DataSheet_1_Addition of PD-1/PD-L1 inhibitors to chemotherapy for triple-negative breast cancer: a meta-analysis.pdf

BackgroundIn recent years, the addition of immune checkpoint inhibitors (ICI) to chemotherapy (CT) has become a research hotspot in the therapy of metastatic triple-negative breast cancer. Nevertheless, controversial results have been revealed among the published randomized controlled trials. Hence, a meta-analysis was performed to assess the therapeutic effect of this treatment regimen.MethodsFive English databases (PubMed, WOS, CENTRAL, Scopus, and Embase), and four Chinese databases (CBM, CNKI, VIP, and Wanfang), as well as oncological meetings, were systematically searched to identify eligible studies that assessed the addition of ICI to CT versus CT alone in metastatic triple-negative breast cancer. The pooled hazard ratios (HR) of progression-free survival (PFS) and overall survival (OS) were estimated using fixed- or random-effect model. Subgroup analyses were also performed in the intention-to-treat (ITT) and PD-L1-positive individuals.ResultsAll told there are five eligible randomized controlled trials involving 3,000 patients were enrolled in this meta-analysis. Compared with CT alone, the ICI plus CT regimen significantly increased PFS in the ITT (HR = 0.80, 95% CI: 0.73–0.88) and PD-L1-positive (HR = 0.70, 95% CI: 0.62–0.79) populations, as well as OS in the ITT (HR = 0.89, 95% CI: 0.81–0.97) and PD-L1-positive populations (HR = 0.80, 95% CI: 0.71–0.91). Moreover, the PFS of sufferers treated with the combination strategy of ICI with CT increased alongside PD-L1 enrichment. A clinical benefit in terms of objective response rate was also distinctly observed in both populations treated with ICI plus CT. In the subgroup analysis, patients in the no prior CT subgroup experienced a striking increase in PFS in both populations; however, a difference was not observed in other subgroups.ConclusionsThe combination strategy striking improves PFS and OS in both ITT and PD-L1-positive populations, and PFS is prolonged with PD-L1 enrichment. Patients who do not receive CT prior to this treatment are associated with longer PFS in both populations.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier CRD42021289817.</p

DataSheet_2_Addition of PD-1/PD-L1 inhibitors to chemotherapy for triple-negative breast cancer: a meta-analysis.pdf

BackgroundIn recent years, the addition of immune checkpoint inhibitors (ICI) to chemotherapy (CT) has become a research hotspot in the therapy of metastatic triple-negative breast cancer. Nevertheless, controversial results have been revealed among the published randomized controlled trials. Hence, a meta-analysis was performed to assess the therapeutic effect of this treatment regimen.MethodsFive English databases (PubMed, WOS, CENTRAL, Scopus, and Embase), and four Chinese databases (CBM, CNKI, VIP, and Wanfang), as well as oncological meetings, were systematically searched to identify eligible studies that assessed the addition of ICI to CT versus CT alone in metastatic triple-negative breast cancer. The pooled hazard ratios (HR) of progression-free survival (PFS) and overall survival (OS) were estimated using fixed- or random-effect model. Subgroup analyses were also performed in the intention-to-treat (ITT) and PD-L1-positive individuals.ResultsAll told there are five eligible randomized controlled trials involving 3,000 patients were enrolled in this meta-analysis. Compared with CT alone, the ICI plus CT regimen significantly increased PFS in the ITT (HR = 0.80, 95% CI: 0.73–0.88) and PD-L1-positive (HR = 0.70, 95% CI: 0.62–0.79) populations, as well as OS in the ITT (HR = 0.89, 95% CI: 0.81–0.97) and PD-L1-positive populations (HR = 0.80, 95% CI: 0.71–0.91). Moreover, the PFS of sufferers treated with the combination strategy of ICI with CT increased alongside PD-L1 enrichment. A clinical benefit in terms of objective response rate was also distinctly observed in both populations treated with ICI plus CT. In the subgroup analysis, patients in the no prior CT subgroup experienced a striking increase in PFS in both populations; however, a difference was not observed in other subgroups.ConclusionsThe combination strategy striking improves PFS and OS in both ITT and PD-L1-positive populations, and PFS is prolonged with PD-L1 enrichment. Patients who do not receive CT prior to this treatment are associated with longer PFS in both populations.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier CRD42021289817.</p

Image_2_Addition of PD-1/PD-L1 inhibitors to chemotherapy for triple-negative breast cancer: a meta-analysis.tif

BackgroundIn recent years, the addition of immune checkpoint inhibitors (ICI) to chemotherapy (CT) has become a research hotspot in the therapy of metastatic triple-negative breast cancer. Nevertheless, controversial results have been revealed among the published randomized controlled trials. Hence, a meta-analysis was performed to assess the therapeutic effect of this treatment regimen.MethodsFive English databases (PubMed, WOS, CENTRAL, Scopus, and Embase), and four Chinese databases (CBM, CNKI, VIP, and Wanfang), as well as oncological meetings, were systematically searched to identify eligible studies that assessed the addition of ICI to CT versus CT alone in metastatic triple-negative breast cancer. The pooled hazard ratios (HR) of progression-free survival (PFS) and overall survival (OS) were estimated using fixed- or random-effect model. Subgroup analyses were also performed in the intention-to-treat (ITT) and PD-L1-positive individuals.ResultsAll told there are five eligible randomized controlled trials involving 3,000 patients were enrolled in this meta-analysis. Compared with CT alone, the ICI plus CT regimen significantly increased PFS in the ITT (HR = 0.80, 95% CI: 0.73–0.88) and PD-L1-positive (HR = 0.70, 95% CI: 0.62–0.79) populations, as well as OS in the ITT (HR = 0.89, 95% CI: 0.81–0.97) and PD-L1-positive populations (HR = 0.80, 95% CI: 0.71–0.91). Moreover, the PFS of sufferers treated with the combination strategy of ICI with CT increased alongside PD-L1 enrichment. A clinical benefit in terms of objective response rate was also distinctly observed in both populations treated with ICI plus CT. In the subgroup analysis, patients in the no prior CT subgroup experienced a striking increase in PFS in both populations; however, a difference was not observed in other subgroups.ConclusionsThe combination strategy striking improves PFS and OS in both ITT and PD-L1-positive populations, and PFS is prolonged with PD-L1 enrichment. Patients who do not receive CT prior to this treatment are associated with longer PFS in both populations.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier CRD42021289817.</p

Image_1_Addition of PD-1/PD-L1 inhibitors to chemotherapy for triple-negative breast cancer: a meta-analysis.tif

BackgroundIn recent years, the addition of immune checkpoint inhibitors (ICI) to chemotherapy (CT) has become a research hotspot in the therapy of metastatic triple-negative breast cancer. Nevertheless, controversial results have been revealed among the published randomized controlled trials. Hence, a meta-analysis was performed to assess the therapeutic effect of this treatment regimen.MethodsFive English databases (PubMed, WOS, CENTRAL, Scopus, and Embase), and four Chinese databases (CBM, CNKI, VIP, and Wanfang), as well as oncological meetings, were systematically searched to identify eligible studies that assessed the addition of ICI to CT versus CT alone in metastatic triple-negative breast cancer. The pooled hazard ratios (HR) of progression-free survival (PFS) and overall survival (OS) were estimated using fixed- or random-effect model. Subgroup analyses were also performed in the intention-to-treat (ITT) and PD-L1-positive individuals.ResultsAll told there are five eligible randomized controlled trials involving 3,000 patients were enrolled in this meta-analysis. Compared with CT alone, the ICI plus CT regimen significantly increased PFS in the ITT (HR = 0.80, 95% CI: 0.73–0.88) and PD-L1-positive (HR = 0.70, 95% CI: 0.62–0.79) populations, as well as OS in the ITT (HR = 0.89, 95% CI: 0.81–0.97) and PD-L1-positive populations (HR = 0.80, 95% CI: 0.71–0.91). Moreover, the PFS of sufferers treated with the combination strategy of ICI with CT increased alongside PD-L1 enrichment. A clinical benefit in terms of objective response rate was also distinctly observed in both populations treated with ICI plus CT. In the subgroup analysis, patients in the no prior CT subgroup experienced a striking increase in PFS in both populations; however, a difference was not observed in other subgroups.ConclusionsThe combination strategy striking improves PFS and OS in both ITT and PD-L1-positive populations, and PFS is prolonged with PD-L1 enrichment. Patients who do not receive CT prior to this treatment are associated with longer PFS in both populations.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier CRD42021289817.</p

Boxplots showing the effect of <i>WDR5</i> knockdown on cell viability in the MCF7 breast cancer cell line.

<p>Boxplots showing the effect of <i>WDR5</i> knockdown on cell viability in the MCF7 breast cancer cell line.</p

The top network of <i>WDR5</i> eQTL associated genes predicted using IPA.

<p>35 components were chosen to be included. Genes in gray are <i>WDR5</i> and its eQTL associated genes, and the rest are genes closely related to them.</p

<i>WDR5</i> Expression Is Prognostic of Breast Cancer Outcome

<div><p>WDR5 is a core component of the human mixed lineage leukemia-2 complex, which plays central roles in ER positive tumour cells and is a major driver of androgen-dependent prostate cancer cell proliferation. Given the similarities between breast and prostate cancers, we explore the potential prognostic value of <i>WDR5</i> gene expression on breast cancer survival. Our findings reveal that <i>WDR5</i> over-expression is associated with poor breast cancer clinical outcome in three gene expression data sets and BreastMark. The eQTL analysis reveals 130 trans-eQTL SNPs whose genes mapped with statistical significance are significantly associated with patient survival. These genes together with <i>WDR5</i> are enriched with “cellular development, gene expression, cell cycle” signallings. Knocking down <i>WDR5</i> in MCF7 dramatically decreases cell viability, but does not alter tumour cell response to doxorubicin. Our study reveals the prognostic value of <i>WDR5</i> expression in breast cancer which is under long-range regulation of genes involved in cell cycle, and anthracycline could be coupled with treatments targeting <i>WDR5</i> once such a regimen is available.</p></div

Summarized statistics of the association between <i>WDR5</i> gene expression and breast cancer patient survival.

<p>The p value and hazard ratio (HR) of tumours over-expressing <i>WDR5</i> are depicted below. In the ‘Subgroup’ column, ‘Anthr+’ and ‘Anthr-’ labels represent the anthracycline treated and untreated group respectively, and ‘main’ means all samples are used in the analysis. The number of patients is shown in the ‘Sample’ column, with the number of events listed in the brackets.</p><p>Summarized statistics of the association between <i>WDR5</i> gene expression and breast cancer patient survival.</p

The Polymorphic AluYb8 Insertion in the <i>MUTYH</i> Gene is Associated with Reduced Type 1 Protein Expression and Reduced Mitochondrial DNA Content

<div><p>The human <i>mutY homolog</i> (<i>MUTYH</i>) participates in base excision repair (BER), which is critical for repairing oxidized DNA bases and maintaining DNA replication fidelity. The polymorphic AluYb8 insertion in the 15^th intron of the <i>MUTYH</i> gene (<i>AluYb8MUTYH</i>) has been shown to associate with an aggregated 8-hydroxy-2′-deoxyguanosine (8-OH-dG) lesion in genomic DNA and to serve as a risk factor for age-related diseases. In this work, we demonstrate that this variant is associated with a significant reduction of the type 1 MUTYH protein that localizes to mitochondria. Notably, this variant affects mitochondrial DNA (mtDNA) maintenance and functional mitochondrial mass in individuals homozygous for the <i>AluYb8MUTYH</i> variant. These findings provide evidence for an association between the <i>AluYb8MUTYH</i> variant and decreased mitochondrial homeostasis and, consequently, contribute to elucidating the roles of the <i>AluYb8MUTYH</i> variant in impairing the mitochondrial base excision repair (mtBER) system and increasing the risk of acquiring an age-related disease.</p></div

MUTYH protein expression detected by immunoblot analysis with MUTYH antibody (sc-25169).

<p>The two major MUTYH proteins, type 1 and type 2, are indicated. GAPDH was used as a protein loading control. The <i>AluYb8MUTYH</i> genotypes and individual IDs are shown, respectively.</p