecular mechanism remains unclear. ß3-integrin plays an important role in invasion of various kinds of tumors. Yet, its role in bone-metastasis of SCLC is still unknown. In this study, we first examined the expression of ß3-integrin in SBC-5 and SBC-3 cells by real-time PCR, western blot and immunofluorescence. We found that, compared to none bone-metastatic SBC-3 cells, ß3-integrin was highly expressed in SBC-5 cells, a specific bone-metastatic SCLC cells line characterized in our previous study. We next constructed ß3-integrin siRNA and transfected SBC-5 cell line, and found that ß3-integrin siRNA significantly down-regulated the ß3-integrin mRNA level and protein expression in SBC-5 cell line. We further found that inhibition of ß3-integrin significantly reduced tumor cell proliferation and induced apoptosis. In addition, the ß3-integrin down-regulated cells presented significant decrease in cell adhesion, migration and invasion activity. Our results suggest the ß3-integrin has an essential effect on tumor cell proliferation and progression, and may be a potential therapeutic target for the prevention of skeletal metastases of lung cancer.

Combining a CDK4/6 Inhibitor With Pemetrexed Inhibits Cell Proliferation and Metastasis in Human Lung Adenocarcinoma.

Background: Recent clinical trials of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in human lung adenocarcinoma (LUAD) have not achieved satisfactory results. The disappointing results of single-drug treatments have prompted studies about synergistic therapies of CDK4/6i with other drugs. We aimed to test the anti-tumor effect of ribociclib (a CDK4/6i) combined with pemetrexed on LUAD and the potential mechanisms. Methods: Cell lines were exposed to ribociclib and pemetrexed at different doses. Antitumor effects were measured using growth inhibition. Cell cycle distribution and apoptosis were evaluated using flow cytometry. Cell migration and invasion were measured using wound healing and transwell invasion assays, respectively. The expression levels of proteins were analyzed using western blotting. Mice xenograft models were used for validation in vivo. Results: Synergism was associated with a combination of cell cycle effects from both agents. Cell cycle analysis revealed that pemetrexed blocked cells in the S phase, whereas ribociclib arrested cells in the G1 phase. Concomitant treatment with pemetrexed and ribociclib resulted in a significantly stronger antitumor ability than treatment alone. We also found that ribociclib strongly enhanced the pro-apoptotic activity of pemetrexed via the caspase/bcl-2 signaling pathway. In addition, we report for the first time that combination treatment with ribociclib and pemetrexed significantly inhibits the migration and invasion of LUAD cells. Conclusions: Combining ribociclib and pemetrexed showed a powerful ability to inhibit cancer proliferation, invasion, and metastasis, and it holds potential as a novel effective combinative therapy for patients with LUAD.

Osimertinib Versus Comparator EGFR TKI as First-Line Treatment for EGFR-Mutated Advanced NSCLC: FLAURA China, A Randomized Study.

BACKGROUND: In the global FLAURA study, first-line osimertinib, a third-generation irreversible tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), significantly improved progression-free survival (PFS) and overall survival (OS) versus comparator EGFR TKIs in patients with EGFR mutation-positive (EGFRm) advanced non-small-cell lung cancer (NSCLC). OBJECTIVE: The FLAURA China study assessed first-line osimertinib in Chinese patients with EGFRm advanced NSCLC (NCT02296125). METHODS: FLAURA China was a double-blind, randomized, phase III study. Adults from mainland China with previously untreated EGFRm (Exon 19 deletion or L858R) advanced NSCLC were enrolled in the global study or a China-only study under the same protocol; 136 patients were randomized to osimertinib (80 mg once daily [od]; n = 71) or comparator EGFR TKI (gefitinib or erlotinib; all sites selected gefitinib 250 mg od; n = 65). Patients were randomized and allocated to treatment groups by a central computer system. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed PFS; OS was a secondary endpoint. RESULTS: All 136 randomized patients were analyzed. Osimertinib extended median PFS by 8.0 months versus comparator EGFR TKI (17.8 vs. 9.8 months; hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.37-0.85). Median OS was 33.1 months in the osimertinib group versus 25.7 months in the comparator group (HR 0.85; 95% CI 0.56-1.29). At 3 years, 20% of patients on osimertinib and 8% on the comparator remained on randomized treatment. Grade 3 or higher adverse events (AEs) were reported in 54 and 28% of patients in the osimertinib and comparator groups, respectively, driven by increased local reporting of laboratory- and disease-related AEs. No new safety signals were identified. CONCLUSIONS: First-line osimertinib treatment resulted in a clinically meaningful PFS and OS benefit versus comparator EGFR TKI in Chinese patients with EGFRm advanced NSCLC. Safety data were consistent with the known safety profile of osimertinib. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02296125, registered 20 November 2014.

Calcineurin promotes proliferation, migration, and invasion of small cell lung cancer.

A novel role for calcineurin (Cn) has been reported recently regarding the oncogenic potential in pancreatic and colorectal cancer. The aim of this study was to investigate the putative causal role calcineurin could play in the development of lung cancer with bone metastases. We found that CnAalpha, an isoform of calcineurin, was significantly overexpressed in lung cancer tissues with bone metastasis as compared to tumors with non-bone metastases as investigated by RT-PCR. Strong nuclear staining of tumor cells was observed in small cell lung cancer tissues with bone metastasis. Conversely, cytoplasmic staining of tumor cells was observed in small cell lung cancer tissues with non-bone metastasis. Western blots of nuclear proteins from lung cancer tissues indicated that CnAalpha was highly expressed in lung cancer tissues with bone metastases, but not in those with non-bone metastases. In vitro, it was demonstrated that the CnAalpha gene obviously promoted cell proliferation and inhibited cell apotosis. The CnAalpha gene affected the cell cycle and promoted G1[Symbol: see text]S transition in SBC-3 cells. Transfection with the CnAalpha gene promoted cell migration and invasion. These results indicated that CnAalpha may affect the biological behavior of the human small cell lung cancer cell line SBC-3 in vitro and may be a candidate tumor promotor gene for developing bone metastases.

Effect of CUL4A on the metastatic potential of lung adenocarcinoma to the bone.

Cullin 4A (CUL4A) is a member of the cullin family of proteins and has been demonstrated to be abnormally expressed in various types of malignancies. However, the function of CUL4A in metastasis of lung adenocarcinoma to the bone has rarely been reported. The aim of present of the study was to explore the biological functions and potential underlying molecular mechanisms of CUL4A in lung adenocarcinoma, highlighting a novel therapeutic target for the diagnosis and treatment of patients with lung adenocarcinoma. A549­CUL4A, H1299­CUL4A and H460­shCUL4A cells were created using lentiviral infection. The efficiency of knockdown or overexpression was assessed using reverse transcription­quantitative PCR and western blotting. The effects of CUL4A on proliferation, migration and invasion of lung adenocarcinoma cells in vitro and metastasis to the bone in vivo were determined using an MTT assay, colony formation assay, wound­healing assay, Transwell assay and a mouse model of bone metastasis. The relationship between CUL4A and the EMT­activator zinc finger E­box binding homeobox 1 (ZEB1) were detected by western blotting. The results showed that overexpression of CUL4A in lung adenocarcinoma cells increased proliferation, migration and invasion, and increased metastasis of A549 to the bones in vivo. Silencing of CUL4A expression in lung adenocarcinoma cells reduced proliferation, migration and invasion in vitro. Mechanistically, CUL4A transcriptionally upregulated expression of ZEB1 which resulted in epithelial­mesenchymal transition, which in turn promoted metastasis of lung adenocarcinoma to the bones. Taken together, these results suggest that CUL4A may serve an important regulatory role in the development of metastasis of lung adenocarcinoma to the bone.

Trastuzumab plus docetaxel and capecitabine as a first-line treatment for HER2-positive advanced gastric or gastroesophageal junction cancer: a phase II, multicenter, open-label, single-arm study.

Gastric cancer (GC) is the second most common cancer in China. The ToGA study showed that trastuzumab in combination with fluoropyrimidine plus cisplatin prolonged overall survival (OS) in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced GC (AGC). However, some patients may not be able to receive this regimen. We conducted a clinical study to evaluate the efficacy and safety of trastuzumab in combination with docetaxel+capecitabine (DX) in patients with HER2-positive AGC. This phase II, multi-center, open-label, single arm study enrolled patients with HER2-positive AGC who had not received prior treatment for metastatic disease. Patients were treated with a regimen of trastuzumab (8 mg/kg loading dose followed by 6 mg/kg, day 1), capecitabine (1000 mg/m2 twice daily, days 1-14) and docetaxel (60 mg/m2, day 1 for 6 cycles) every 3 weeks. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR), OS and safety profiles. Sixty-seven patients with AGC were enrolled from 14 centers. 64 were included in the full analysis set (FAS). The median PFS was 8.1 months (95% confidence interval [CI]: 5.6-12.8) and the median OS was 20.9 months (95% CI: 15.1-33.0). Response was evaluated in 59 patients. The ORR was 67.8%. The most common adverse events of Grade ≥3 were neutropenia, leukopenia, hand-foot syndrome, febrile neutropenia and anemia. We concluded that combination treatment with trastuzumab and DX was well-tolerated and highly effective in patients with HER2-positive AGC, and may offer an alternative to current treatments.

Survival Benefit and Genetic Profile of Pemetrexed as Initial Chemotherapy in Selected Chinese Patients With Advanced Lung Adenocarcinoma.

Objective: This study investigated survival in selected Chinese patients with advanced lung adenocarcinoma who received initial chemotherapy with pemetrexed. We also explored the relationship between genetic biomarkers and pemetrexed efficacy. Methods: We retrospectively collected patients (n = 1,047) enrolled in the Chinese Patient Assistance Program from multiple centers who received pemetrexed alone or combined with platinum as initial chemotherapy and continued pemetrexed maintenance therapy for advanced lung adenocarcinoma from November 2014 to June 2017. The outcomes were duration of treatment (DOT) and overall survival (OS). Clinical features were analyzed for their influence on the treatment effect and prognosis. Next-generation sequencing (NGS) was performed to identify genetic biomarkers associated with the efficacy of pemetrexed. Results: The median DOT was 9.1 months (95% CI: 8.5-9.8), and the median OS was 26.2 months (95% CI: 24.2-28.1). OS was positively correlated with DOT (r = 0.403, P < 0.001). Multivariable analysis showed that smoking status and Eastern Cooperative Oncology Group (ECOG) performance status (PS) were independently associated with DOT; smoking status, ECOG PS, targeted therapy, and EGFR/ALK/ROS1 status were independently associated with OS. NGS in 22 patients with available samples showed genes with high mutation rates were: TP53 (54.5%), EGFR (50.0%), MYC (18.2%), and PIK3CA (13.6%). When grouped based on progression-free survival (PFS) reported in the PARAMOUNT study, the DOT > 6.9 months set was associated with PIK3CA, ALK, BRINP3, CDKN2A, CSMD3, EPHA3, KRAS, and RB1 mutations, while ERBB2 mutation was observed only in the DOT ≤ 6.9 months set. Conclusion: This study shows that initial chemotherapy with pemetrexed is an effective regimen for advanced lung adenocarcinoma in selected Chinese patients. There is no specific genetic profile predicting the benefit of pemetrexed found by NGS. Biomarkers predicting the efficacy of pemetrexed need further exploration.

The role of GDF15 in bone metastasis of lung adenocarcinoma cells.

Lung cancer is the most common malignant tumor in China. It often metastasizes to bone, thereby significantly shortening the lives of patients, and reducing their quality of life. However, the efficacy of treatment for bone metastasis of lung cancer at this stage is very limited. The development and clinical application of molecular­targeted drugs for the effective targeted therapy of bone metastasis of lung cancer are urgently required. The growth differentiation factor 15 (GDF15) gene which may be associated with bone metastasis of lung cancer, was screened out by whole­genome sequencing. In the present study, we used a recombinant GDF15 lentivirus technique to upregulate the expression of GDF15 in lung adenocarcinoma A549 cells, and the results revealed that GDF15 could inhibit the proliferation, migration and invasion, while promoting apoptosis of A549 cells. In addition, GDF15 significantly decreased the number and sites of lung metastases and bone metastases in vivo compared to the control group. Finally, it was revealed that Smad2 and phospho­Smad2 protein expression was lower in the GDF15­overexpressing A549 cells. This result indicated that the tumor suppressive effect of GDF15 may be related to the TGF­ß/Smad signaling pathway, although more studies are still required for confirmation. In summary, GDF15 inhibited the growth and bone metastasis of lung adenocarcinoma A549 cells, and this effect may be achieved through the TGF­ß/Smad signaling pathway.

A consensus on immunotherapy from the 2017 Chinese Lung Cancer Summit expert panel.

The notable clinical success of cancer immunotherapy using checkpoint blockade suggests that it is likely to form the foundation of curative therapy for many malignancies. However, checkpoint blockades do not achieve sustained clinical response in most patients and thus amounts of problems needed to be figured out. Regarding these challenges, the 2017 Chinese Lung Cancer Summit expert panel organized a forum on the 14th Chinese Lung Cancer Summit to formally discuss these controversies. Five consensuses finally were reached to guide the application of checkpoint blockades.

Primary mucinous adenocarcinoma of the lung: A case report and review of the literature.

Mucinous adenocarcinoma is an unusual histological type of lung cancer, and its clinicopathological feature is distinctive from that of other histopathological types of lung adenocarcinoma. Mucinous adenocarcinoma has a mucus-producing function, which explains its name. The present study reports a rare case of a mucus-producing adenocarcinoma of the lung. A 60-year-old Chinese female patient was diagnosed with mucinous adenocarcinoma of the lung, which manifested as respiratory symptoms, including fever, cough and expectoration. The patient received thoracic exploratory operation and right pneumonectomy, since the above respiratory symptoms seriously affected her daily life, and other inspections could not establish the diagnosis. Histopathology revealed no mutations in epidermal growth factor receptor. The patient received adjuvant chemotherapy using taxol and cisplatin. However, metastases in the left lung were detected 7 months after the operation. Pemetrexed and cisplatin were used as the second-line treatment. The patient survived 3 years after the initial diagnosis. The present study reports a rare mucus-producing adenocarcinoma of the lung, which is of bad prognosis. Therefore, further studies on this type of cancer are urgently required.

EGFR T790M ctDNA testing platforms and their role as companion diagnostics: Correlation with clinical outcomes to EGFR-TKIs.

Somatic mutation in the epidermal growth factor receptor (EGFR) predict clinical response to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) and is a promising target for personalised medicine. EGFR mutations have prognostic value. Initially patients respond well to tyrosine kinase inhibitors but finally they would develop resistance and about 50% of this resistance can be attributed to the emergence of EGFR resistant mutation, T790M. This necessitates the need for genetic testing for clinical management of patients. Molecular testing has become the standard of care in patients with NSCLCs based on the recommendations of standard guidelines. Though there are several platforms for EGFR mutation detection, highly sensitive platforms for clinical applicability as companion diagnostics for ctDNA based testing are emerging. Due to the dynamic changes in the T790M mutation during tyrosine kinase inhibitor (TKI) treatment, real-time monitoring of these genetic alterations is mandate for planning treatment strategies. With the advent of third generation TKIs that potentially target T790M, improvement in clinical outcome is documented in patients with NSCLCs. Managing these outcomes with appropriate companion diagnostics using ctDNA in early detection of these genetic alterations will improve patient care.

Managing Pain in Patients With Cancer: The Chinese Good Pain Management Experience.

PURPOSE: The number of cancer cases in China has increased rapidly from 2.1 million in 2000 to 4.3 million in 2015. As a consequence, pain management as an integral part of cancer treatment became an important health care issue. In March 2011, the Good Pain Management (GPM) program was launched to standardize the treatment of cancer pain and improve the quality of life for patients with cancer. With this work, we will describe the GPM program, its implementation experience, and highlight key lessons that can improve pain management for patients with cancer. METHODS: We describe procedures for the selection, implementation, and assessment procedures for model cancer wards. We analyzed published results in areas of staff training and patient education, pain management in practice, analgesic drugs administration, and patient follow-up and satisfaction. RESULTS: Pain management training enabled medical staff to accurately assess the level of pain and to provide effective pain relief through timely dispensation of medication. Patients with good knowledge of treatment of pain were able to overcome their aversion to opioid drugs and cooperate with nursing staff on pain assessment to achieve effective drug dose titration. Consumption of strong opioid drugs increased significantly; however, there was no change for weaker opioids. Higher pain remission rates were achieved for patients with moderate-to-severe pain levels. Proper patient follow-up after discharge enabled improved outcomes to be maintained. CONCLUSION: The GPM program has instituted a consistent and high standard of care for pain management at cancer wards and improved the quality of life for patients with cancer.