A Network Meta‐Analysis of Short and Long‐Term Efficacy of Targeted Therapy With Single or Double‐Drug Regimens in the Treatment of Stage III/IV Malignant Melanoma Based on 16 Randomized Controlled Trials

For the treatment of stage III/IV malignant melanoma (MM), a network meta‐analysis (NMA) was conducted to compare the short and long‐term efficacy of targeted therapy with single or double‐drug regimens. All conducted randomized controlled trials (RCTs) searched from PubMed and Cochrane Library were included in the study for direct and indirect comparison for MM. The odds ratio (OR) and surface under the cumulative ranking curves (SUCRA) value of the targeted therapy with single or double‐drug regimens for treatment of stage III/IV MM were also analyzed. To group the treatments according to their similarity with regards to both outcomes, cluster analyses were performed. Ultimately, 16 RCTs were incorporated for this NMA. The NMA revealed that the overall response rate (ORR) values of single‐drug regimens (Vemurafenib [Vem], Dabrafenib [Dab], and Nivolumab [Niv]) were higher than those of Dacarbazine (Dac). Also the ORR values of double‐drug regimens (Dab + Trametinib [Dab + Tra], Niv + Ipilimumab [Niv + Ipi], and Vem + Cobimetinib [Vem + Cob]) were moderately higher than those of Dac. The results of the SUCRA showed that short‐term efficacy of single‐drug regimens (Vem and Dab) were better, while the short‐term efficacy of double‐drug regimens (Dab + Tra and Vem + Cob) were relatively better. It was determined that Vem, Dab, and Niv might be the best choice in evaluating the treatment of stage III/IV MM among different single‐drug targeted therapy regimens, while Dab + Tra, Niv + Ipi, and Vem + Cob might have better short‐term efficacy among different double‐drug targeted therapy regimens. J. Cell. Biochem. 119: 640–649, 2018. © 2017 Wiley Periodicals, Inc.     

Efficacy and adverse events of five targeted agents in the treatment of advanced or metastatic non-small-cell lung cancer: A network meta-analysis of nine eligible randomized controlled trials involving 5,059 patients

Recently, targeted agents were reported to improve overall survival, progression-free survival (PFS), response rate, and quality of life compared with cytotoxic chemotherapies, which provides hope for the treatment of non-small-cell lung cancer (NSCLC). The network meta-analysis is applied to compare the efficacies and adverse events of five targeted agents (erlotinib, gefitinib, vandetanib, dacomitinib, and icotinib) for advanced or metastatic NSCLC. Nine eligible randomized controlled trials from PubMed and Cochrane Library database were included. Weighted mean difference, odds ratio, and surface under the cumulative ranking curve (SUCRA) values were evaluated for the efficacy and adverse events of the five targeted agents in the treatment of NSCLC. With regard to efficacy, the overall response rate (ORR) of advanced or metastatic NSCLC patients treated with gefitinib was relatively higher than those treated with placebo. Compared with patients treated with placebo, the disease control rate (DCR) of patients treated with erlotinib and with gefitinib was relatively higher. Furthermore, in terms of PFS and DCR, the SUCRA value of icotinib was the highest among the five targeted drugs. With regard to ORR, the SUCRA value of gefitinib was the highest among the five targeted drugs. In terms of fatigue, rash, and cough, erlotinib had the lowest SUCRA value, whereas vandetanib exhibited the lowest SUCRA value in terms of diarrhea. Our study suggests that the efficacies of gefitinib and icotinib for advanced or metastatic NSCLC were comparatively better, whereas the toxicities of erlotinib and vandetanib were relatively greater.     

Efficacy Comparison of Six Chemotherapeutic Combinations for Osteosarcoma and Ewing's Sarcoma Treatment: A Network Meta‐Analysis

This study aimed to address the insufficiency of traditional meta‐analysis and provide improved guidelines for the clinical practice of osteosarcoma treatment. The heterogeneity of the fixed‐effect model was calculated, and when necessary, a random‐effect model was adopted. Furthermore, the direct and indirect evidence was pooled together and exhibited in the forest plot and slash table. The surface under the cumulative ranking curve (SUCRA) value was also measured to rank each intervention. Finally, heat plot was introduced to demonstrate the contribution of each intervention and the inconsistency between direct and indirect comparisons. This network meta‐analysis included 32 trials, involving a total of 5,626 subjects reported by 28 articles. All the treatments were classified into six chemotherapeutic combinations: dual agent with or without ifosfamide (IFO), multi‐agent with or without IFO, and dual agent or multi‐agent with IFO and etoposide. For the primary outcomes, both overall survival (OS) and event‐free survival (EFS) rates were considered. The multi‐agent integrated with IFO and etoposide showed an optimal performance for 5‐year OS, 10‐year OS, 3‐year EFS, 5‐year EFS, and 10‐year EFS when compared with placebo. The SUCRA value of this treatment was also the highest of these six interventions. However, multi‐drug with IFO alone had the highest SUCRA value of 0.652 and 0.516 when it came to relapse and lung‐metastasis. It was efficient to some extent, but no significant difference was observed in both outcomes. Chemotherapy, applied as induction or adjuvant treatment with radiation therapy or surgery, is able to increase the survival rate of patients, especially by combining multi‐drug with IFO and etoposide, which demonstrated the best performance in both OS and EFS. As for relapse and the lung‐metastasis, multiple agents with IFO alone seemed to have the optimal efficiency, although no significant difference was observed here. J. Cell. Biochem. 119: 250–259, 2018. © 2017 Wiley Periodicals, Inc.     

Comparative efficacy and safety of antiplatelet agents in cerebral ischemic disease: A network meta-analysis

We performed a network meta-analysis (NMA) to enhance the corresponding evidence of the relative efficacy and safety of different antiplatelet agents in cerebral ischemic disease. PubMed and EMBASE were searched systematically for relevant studies. Outcomes were compared using odds ratios and 95% credible intervals. Each agent was ranked according to the value of surface under the cumulative ranking curve (SUCRA). Publication bias was evaluated by funnel plots, while consistency between direct and indirect comparison was analyzed by node-splitting and heat plots. Besides, the clustering technique was used to categorize similar agents. A number of 44 eligible studies with 148 578 patients were included in this NMA. In terms of efficacy (including mortality, recurrent stroke, and vascular event), all six interventions were better than placebo. clopidogrel (Clop) and aspirin (ASA)+Clop were the best two interventions from SUCRA. However, the performance of ASA+Clop declined significantly when considering safety (including myocardial infarction, all-cause withdrawal, and intracranial hemorrhage), especially worse in intracranial hemorrhage. In conclusion, Clop was potentially the most preferable treatment for preventing cerebral ischemic in terms of efficacy and safety. However, the addition of ASA was associated with a potential increase in intracranial hemorrhage, therefore, combination therapy of ASA and Clop should be introduced with caution although it may be more effective than the monotherapy of ASA.     

Neoadjuvant Sequential Docetaxel Followed by High‐Dose Epirubicin in Combination With Cyclophosphamide Administered Concurrently With Trastuzumab. The DECT Trial

To report the results of the DECT trial, a phase II study of locally advanced or operable HER2‐positive breast cancer (BC) treated with taxanes and concurrent anthracyclines and trastuzumab. Eligible patients (stage IIA‐IIIB HER2‐positive BC, 18–75 years, normal organ functions, ECOG ≤1, and left ventricular ejection fraction (LVEF) ≥55%) received four cycles of neoadjuvant docetaxel, 100 mg/m² intravenously, plus trastuzumab 6 mg/kg (loading dose 8 mg/kg) every 3 weeks, followed by four 3‐weekly cycles of epirubicin 120 mg/m² and cyclophosphamide, 600 mg/m², plus trastuzumab. Primary objective was pathologic complete response (pCR) rate, defined as ypT0/is ypN0 at definitive surgery. We enrolled 45 consecutive patients. All but six patients (13.3%) completed chemotherapy and all underwent surgery. pCR was observed in 28 patients (62.2%) overall and in 6 (66.7%) from the inflammatory subgroup. The classification and regression tree analysis showed a 100% pCR rate in patients with BMI ≥25 and with hormone negative disease. The median follow up was 46 months (8–78). Four‐year recurrence‐free survival was 74.7% (95%CI, 58.2–91.2). Seven patients (15.6%) recurred and one died. Treatment was well tolerated, with limiting toxicity being neutropenia. No clinical cardiotoxicity was observed. Six patients (13.4%) showed a transient LVEF decrease (<10%). In one patient we observed a ≥10% asymptomatic LVEF decrease persisting after surgery. Notwithstanding their limited applicability due to the current guidelines, our findings support the efficacy of the regimen of interest in the neoadjuvant setting along with a fairly acceptable toxicity profile, including cardiotoxicity. Results on BMI may invite further assessment in future studies. J. Cell. Physiol. 231: 2541–2547, 2016. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.     

Comparison of efficacy of eight treatments for plantar fasciitis: A network meta-analysis

The objective of this network meta-analysis (NMA) was to assess the pain relief performance of eight different plantar fasciitis therapies, including nonsteroidal anti-inflammatory medications, corticosteroid injections (CSs), autologous whole blood, platelet-rich plasma (PRP), extracorporeal shockwave therapy (ESWT), ultrasound therapy (US), botulinum toxin A (BTX-A), and dry needling (DN). Published prospective or randomized controlled trials (RCTs) as for the above eight therapies were identified by searching CNKI, PubMed, and Embase. Mean difference (MD) and 95% credible intervals (CrIs) of visual analogue scale (VAS) were used to evaluate multiaspect comparisons. The ranking result was obtained by utilizing surface under cumulative ranking curve (SUCRA). Node-splitting plots were conducted to assess the consistency between direct and indirect evidence. Egger’s test and funnel plots were performed to examine publication bias. Forty-one trials with a total of 2,889 cases were involved in this NMA. In terms of 1-month VAS, only ESWT turned out to be of better efficacy than placebo (MD = −3.3; CrI: [−5.3, −1.1]). No statistically significant difference was found between pair-wise comparisons concerning 2-month VAS. ESWT also demonstrated better efficacy as for 3-month results (MD = −2.7; CrI: [−4.2, −1.3]). Besides, CSs was significantly better than placebo as well in 3-month results (MD = −2.1; CrI: [−4.1, −0.19]). With regard to 6-month VAS results, ESWT performed better than placebo (MD = −3.0; CrI: [−5.0, −0.51]). According to the SUCRA, ESWT ranked the first as for all seven outcomes. ESWT might be the optimal treatment. In addition, BTX-A and PRP were considered as suboptimal.     

Quality‐of‐life outcomes in patients with advanced melanoma: A review of the literature

For patients with metastatic melanoma, the emergence of immune checkpoint inhibitors and targeted BRAF and MEK inhibitors has markedly enhanced clinical outcomes compared with chemotherapy. However, these novel agents are also associated with unique sets of adverse events, and increased overall survival can lead to prolonged exposure to some novel agents. Therefore, clinical evaluation of these therapies has now included the analysis of health‐related quality of life (HRQoL) in addition to more traditional efficacy and safety outcomes as a measure of patient perception of benefit. The current review focuses on HRQoL outcomes in clinical trials of immune checkpoint inhibitors and targeted therapies in patients with advanced and metastatic melanoma to inform healthcare providers about patient perception of HRQoL as a new perspective in treatment decision making.     

Safe and effective treatment of spontaneous neoplasms with interleukin 12 electro‐chemo‐gene therapy

Electroporation improves the anti‐tumour efficacy of chemotherapeutic and gene therapies. Combining electroporation‐mediated chemotherapeutics with interleukin 12 (IL‐12) plasmid DNA produces a strong yet safe anti‐tumour effect for treating primary and refractory tumours. A previously published report demonstrated the efficacy of a single cycle of IL‐12 plasmid DNA and bleomycin in canines, and, similarly, this study further demonstrates the safety and efficacy of repeated cycles of chemotherapy plus IL‐12 gene therapy for long‐term management of aggressive tumours. Thirteen canine patients were enrolled in this study and received multiple cycles of electro‐chemo‐gene therapy (ECGT) with IL‐12 pDNA and either bleomycin or gemcitabine. ECGT treatments are very effective for inducing tumour regression via an antitumour immune response in all tested histotypes except for sarcomas, and these treatments can quickly eradicate or debulk large squamous cell carcinomas. The versatility of ECGT allows for response‐based modifications which can overcome treatment resistance for affecting refractory lesions. Importantly, not a single severe adverse event was noted even in animals receiving the highest doses of chemotherapeutics and IL12 pDNA over multiple treatment cycles. This report highlights the safety, efficacy and versatility of this treatment strategy. The data reveal the importance of inducing a strong anti‐tumour response for successfully affecting not only the treated tumours, but also non‐treated metastatic tumours. ECGT with IL12 pDNA plus chemotherapy is an effective strategy for treating multiple types of spontaneous cancers including large, refractory and multiple tumour burdens.     

Comparing six antihypertensive medication classes for preventing new‐onset diabetes mellitus among hypertensive patients: a network meta‐analysis

Hypertensive patients usually have a higher risk of new‐onset diabetes mellitus (NOD) which may trigger cardiovascular diseases. In this study, the effectiveness of six antihypertensive agents with respect to NOD prevention in hypertensive patients was assessed. A network meta‐analysis was conducted to compare the efficacy of specific drug classes. PubMed and Embase databases were searched for relevant articles. Results of the pairwised meta‐analysis were illustrated by odd ratios (OR) and a corresponding 95% confidence interval (CI). The probabilities and outcome of each treatment were ranked and summarized using the surface under the cumulative ranking curve (SUCRA).Twenty‐three trials were identified, including 224,832 patients with an average follow‐up period of 3.9 ± 1.0 years. The network meta‐analysis showed that patients treated by angiotensin II receptor blockers (ARBs) were associated with a lower risk of NOD compared to placebo (PCB), calcium channel blockers (CCBs) and β‐blockers, while diuretic appeared to be ineffective for NOD prevention. Network meta‐analysis results of specific drugs showed that enalapril exhibited distinct advantages and hydrochlorothiazide also exhibited a reliable performance. Our results suggested that both ARBs and angiotensin converse enzyme inhibitors (ACEIs), especially candesartan and enalapril, were preferable for NOD prevention in hypertensive patients. Hydrochlorothiazide also exhibited a reliable performance in comparison with other agents.     

Review: Gastric cancer—Clinical aspects

Gastric cancer (GC) was responsible for over 1 000 000 new cases in 2018 and an estimated 783 000 deaths, making it still the fifth most frequently diagnosed cancer and the third leading cause of cancer deaths in both sexes worldwide. Divergent trends for GC incidence were observed in the USA. Incidence rates, particularly for non‐cardia GC, were stable or increasing among persons aged <50 years. In an analysis of data from a public hospital database in Hong Kong, treatment of Helicobacter pylori infection was associated with a lower risk of GC, particularly in older subjects who received treatment ≥10 years before. Based on the results of a 16‐year endoscopy‐based follow‐up eradication trial, patients with incomplete‐type intestinal metaplasia (IM) should receive endoscopic surveillance upon H. pylori eradication therapy. Updated guidelines on the endoscopic surveillance of preneoplastic conditions of the stomach (MAPS II) have been published. In the RAINFALL trial, the addition of ramucirumab to a backbone chemotherapy as a first‐line regimen failed to improve overall survival (OS) of patients with metastatic disease. Also, pembrolizumab did not prolong OS when compared to paclitaxel in the second‐line treatment of patients with advanced GC or esophagogastric junction (EGJ) cancer. Trifluridine/tipiracil improved OS by 2.1 months in the third or further treatment line of patients with advanced GC. In a systematic investigation conducted on Chinese patients with GC, CLDN18‐ARHGAP26/6 fusion was associated with signet‐ring cell content and was prognostic for a worse outcome and predictive for no benefit from oxaliplatin/fluoropyrimidine‐based chemotherapy. Organoid cultures represent an appealing model that may be applied for therapy response testing in the near future.     

Evaluation of changes in serum protein profiles during neoadjuvant chemotherapy in HER2‐positive breast cancer using an LC‐MALDI‐TOF/MS procedure

Comparison of protein profiles of sera acquired before and after preoperative chemotherapy for breast cancer may reveal tumor markers that could be used to monitor tumor response. In this study, we analyzed pre‐ and post‐chemotherapy protein profiles of sera from 39 HER2‐postive breast cancer patients (n=78 samples) who received 6 months of preoperative chemotherapy using LC‐MALDI‐TOF/MS technology. We detected qualitative and quantitative differences in pair‐wise comparison of pre‐ and post chemotherapy samples that were different in patients who achieved pathological complete response (pCR, n=21) compared with those with residual disease (n=18). We identified 2329 and 3152 peaks as differentially expressed in the pre‐chemotherapy samples of the responders and non‐responders. Comparison of matching pre‐ and post‐chemotherapy samples identified 34 (32 decreased, two increased) and 304 peaks (157 decreased, 147 increased) that significantly changed (p<0.01, false discovery rate ≤20%) after treatment in responders and non‐responders, respectively. The top 11 most significantly altered peptide peaks with the greatest change in intensity were positively identified. These corresponded to eight proteins including α‐2‐macroglobulin, complement 3, hemopexin, and serum amyloid P in the responder group and chains C and A of apolipoprotein A‐I, hemopexin precursor, complement C, and amyloid P component in the non‐responding groups. All proteins decreased after therapy, except chain C apolipoprotein A and hemopexin precursor that increased. These results suggest that changes in serum protein levels occur in response to chemotherapy and these changes partly appear different in patients who are highly sensitive to chemotherapy compared with those with lesser response.     

Efficacy and Toxicity of Different Chemotherapy Regimens in the Treatment of Advanced or Metastatic Pancreatic Cancer: A Network Meta‐Analysis

Objective A network meta‐analysis was conducted to compare the efficacy and toxicity of different chemotherapy regimens in treating advanced or metastatic pancreatic cancer (PC). PubMed, Cochrane Library and EMBASE databases from inception to June 2016 were searched. A combination of direct and indirect evidences was referred to for calculating the weighted mean difference (WMD) or the odds ratio (OR) and to establish surface under the cumulative ranking (SUCRA) curves, so as to evaluate the efficacy and toxicity of different chemotherapy regimens in treating advanced or metastatic PC. Twenty randomized controlled trials were enrolled. Twelve chemotherapy regimens included Gemcitabine, S‐1 (Tegafur), Gemcitabine + Cisplatin, Gemcitabine + Capecitabine, Gemcitabine + S‐1, Gemcitabine + 5‐FU (5‐fluorouracil), Gemcitabine + Exatecan, Gemcitabine + Irinotecan, Gemcitabine + Nab‐paclitaxel, FOLFIRINOX (Oxaliplatin + Irinotecan + Fluorouracil + Leucovorin), Gemcitabine + Oxaliplatin, and Gemcitabine + Pemetrexed. Higher overall response rate (ORR) was observed in patients treated with the gemcitabine + S‐1 and FOLFIRINO regimens. Thrombocytopenia reduced in patients treated with the S‐1 regimen. The Gemcitabine + S‐1 and FOLFIRINO regimens had better short‐ and long‐term efficacies than the other regimens; S‐1 regimen had the lowest hematologic toxicity, while Gemcitabine + Nab‐paclitaxel, FOLFIRINOX, and Gemcitabine + Pemetrexed regimens had higher incidence of non‐hematologic toxicity among twelve chemotherapy regimens. The efficacy of Gemcitabine + S‐1 and FOLFIRINOX regimens may be better in treating patients with advanced or metastatic pancreatic cancer, while FOLFIRINOX and Gemcitabine + Pemetrexed regimens may have relatively higher incidence of toxicity than other regimens. J. Cell. Biochem. 119: 511–523, 2018. © 2017 Wiley Periodicals, Inc.     

Lapatinib,a dual HER1/HER2 tyrosine kinase inhibitor,augments basal cleavage of HER2 extracellular domain (ECD) to inhibit HER2‐driven cancer cell growth

The ultimate biological and clinical meaning of shed HER2 extracellular domain (ECD) has remained largely unclear until recently. Oversecretion of soluble HER2 ECD has been shown to inhibit growth of HER2‐overexpressing cancer cells by promoting HER2 ECD dimerization with HER transmembrane receptors thus impairing their cross‐tyrosine phosphorylation and decreasing their activation status. HER2‐targeted drugs capable to enhance the occurrence of basal HER2 ECD shedding but simultaneously preventing formation of truncated cell membrane‐bound HER2 intracellular fragment, which exhibits an undesirable constitutive kinase activity, might be extremely efficient at managing HER2‐positive cancer disease. The dual HER1/HER2 Tyrosine Kinase inhibitor lapatinib, which works intracellularly and directly targets the TK domain of HER2, drastically augments basal shedding of HER2 ECD to inhibit HER2‐driven cancer cell growth. Lapatinib treatment significantly augments the concentration of the inactive (unphosphorylated) form of HER2 protein at the tumor cell membrane and promotes an exacerbated HER2 ECD shedding to the extracellular milieu of HER2‐overexpressing cancer cells. Exacerbated sensitivity of trastuzumab‐resistant cancer cells, which contain nearly undetectable levels of soluble HER2 ECD when compared with trastuzumab‐sensitive parental cells to lapatinib‐induced cell growth inhibition, takes place when lapatinib treatment fully restores high levels of basal HER2 ECD shedding. The dramatic augmentation of HER2 ECD shedding that occurs upon treatment of with lapatinib is fully suppressed in lapatinib‐refractory HER2‐positive cells. These findings, altogether, may provide crucial insights concerning clinical studies aimed to accurately describe HER2 ECD as a potential predictor of response or resistance to the HER2‐targeted drugs trastuzumab and lapatinib. J. Cell. Physiol. 226: 52–57, 2010. © 2010 Wiley‐Liss, Inc.     

Chemotherapy or Targeted Therapy as Second-Line Treatment of Advanced Gastric Cancer. A Systematic Review and Meta-Analysis of Published Studies

Chemotherapy is a cornerstone in treatments of gastric cancer, but despite its benefit, less than 60% of patients receive salvage therapy in clinical practice. We performed a systematic review and meta-analysis based on trial data on the role of second-line treatment of advanced gastric cancer. MEDLINE/PubMed and Cochrane Library were searched for randomized phase III trials that compared active therapy to best supportive care in advanced gastric cancer. Data extraction was conducted according to the PRISMA statement. Summary HR for OS was calculated using a hierarchical Bayesian model and subgroup analysis was performed based on baseline Eastern Cooperative Oncology Group Performance Status (ECOG) performance status (0 vs. 1 or more). A total of 1,407 patients were evaluable for efficacy, 908 were treated in the experimental arms, with chemotherapy (231 pts) or with targeted therapies (677 pts). The risk of death was decreased by 18% (HR = 0.82; 95% CI, 0.79–0.85; posterior probability HR≥1: <0.00001) with active therapies. Chemotherapy and ramucirumab were able to decrease this risk by 27% and 22%, respectively. No differences were found between chemotherapy and ramucirumab. In patients with ECOG = 0 a greater benefit was found for chemotherapy with a reduction of the risk of death by 43% and no benefits were found for ramucirumab or everolimus. In patients with ECOG = 1 or more a significant reduction of the risk of death by 32% was reported in patients treated with ramucirumab, even if no significant difference was reported between chemotherapy and ramucirumab. This analysis reports that active and available therapies are able to prolong survival in patients with advanced gastric cancer with a different outcome based on initial patient’s performance status. New trials based on a better patient stratification are awaited.     

Hsp90 inhibition and co‐incubation with pertuzumab induce internalization and degradation of trastuzumab: Implications for use of T‐DM1

The receptor tyrosine kinase HER2 is associated with a number of human malignancies and is an important therapeutic target. The antibody‐drug conjugate trastuzumab emtansine (T‐DM1; Kadcyla^®) is recommended as a first‐line treatment for patients with HER2‐positive metastatic breast cancer. T‐DM1 combines the antibody‐induced effects of the anti‐HER2 antibody trastuzumab (Herceptin^®) with the cytotoxic effect of the tubulin inhibitor mertansine (DM1). For DM1 to have effect, the T‐DM1‐HER2 complex has to be internalized and the trastuzumab part of T‐DM1 has to be degraded. HER2 is, however, considered endocytosis‐resistant. As a result of this, trastuzumab is only internalized to a highly limited extent, and if internalized, it is rapidly recycled. The exact reasons for the endocytosis resistance of HER2 are not clear, but it is stabilized by heat‐shock protein 90 (Hsp90) and Hsp90 inhibitors induce internalization and degradation of HER2. HER2 can also be internalized upon activation of protein kinase C, and contrary to trastuzumab alone, the combination of two or more anti‐HER2 antibodies can induce efficient internalization and degradation of HER2. With intention to find ways to improve the action of T‐DM1, we investigated how different ways of inducing HER2 internalization leads to degradation of trastuzumab. The results show that although both Hsp90 inhibition and activation of protein kinase C induce internalization of trastuzumab, only Hsp90 inhibition induces degradation. Furthermore, we find that antibody internalization and degradation are increased when trastuzumab is combined with the clinically approved anti‐HER2 antibody pertuzumab (Perjeta^®).     

Efficacy and safety of trastuzumab with or without a tyrosine kinase inhibitor for HER2-positive breast cancer: A systematic review and meta-analysis

BackgroundThis study aimed to explore the efficacy and safety of trastuzumab plus tyrosine kinase inhibitors (TKIs) compared with those of trastuzumab monotherapy in patients with human epidermal growth factor receptor (HER2)-positive breast cancer.MethodsThe PubMed, Embase, Cochrane, and Web of Science databases were systematically searched for relevant articles from inception until September 2022. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Subgroup analyses were performed based on disease status, TKI type, and hormone receptor status.ResultsSixteen studies were included in the current analysis. Trastuzumab plus TKI significantly improved OS and PFS compared to trastuzumab monotherapy. In the neoadjuvant setting, trastuzumab plus TKI significantly increased the pathologic complete response (pCR) rate compared to trastuzumab monotherapy. Moreover, a higher objective response rate (ORR) was observed with trastuzumab plus TKI. Patients who received the combination therapy had a higher incidence of discontinuation, all-grade diarrhea, and grade ≥ 3 diarrhea.ConclusionsTrastuzumab plus TKI was better than trastuzumab monotherapy for treating different stages of HER2-positive breast cancer. The safety of trastuzumab plus TKI anti-HER2 therapy was controllable. The different efficacies of TKIs combined with trastuzumab may be related to the mechanism of action of the different TKIs, needing further investigations.     

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

Studies over the last two decades have identified that amplified human epidermal growth factor receptor (HER‐2; c‐erbB‐2, neu) and its overexpression have been frequently implicated in the carcinogenesis and prognosis in a variety of solid tumours, especially breast cancer. Lots of painstaking efforts were invested on the HER‐2 targeted agents, and significantly improved outcome and prolonged the survival of patients. However, some patients classified as ‘HER‐2‐positive’ would be still resistant to the anti‐HER‐2 therapy. Various mechanisms of drug resistance have been illustrated and the alteration of HER‐2 was considered as a crucial mechanism. However, systematic researches in regard to the HER‐2 mutations and variants are still inadequate. Notably, the alterations of HER‐2 play an important role in drug resistance, but also have a potential association with the cancer risk. In this review, we summarize the possible mutations and focus on HER‐2 variants’ role in breast cancer tumourigenesis. Additionally, the alteration of HER‐2, as a potential mechanism of resistance to trastuzumab, is discussed here. We hope that HER‐2 related activating mutations could potentially offer more therapeutic opportunities to a broader range of patients than previously classified as HER‐2 overexpressed.     

Efficacy and Safety of HER2-Targeted Agents for Breast Cancer with HER2-Overexpression: A Network Meta-Analysis

BackgroundClinical trials of human epidermal growth factor receptor 2 (HER2)-targeted agents added to standard treatment have been efficacious for HER2-positive (HER2+) advanced breast cancer. To our knowledge, no meta-analysis has evaluated HER2-targeted therapy including trastuzumab emtansine (T-DM1) and pertuzumab for HER2-positive breast caner and ranked the targeted treatments. We performed a network meta-analysis of both direct and indirect comparisons to evaluate the effect of adding HER2-targeted agents to standard treatment and examined side effects.MethodsWe performed a Bayesian-framework network meta-analysis of randomized controlled trials to compare 6 HER2-targeted treatment regimens and 1 naïve standard treatment (NST, without any-targeted drugs) in targeted treatment of HER2+ breast cancer in adults. These treatment regimens were T-DM1, LC (lapatinib), HC (trastuzumab), PEC (pertuzumab), LHC (lapatinib and trastuzumab), and PEHC (pertuzumab and trastuzumab). The main outcomes were overall survival and response rates. We also examined side effects of rash, LVEF (left ventricular ejection fraction), fatigue, and gastrointestinal disorders, and performed subgroup analysis for the different treatment regimens in metastatic or advanced breast cancer.ResultsWe identified 25 articles of 21 trials, with data for 11,276 participants. T-DM1 and PEHC were more efficient drug regimens with regard to overall survival as compared with LHC, LC, HC and PEC. The incidence of treatment-related rash occurs more frequently in the patients who received LC treatment regimen than PEHC and T-DM1 and HC. In subgroup analysis, T-DM1 was associated with increased overall survival as compared with LC and HC. PEHC was associated with increased overall response as compared with LC, HC, and NST.ConclusionsOverall, the regimen of T-DM1 as well as pertuzumab in combination with trastuzumab and docetaxel is efficacious with fewer side effects as compared with other regimens, especially for advanced HER2+ breast cancer.ImpactThis study suggests that both T-DM1 and PEHC therapy are potentially and equally useful treatments for HER2+ breast cancer.     

Current therapeutic options for gastric adenocarcinoma

Gastric cancer inflicts significant health issues globally despite its declining incidence. The disease is known to be diagnosed at its advanced stages also corresponding with a poor prognosis for patients. The integral therapeutic choices to cure advanced gastric cancer have progressed swiftly in modern days. The preface of molecularly targeted therapeutic techniques would potentiate the personalized approach depending on patient-specific and tumor-specific features, exasperating the advantages of chemotherapy. Here we have reviewed the modern therapeutics such as immune therapy, chemotherapy, m-RNA based therapeutics, alongside evaluating the influence of age, sex and comorbidities-like factors on the occurrence of gastric cancer. Gastric cancer therapy consolidated target agents comprising inhibitors of programmed death-1(PD-1), human epidermal growth factor receptor 2 (HER2), mRNA, and epidermal growth factor receptor (EPGF). A combination of trastuzumab to platinum-mediated chemotherapy evolved has a typical front-line therapy in advanced gastric cancer. An attempt has been made to epitomize the contemporary-modern research on targeted therapy for advanced gastric cancer.