Efficacy and safety of combination immunotherapy for malignant solid tumors: A systematic review and meta-analysis.

BACKGROUND: Combination immunotherapy has become an actively growing field of clinical investigation. METHODS: We searched for clinical trials of combination immunotherapy and calculated the pooled hazard ratio (HR), odds ratio (OR) of clinical outcomes and safety by subgroups of different combination regimens. RESULTS: Totally 28 clinical trials were analyzed. The study showed that the pooled HRs of overall survival and progression-free survival for combination therapy were 0.77 (95% CI: 0.70-0.84, p < 0.001) and 0.72 (95% CI: 0.66-0.79, p < 0.001) while the pooled OR of high-grade adverse effects was 1.45 (p = 0.004). Subgroup analysis showed that the HR of overal survival were 0.74 (p = 0.005), 0.79 (p < 0.001), 0.70 (p = 0.003) and 0.85 (p = 0.052) for immunotherapy combined with immunotherapy, chemotherapy, targeted therapy and radiotherapy group, respectively. CONCLUSIONS: The meta-analysis indicated that combination immunotherapy could bring more clinical benefits with increased high-grade adverse effects.

Clinical outcomes comparison of 10 years versus 5 years of adjuvant endocrine therapy in patients with early breast cancer.

BACKGROUND: Adjuvant endocrine therapy undoubtedly prolongs the time to recurrence for patients with hormone-positive early breast cancer. Extended endocrine therapy to 10 years or longer has been expected to bring a greater clinical advantage. However, the related research conclusions are controversial. METHODS: Tamoxifen (TAM), Aromatase Inhibitor (AI), Exemestane, letrozole (LET) and anastrozole were used as key words in the literature search. After the patients completed 5 years of adjuvant endocrine treatment, they were allocated to continue endocrine treatment for 5 years or receive placebo/observation for 5 years. Disease-free survival (DFS) and overall survival (OS) were the end points. Systematic assessment was performed using Stata 12.0. RESULTS: Twelve trials including 30,848 cases were involved. The overall analysis demonstrated that extended endocrine therapy to 10 years significantly prolonged DFS compared with 5 years of endocrine therapy [hazard ratio (HR) = 0.84, 95% CI: 0.73-0.97]. Subgroup analysis showed that DFS was significant prolonged with TAM 5y - AI 5y treatment versus TAM 5y treatment and with (AI and/or TAM) 5y - LET 5y treatment versus (AI and/or TAM) 5y treatment [(HR = 0.61, 95% CI: 0.50-0.76) and (HR = 0.81, 95% CI: 0.71-0.93), respectively]. However, no significant difference was found in the DFS with TAM 5y - TAM 5y treatment versus TAM 5y treatment (HR = 0.97, 95% CI: 0.81-1.17). Overall and subgroup analysis did not demonstrate an OS benefit of therapy extended to 10 years. A DFS benefit of extended endocrine therapy to 10 years was verified in the lymph node-positive subgroup, postmenopausal subgroup and ER+ and/or PR+ subgroup (HR = 058, 95% CI: 0.45-0.75; HR = 0.70, 95% CI: 0.58-0.80; HR = 0.80, 95% CI: 0.67-0.96). CONCLUSIONS: An extended 10 years of endocrine treatment yields a DFS benefit for patients with early breast cancer; (AI and/or TAM) 5y - AI 5y treatment is the optimal choice. ER+ and/or PR+, postmenopausal and lymph node-positive patients are the most suitable groups.

Irinotecan-containing doublet treatment versus irinotecan monotherapy as second-line choice for advanced gastric cancer.

BACKGROUND: For patients with advanced gastric cancer (AGC), second-line chemotherapy regimen remains controversial. The efficacy and safety of irinotecan-containing doublet treatment and irinotecan monotherapy were compared in this systematic analysis. METHODS: A search was conducted on EMBASE and Medline databases. All articles compared irinotecan-containing doublet to irinotecan as second-line chemotherapy for AGC. STATA statistical software (Version 12.0) was used to analyze the data. RESULTS: Seven studies, including 905 cases, were included in the analysis. Irinotecan-containing doublet treatment significantly prolonged progression-free survival compared to irinotecan monotherapy (HR = 0.82, 95% CI: 0.70-0.95). However, doublet treatment neither significantly prolong overall survival compared to monotherapy (HR = 0.94, 95% CI: 0.81-1.10), nor did it significantly increase the overall response rates and disease control rates, when compared to monotherapy. In addition, the irinotecan-containing doublet group had an increase in incidences of ≥ Grade 3 neutropenia (RR = 1.23, 95% CI: 1.01-1.51) and anemia (RR = 2.00, 95% CI: 1.37-2.92). CONCLUSIONS: When compared to irinotecan monotherapy, irinotecan-containing doublet treatment increased progression free survival and was tolerable as a second- line chemotherapy for AGC.

NRG1-dependent activation of HER3 induces primary resistance to trastuzumab in HER2-overexpressing breast cancer cells.

This study was conducted to determine the role of neuregulin 1 (NRG1)-dependent human epidermal growth factor receptor 3 (HER3) activation in trastuzumab primary resistance, and to observe the inhibitory effect of HER3 monoclonal antibody on HER2-overexpressing breast cancer cells. BT474 cells (trastuzumab sensitive) and MDA-MB-453 cells (trastuzumab resistant) were first stimulated with NRG1 and then treated with either trastuzumab, HER3 antibody, or a combination of both. The expression of phospho human epidermal growth factor receptor 2 (p-HER2), phospho human epidermal growth factor receptor 3 (p-HER3), phospho protein kinase B (p-Akt) and phospho mitogen-activated protein kinase (p-MAPK) were detected by western blotting. Apoptosis was detected by flow cytometry. Cell viability was detected by MTT assay. Without NRG1 stimulation, trastuzumab treatment significantly down-regulated the expression of p-HER2, increased early apoptosis, and decreased cell viability in BT474 cells. After NRG1 stimulation, the aforementioned effects weakened or disappeared in the trastuzumab treatment group, whereas in the HER3 antibody treatment group, there was significant downregulation in p-HER3 expression and increase in early apoptosis of BT474 cells. In MDA-MB-453 cells, the HER3 antibody significantly downregulated both p-HER2 and p-HER3 and promoted early apoptosis after NRG1 stimulation, however, trastuzumab hardly played a role. p-Akt and p-MAPK were also significantly downregulated by the HER3 antibody after NRG1 stimulation. The expressions of p-HER2, p-HER3, p-Akt and p-MAPK were all downregulated after HER3 gene silencing, compared to the control. NRG1-dependent activation of HER3 induces primary resistance to trastuzumab in HER2-overexpressing breast cancer cells. HER3 monoclonal antibody combined with trastuzumab may serve as a treatment choice for patients with primary resistance to trastuzumab.