Volume 10 - 2020 | https://doi.org/10.3389/fonc.2020.526850 This article is part of the Research TopicEmerging Diagnostic Approaches for Triple-Negative Breast CancerView all 10 articles Noncoding RNAs (ncRNAs) include a diverse range of RNA species including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) ncRNAs of approximately 19–25 nucleotides in length are involved in gene expression regulation either via degradation or silencing of the messenger RNAs (mRNAs) and have roles in multiple biological processes comprise one of the largest and most heterogeneous RNA families LncRNAs can activate or repress gene expression through various mechanisms acting alone or in combination with miRNAs and other molecules as part of various pathways most research has focused on individual lncRNA and miRNA functions as regulators and there is limited available data on ncRNA interactions relating to the tumor growth acting either on mRNA alone or as competing endogenous RNA (ceRNA) networks Triple-negative breast cancer (TNBC) represents approximately 10%–20% of all breast cancers (BCs) and is highly heterogenous and more aggressive than other types of BC for which current targeted treatment options include hormonotherapy no targeted therapies for TNBC are available partly because of a lack of predictive biomarkers new evidence has emerged demonstrating the implications of dysregulation of ncRNAs in TNBC etiology we review the roles of lncRNAs and miRNAs implicated in TNBC including their interactions and regulatory networks Our synthesis provides insight into the mechanisms involved in TNBC progression and has potential to aid the discovery of new diagnostic and therapeutic strategies and LAR tumors are associated with the best overall survival (OS) rates To improve the survival of patients with TNBC identification of predictive biomarkers is necessary to assess the risk of metastasis Of novel and potentially useful biomarkers there is good evidence for close correlation of abnormal expression of noncoding RNAs (ncRNAs) and TNBC development and progression MiRNAs are short, single-stranded, ncRNAs (19–25 nucleotides) that account for 1%–5% of the human genome (28,000 mature miRNAs have been identified) and regulate at least 30% of protein-coding genes (18, 19). They are involved in the regulation of tumor growth, proliferation, differentiation, and apoptosis as oncogenes and tumor suppressors (17, 20) The pre-miRNA crosses the nuclear membrane into the cytoplasm through the exportin-5 channel double-stranded RNA fragments whose strands separate and the mature single-stranded molecule adheres to the RNA-induced silencing complex (RISC) which is an effector molecule comprising miRNA and specific proteins MiRNAs can also promote ribosome biogenesis, resulting in target gene repression (24). Further, miRNAs are implicated in various biological and pathological regulatory processes, including the most malignant phenotype processes (25) To date, studies have focused on specific miRNA profiles that intervene at different levels of the malignant process; however, the reasons why miRNAs are over- or under-expressed remain unclear although multiple hypotheses have been proposed (36) Table 1 Summary of the cellular functions of miRNAs in tumorigenesis of TNBC The definition and classification of lncRNAs remains somewhat unclear as the exact mechanisms and pathways of action of these molecules have not been fully elucidated although some classes of lncRNA have been intensively studied and no longer represent a mystery Most lncRNAs localize to the nucleus and chromatin, where they control DNA sequences and are involved in transcriptional regulation with different functions in the cytoplasm, and a fraction of molecules occur as circulating lncRNAs, which are transmitted via exosomes (78) LncRNAs can interact with various molecules, including transcription factors, mature mRNAs, chromatin-modifying complexes, RNA binding proteins, DNA, nascent RNA transcripts, microRNA, and chromatin. LncRNA transcripts can bind to active proteins and establish an exact position (cis or trans) (80). Consequently, lncRNAs have important functions in regulating gene expression at the epigenetic, transcription, and post-transcription levels (82) Several lncRNAs have important roles in cancer development, some of which have also been identified in TNBC (Table 2). From oncogenic lncRNAs, the main important ones are HOTAIR, MALAT1, HULC, AWPPH and ARNILA. HOTAIR (Hox transcript antisense intergenic RNA) is one of the best-studied lncRNA regulators. It is a spliced, polyadenylated transcript comprising 6 exons; is approximately 2200 nucleotides in length; and maps to chromosome 12q13.13 (83) This sequence has roles in the progression of multiple neoplasms HOTAIR is oncogenic when upregulated; hence its expression levels are correlated with patient prognosis and HOTAIR can be used as a predictive biomarker Table 2 Summary of the cellular functions of miRNAs in tumorigenesis of TNBC Fully mature miRNAs interact with complementary regions in the 3’-UTRs of target mRNA transcripts, referred to as miRNA recognition elements (MREs). The consequence is the destruction of targets that are a perfect match or inhibition of translation when the target is a partial match (110) It is generally accepted that ceRNA networks could be the next candidates to serve as prognostic biomarkers and possibly targets for new therapies in TNBC Based on recent topics of research focus, which involve genomic sponges and interactions among them, databases (ceRDB, starBAse, lnCeDB, LncACTdb, HumanViCe) have been created to archive all available information. Relationships are predicted virtually and validated experimentally (125) Many lncRNAs have been proposed as ceRNAs for miRNAs. In TNBC, ARF6 overexpression causes loss of MiR-145, resulting in promotion of cell invasion. LincRNA-RoR, a regulator of reprogramming, is a ceRNA for miR-145, leading to competitive inhibition with ARF6, and loss of mature miR-145 expression (126–130) Another important discovery is circular RNAs (circRNAs), which are ceRNAs created by the direct ligation of the 5′ and 3′ ends of linear RNA. Circular forms are transitional in the course of RNA splicing, exhibit superior stability relative to linear RNAs, and could consequently serve as effective miRNA sponges (131) Direct regulatory relationships in these networks manifest as correlations among genes regulated by the same transcription factors, transcription factors with their individual correlated targets, or incidental correlations between gene expression levels. It has become clear that co-expression networks created in this way do not accurately represent the underlying regulatory processes and do not retain many of the properties associated with biological networks (132) A study of 116 TNBC and 11 normal tissues from TCGA analyzed integrated expression profiles, including data on miRNAs, lncRNAs, and mRNAs in a WGCNA to identify the features of dysregulated genes. Seven key molecules (AKAP12, FOS, EMX2OS, MYCNOS, RP11-542B15.1, hsa-miR-9, and hsa-miR-183) were overexpressed and correlated with poor patient outcomes; however, overexpression of hsa-miR-145, LINC00461, RP11-576D8.4, and RP11-496D24.2 was correlated with better OS (134) An lncRNA-miRNA-mRNA regulatory axis was also hypothesized as positively correlated with TNBC in a ceRNA, in which five molecules (TERT, TRIML2, PHBP4, miR-1-3p, and miR-133a-3p) were significantly associated with prognosis in patients with TNBC (135) In a study of 155 DElncRNAs, DEmRNAs, and DEmiRNAs, OSTN-AS1 was identified as related to immunologic function and immune-related marker co-expression and proposed as a novel, possibly immune-related, prognostic marker (137) A biomarker is a molecule that, ideally, is easy to detect and offers credible information on diagnosis, prognosis, or other disease parameters (138). MiRNAs are considered possible strong biomarkers in TNBC and can be evaluated in tissue specimens and as circulating miRNAs, where the latter present new opportunities for identification of powerful biomarkers in TNBC (139, 140) MiRNAs useful as biomarkers can be identified singly or as part of a group of miRNAs all implicated in TNBC, referred to as miR-signatures. Examples of miRNAs useful as independent markers and also included in various miR-signatures include miR-10b, miR-155, and miR-21. Further, these molecules are dysregulated in numerous neoplasms in addition to TNBC (71, 141) Figure 1 Sources and routes of circulating mRNAs Exosomal secretion- Pri-miRNA is transcribed processed by Drosha and transported in cytoplasm by Exportin5 where is integrated in RISC complex and target mRNA in exosomes which are released in human fluids Budding from plasma membrane and forming microvesicles Measurement of HIF1A-AS2 expression in 86 TNBC specimens, 30 non-TNBC specimens, and 30 adjacent mammary specimens demonstrated that it is upregulated in TNBC tissues compared with non-TNBC tissues, leading to the conclusion that HIF1A-AS2 expression is associated with OS in patients with TNBC (181) A recently discovered lncRNA, hepatocellular carcinoma upregulated EZH2-associated lncRNA (HEIH), is overexpressed in TNBC tissues and cell lines compared with adjacent normal mammary tissues and a normal mammary epithelial cell line. Downregulation of HEIH inhibits TNBC cell proliferation and promotes apoptosis by regulating the miR-4458/SOCS1 axis. HEIH is also involved in clinical progression (183) Comparison between the genome-wide methylation profiles in peripheral blood DNA from 233 patients with TNBC and 231 controls led to the identification and validation of increased methylation at cg06588802 in the long intergenic noncoding RNA, LINC00299 in patients with TNBC compared with controls, suggesting that hypermethylation of LINC00299 in peripheral blood may constitute a useful circulating biomarker for TNBC (184) The paradigm proposed for the origin of cancer related to its hallmarks involves the highly dynamic accumulation of mutations and chromosomal genetic changes occurring at different times and influenced by epigenetic mechanisms Translating current knowledge of TNBC into oncological practice involves identification of new biomarkers/molecules/assays, which reveal new pathways or novel ways to understand these diseases. EMT is a current research focus with the metastatic process involving multiple genes/pathways: for example, ETS, RAS, integrins, WNT/beta-catenin, SRC, and Notch (185–191) Cancer stem cells express phenotypic plasticity, which is a major factor in tumor malignancy, and miRNAs are involved in the maintenance of stemness in TNBC (192–196). Specifically, miRNA-31 promotes mammary stem cell expansion and tumorigenesis by suppressing WNT signaling antagonists (197) LncRNAs are also central players in the battle against malignant diseases LncRNAs contribute to regulatory networks by various mechanisms Nuclear lncRNAs may be considered to have epigenetic functions of regulation or to act as guides by recruiting chromatin modification factors to cytogenetic loci Studies of miRNAs and lncRNAs can also improve information regarding the molecular classification of TNBC. Recently a novel TNBC classification system, the FUSCC classification, was established by integrating the expression profiles of mRNAs and lncRNAs (198) it is essential to explore the mechanisms and interactions involved in the regulatory networks in which lncRNAs can serve as a ceRNAs involved in regulation of mRNA expression and also including miRNAs represents a new perspective regarding ncRNA interactions Possible tissue biomarkers have been identified in numerous studies singly or associated in specific signatures and mRNA interactions in cancer and the molecular mechanisms involved in these interactions correlated with tumorigenesis and cancer progression remain undefined Future biomarkers in TNBC may be represented by genomic signatures developed into clinically accepted tests for the early detection and clinical management of patients with TNBC Circulating miRNAs and lncRNAs are also promising tests for early detection LncRNA-miRNA-mRNA interaction networks provide opportunities for further experimental studies and improvement of biomarker predictions for developing novel therapeutic approaches in TNBC All authors listed have made a substantial and intellectual contribution to the work and approved it for publication The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest PubMed Abstract | CrossRef Full Text | Google Scholar PubMed Abstract | CrossRef Full Text | Google Scholar Triple-negative breast cancer: Clinicopathological characteristics and relationship with basal-like breast cancer Subtypes of breast cancer show preferential site of relapse CrossRef Full Text | Google Scholar Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: High incidence of central nervous system metastases Triple-negative and HER2-overexpressing breast cancers exhibit an elevated risk and an earlier occurrence of cerebral metastases The prognostic impact of age in different molecular subtypes of breast cancer Breast Cancer Res Treat (2015) 152:667–73 5-year Overall survival of triple negative breast cancer: A single institution experience CrossRef Full Text | Google Scholar Availble from seer.cancer.gov/csr/1975_2016/ based on November 2018 SEER data submission Google Scholar Comprehensive molecular portraits of human breast tumours PubMed Abstract | CrossRef Full Text | Google Scholar TNBC type: A Subtyping Tool for Triple-Negative Breast Cancer Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer CrossRef Full Text | Google Scholar Breast Cancer: Current Molecular Therapeutic Targets and New Players Anti-Cancer Agents Medicinal Chem (2017) 17:152–63 doi: 10.2174/1871520616666160502122724 CrossRef Full Text | Google Scholar ISBN: ISBN 978–0–19–957717–0 Google Scholar World J Gastroenterol (2007) 13:497–502 PubMed Abstract | CrossRef Full Text | Google Scholar Phylogenetic shadowing and computational identification of human microRNA genes Decreased expression of key tumour suppressor microRNAs is associated with lymph node metastases in triple negative breast cancer The nuclear RNase III Drosha initiates microRNA processing The Drosha-DGCR8 complex in primary microRNA processing New York:Humana Press (2018)ISSN 1940-6029; ISBN 978-1-4939-7435-1 CrossRef Full Text | Google Scholar Switching from repression to activation: microRNAs can up regulate translation The role of microRNAs in biological processes PubMed Abstract | CrossRef Full Text | Google Scholar How epigenetics can explain human metastasis: A new role for microRNAs PubMed Abstract | CrossRef Full Text | Google Scholar Mechanisms of control of microRNA biogenesis CrossRef Full Text | Google Scholar SNPs in human miRNA genes affect biogenesis and function Human polymorphism at microRNAs and microRNA target sites Proc Natl Acad Sci USA (2007) 104:3300–5 PubMed Abstract | CrossRef Full Text | Google Scholar Mutation Altering the miR-184 Seed Region Causes Familial Keratoconus with Cataract MiR-204 is responsible for inherited retinal dystrophy associated with ocular coloboma Proc Natl Acad Sci USA (2015) (2015) 112:E3236–45 CrossRef Full Text | Google Scholar High copy number variation of cancer-related microRNA genes and frequent amplification of DICER1 and DROSHA in lung cancer Framework for microRNA variant annotation and prioritization using human population and disease datasets Somatic Mutations in miRNA Genes in Lung Cancer-Potential Functional Consequences of Non-Coding Sequence Variants Extracellular/Circulating MicroRNAs: Release Mechanisms Achievements Life Sci (2016) 10(2):175–86 CrossRef Full Text | Google Scholar Many roads to maturity: microRNA biogenesis pathways and their regulation miR-9 and miR-200 regulate PDGFRβ-mediated endothelial differentiation of tumor cells in triple-negative breast cancer regulates E-cadherin and cancer metastasis MicroRNA miR-21 overexpression in human breast cancer is associated with advanced clinical stage lymph node metas¬tasis and patient poor prognosis Critical role of miR-10b in transforming growth factor β1-induced epithelial–mesenchymal transition in breast cancer Breast-cancer-secreted miR-122 reprograms glucose me¬tabolism in premetastatic niche to promote metastasis promotes cell growth and disrupts the cell cycle by regulating LATS2 Down-regulation of BRCA1 expression by miR-146a and miR-146b-5p in triple negative sporadic breast cancers Upregulation of miRNA-155 promotes tumour angiogenesis by targeting VHL and is associated with poor prognosis and triple-negative breast cancer Activin and TGFβ regulate expression of the microRNA-181 family to promote cell migration and invasion in breast cancer cells Expression and regulatory function of miRNA-182 in triple-negative breast cancer cells through its targeting of profilin 1 Secreted uPAR isoform 2 (uPAR7b) is a novel direct target of miR-221 miR-221 promotes tumorigenesis in human triple negative breast cancer cells CrossRef Full Text | Google Scholar Reciprocal regulation of Hsa-miR-1 and long noncoding RNA MALAT1 promotes triple-negative breast cancer development prognostic and predictive value of MicroR- NA-21 in breast cancer patients their daughters and healthy individuals in breast cancer patients Inhibits Invasion and Metastasis of Breast Cancer Cells PubMed Abstract | CrossRef Full Text | Google Scholar MicroR-NA-101 inhibits cell progression and increases paclitaxel sen- sitivity by suppressing MCL-1 expression in human triple- negative breast cancer MiR-125b inhibited epithelial-mesenchymal transition of triple- negative breast cancer by targeting MAP2K7 Onco Tar- gets Ther (2016) 9:2639–48 MiR-136 sup-presses tumor invasion and metastasis by targeting RASAL2 in triple-negative breast cancer MicroRNA-145 inhibits growth and migration of breast cancer cells through targeting oncoprotein ROCK1 MiR-145 promotes TNF-α-induced apoptosis by facilitating the formation of RIP1-FADDcaspase-8 complex in triple-negative breast cancer miR-146a And miR-153 expression in triple negative vs non triple negative breast cancer: potential biomarkers Eribulin upregulates miR-195 expression and downregulates Wnt3a expression in non-basal-like type of triple-negative breast cancer cell MDA-MB-231 miR-199a-5p confers tumorsuppressive role in triple-negative breast cancer Epigenetic regulation of miR-200 as the potential strategy for the therapy against triple-negative breast cancer The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1 The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2 MiR-200a inhibits migration of triple-negative breast can¬cer cells through direct repression of the EPHA2 oncogene Dual regulation by microRNA-200b-3p and microRNA-200b-5p in the inhibition of epithelial-to-mesenchymal transition in triple-negative breast cancer BRCA mutations cause reduction in miR-200c expres- sion in triple negative breast cancer MicroRNA-203 suppresses cell proliferation and migration by targeting BIRC5 and LASP1 in human triple-negative breast cancer cells MiR203 mediates subversion of stem cell properties during mammary epithelial differentiation via repression of ΔNP63α and promotes mesenchymal-to-epithelial transition Oncosuppressive role of p53-induced miR-205 in triple negative breast cancer MicroRNA-205 signaling regulates mammary stem cell fate and tumorigenesis Altered Micro-RNA expression confined to specific epithelial cell subpopulations in breast cancer MiR-206 inhibits cell migration through direct target- ing of the actin-binding protein coronin 1C in triple-negative breast cancer MiR-146a and miR-638 in BRCA1-deficient triple negative breast cancer tumors as potential biomarkers for improved overall survival MiR-655 suppresses epithelial-to-mesenchymal transition by targeting Prrx1 in triple-negative breast cancer Tumor suppressor role of microRNA-1296 in triple-negative breast cancer The role of let-7 in cell differentiation and cancer CrossRef Full Text | Google Scholar High expression of miR-21 in triple negative breast cancers was cor- related with a poor prognosis and promoted tumor cell in vitro proliferation Long Non-Coding RNA in the Pathogenesis of Cancers CrossRef Full Text | Google Scholar Tackling Structures of Long Noncoding RNAs PubMed Abstract | CrossRef Full Text | Google Scholar Molecular mechanisms of long noncoding RNAs CrossRef Full Text | Google Scholar The properties of long noncoding RNAs that regulate chromatin Rev Genom Hum Genet (2016) 17:69–94 doi: 10.1146/annurev-genom-090314-024939 CrossRef Full Text | Google Scholar Long Noncoding RNA: Genome Organization and Mechanism of Action Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis Long non-coding RNA HOTAIR is a powerful predictor of metastasis and poor prognosis and is associated with epithelial-mesenchymal transition in colon cancer Overexpression of long non-coding RNA HOTAIR predicts poor patient prognosis and promotes tumor metastasis in epithelial ovarian cancer The association between LncRNA HOTAIR and cancer lymph node metastasis and distant metastasis: a meta-analysis Long noncoding RNA HOTAIR can serve as a common molecular marker for lymph node metastasis: a meta-analysis Circulating HOTAIR expression predicts the clinical response to neoadjuvant chemotherapy in patients with breast cancer MacroRNA underdogs in a microRNA world: evolutionary and biomedical significance of mammalian long non-protein-coding RNA Biochim Biophys Acta (2010) 1799:597–615 Long Noncoding RNAs as Novel Biomarkers Have a Promising Future in Cancer Diagnostics Plasma long non-coding RNAs (lncRNAs) serve as potential biomarkers for predicting breast cancer Eur Rev Med Pharmacol Sci (2018) 22:1994–9 HOTAIR: A Promising Long Non-coding RNA with Potential Role in Breast Invasive Carcinoma LncRNA HOTAIR up-regulation is strongly related with lymph nodes metastasis and LAR subtype of Triple Negative Breast Cancer The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells MALAT1 promotes the proliferation and metastasis of osteosarcoma cells by activating the PI3K/Akt pathway Tumour Biol (2015) 36:(3) 1477–1486 LncRNA MALAT1 promotes relapse of breast cancer patients with postoperative fever Am J Transl Res (2018) 10:(10) 3186–3197 Google Scholar MALAT1 promotes angiogenesis of breast cancer CrossRef Full Text | Google Scholar Long non-coding RNA MALAT1 promotes proliferation and invasion via targeting miR-129-5p in triple-negative breast cancer Biomed Pharmacother (2017) 95:922–8 Long noncoding RNA highly up-regulated in liver cancer predicts unfavorable outcome and regulates metastasis by MMPs in triple-negative breast cancer The Significance of Long Non-coding RNA HULC in Predicting Prognosis and Metastasis of Cancers: a Meta-Analysis Pathol LncRNA AWPPH promotes the growth of triple-negative breast cancer byup-regulating frizzled homolog 7 (FZD7) CrossRef Full Text | Google Scholar LncRNA AWPPH and miRNA-21 regulates cancer cell proliferation and chemosensitivity in triple-negative breast cancer by interacting with each other J Cell Biochem (2019) 120(9):14860–6 An androgen receptor negatively induced long non-coding RNA ARNILA binding to miR-204 promotes the invasion and metastasis of triple-negative breast cancer Cell Death Differ (2018) 25(12):2209–20 C-MYC-induced upregulation of lncRNA SNHG12 regulates cell proliferation apoptosis and migration in triple-negative breast cancer Knockdown of lncRNA H19 restores chemo-sensitivity inpaclitaxel-resistant triple-negative breast cancer through triggering apoptosis and regulating Aktsignaling pathway Toxicol Appl Pharmacol (2018) 359:55–61 LncRNA POU3F3 promotes proliferation and inhibits apoptosis of cancer cells in triple-negative breast cancer by inactivating caspase 9 Long non-coding RNA (LncRNA) RMST in triple-negative breast cancer (TNBC): Expression analysis and biological roles research J Cell Physiol (2018) 233(10):6603–12 LncRNA NEF is downregulated in triple negative breast cancer and correlated with poor prognosis Acta Biochim Biophys Sin (2019) 51:386–92 Reduced lncRNA Aim enhances the malignant invasion of triple-negative breast cancer cells mainly by activating Wnt/β-catenin/mTOR/PI3K signaling Die Pharmazie (2017) 72(10):599–603(5) Nat Struct Mol Biol (2010) 17:1169–74 PubMed Abstract | CrossRef Full Text | Google Scholar Discovering dysfunction of multiple microRNAs cooperation in disease by a conserved microRNA co-expression network CrossRef Full Text | Google Scholar Cooperative gene regulation by microRNA pairs and their identification using a computational workflow Nucleic Acids Res (2014) 42(12):7539–52 MiR-205-5p and miR-342- 3p cooperate in the repression of the E2F1 transcription factor in the context of anticancer chemotherapy resistance transcription factors and target genes: linking dynamic expression changes to function Nucleic Acids Res (2013) 41(5):2817–31 Topological patterns in microRNA-gene regulatory network: studies in colorectal and breast cancer Integrated microRNA and mRNA signatures associated with survival in triple negative breast cancer A network-biology perspective of microRNA function and dysfunction in cancer “p73-Governed miRNA Networks: Translating BioinformaticsApproaches to Therapeutic Solutions for Cancer Metastasis” In: Computational Biology of Non-Coding RNA-Methods and Protocols Most mammalian mRNAs are conserved targets of microRNAs PubMed Abstract | CrossRef Full Text | Google Scholar Pseudogenes in metazoa: origin and features Brief Funct Genomic Proteomic (2004) 3:157–67 PubMed Abstract | CrossRef Full Text | Google Scholar Pseudogenes: Pseudofunctional or key regulators in health and disease A coding-independent function of gene and pseudogene mRNAs regulates tumour biology Pseudogene-derived endogenous siRNAs and their function Methods Mol Biol (2014) 1167:227–39 PubMed Abstract | CrossRef Full Text | Google Scholar A ceRNA hypothesis: the Rosetta stone of a hidden RNA language Integrated transcriptional and competitive endogenous RNA networks are cross-regulated in permissive molecular environments Proc Natl Acad Sci USA (2013) 110:7154–9 MicroRNAs as prime players in a combinatorial view of evolution PubMed Abstract | CrossRef Full Text | Google Scholar Identification of novel long non-coding RNAs in triple negative breast cancer Endogenous miRNA sponge lincRNA-RoR regulates Nanog and Sox2 in human embryonic stem cell self-renewal Requirement for Arf6 in breast cancer invasive activities Proc Natl Acad Sci U S A (2004) 101:6647–52 lincRNA-RoR and miR-145 regulate invasion in triple-negative breast cancer via targeting ARF6 Circular RNAs: diversity of form and function PubMed Abstract | CrossRef Full Text | Google Scholar Complex Systems in Human Disease and Therapeutics Google Scholar Gene and lncRNA co-expression network analysis reveals novel ceRNA network for triple-negative breast cancer Integrative analysis of lncRNAs and miRNAs with coding RNAs associated with ceRNAcrosstalk network in triple negative breast cancer Onco Targets Ther (2017) 10:5883–97 Characterization of ceRNA network to reveal potential prognostic biomarkers in triple-negative breast cancer doi: 10.7717/peerj.7522 eCollection 2019 Comprehensive Analysis of Differentially Expressed Profiles of lncRNAs/mRNAs and miRNAs with Associated ceRNA Networks in Triple-Negative Breast Cancer Cell Physiol Biochem (2018) 50(2):473–88 lncRNA OSTN-AS1 May Represent a Novel Immune-Related Prognostic Marker for Triple-Negative Breast Cancer Based on Integrated Analysis of a ceRNA Network Benchmarks for the assessment of novel cardiovascular biomarkers doi: 10.1161/CIRCULATIONAHA.106.683110 PubMed Abstract | CrossRef Full Text | Google Scholar MicroRNA profiling implies new markers of chemoresistance of triple-negative breast cancer 200b and receptor status in core biopsies from stage III breast cancer patients Fluorescence-based code-detection with protein markers reveals distinct cellular compartments for altered MicroRNA expression in solid tumors Clin Cancer Res (2010) 16(16):4246–55 miR-629-3p may serve as a novel biomarker and potential therapeutic target for lung metastases of triple-negative breast cancer miR-141-Mediated Regulation of Brain Metastasis From Breast Cancer JNCI J Natl Cancer Inst (2016) 108(8):diw026 CrossRef Full Text | Google Scholar microRNAs exhibit high frequency genomic alterations in human cancer Proc Natl Acad Sci USA (2006) 103:9136–41 Novel prognostic and predictive microRNA targets for triple-negativebreast cancer CrossRef Full Text | Google Scholar microRNA expression pro- filing identifies a four microRNA signature as a novel diagnostic and prognostic biomarker in triple negative breast cancers Tumor MicroRNA Expression Profiling Identifies Circulating MicroRNAs for Early Breast Cancer Detection Cigarette smoking substantially alters plasma microRNA profiles in healthy subjects Toxicol Appl Pharmacol (2013) 272:154–60 Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training XenomiRs and miRNA homeostasis in health and disease: Evidence that diet and dietary miRNAs directly and indirectly influence circulating miRNA profiles CrossRef Full Text | Google Scholar Estimation of the imprecision on clinical chemistry testing due tofist clenching and maintenance during venipuncture doi: 10.1016/j.clinbiochem.2016.07.007 Plasma Processing Conditions Substantially Influence Circulating microRNA Biomarker Levels CrossRef Full Text | Google Scholar Pitfalls of Quantitative Real-Time Reverse-Transcription Polymerase Chain Reaction PubMed Abstract | Google Scholar Haemolysis during Sample Preparation Alters microRNA Content of Plasma Circulating MicroRNAs as Novel Biomarkers for Platelet Activation Heparin Selectively A_ects the Quantification of MicroRNAs in Human Blood Samples Free Circulating miRNAs Measurement in Clinical Settings: The Still Unsolved Issue of the Normalization CrossRef Full Text | Google Scholar The level of circulating miRNA-10b and miRNA-373 in detecting lymph node metastasis of breast cancer: potential biomarkers miRNA-10b and miRNA-200c in triple-negative breast cancer patients Ginekologia Polska (2018) 89:415–20 Circulating miRNAs as Diagnostic and Prognostic Biomarkers in Common Solid Tumors: Focus on Lung CrossRef Full Text | Google Scholar Circulating cell-free miRNAs as biomarker for triple-negative breast cancer miR-105/93-3p promotes chemoresistance and circulating miR-105/93-3p acts as a diagnostic biomarker for triple negative breast cancer MiR-489 Regulates Chemoresistance in Breast Cancer via EpithelialMesenchymal Transition Pathway CrossRef Full Text | Google Scholar therapeuticresistance and applications in human triple-negative breast cancer Why the Gold Standard Approach by Mammography Demands Extension by Multiomics Application of Liquid Biopsy miRNA Profiles to Breast Cancer Disease Management Deregulated Serum Concentrations of Circulating Cell–Free MicroRNAs miR-17 and miR-373 in Human Breast Cancer Development and Progression Circulating non coding RNA biomarker potential in neoadjuvant chemotherapy of triple negative breast cancer doi: 10.3892/ijo.2019.4920 Advance online publication miR-200c: a versatile watchdog in cancer progression Low Expression of Circulating MicroRNA-34c is Associated with Poor Prognosis in Triple-Negative Breast Cancer Circulating miRNAs revealed as surrogate molecular signatures for the early detection of breast cancer Robust expression of tumor suppressor miRNA’s let-7 and miR-195 detected in plasma of Saudi female breast cancer patients Novel circulating microRNA signature as a potential non-invasive multi-marker test in ER-positive early-stage breast cancer: a case control study Novel combination of serum microRNA for detecting breast cancer in the early stage Plasma MicroRNA panel for minimally invasive detection of breastcancer The function of MiR-21 expression differences and pathogenesis on familial and triple negative breast Cancer serum PubMed Abstract | Google Scholar Dynamics of circulating microRNAs as a novel indicator of clinical response to neoadjuvant chemotherapy in breast cancer MicroRNAs in the prognosis of triple-negative breast cancer: A systematic review and meta-analysis CrossRef Full Text | Google Scholar Comprehensive analysis of novel three-long noncoding RNA signatures as a diagnostic and prognostic biomarkers of human triple-negative breast cancer J Cell Biochem (2019) 120(3):3185–96 Long noncoding RNA Linc00339 promotes triple-negative breast cancer progression through miR-37-3p/HOXC6 signaling pathway J Cell Physiol (2019) 234(8):13303–17 HIF1A-AS2 predicts poor prognosis and regulates cell migration and invasion in triple-negative breast cancer J Cell Biochem (2019) 120(6):10513–8 A three-long noncoding RNA signature as a diagnostic biomarker for differentiating between triple-negative and non-triple-negative breast cancers CrossRef Full Text | Google Scholar LncRNA HEIH regulates cell proliferation and apoptosis through miR-4458/SOCS1 axis in triple-negative breast cancer Long intergenic noncoding RNA 299 methylation in peripheral blood isa biomarker for triple-negative breast cancer Beta3 integrin and Src facilitate transforming growth factor-beta mediated induction of epithelial-mesenchymal transition in mammary epithelial cells CrossRef Full Text | Google Scholar HMGA2 maintains oncogenic RAS-induced epithelial-mesenchymal transition in human pancreatic cancer cells Am J Pathol (2009) (2009) 174:854–68 Involvement of ETS-1 transcription factor in inducing matrix metalloproteinase-2 expression by epithelial-mesenchymal transition in human squamous carcinoma cells aV integrins and TGF-beta-induced EMT: A circle of regulation doi: 10.1111/j.1582-4934.2011.01419.x PubMed Abstract | CrossRef Full Text | Google Scholar Role for _3 integrin in EMT and pulmonary fibrosis PubMed Abstract | CrossRef Full Text | Google Scholar Induction of a mesenchymal expression program in lung epithelial cells by Wnt/_-catenin requires the presence of c-Jun N-terminal kinase 1 Am J Respir Cell Mol Biol (2012) 47:306–14 Notch-1 induces epithelial-mesenchymal transition consistent with cancer stem cell phenotype in pancreatic cancer cells Identification of mammalian microRNA host genes and transcription units Epigenetic inactivation of microRNA gene hsa-miR-9-1 in human breast cancer miR-31 and its host gene LncRNA LOC554202 are regulated by promoter hypermethylation in triple-negative breast cancer doi: 10.1016/B978-0-12-380866-0.60004-6 PubMed Abstract | CrossRef Full Text | Google Scholar Prospective identification of tumorigenic breast cancer cells Proc Natl Acad Sci (2003) 100:3983–8 PubMed Abstract | CrossRef Full Text | Google Scholar Comprehensive transcriptome analysis identifies novel molecular subtypes and subtype-specific RNAs of triple-negative breast cancer Circulating microRNA profiles reflect the presence of breast tumours but not the profiles of microRNAs within the tumours Volovat CC and Augustin I (2020) MiRNA and LncRNA as Potential Biomarkers in Triple-Negative Breast Cancer: A Review Received: 14 January 2020; Accepted: 13 October 2020;Published: 20 November 2020 Copyright © 2020 Volovat, Volovat, Hordila, Hordila, Mirestean, Miron, Lungulescu, Scripcariu, Stolniceanu, Konsoulova-Kirova, Grigorescu, Stefanescu, Volovat and Augustin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) distribution or reproduction in other forums is permitted provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited in accordance with accepted academic practice distribution or reproduction is permitted which does not comply with these terms *Correspondence: Constantin Volovat, dm9sb3ZhdGNvbnN0YW50aW5AZ21haWwuY29t Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. 94% of researchers rate our articles as excellent or goodLearn more about the work of our research integrity team to safeguard the quality of each article we publish. Methods: Medication adherence was assessed using the Proportion of Days Covered (PDC) method, and Spearman correlation analysis was conducted to explore the relationships between adherence, age, gender, and follow-up duration. Discussion: High adherence rates were observed among patients treated with CDK 4/6i drugs, with no significant differences noted among the three drugs in this class. However, the collected patient data was limited, lacking information on adverse reactions that could potentially lead to treatment discontinuation, as determined by the oncologist’s decision not to prescribe. Consequently, a comprehensive understanding of all factors contributing to the low adherence levels is hindered. Volume 15 - 2024 | https://doi.org/10.3389/fphar.2024.1345482 Introduction: It is imperative for patients to respect the prescribed treatments to achieve the anticipated clinical outcomes including the outpatients receiving oral anti-cancer drugs such as selective cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i) With the introduction of three CDK 4/6i drugs in the Romanian pharmaceutical market in 2018 our study aimed to evaluate medication adherence and the influencing factors among patients undergoing treatment with palbociclib or abemaciclib for advanced or metastatic breast cancer Methods: Medication adherence was assessed using the Proportion of Days Covered (PDC) method and Spearman correlation analysis was conducted to explore the relationships between adherence Results: The study enrolled 330 breast cancer patients with an average follow-up period of 14.6 ± 12.5 months for palbociclib and 8.6 ± 6.4 months for abemaciclib-treated patients A small proportion of patients demonstrated non-adherence: 12.8% for palbociclib there was no significant correlation between adherence a significant correlation was found with the duration of follow-up (rho = −0.304 Similar results were observed for patients receiving ribociclib or abemaciclib Most patients received combination therapy with letrozole (46%) and exemestane (13%) for palbociclib letrozole (48%) and fulvestrant (19%) for ribociclib and fulvestrant (39%) and letrozole (27%) for abemaciclib Discussion: High adherence rates were observed among patients treated with CDK 4/6i drugs with no significant differences noted among the three drugs in this class lacking information on adverse reactions that could potentially lead to treatment discontinuation as determined by the oncologist’s decision not to prescribe a comprehensive understanding of all factors contributing to the low adherence levels is hindered According to the submission of its dossier to EMA abemaciclib was approved in combination with an aromatase inhibitor (AI or examestan) as initial endocrine-based therapy or in combination with fulvestrant as initial endocrine-based therapy or following endocrine therapy All three medications were recommended for the treatment of women with locally advanced or metastatic breast cancer (a/mBC) or in women who have received prior hormonal therapy hormonal therapy should be combined with a luteinizing hormone-releasing hormone (LHRH) agonist Medication adherence is a hey enabler of best health outcomes and some medication adherence supporting activities were reported in order to guide research and practice on enhancing medication adherence (Kardas et al., 2023). Treatment nonadherence is associated with disease progression and mortality among patients with breast cancer (Chirgwin et al., 2016) The existing research on adherence to CDK4/6i anticancer agents is limited the primary aim of our research was to assess the adherence levels of CDK 4/6i and to explore potential correlations with variables such as age our study also sought to investigate potential disparities in medication adherence among the three distinct CDK 4/6i currently available within the pharmaceutical market in Romania we aimed to contribute valuable insights into the patterns of medication adherence and its associations with demographic factors thereby enhancing our understanding of the real-world usage of these CDK 4/6i in clinical practice from Romania In the context of our study conducted in Romania electronic information pertaining to reimbursed medications is exclusively accessible through the database maintained by the Romanian Health Insurance House Ethical approval for our research endeavor granted under Ethics Council approval number 175/29.10.2021 allowed us access to anonymized patient data sourced from community pharmacies in Dolj County which were reported to the Health Insurance House of Dolj The study focused on data spanning the past 5 years corresponding to the period during which the first CDK 4/6 inhibitor was approved for entry into the Romanian pharmaceutical market our study inquired about patient records identified by the ICD-10 code C50 with a subsequent focus on individuals receiving treatment with palbociclib The data obtained for analysis encompassed essential demographic information as well as details concerning prescription refills including the quantity of medicines dispensed and the dates of prescription release from community pharmacies our access to information was limited to these parameters and we did not have access to additional patient-specific data such as comorbidities or other health covariates This approach was undertaken within the confines of ethical guidelines and regulations ensuring the confidentiality and privacy of patient information while enabling us to analyze patterns of CDK 4/6i usage in the studied population The utilization of this restricted dataset was essential for our investigation into medication adherence and its potential correlations with demographic factors within the Romanian context All patients with breast cancer (code of disease = 124) who raised their reimbursed prescriptions from a community pharmacy from Dolj County in the period 1 January 2018 -31 December 2022 The first patient received the first palbociclib prescription from the community pharmacy in July 2018 the first patient was a female of 73 years old We included all patients who had at least two fills of CDK 4/6i because it is required to compute medication adherence CDK 4/6i cycle dates were determined based on the electronic records from the Dolj Health Insurance House for the reimbursed prescriptions written by the oncologist The duration of follow-up was defined as the time in months from the first prescription issuing by the pharmacist in the community pharmacy to the last prescription reimbursed by the Dolj Health Insurance House according to the analyzed period (1 January 2018-31 December 2022) We considered it as the time elapsed from the medication’s starting date to the last treatment’s discontinuation date which could be death or treatment modification We conducted descriptive analysis of continuous variables (age adherence) using means±standard deviations (SD) median and interquartile range (IQR) and range (minimum-maximum) and of categorical variables (gender categories of age) using frequencies and percentages to demonstrate the potential correlation between medication adherence and age we calculated the Spearman’s coefficients and visually presented with heatmaps To evaluate the differences between the characteristics and medication adherence of patients with different treatment we used Kruskal–Wallis H test for continuous variables and Chi-square test for categorical variables We visually presented the differences of medication adherence among patients with different treatments using violin graphs We conducted statistical analysis using GraphPad Prism 10.1 (GraphPad Software Boston with the statistical significance level set at p less than 0.05 During the study period from 1 January 2018 a total of 330 patients were prescribed CDK 4/6i 180 patients (55%) were administered palbociclib Table 1 summarizes descriptive statistics of patient characteristics as well as the p-value after performing the comparison between them The median (range) age was 66 (30–90) years for the palbociclib group 71 (36–92) years for the ribociclib group and 66 (43–93) years for the abemaciclib group of patients Most of the patients were more than 60 years old: 70% in palbociclib patients 79.3% in ribociclib patients and 73.5% in abemaciclib patients but more male patients were treated with palbociclib (3.3%) than with ribociclib (1.2%) or abemaciclib (1.5%) The follow-up varies significantly between the three groups of patients (p-value = 0.004) with higher follow-up for patients treated with palbociclib because it was earlier introduced on the Romanian pharmaceutical market Characteristics of the patients treated with CDK 4/6 inhibitors Gosereline was more combined with ribociclibum (5.4%) Combination of CDK 4/6i with endocrine therapy by month over the study period Combination of palbociclib (PALBO) with endocrine therapy Combination of ribociclib (RIBO) with endocrine therapy Combination of abemaciclib (ABEMA) with endocrine therapy The percentages were computed based on the total number of patients undergoing treatment with both CDK 4/6i and endocrine therapy Combinations of the CDK 4/6 inhibitors with aromatase inhibitors or/and luteinizing hormone-releasing hormone agonists We observed the peaks in the CDK 4/6i and the most patients had 100% adherence for all three groups of patients was observed among patients treated with abemaciclib (mean ± SD 0.93 ± 0.14) than among patients treated with palbociclib (mean ± SD 0.92 ± 0.14) or ribociclib (mean ± SD The smallest adherence was observed for a patient treated with palbociclib (0.11) while the smallest adherence observed for a patient treated with ribociclib was 0.15 and the smallest adherence observed for a patient treated with abemaciclib was 0.43 Adherence as proportion of days covered (PDC) in patients treated with either CDK 4/6i Correlation between adherence of CDK 4/6i treatment The colors from heatmaps correspond to the Spearman coefficient from negative values (light orange color) to positive values (green color) Heatmap of correlations in the case of palbociclib therapy Heatmap of correlations in the case of ribociclib therapy Heatmap of correlations in the case of abemaciclib therapy similar values for mean PDC for palbociclib (90%) and abemaciclib (88.1%) in the same way we obtained for abemaciclib (93%) and palbociclib (92%) Using another method to measure palbociclib adherence the same results were obtained in a real-world assessment of palbociclib adherence in USA The routine of frequent medication intake was proved to be one of the important barriers of adherence to oral anticancer medications among patients with breast cancer (Onwusah et al., 2023) despite the distinct administration schedules of CDK 4/6 inhibitors (ribociclib and palbociclib are administered once daily for 21 consecutive days followed by 7 days without treatment while abemaciclib is administered continuously) medication adherence did not differ among the three patient groups Few studies were published regarding CDK 4/6i non-adherence negatively effects. Regarding palbociclib adherence, it was measured its impact on pharmacokinetic and pharmacodynamic profiles and proved that catching up on a missed dose at the end of the cycle increases the risk of severe neutropenia in the next cycle (Bandiera et al., 2023) In our study, we found no significant association between gender and adherence to CDK4/6i, a finding that contrasts with some research indicating gender-specific differences in medication adherence, especially in the context of experiencing adverse effects. For example, a significant difference has been noted in the occurrence of side effects in tamoxifen treatments (Xu et al., 2012) This distinction is important to take into account because the likelihood of side effects is a major factor affecting patients’ compliance with their prescription regimens The lack of a gender-based difference in adherence to CDK4/6i in our study is particularly intriguing when juxtaposed with these observations It prompts further inquiry into the distinctive characteristics of CDK4/6i and their reception and tolerance by different genders and it is important to consider the variety of treatments used for male breast cancer patients A study published in Breast in 2022 (Yıldırım et al., 2022) highlights that most male patients were treated with CDK4/6i in combination with fulvestrant or AI rather than tamoxifen. This diverges from the general perception and findings in some interviews (Chalasani, 2023) which suggest that tamoxifen is a more commonly used treatment in male breast cancer patients This discrepancy in treatment choices is noteworthy because it suggests variability in the clinical management of male breast cancer and potentially different side effect profiles and adherence challenges associated with each treatment among the patients who received ribociclib 53.7% patients received ribociclib + AI and 19% patients received ribociclib + LHRH Regarding the patients who received abemaciclib more patients were treated in combination with LHRH (39%) than with AI (33%) The choice of treatment - whether tamoxifen or CDK4/6i - can have significant implications for adherence Each medication comes with its own set of potential side effects and impacts on quality of life which can influence a patient’s willingness and ability to remain adherent The fact that different treatments are being chosen for male patients in various studies and clinical settings underlines the need for a deeper understanding of how treatment decisions are made and how these decisions affect adherence This understanding is crucial in developing strategies to improve adherence especially considering the unique challenges male breast cancer patients may face The finding in our study that adherence to CDK4/6i was not significantly associated with age is a notable observation in the context of breast cancer treatment This outcome aligns interestingly with other publications as the adherence of older women to CDK4/6i in our study is encouraging especially considering the potential survival benefits highlighted by Petrelli et al The high adherence rate among older women in our study may reflect the effectiveness of these medications on quality of life or possibly a good understanding and acceptance of treatment regimens among older patients This observation is important as it suggests that age alone may not be a significant barrier to adherence in the context of CDK4/6i therapy emphasizing the need for personalized treatment approaches that account for individual patient profiles rather than solely age-based strategies Adherence to CDK 4/6i was significantly associated with the follow-up. This aligns with the findings from other studies (Eliassen et al., 2023) which highlights that adherence and persistence to endocrine treatment are critical for improving event-free and overall survival in non-metastatic breast cancer patients it is plausible that the patients in our study who demonstrated better adherence over extended treatment periods might have experienced improved health outcomes This potential link between sustained adherence and survival emphasizes the importance of strategies to enhance and maintain adherence in breast cancer treatment patients may begin to see the benefits or stabilization of their condition reinforcing their trust in the effectiveness of the therapy and motivating them to adhere to the regimen Based on these results, different interventions could be developed to enhance CDK4/6i adherence. A mobile health intervention was tested integrating a connected electronic adherence monitoring smartbox and automated texting alerts, resulting a palbociclib adherence of 95.8% ± 7.6% (Sadigh et al., 2023) the reported barriers were inconvenience to get prescription filled Our results regarding the adherence to palbociclib were 92.5% ± 13.7% but without any interventions and costs could not be among the barriers because the drugs are free The Romanian National Oncology Program covers these medicines for people diagnosed with cancer being fully reimbursed by the National Health Insurance House in Romania Inherent limitations of real-world analyses using data collected during providing reimbursed drugs include the lack of important information (the stage of the disease) and variations in follow-up/short duration of follow-up Despite these limitations from the information extracted from our data sources our results are the beginning of future research in measuring CDK 4/6i adherence The original contributions presented in the study are included in the article/Supplementary material further inquiries can be directed to the corresponding authors The studies involving humans were approved by the Ethics Committee of the University of Medicine and Pharmacy of Craiova The studies were conducted in accordance with the local legislation and institutional requirements Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements The author(s) declare financial support was received for the research The Article Processing Charges were funded by the University of Medicine and Pharmacy of Craiova All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher The consequences of diarrhea occurring during chemotherapy for colorectal cancer: a retrospective study PubMed Abstract | CrossRef Full Text | Google Scholar Adherence to the CDK 4/6 inhibitor palbociclib and omission of dose management supported by pharmacometric modelling as part of the OpTAT study PubMed Abstract | CrossRef Full Text | Google Scholar PubMed Abstract | CrossRef Full Text | Google Scholar Real-world safety of palbociclib in breast cancer patients in the United States: a new user cohort study PubMed Abstract | CrossRef Full Text | Google Scholar and ribociclib in real-world data: a direct comparison of first- line treatment for endocrine-receptor-positive metastatic breast cancer PubMed Abstract | CrossRef Full Text | Google Scholar Chalasani, P. (2023). Use of CDK inhibitors in male (2019). CDK inhibitors, endocrine therapy for male patients with breast cancer. [Accessed 25th November 2023]. Available from: https://dailynews.ascopubs.org/do/cdk-inhibitors-endocrine-therapy-male-patients-breast-cancer Google Scholar Treatment adherence and its impact on disease-free survival in the breast international group 1-98 trial of tamoxifen and letrozole PubMed Abstract | CrossRef Full Text | Google Scholar Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive HER2–negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre Treatment satisfaction in women receiving palbociclib combination therapies for advanced/metastatic breast cancer PubMed Abstract | CrossRef Full Text | Google Scholar Dezentjé Effect of concomitant CYP2D6 inhibitor use and tamoxifen adherence on breast cancer recurrence in early-stage breast cancer PubMed Abstract | CrossRef Full Text | Google Scholar PubMed Abstract | CrossRef Full Text | Google Scholar in patients with refractory hr+/her2− metastatic breast cancer PubMed Abstract | CrossRef Full Text | Google Scholar Computation of adherence to medication and visualization of medication histories in R with AdhereR: towards transparent and reproducible use of electronic healthcare data PubMed Abstract | CrossRef Full Text | Google Scholar Importance of endocrine treatment adherence and persistence in breast cancer survivorship: a systematic review PubMed Abstract | CrossRef Full Text | Google Scholar Abstract P4-01-03: progression-free survival and patient-reported outcomes in HR+ HER2– ABC patients treated with first-line ribociclib + endocrine therapy (ET) or ET monotherapy or chemotherapy in real world setting: 5th interim analysis of RIBANNA P4–doi:10.1158/1538-7445.SABCS22-P4-01-03 CrossRef Full Text | Google Scholar The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study Palbociclib and letrozole in advanced breast cancer PubMed Abstract | CrossRef Full Text | Google Scholar Influence of adherence to adjuvant endocrine therapy on disease-free and overall survival: a population-based study in Catalonia PubMed Abstract | CrossRef Full Text | Google Scholar Breast cancer mortality gaps in Romanian women compared to the EU after 10 years of accession: is breast cancer screening a priority for action in Romania PubMed Abstract | CrossRef Full Text | Google Scholar Ribociclib as first-line therapy for HR-positive PubMed Abstract | CrossRef Full Text | Google Scholar Medication adherence to oral anticancer drugs: systematic review PubMed Abstract | CrossRef Full Text | Google Scholar Inclusion of abemaciclib in Romania, (2022b). Inclusion of abemaciclib in the Positive Drug List in Romania in April 2022. (Accessed November 20, 2023). Available from: [ https://www.anm.ro/_/EVALUARE%20TEHNOLOGII%20MEDICALE/16243_Verzenios_Abemaciclibum.pdf Google Scholar Inclusion of ribociclib in Romania (2022a). Inclusion of ribociclib in the positive drug list in Romania in August 2022. Accessed November 20, 2023). Available from: https://www.anm.ro/_/EVALUARE%20TEHNOLOGII%20MEDICALE/CONTESTATII/11408_2021_Kisqali_Contestatie_Ribociclibum.pdf Google Scholar Combining CDK4/6 inhibitors ribociclib and palbociclib with cytotoxic agents does not enhance cytotoxicity PubMed Abstract | CrossRef Full Text | Google Scholar New terminology of medication adherence enabling and supporting activities: ENABLE terminology PubMed Abstract | CrossRef Full Text | Google Scholar Real-world data of palbociclib in combination with endocrine therapy for the treatment of metastatic breast cancer in men PubMed Abstract | CrossRef Full Text | Google Scholar Association between adherence to oral therapies in cancer patients and clinical outcome: a systematic review of the literature CrossRef Full Text | Google Scholar Over-adherence to capecitabine: a potential safety issue in breast and colorectal cancer patients PubMed Abstract | CrossRef Full Text | Google Scholar Oral adverse effects of CDK4/6 inhibitors among breast cancer patients: a systematic review and meta-analysis PubMed Abstract | CrossRef Full Text | Google Scholar or hormonal therapy in breast cancer patients PubMed Abstract | CrossRef Full Text | Google Scholar Oncologist and patient preferences for attributes of CDK4/6 inhibitor regimens forthe treatment of advanced/metastatic HR positive/HER2 negative breast cancer: discrete choice experiment and best-worst scaling PubMed Abstract | CrossRef Full Text | Google Scholar Cyclin-dependent kinase 4/6 inhibitor treatment use in women treated for advanced breast cancer: integrating ASCO/NCODA patient-centered standards in a community pharmacy PubMed Abstract | CrossRef Full Text | Google Scholar Estimation of the number of women living with metastatic breast cancer in the United States PubMed Abstract | CrossRef Full Text | Google Scholar Ministry of Health of Romania (2017). Inclusion of palbociclib in Romania. Inclusion of palbociclib in the Positive Drug List in Romania in November 2017. (Accessed November 20, 2023). Available from: https://www.anm.ro/_/EVALUARE%20TEHNOLOGII%20MEDICALE/6300_23.11.2017_Palbociclib_Ibrance.pdf Google Scholar Adherence to adjuvant hormonal therapy among breast cancer survivors in clinical practice: a systematic review PubMed Abstract | CrossRef Full Text | Google Scholar National Cancer Institute (USA) (2023). Cancer statistics in US. [Accessed 23rd November 22023]. Available from: https://www.cancer.gov/types/breast Google Scholar Barriers and facilitators of adherence to oral anticancer medications among women with breast cancer: a qualitative study PubMed Abstract | CrossRef Full Text | Google Scholar Adherence and persistence with oral adjuvant chemotherapy in older women with early-stage breast cancer in CALGB 49907: adherence companion study 60104 PubMed Abstract | CrossRef Full Text | Google Scholar Methods for measuring multiple medication adherence: a systematic review-report of the ISPOR medication adherence and persistence special interest group PubMed Abstract | CrossRef Full Text | Google Scholar ribociclib and abemaciclib for ER+ metastatic breast cancer: an adjusted indirect analysis of randomized controlled trials PubMed Abstract | CrossRef Full Text | Google Scholar Rodrigues Guedes Factors associated with adherence and persistence to hormonal therapy in women with breast cancer PubMed Abstract | CrossRef Full Text | Google Scholar Cyclin-dependent protein serine/threonine kinase inhibitors as anticancer drugs PubMed Abstract | CrossRef Full Text | Google Scholar Abstract PS10-09: real-world analysis of concomitant medication use with potential drug-drug interactions (DDI) in patients with metastatic breast cancer (MBC) treated with cylin dependent kinase (CDK) 4/6 inhibitors CrossRef Full Text | Google Scholar Improving palbociclib adherence among women with metastatic breast cancer using a CONnected CUstomized Treatment Platform: a pilot study PubMed Abstract | CrossRef Full Text | Google Scholar Overall survival with ribociclib plus fulvestrant in advanced breast cancer PubMed Abstract | CrossRef Full Text | Google Scholar Adherence to adjuvant endocrine therapy: is it a factor for ethnic differences in breast cancer outcomes in New Zealand PubMed Abstract | CrossRef Full Text | Google Scholar Phase III randomized study of ribociclib and fulvestrant in hormone receptorpositive human epidermal growth factor receptor 2–negative advanced breast cancer: MONALEESA-3 PubMed Abstract | CrossRef Full Text | Google Scholar MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2-advanced breast cancer who had progressed while receiving endocrine therapy PubMed Abstract | CrossRef Full Text | Google Scholar Control of cell cycle progression by phosphorylation of cyclin-dependent kinase (CDK) substrates PubMed Abstract | CrossRef Full Text | Google Scholar RWD117 impact of COVID-19 pandemic on the Romanian breast cancer burden: a county population-based study CrossRef Full Text | Google Scholar Adherence to adjuvant hormonal therapy and its relationship to breast cancer recurrence and survival among low-income women PubMed Abstract | CrossRef Full Text | Google Scholar Quantifying CDK inhibitor selectivity in live cells PubMed Abstract | CrossRef Full Text | Google Scholar Tamoxifen adherence and its relationship to mortality in 116 men with breast cancer PubMed Abstract | CrossRef Full Text | Google Scholar Yıldırım Clinical outcomes of cyclin-dependent kinase 4–6 (CDK 4–6) inhibitors in patients with male breast cancer: a multicenter study PubMed Abstract | CrossRef Full Text | Google Scholar Median DM and Lungulescu CV (2024) Digging in real-word electronic database for assessing CDK 4/6 inhibitors adherence in breast cancer patients from Romania Received: 27 November 2023; Accepted: 12 February 2024;Published: 23 February 2024 Copyright © 2024 Turcu-Stiolica, Udristoiu, Subtirelu, Gheorman, Aldea, Dumitrescu, Volovat, Median and Lungulescu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use *Correspondence: Ion Udristoiu, aW9uLnVkcmlzdG9pdUB1bWZjdi5ybw==; Adina Turcu-Stiolica, YWRpbmEudHVyY3VAdW1mY3Yucm8= †These authors have contributed equally to this work Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher 94% of researchers rate our articles as excellent or goodLearn more about the work of our research integrity team to safeguard the quality of each article we publish