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Radiotherapy and Oncology : Journal of... Oct 2023The addition of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) to endocrine therapy in hormone receptor-positive (HR+) human epidermal growth factor 2-negative (HER2-)... (Meta-Analysis)
Meta-Analysis
Safety and feasibility of CDK4/6 inhibitors treatment combined with radiotherapy in patients with HR-positive/HER2-negative breast cancer. A systematic review and meta-analysis.
BACKGROUND AND PURPOSE
The addition of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) to endocrine therapy in hormone receptor-positive (HR+) human epidermal growth factor 2-negative (HER2-) breast cancer has led to practice-changing improvements in overall survival. However, there are conflicting data concerning the safety of CDK4/6i combination with radiotherapy, and no consensus guidelines exist to guide practice. We conducted a meta-analysis to assess the safety and feasibility of CDK4/6i treatment with radiotherapy.
MATERIALS AND METHODS
A comprehensive search was performed in PubMed/MEDLINE, Web of Science, and Scopus, for studies in advanced/metastatic breast cancer receiving CDK4/6i and radiotherapy with the provided safety data on the occurrence of toxicity. The main outcomes were safety (grade 3-5 adverse events), CDK 4/6i dose reduction, and the discontinuation rate due to toxicity.
RESULTS
Fifteen studies comprising 1133 patients with HR+/HER2- breast cancer patients were included. Among them, 617 pts received CDK4/6i and radiotherapy; the median follow-up was 17.0 months (IQR 9.2 - 18.0), and the median age was 58.8 years (IQR 55.5---62.5). The pooled prevalence of severe hematologic toxicity was 29.4% (95% CI 14.0% - 47.4%; I = 93%; τ = 0.084; p < 0.01 and severe non-hematologic toxicity was 2.8% (95% CI 1.1% - 4.8%; I = 0%; τ = 0.0; p = 0.67). The pooled prevalence of CDK4/6i dose reduction was 24.0% (95% CI 11.1% - 39.4%; I = 90%; τ = 0.052; p < 0.01) with no difference between CDK4/6i plus RT vs. CDK4/6i (odds ratio of 0.934; 95% CI 0.66 - 1.33; I = 0%; τ = 0.0; p = 0.56). The pooled prevalence of CDK4/6i discontinuation due to toxicity was 2.3% (95% CI 0.4% - 5.2%; I = 23%; τ = 0.002; p = 0.24).
CONCLUSION
The findings of this study suggest that radiotherapy in addition to CDK4/6i treatment in breast cancer patients is generally safe and well tolerated and remains a viable treatment option.
Topics: Female; Humans; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Consensus; Cyclin-Dependent Kinase 4; Epidermal Growth Factor; Feasibility Studies; Protein Kinase Inhibitors; Radiotherapy
PubMed: 37536378
DOI: 10.1016/j.radonc.2023.109839 -
BMC Cancer Nov 2023RAS mutations affect prognosis in patients with metastatic colorectal cancer (mCRC) and have been identified as strong negative predictive markers for anti-epidermal... (Meta-Analysis)
Meta-Analysis
BACKGROUND
RAS mutations affect prognosis in patients with metastatic colorectal cancer (mCRC) and have been identified as strong negative predictive markers for anti-epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb) therapy, but many tumors containing wild-type RAS genes still do not respond to these therapies. Some additional biomarkers may have prognostic or predictive roles, but conclusions remain controversial.
METHODS
We performed a meta-analysis and systematic review of randomized controlled trials comparing anti-EGFR mAb therapy with alternative therapy that investigated the prognostic and predictive impact of additional biomarkers in RAS wild-type (wt) mCRC patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) and odds ratios (ORs) for objective response rate (ORR) were calculated. The prognostic value of biomarkers was investigated by separately pooling HR and OR for different treatment groups in an individual study. The predictive value was assessed by pooling study interactions between treatment effects and biomarker subgroups.
RESULTS
Thirty publications reporting on eighteen trials were selected, including a total of 13,507 patients. In prognostic analysis, BRAF mutations were associated with poorer PFS [HRs = 3.76 (2.47-5.73) and 2.69 (1.82-3.98)] and OS [HRs = 2.66 (1.95-3.65) and 2.45 (1.55-3.88)] in both the experimental and control arms; low miR-31-3p expression appeared to have longer PFS and OS. In terms of predictive effect, a lack of response to anti-EGFR therapy was observed in patients with BRAF mutant tumors (P < 0.01 for PFS). Patients with tumors with any mutation in the KRAS/NRAS/BRAF/PIK3CA gene also showed similar results compared with all wild-type tumors (P for PFS, OS, and ORR were < 0.01, < 0.01 and 0.01, respectively). While low miR-31-3p expression could predict PFS (P = 0.01) and OS (P = 0.04) benefit. The prognostic and predictive value regarding PIK3CA mutations, PTEN mutations or deletions, EGFR, EREG/AREG, HER2, HER3, and HER4 expression remains uncertain.
CONCLUSIONS
In RAS wt mCRC patients receiving EGFR-targeted therapy, BRAF mutation is a powerful prognostic and therapy-predictive biomarker, with no effect found for PIK3CA mutation, PTEN mutation or deletion, but the combined biomarker KRAS/NRAS/BRAF/PIK3CA mutations predict resistance to anti-EGFR therapy. Low miR-31-3p expression may have positive prognostic and therapy predictive effects. Evidence on the prognostic and predictive roles of EGFR and its ligands, and HER2/3/4 is insufficient.
Topics: Humans; Prognosis; Proto-Oncogene Proteins B-raf; Colorectal Neoplasms; Proto-Oncogene Proteins p21(ras); ErbB Receptors; Antibodies, Monoclonal; Colonic Neoplasms; Rectal Neoplasms; Biomarkers; Class I Phosphatidylinositol 3-Kinases; Mutation; MicroRNAs; Biomarkers, Tumor
PubMed: 37974093
DOI: 10.1186/s12885-023-11600-z -
The Breast Journal 2023Third-generation aromatase inhibitors (AIs) are the mainstay of treatment in hormone receptor (HR)-positive breast cancer. Even though it is considered to be a... (Review)
Review
BACKGROUND
Third-generation aromatase inhibitors (AIs) are the mainstay of treatment in hormone receptor (HR)-positive breast cancer. Even though it is considered to be a well-tolerated therapy, AI-induced musculoskeletal symptoms are common and may be accused for treatment discontinuation. Recently, selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors changed the therapeutic setting, and currently, ribociclib, palbociclib, and abemaciclib are all approved in combination with nonsteroidal AIs in patients with ER-positive, HER2-negative advanced or metastatic breast cancer. This systematic review aims to identify the frequency of aromatase inhibitor-associated musculoskeletal syndrome (AIMSS) in the adjuvant setting in patients under AI monotherapy compared to patients under combination therapy with AIs and CDK4/6 inhibitors and demonstrate the underlying mechanism of action.
METHODS
This study was performed in accordance with PRISMA guidelines. The literature search and data extraction from all randomized clinical trials (RCTs) were done by two independent investigators. Eligible articles were identified by a search of MEDLINE and ClinicalTrial.gov database concerning the period 2000/01/01-2021/05/01.
RESULTS
Arthralgia was reported in 13.2 to 68.7% of patients receiving AIs for early-stage breast cancer, while arthralgia induced by CDK4/6 inhibitors occurred in a much lower rate [20.5-41.2%]. Bone pain (5-28.7% vs. 2.2-17.2%), back pain (2-13.4% vs. 8-11.2%), and arthritis (3.6-33.6% vs. 0.32%) were reported less frequently in patients receiving the combination of CDK4/6 inhibitors with ET.
CONCLUSIONS
CDK4/6 inhibitors might have a protective effect against joint inflammation and arthralgia occurrence. Further studies are warranted to investigate arthralgia incidence in this population.
Topics: Humans; Female; Aromatase Inhibitors; Breast Neoplasms; Arthralgia; Cyclin-Dependent Kinase 4
PubMed: 37293258
DOI: 10.1155/2023/3614296 -
Oral and Maxillofacial Surgery Jun 2021This systematic review analysed evidence relating to medication-related osteonecrosis of the jaws (MRONJ) associated with protein kinase inhibitors in antiresorptive... (Review)
Review
This systematic review analysed evidence relating to medication-related osteonecrosis of the jaws (MRONJ) associated with protein kinase inhibitors in antiresorptive naïve patients. A literature search of major biomedical databases was conducted in March 2020. Information extracted from relevant articles included bibliographic information, patient characteristics, MRONJ characteristics at diagnosis, management strategies and outcomes. Sixteen studies, representing data from 17 patients, were included for final analysis. Descriptive statistics were used to synthesis available data. Eleven protein kinase inhibitors were implicated, with a mean exposure of 13 months prior to MRONJ. Renal cell carcinoma was the primary diagnosis in 41.2% of patients. Patient symptoms, clinical features, radiographic findings and histological findings were consistent with those previously described in patients with MRONJ associated with antiresorptive medications. Overall, there was a 75% rate of cure, with a mean healing time of 17.2 weeks. Patients were treated surgically in 53.3% of the cases. Patients treated surgically achieved complete healing in 100% of cases, compared with 58% in those treated conservatively. Drug discontinuation was reported in 69.2% of patients. Patients who had the offending drug discontinued achieved complete healing in 75% of cases, compared with 50% in those who did not. Evidence relating to MRONJ associated with protein kinase inhibitors is of low quality. From the available data, there are notable differences relating to patient characteristics, treatment strategies and outcomes, between MRONJ associated with protein kinase inhibitors compared with antiresorptives. Higher quality evidence is required to support the findings of this review.
Topics: Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Humans; Jaw; Protein Kinase Inhibitors
PubMed: 33037971
DOI: 10.1007/s10006-020-00913-z -
Cytokine & Growth Factor Reviews Apr 2023Epidermal growth factor receptor (EGFR) mutation is the most common driver mutation in non-small cell lung cancer (NSCLC). The first-line therapy for advanced NSCLC... (Review)
Review
Epidermal growth factor receptor (EGFR) mutation is the most common driver mutation in non-small cell lung cancer (NSCLC). The first-line therapy for advanced NSCLC patients with EGFR-sensitive mutation is the EGFR tyrosine kinase inhibitor (EGFR-TKI). However, most NSCLC patients with EGFR mutation will develop resistant mutations in EGFR-TKI therapy. With further studies, resistance mechanisms represented by EGFR-T790M mutations have revealed the impact of EGFR mutations in situ on EGFR-TKIs sensitivity. The third-generation EGFR-TKIs inhibit both EGFR-sensitive mutations and T790M mutations. The emergence of novel mutations such as EGFR-C797S and EGFR-L718Q may decrease efficacy. Searching for new targets to overcome EGFR-TKI resistance becomes a key challenge. Therefore, an in-depth understanding of the regulatory mechanisms of EGFR is essential to find novel targets to overcome drug-resistant mutations in EGFR-TKIs. EGFR, as a receptor-type tyrosine kinase, undergoes homo/heterodimerization and autophosphorylation upon binding to ligands, which activates multiple downstream signaling pathways. Interestingly, there is growing evidence that the kinase activity of EGFR is affected not only by phosphorylation but also by various post-translational modifications (PTMs, such as S-palmitoylation, S-nitrosylation, Methylation, etc.). In this review, we systematically review the effects of different protein PTMs on EGFR kinase activity and its functionality and suggest that influencing EGFR kinase activity by modulating multiple EGFR sites are potential targets to overcome EGFR-TKIs resistance mutations.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; ErbB Receptors; Drug Resistance, Neoplasm; Protein Kinase Inhibitors; Mutation; Receptor Protein-Tyrosine Kinases; Protein Processing, Post-Translational
PubMed: 36934069
DOI: 10.1016/j.cytogfr.2023.03.003 -
European Journal of Clinical Nutrition Aug 2022Placental-origin microRNA (miRNA) profiles can be useful toward early diagnosis and management of fetal growth restriction (FGR) and associated complications. We... (Review)
Review
Placental-origin microRNA (miRNA) profiles can be useful toward early diagnosis and management of fetal growth restriction (FGR) and associated complications. We conducted a systematic review to identify case-control studies that have examined miRNA signatures associated with human FGR. We systematically searched PubMed and ScienceDirect databases for relevant articles and manually searched reference lists of the relevant articles till May 18th, 2021. Of the 2133 studies identified, 21 were included. FGR-associated upregulation of miR-210 and miR-424 and downregulation of a placenta-specific miRNA cluster miRNA located on C19MC (miR-518b, miR-519d) and miR-221-3p was reported by >1 included studies. Analysis of the target genes of these miRNA as well as pathway analysis pointed to the involvement of angiogenesis and growth signaling pathways, such as the phosphatidylinositol 3-kinase- protein kinase B (PI3K-Akt) pathway. Only 3 out of the 21 included studies reported FGR-associated miRNAs in matched placental and maternal blood samples. We conclude that FGR-associated placental miRNAs could be utilized to inform clinical practice towards early diagnosis of FGR, provided enough evidence from studies on matched placental and maternal blood samples become available.Prospective Register of Systematic Reviews (PROSPERO) registration number: CRD42019136762.
Topics: Female; Fetal Growth Retardation; Humans; MicroRNAs; Phosphatidylinositol 3-Kinases; Placenta; Pregnancy
PubMed: 34741137
DOI: 10.1038/s41430-021-01041-x -
Biomedicine & Pharmacotherapy =... Sep 2022Development and identification of molecular compounds capable of killing or inhibiting transformed cells promoting carcinogenesis without inducing toxic effects to the... (Review)
Review
Development and identification of molecular compounds capable of killing or inhibiting transformed cells promoting carcinogenesis without inducing toxic effects to the normal cells are of utmost significance. A systematic review was conducted in screening for important literature was extensively performed by searching the Web of Science, Ovid, BMC Springer, Elsevier, Embase, and MEDLINE databases for optimum selectivity. Google Scholar was also used to supplement information. Pharmacotherapeutic biomolecules active against colon cancer carcinogenesis in Musa acuminata and Musa balbisiana (bananas), Punica granatum L (pomegranate), Glycine max (Soybean), Brassica oleracea L var. italica Plenck (Broccoli), and Hibiscus rosa-sinesis and Hibiscus sabdariffa (hibiscus) were evaluated. Signaling pathways like phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), protein kinase B (AKT), and nuclear factor-kappa B (NFκB) correlate the mediation of COX-2 expression. Increased levels of COX-2 are correlated with the occurrence and progression of colon cancer. Natural antioxidants in herbal plants including polyphenols and carotenoids inhibit the oxidation of lipids, proteins, and nucleic acids and thereby preventing the initiation of oxidizing chain reactions. These bioactive compounds should be considered an important dietary supplement.
Topics: Carcinogenesis; Colonic Neoplasms; Cyclooxygenase 2; Hibiscus; Humans; Phosphatidylinositol 3-Kinases; Plants, Medicinal
PubMed: 35820316
DOI: 10.1016/j.biopha.2022.113383 -
Cancer Reports (Hoboken, N.J.) Jan 2023Accumulating studies have evaluated the association between MAP3K1 polymorphisms and cancer prognosis. However, the results of these studies are conflicting. Given the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Accumulating studies have evaluated the association between MAP3K1 polymorphisms and cancer prognosis. However, the results of these studies are conflicting. Given the potential impact of MAP3K1 rs889312 SNP on the prognosis of various cancers, this meta-analysis was performed to obtain solid and credible evidence.
METHODS AND MATERIALS
This study was performed according to the PRISMA 2020 statement. A comprehensive article search was conducted to find and select articles from multiple databases, including PubMed, Google Scholar, Web of Science, EMBASE and the Cochrane Library, published up to 15th September 2022. The data analysis was performed with Review Manager v5.2. Pooled HR with its 95% CI and p-value was calculated where HR >1 suggests worse/poor survival and HR <1 suggests better survival of cancer patients.
RESULTS
A total of five articles comprising 24 439 patients were included for both qualitative and quantitative data synthesis. It was found that only the dominant genetic model (AC + CC vs. AA) showed a statistically significant poor overall survival for MAP3K1 rs889312 polymorphism (HR = 1.25, 95% CI = 1.06-1.47, p = .01). In addition, publication bias analysis by the Egger's test and the Begg-Mazumdar test reported no significant bias in the analysis of overall survival (p > .05).
CONCLUSIONS
The present study concludes that MAP3K1 gene rs889312 polymorphism plays a prognostic role in the survival of cancer patients. However, future research is recommended that will analyze more MAP3K SNPs along with rs889312, which may reveal more credible outcomes in terms of cancer prognosis.
Topics: Humans; Neoplasms; Polymorphism, Single Nucleotide; Prognosis; MAP Kinase Kinase Kinase 1
PubMed: 36560873
DOI: 10.1002/cnr2.1773 -
Journal of Cellular Physiology Jul 2022Pemphigus vulgaris (PV) is a potentially fatal autoimmune blistering disease characterized by cell-cell detachment (or acantholysis) and blister formation. While the... (Review)
Review
Pemphigus vulgaris (PV) is a potentially fatal autoimmune blistering disease characterized by cell-cell detachment (or acantholysis) and blister formation. While the signaling mechanisms that associate with skin/mucosal blistering are being elucidated, specific treatment strategies targeting PV-specific pathomechanisms, particularly kinase signaling, have yet to be established. Hence, the aim of this review was to systematically evaluate molecules in the class of kinases that are essential for acantholysis and blister formation and are therefore candidates for targeted therapy. English articles from PubMed and Scopus databases were searched, and included in vitro, in vivo, and human studies that investigated the role of kinases in PV. We selected studies, extracted data and assessed risk of bias in duplicates and the results were reported according to the methodology outlined by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). The risk of bias assessment was performed on in vivo studies utilizing SYRCLE's risk of bias tool. Thirty-five studies were included that satisfied the pathogenicity criterion of kinases in PV, the vast majority being experimental models that used PV sera (n = 13) and PV-IgG (n = 22). Inhibition of kinase activity (p38MAPK, PKC, TK, c-Src, EGFR, ERK, mTOR, BTK, and CDK2) was achieved mostly by pharmacological means. Overall, we found substantial evidence that kinase inhibition reduced PV-associated phosphorylation events and keratinocyte disassociation, prevented acantholysis, and blocked blister formation. However, the scarce adherence to standardized reporting systems and the experimental protocols/models used did limit the internal and external validity of these studies. In summary, this systematic review highlighted the pathogenic intracellular events mediated by kinases in PV acantholysis and presented kinase signaling as a promising avenue for translational research. In particular, the molecules identified and discussed in this study represent potential candidates for the development of mechanism-based interventions in PV.
Topics: Acantholysis; Autoantibodies; Blister; Humans; Immunoglobulin G; Keratinocytes; Pemphigus; Phosphorylation
PubMed: 35616233
DOI: 10.1002/jcp.30784 -
CNS Neuroscience & Therapeutics Aug 2023Rapid diagnosis of acute ischemic stroke (AIS) patients is still challenging, and reliable biomarkers are needed. Noncoding RNAs are important for many physiological... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Rapid diagnosis of acute ischemic stroke (AIS) patients is still challenging, and reliable biomarkers are needed. Noncoding RNAs are important for many physiological activities, among which circular RNAs (circRNAs) have been proven to be more tissue-specific and conservative. Many recent studies found the potential of circRNAs as biomarkers for many diseases, including cardiovascular diseases, cancers, and ischemic stroke. This systemic review and meta-analysis aimed to identify circRNAs as potential biomarkers for AIS.
METHODS
This study has been prospectively registered in PROSPERO (Registration No. 11 CRD42021288033). Published literature comparing circRNA expression profiles between AIS and non-AIS in human and animal models were retrieved from the articles published by January 2023 in major databases. We descriptively summarized the included studies, conducted meta-analysis under a random effects model, and did bioinformatics analysis including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis.
RESULTS
Totally 23 studies were included, reporting 18 distinctive upregulated and 20 distinctive downregulated circRNAs. Diagnostic meta-analysis indicated discriminative ability of the circRNAs. Furthermore, circRNA HECTD1, circRNA DLGAP4, circRNA CDC14A, circRNA SCMH1, and circRNA TLK1 were reported with the same regulation trend in more than one study (animal studies included). GO and KEGG enrichment analyses indicated that the target genes of these five circRNAs were enriched in regulating cell proliferation, apoptosis, and oxidative stress.
CONCLUSIONS
This study demonstrates that circRNAs (circRNA HECTD1, circRNA DLGAP4, circRNA CDC14A, circRNA SCMH1, and circRNA TLK1) generally are promising as potential biomarkers for AIS. However, due to the limited number of studies, diagnostic value of individual circRNA could not be validated. More in vitro and in vivo functional studies are needed.
Topics: Animals; Humans; RNA, Circular; Ischemic Stroke; Stroke; Biomarkers; MicroRNAs; RNA; Gene Expression Profiling; Protein Serine-Threonine Kinases
PubMed: 37186176
DOI: 10.1111/cns.14220