MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.

MicroRNAs: Target Recognition and Regulatory Functions

Background

We aimed to assess the effect of afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from two open-label, randomised, phase 3 trials.

Methods

Previously untreated patients with EGFR mutation-positive stage IIIB or IV lung adenocarcinoma were enrolled in LUX-Lung 3 (n=345) and LUX-Lung 6 (n=364). These patients were randomly assigned in a 2:1 ratio to receive afatinib or chemotherapy (pemetrexed-cisplatin [LUX-Lung 3] or gemcitabine-cisplatin [LUX-Lung 6]), stratified by EGFR mutation (exon 19 deletion [del19], Leu858Arg, or other) and ethnic origin (LUX-Lung 3 only). We planned analyses of mature overall survival data in the intention-to-treat population after 209 (LUX-Lung 3) and 237 (LUX-Lung 6) deaths. These ongoing studies are registered with ClinicalTrials.gov, numbers NCT00949650 and NCT01121393.

Findings

Median follow-up in LUX-Lung 3 was 41 months (IQR 35–44); 213 (62%) of 345 patients had died. Median follow-up in LUX-Lung 6 was 33 months (IQR 31–37); 246 (68%) of 364 patients had died. In LUX-Lung 3, median overall survival was 28·2 months (95% CI 24·6–33·6) in the afatinib group and 28·2 months (20·7–33·2) in the pemetrexed-cisplatin group (HR 0·88, 95% CI 0·66–1·17, p=0·39). In LUX-Lung 6, median overall survival was 23·1 months (95% CI 20·4–27·3) in the afatinib group and 23·5 months (18·0–25·6) in the gemcitabine-cisplatin group (HR 0·93, 95% CI 0·72–1·22, p=0·61). However, in preplanned analyses, overall survival was significantly longer for patients with del19-positive tumours in the afatinib group than in the chemotherapy group in both trials: in LUX-Lung 3, median overall survival was 33·3 months (95% CI 26·8–41·5) in the afatinib group versus 21·1 months (16·3–30·7) in the chemotherapy group (HR 0·54, 95% CI 0·36–0·79, p=0·0015); in LUX-Lung 6, it was 31·4 months (95% CI 24·2–35·3) versus 18·4 months (14·6–25·6), respectively (HR 0·64, 95% CI 0·44–0·94, p=0·023). By contrast, there were no significant differences by treatment group for patients with EGFR Leu858Arg-positive tumours in either trial: in LUX-Lung 3, median overall survival was 27·6 months (19·8–41·7) in the afatinib group versus 40·3 months (24·3–not estimable) in the chemotherapy group (HR 1·30, 95% CI 0·80–2·11, p=0·29); in LUX-Lung 6, it was 19·6 months (95% CI 17·0–22·1) versus 24·3 months (19·0–27·0), respectively (HR 1·22, 95% CI 0·81–1·83, p=0·34). In both trials, the most common afatinib-related grade 3–4 adverse events were rash or acne (37 [16%] of 229 patients in LUX-Lung 3 and 35 [15%] of 239 patients in LUX-Lung 6), diarrhoea (33 [14%] and 13 [5%]), paronychia (26 [11%] in LUX-Lung 3 only), and stomatitis or mucositis (13 [5%] in LUX-Lung 6 only). In LUX-Lung 3, neutropenia (20 [18%] of 111 patients), fatigue (14 [13%]) and leucopenia (nine [8%]) were the most common chemotherapy-related grade 3–4 adverse events, while in LUX-Lung 6, the most common chemotherapy-related grade 3–4 adverse events were neutropenia (30 [27%] of 113 patients), vomiting (22 [19%]), and leucopenia (17 [15%]).

Interpretation

Although afatinib did not improve overall survival in the whole population of either trial, overall survival was improved with the drug for patients with del19 EGFR mutations. The absence of an effect in patients with Leu858Arg EGFR mutations suggests that EGFR del19-positive disease might be distinct from Leu858Arg-positive disease and that these subgroups should be analysed separately in future trials.

Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials

Faculty of 1000 evaluation for A transfer-RNA-derived small RNA regulates ribosome biogenesis.

Background Immune checkpoint inhibitors (ICIs) targeting the PD‐1/PD‐L1 axis have changed the first‐line treatment of people with advanced non‐small cell lung cancer (NSCLC). Single‐agent pembrolizumab (a PD‐1 inhibitor) is currently the standard of care as monotherapy in patients with PD‐L1 expression ≥ 50%, either alone or in combination with chemotherapy when PD‐L1 expression is less than 50%. Atezolizumab (PD‐L1 inhibitor) has also been approved in combination with chemotherapy and bevacizumab (an anti‐angiogenic antibody) in first‐line NSCLC regardless of PD‐L1 expression. The combination of first‐line PD‐1/PD‐L1 inhibitors with anti‐CTLA‐4 antibodies has also been shown to improve survival compared to platinum‐based chemotherapy in advanced NSCLC, particularly in people with high tumour mutational burden (TMB). The association of ipilimumab (an anti CTLA4) and nivolumab (PD‐1 inhibitor) has been approved by the US Food and Drug Administration (FDA) in all patients with PD‐L1 expression ≥1%. Although these antibodies are currently used in clinical practice, some questions remain unanswered, such as the best‐treatment strategy, the role of different biomarkers for treatment selection and the effectiveness of immunotherapy according to specific clinical characteristics. Objectives To determine the effectiveness and safety of first‐line immune checkpoint inhibitors (ICIs), as monotherapy or in combination, compared to platinum‐based chemotherapy, with or without bevacizumab for people with advanced NSCLC, according to the level of PD‐L1 expression. Search methods We performed an electronic search of the main databases (Cochrane Central Register of Controlled Trials, MEDLINE, Embase) from inception until 31 December 2020 and conferences meetings from 2015 onwards. Selection criteria We included randomised controlled trials (RCTs) reporting on the efficacy or safety of first‐line ICI treatment for adults with advanced NSCLC who had not previously received any anticancer treatment. We included trials comparing single‐ or double‐ICI treatment to standard first‐line therapy (platinum‐based chemotherapy +/‐ bevacizumab). All data come from ‘international multicentre studies involving adults, age 18 or over, with histologically‐confirmed stage IV NSCLC. Data collection and analysis Three review authors independently assessed the search results and a fourth review author resolved any disagreements. Primary outcomes were overall survival (OS) and progression‐free survival (PFS); secondary outcomes were overall objective response rate (ORR) by RECIST v 1.1, grade 3 to 5 treatment‐related adverse events (AEs) (CTCAE v 5.0) and health‐related quality of life (HRQoL). We performed meta‐analyses where appropriate using the random‐effects model for hazard ratios (HRs) or risk ratios (RRs), with 95% confidence intervals (95% CIs), and used the I² statistic to investigate heterogeneity. Main results Main results We identified 15 trials for inclusion, seven completed and eight ongoing trials. We obtained data for 5893 participants from seven trials comparing first‐line single‐ (six trials) or double‐ (two trials) agent ICI with platinum‐based chemotherapy, one trial comparing both first‐line single‐ and double‐agent ICsI with platinum‐based chemotherapy. All trials were at low risk of selection and detection bias, some were classified at high risk of performance, attrition or other source of bias. The overall certainty of evidence according to GRADE ranged from moderate‐to‐low because of risk of bias, inconsistency, or imprecision. The majority of the included trials reported their outcomes by PD‐L1 expressions, with PD‐L1 ≥ 50 being considered the most clinically useful cut‐off level for decision makers. Also, iIn order to avoid overlaps between various PDL‐1 expressions we prioritised the review outcomes according to PD‐L1 ≥ 50. Single‐agent ICI In the PD‐L1 expression ≥ 50% group single‐agent ICI probably improved OS compared to platinum‐based chemotherapy (hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.60 to 0.76, 6 RCTs, 2111 participants, moderate‐certainty evidence). In this group, single‐agent ICI also may improve PFS (HR: 0.68, 95% CI 0.52 to 0.88, 5 RCTs, 1886 participants, low‐certainty evidence) and ORR (risk ratio (RR):1.40, 95% CI 1.12 to 1.75, 4 RCTs, 1672 participants, low‐certainty evidence). HRQoL data were available for only one study including only people with PD‐L1 expression ≥ 50%, which suggested that single‐agent ICI may improve HRQoL at 15 weeks compared to platinum‐based chemotherapy (RR: 1.51, 95% CI 1.08 to 2.10, 1 RCT, 297 participants, low‐certainty evidence). In the included studies, treatment‐related AEs were not reported according to PD‐L1 expression levels. Grade 3‐4 AEs may be less frequent with single‐agent ICI compared to platinum‐based chemotherapy (RR: 0.41, 95% CI 0.33 to 0.50, I² = 62%, 5 RCTs, 3346 participants, low‐certainty evidence). More information about efficacy of single‐agent ICI compared to platinum‐based chemotherapy according to the level of PD‐L1 expression and to TMB status or specific clinical characteristics is available in the full text. Double‐agent ICI Double‐ICI treatment probably prolonged OS compared to platinum‐based chemotherapy in people with PD‐L1 expression ≥50% (HR: 0.72, 95% CI 0.59 to 0.89 2 RCTs, 612 participants, moderate‐certainty evidence). Trials did not report data on HRQoL, PFS and ORR according to PD‐L1 groups.
Treatment related AEs were not reported according to PD‐L1 expression levels. The frequency of grade 3‐4 AEs may not differ between double‐ICI treatment and platinum‐based chemotherapy (RR: 0.78, 95% CI 0.55 to 1.09, I² = 81%, 2 RCTs, 1869 participants, low‐certainty evidence). More information about efficacy of double‐agent ICI according to the level of PD‐L1 expression and to TMB status is available in the full text. Authors' conclusions Authors' conclusions The evidence in this review suggests that single‐agent ICI in people with NSCLC and PD‐L1 ≥50% probably leads to a higher overall survival rate and may lead to a higher progression‐free survival and overall response rate when compared to platinum‐based chemotherapy and may also lead to a lower rate of adverse events and higher HRQoL. Combined ICI in people with NSCLC and PD‐L1 ≥50% also probably leads to a higher overall survival rate when compared to platinum‐based chemotherapy, but its effect on progression‐free survival, overall response rate and HRQoL is unknown due to a lack of data. The rate of adverse events may not differ between groups. This review used to be a living review. It is transitioned out of living mode because current research is exploring ICI in association with chemotherapy or other immunotherapeutic drugs versus ICI as single agent rather than platinum based chemotherapy.

Single or combined immune checkpoint inhibitors compared to first‐line platinum‐based chemotherapy with or without bevacizumab for people with advanced non‐small cell lung cancer

Stage III non-small cell lung cancer (NSCLC) is a very heterogeneous disease that encompasses patients with resected, potentially resectable and unresectable tumours. To improve the prognostic capacity of the TNM classification, it has been agreed to divide stage III into sub-stages IIIA, IIIB and IIIC that have very different 5-year survival rates (36, 26 and 13%, respectively). Currently, it is considered that both staging and optimal treatment of stage III NSCLC requires the joint work of a multidisciplinary team of expert physicians within the tumour committee. To improve the care of patients with stage III NSCLC, different scientific societies involved in the diagnosis and treatment of this disease have agreed to issue a series of recommendations that can contribute to homogenise the management of this disease, and ultimately to improve patient care.

/pdf/multidisciplinary-consensus-statement-on-the-clinical-398ur19lis.pdf

Multidisciplinary consensus statement on the clinical management of patients with stage III non-small cell lung cancer.

MicroRNAs (miRNAs), small non-coding RNAs (ncRNAs) of about 22 nucleotides in size, play important roles in gene regulation, and their dysregulation is implicated in human diseases including cancer. A variety of miRNAs could take roles in the cancer progression, participate in the process of tumor immune, and function with miRNA sponges. During the last two decades, the connection between miRNAs and various cancers has been widely researched. Based on evidence about miRNA, numerous potential cancer biomarkers for the diagnosis and prognosis have been put forward, providing a new perspective on cancer screening. Besides, there are several miRNA-based therapies among different cancers being conducted, advanced treatments such as the combination of synergistic strategies and the use of complementary miRNAs provide significant clinical benefits to cancer patients potentially. Furthermore, it is demonstrated that many miRNAs are engaged in the resistance of cancer therapies with their complex underlying regulatory mechanisms, whose comprehensive cognition can help clinicians and improve patient prognosis. With the belief that studies about miRNAs in human cancer would have great clinical implications, we attempt to summarize the current situation and potential development prospects in this review.

/pdf/mirna-based-biomarkers-therapies-and-resistance-in-cancer-2qc8wg0a70.pdf

miRNA-based biomarkers, therapies, and resistance in Cancer.

Induction chemotherapy has been shown to improve survival of patients with stage III A/N2 (T1–3, N2, M0) non-small cell lung cancer (NSCLC), followed by resection, but the benefits of neoadjuvant radiotherapy still remain controversial. PubMed, Embase, and Cochrane library databases were searched for relevant randomized controlled trials (RCTs) comparing the outcomes of induction chemoradiotherapy over induction chemotherapy, in patients with resectable stage IIIA/N2 NSCLC. Odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) were calculated using random- or fixed-effects model, and heterogeneity was assessed using I2 test. Publication bias was examined by funnel plots analysis. A total of three RCTs met the inclusion criteria of our meta-analysis. The pooled results demonstrated that, in comparison to induction chemotherapy, induction chemoradiotherapy has a significant benefit in tumor response, mediastinal downstaging, and pathological complete response of mediastinal lymph nodes. In addition, no more peri-intervention mortality was detected in patients from chemoradiotherapy group, and a higher number of patients from this group had R0 resection. However, our results did not show any difference between overall survival and progression-free survival after 2, 4, and 6 years of follow-ups, in patients undergoing radiation therapy vs. induction chemotherapy. Preoperative chemoradiotherapy, as compared to induction chemotherapy alone, is associated with similar peri-intervention mortality, a greater tumor response, mediastinal nodule downstaging, and rate of R0 resection, but does not improve survival of resectable stage IIIA/N2 NSCLC patients.

/pdf/comparing-the-benefits-of-chemoradiotherapy-and-chemotherapy-1om7qe4gij.pdf

Comparing the benefits of chemoradiotherapy and chemotherapy for resectable stage III A/N2 non-small cell lung cancer: a meta-analysis

Background: This meta-analysis aimed to explore if immunotherapy or chemotherapy alone or in combination is a better first line treatment strategy for advanced non-small cell lung cancer (NSCLC) patients. Methods: Electronic databases including Google Scholar, PMC, PubMed, EMBASE, Scopus and the major conference proceedings were searched for relevant randomized controlled trials (RCTs) comparing outcomes of immune-checkpoint inhibitor combined with chemotherapy or immune-checkpoint inhibitor alone over chemotherapy alone in patients with advanced NSCLC without previous treatment. Study heterogeneity was assessed using the I2 test. Results: A total of 14 RCTs including 8,081 treatment naive advanced NSCLC patients were enrolled in this study. Our results showed that in comparison to chemotherapy alone, introducing immunotherapy into first-line chemotherapy has significant benefit in tumor response (RR, 1.27; 95% CI, 1.09 to 1.48), progression-free survival (PFS) (HR, -0.43; 95% CI, -0.56 to -0.31), and overall survival (OS) (HR, -0.30; 95% CI, -0.45 to -0.14) but with an increased risk of grade3 - 5 toxicity (RR, 1.11; 95% CI, 1.04 to 1.18). The pooled results of comparison of immune therapy alone with chemotherapy alone in selected patients with positive expression of Programmed Death-ligament (PD-L1) or with a high tumor mutational burden, demonstrated similar tumor response (RR, 1.13; 95% CI, 0.88 to 1.46), 3 - 5 grade toxicity (RR, 0.69; 95% CI, 0.40 to 1.19) and long-term outcomes, including OS (HR, -0.20; 95% CI, -0.43 to 0.03) and PFS (HR, -0.24; 95% CI, -0.61 to 0.14). Conclusions: Our meta-analysis showed the superiority of combination therapy over monotherapy with chemotherapeutic agents in terms of tumor response, and long-term survival, but with an increased the 3 - 5 grade toxicity. And immune-checkpoint inhibitors alone showed similar tumor response, toxicity and long-term outcomes compared to platinum-based chemotherapy in selected patients.

/pdf/immune-checkpoint-inhibitors-as-the-first-line-treatment-of-1e1wc84x9c.pdf

Immune-Checkpoint Inhibitors as the First Line Treatment of Advanced Non-Small Cell Lung Cancer: A Meta-Analysis of Randomized Controlled Trials.

Aberrant N6-methyladenosine (m6A) RNA methylation regulatory genes and related gene alternative splicing (AS) could be used to predict the prognosis of non-small cell lung carcinoma. This study focused on 13 m6A regulatory genes (METTL3, METTL14, WTAP, KIAA1429, RBM15, ZC3H13, YTHDC1, YTHDC2, YTHDF1, YTHDF2, HNRNPC, FTO, and ALKBH5) and expression profiles in TCGA-LUAD (n = 504) and TCGA-LUSC (n = 479) datasets from the Cancer Genome Atlas database. The data were downloaded and bioinformatically and statistically analyzed, including the gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. There were 43,948 mRNA splicing events in lung adenocarcinoma (LUAD) and 46,020 in lung squamous cell carcinoma (LUSC), and the data suggested that m6A regulators could regulate mRNA splicing. Differential HNRNPC and RBM15 expression was associated with overall survival (OS) of LUAD and HNRNPC and METTL3 expression with the OS of LUSC patients. Furthermore, the non-small cell lung cancer prognosis-related AS events signature was constructed and divided patients into high- vs. low-risk groups using seven and 14 AS genes in LUAD and LUSC, respectively. The LUAD risk signature was associated with gender and T, N, and TNM stages, but the LUSC risk signature was not associated with any clinical features. In addition, the risk signature and TNM stage were independent prognostic predictors in LUAD and the risk signature and T stage were independent prognostic predictors in LUSC after the multivariate Cox regression and receiver operating characteristic analyses. In conclusion, this study revealed the AS prognostic signature in the prediction of LUAD and LUSC prognosis.

/pdf/n6-methyladenosine-rna-methylation-regulator-related-ok3mc8bdp3.pdf

N6-Methyladenosine RNA Methylation Regulator-Related Alternative Splicing (AS) Gene Signature Predicts Non-Small Cell Lung Cancer Prognosis.

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers, and long noncoding RNAs (lncRNAs) regulate gene expression or activities. This study investigated the role of lncRNA LINC00551 in ESCC development and progression. Three paired ESCC and normal tissues were subjected to next-generation sequencing and we identified 82 upregulated and 60 downregulated lncRNAs, including LINC00551, which was confirmed to markedly downregulated in 78 ESCC tissues and in the Gene Expression Profiling Interactive Analysis data set. Downregulated LINC00551 expression was associated with lymph node metastasis, advanced TNM stage, and tumor size. Moreover, downregulated LINC00551 expression was also associated with poor progression-free survival and overall survival of ESCC patients. In vitro and in vivo, LINC00551 overexpression inhibited ESCC cell proliferation and invasion, whereas knockdown of LINC00551 expression promoted ESCC cell proliferation and invasion. RNA pull-down and mass spectrometry assays identified the potential LINC00551 binding proteins, and HSP27 was a promising LINC00551 targeting proteins after RNA immunoprecipitation assay. At the protein level, LINC00551 bound to and decreased HSP27 phosphorylation, and in turn, downregulated ESCC cell proliferation and invasion. The current study demonstrated the functional significance of LINC00551 in ESCC development, progression, and prognosis. Further study will assess LINC00551 as a novel prognostic marker or therapeutic target for ESCC.

Xiong Peng

Papers

miRNA-based biomarkers, therapies, and resistance in Cancer.

Comparing the benefits of chemoradiotherapy and chemotherapy for resectable stage III A/N2 non-small cell lung cancer: a meta-analysis

Immune-Checkpoint Inhibitors as the First Line Treatment of Advanced Non-Small Cell Lung Cancer: A Meta-Analysis of Randomized Controlled Trials.

N6-Methyladenosine RNA Methylation Regulator-Related Alternative Splicing (AS) Gene Signature Predicts Non-Small Cell Lung Cancer Prognosis.

Reduced LINC00551 expression promotes proliferation and invasion of esophageal squamous cancer by increase in HSP27 phosphorylation