ABSTRACT
BACKGROUND: In the two European Union (EU)-funded projects, PCM4EU (Personalized Cancer Medicine for all EU citizens) and PRIME-ROSE (Precision Cancer Medicine Repurposing System Using Pragmatic Clinical Trials), we aim to facilitate implementation of precision cancer medicine (PCM) in Europe by leveraging the experience from ongoing national initiatives that have already been particularly successful. PATIENTS AND METHODS: PCM4EU and PRIME-ROSE gather 17 and 24 partners, respectively, from 19 European countries. The projects are based on a network of Drug Rediscovery Protocol (DRUP)-like clinical trials that are currently ongoing or soon to start in 11 different countries, and with more trials expected to be established soon. The main aims of both the projects are to improve implementation pathways from molecular diagnostics to treatment, and reimbursement of diagnostics and tumour-tailored therapies to provide examples of best practices for PCM in Europe. RESULTS: PCM4EU and PRIME-ROSE were launched in January and July 2023, respectively. Educational materials, including a podcast series, are already available from the PCM4EU website (http://www.pcm4eu.eu). The first reports, including an overview of requirements for the reimbursement systems in participating countries and a guide on patient involvement, are expected to be published in 2024. CONCLUSION: PCM4EU and PRIME-ROSE were launched in January and July 2023, respectively. Educational materials, including a podcast series, are already available from the PCM4EU website (http://www.pcm4eu.eu). The first reports, including an overview of requirements for the reimbursement systems in participating countries and a guide on patient involvement, are expected to be published in 2024. CONCLUSION: European collaboration can facilitate the implementation of PCM and thereby provide affordable and equitable access to precision diagnostics and matched therapies for more patients.
Subject(s)
Neoplasms , Precision Medicine , Humans , Precision Medicine/methods , Europe , Neoplasms/therapy , European Union , Drug Repositioning , Clinical Trials as Topic/organization & administrationABSTRACT
Various tests based on different biomarkers have been developed to identify the best candidates for poly(ADP-ribose) polymerase (PARP)-inhibitor therapy. However, due to the absence of harmonization regarding these complex biomarkers, along with various cutoff points and unknown spatial and temporal variations, it is difficult to define the clinical utility of each test and ensure uniformity in treatment decision-making. Here, we propose measures to align biomarker definitions and minimum analytical performance characteristics for diagnostics to ensure equitable and sustainable access to precision medicine.
Subject(s)
Biomarkers, Tumor , Drug Development , Poly(ADP-ribose) Polymerase Inhibitors , Precision Medicine , Humans , Drug Development/methods , Precision Medicine/methods , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Neoplasms/drug therapyABSTRACT
The Cancer Drug Development Forum (CDDF)'s 'Histology independent drug development - is this the future for cancer drugs?' workshop was set up to explore the current landscape of histology independent drug development, review the current regulatory landscape and propose recommendations for improving the conduct of future trials. The first session considered lessons learnt from previous trials, including innovative solutions for reimbursement. The session explored why overall survival represents the most valuable endpoint, and the importance of duration of response, which can be captured with swimmer and spider plots. The second session on biomarker development and treatment optimisation considered current regulations for companion diagnostics, FDA guidance on histology independent drug development in oncology, and the need to establish cut-offs for the biomarker of tumour mutational burden to identify the patients most likely to benefit from PDL1 treatment. The third session reviewed novel trial designs, including basket, umbrella and platform trials, and statistical approaches of hierarchical modelling where homogeneity between study cohorts enables information to be borrowed between cohorts. The discussion highlighted the need to agree 'common assessment standards' to facilitate pooling of data across studies. In the fourth session, the sharing of data sets was recognised as a key step for improving equity of access to precision medicines across Europe. The session considered how the European Health Data Space (EHDS) could streamline access to medical records, emphasizing the importance of introducing greater accountability into the digital space. In conclusion the workshop proposed 11 recommendations to facilitate histology agnostic drug development.
Subject(s)
Antineoplastic Agents , Neoplasms , Humans , Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Drug Development , Medical Oncology , Biomarkers, TumorABSTRACT
Background: The DRUG Access Protocol provides patients with cancer access to registered anti-cancer drugs that are awaiting reimbursement in the Netherlands and simultaneously collects prospective real-world data (RWD). Here, we present RWD from PD-1 blocker cemiplimab in patients with locally advanced or metastatic cutaneous squamous cell carcinoma (laCSCC; mCSCC). Methods: Patients with laCSCC or mCSCC received cemiplimab 350 mg fixed dose every three weeks. Primary endpoints were objective clinical benefit rate (CBR), defined as objective response (OR) or stable disease (SD) at 16 weeks, physician-assessed CBR, defined as clinician's documentation of improved disease or SD based on evaluation of all available clinical parameters at 16 weeks, objective response rate (ORR), and safety, defined as grade ≥ 3 treatment related adverse events (TRAEs) occurring up to 30 days after last drug administration. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Findings: Between February 2021 and December 2022, 151 patients started treatment. Objective and physician-assessed CBR were 54.3% (95% CI, 46.0-62.4) and 59.6% (95% CI, 51.3-67.5), respectively. ORR was 35.1% (95% CI, 27.5-43.3). After a median follow-up of 15.2 months, median DoR was not reached. Median PFS and OS were 12.2 (95% CI, 7.0-not reached) and 24.2 months (95% CI, 18.8-not reached), respectively. Sixty-eight TRAEs occurred in 29.8% of patients. Most commonly reported TRAE was a kidney transplant rejection (9.5%). Interpretation: Cemiplimab proved highly effective and safe in this real-world cohort of patients with laCSCC or mCSCC, confirming its therapeutic value in the treatment of advanced CSCC in daily clinical practice. Funding: The DRUG Access Protocol is supported by all participating pharmaceutical companies: Bayer, Janssen, Lilly, Merck, Novartis, Roche, and Sanofi.
ABSTRACT
It can be a challenge for a healthcare system to facilitate access to novel cancer drugs. This can be due to lack of transparency regarding alternative access pathways before or after authorisation, absence of reimbursement due to uncertainties regarding clinical value and cost-effectiveness, lengthy price-negotiations and practice variation among hospitals, for instance in conducting molecular diagnostics. Based on three daily practice examples, we discuss the current challenges and complex procedures in providing access through alternative pathways, such as early-access or free-of-charge programmes in the Netherlands. Policymakers, funders, and medical societies need to harmonise procedures, increase transparency regarding treatment and testing options and collaborate more to ensure equal and timely access to valuable cancer therapies. Accurate and responsible communication and reporting regarding the efficacy and availability of novel treatments is crucial to prevent unrealistic expectations, disappointment, and distress among patients and the public.
Subject(s)
Antineoplastic Agents , Neoplasms , Humans , Antineoplastic Agents/therapeutic use , Netherlands , Hospitals , Communication , Neoplasms/drug therapyABSTRACT
Recent studies demonstrate that maternal diet during pregnancy results in long-lasting effects on the progeny. Supplementation of maternal diet with genistein, a phytoestrogen ubiquitous in the daily diet, altered coat color of agouti mice due to epigenetic changes. We studied hematopoiesis of mice prenatally exposed to genistein (270 mg/kg feed) compared with that of mice prenatally exposed to phytoestrogen-poor feed and observed a significant increase in granulopoiesis, erythropoiesis, and mild macrocytosis at the adult age of 12 wk. Genistein exposure was associated with hypermethylation of certain repetitive elements, which coincided with a significant down-regulation of estrogen-responsive genes and genes involved in hematopoiesis in bone marrow cells of genistein-exposed mice, as assessed by microarray technology. Although genistein exposure did not affect global methylation in fetal liver of fetuses at embryonic day 14.5, it accelerated the switch from primitive to definitive erythroid lineage. Taken together, our data demonstrate that prenatal exposure to genistein affects fetal erythropoiesis and exerts lifelong alterations in gene expression and DNA methylation of hematopoietic cells.
Subject(s)
Bone Marrow Cells/drug effects , Erythropoiesis/drug effects , Genistein/toxicity , Phytoestrogens/toxicity , Prenatal Exposure Delayed Effects , Animals , DNA Methylation , Epigenomics , Female , Gene Expression Regulation/drug effects , Liver/metabolism , Male , Mice , PregnancyABSTRACT
BACKGROUND: In patients with acute myeloid leukemia (AML) a combination of methods must be used to classify the disease, make therapeutic decisions, and determine the prognosis. However, this combined approach provides correct therapeutic and prognostic information in only 50 percent of cases. METHODS: We determined the gene-expression profiles in samples of peripheral blood or bone marrow from 285 patients with AML using Affymetrix U133A GeneChips containing approximately 13,000 unique genes or expression-signature tags. Data analyses were carried out with Omniviz, significance analysis of microarrays, and prediction analysis of microarrays software. Statistical analyses were performed to determine the prognostic significance of cases of AML with specific molecular signatures. RESULTS: Unsupervised cluster analyses identified 16 groups of patients with AML on the basis of molecular signatures. We identified the genes that defined these clusters and determined the minimal numbers of genes needed to identify prognostically important clusters with a high degree of accuracy. The clustering was driven by the presence of chromosomal lesions (e.g., t(8;21), t(15;17), and inv(16)), particular genetic mutations (CEBPA), and abnormal oncogene expression (EVI1). We identified several novel clusters, some consisting of specimens with normal karyotypes. A unique cluster with a distinctive gene-expression signature included cases of AML with a poor treatment outcome. CONCLUSIONS: Gene-expression profiling allows a comprehensive classification of AML that includes previously identified genetically defined subgroups and a novel cluster with an adverse prognosis.
Subject(s)
Chromosome Aberrations , Gene Expression Profiling , Leukemia, Myeloid/genetics , Acute Disease , Adult , Algorithms , Cluster Analysis , Cytogenetic Analysis , Female , Gene Expression , Gene Expression Profiling/methods , Humans , Karyotyping , Leukemia, Myeloid/classification , Leukemia, Myeloid/mortality , Male , Middle Aged , Multivariate Analysis , Mutation , Oligonucleotide Array Sequence Analysis/methods , Prognosis , Software , Survival AnalysisABSTRACT
ETV6 (ets translocation variant gene 6) TEL (translocation ets leukemia), encoding a transcriptional repressor, is involved in various translocations associated with human malignancies. Strikingly, the nonrearranged ETV6 allele is often deleted or inactivated in cells harboring these translocations. Although ETV6 translocations are infrequent in acute myeloid leukemia (AML), mutations or deregulated expression of ETV6 may contribute to leukemogenesis. To investigate the involvement of ETV6 in AML, we analysed 300 newly diagnosed patients for mutations in the coding region of the gene. Furthermore, we studied protein expression in 77 patients using two ETV6-specific antibodies. Five somatic heterozygous mutations were detected, which affected either the homodimerization- or the DNA-binding domain of ETV6. The proteins translated from the cDNAs of these mutants were unable to repress transcription and showed dominant-negative effects. In addition, we demonstrate that one-third of AML patients have deficient ETV6 protein expression, which is not related to ETV6 mRNA expression levels. In conclusion, we demonstrate that ETV6 abnormalities are not restricted to translocations and occur more frequently in AML than previously thought. Additional comprehensive studies are required to define the clinical consequence of ETV6 loss of function in AML.
Subject(s)
DNA-Binding Proteins/genetics , Gene Deletion , Heterozygote , Leukemia, Myeloid/genetics , Mutation , Nuclear Proteins/genetics , Repressor Proteins/genetics , Translocation, Genetic , Acute Disease , Bone Marrow Cells/pathology , Gene Frequency , Humans , Leukemia, Myeloid/pathology , Phosphoproteins/genetics , Proto-Oncogene Proteins c-ets , Sequence Deletion , ETS Translocation Variant 6 ProteinABSTRACT
OBJECTIVE: The expression of an MDS1-EVI1-like-1 (MEL1) gene is reported in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with translocation t(1;3)(p36;q21). MEL1 (at chromosome band 1p36.3) is thought to be transcriptionally activated as a result of juxtaposition to the RPN1 gene at 3q21. It is not known whether MEL1 expression is restricted to cases with this particular translocation. MATERIALS AND METHODS: Using real-time polymerase chain reaction, we measured MEL1 expression levels, normal bone marrow, and distinct blood cell fractions in 162 de novo AML patients. We also investigated the existence of an EVI1-like gene (EL1) by applying the same method. The existence of these transcripts was confirmed by Northern blot analysis. RESULTS: MEL1 expression was detected in 87% (141/162) of de novo AML patients. The EL1 transcript also was detected in the majority of the patients. EL1 expression levels highly correlated with MEL1 expression levels in AML cases. Variable MEL1/EL1 expression levels were observed. However, all the patients with favorable-risk karyotypes, i.e., with t(15;17), t(8;21), or inv(16), showed low MEL1/EL1 expression levels. Expression analysis of MEL1/EL1 compared with MDS1-EVI1/EVI1 in distinct normal marrow or blood cell fractions revealed that 1) all four gene products are expressed in CD34(+) progenitor cell fractions; 2) both MEL1 and EVI1 are turned down in neutrophils and monocytes/macrophages; while 3) MDS1-EVI1 and EL1 remain expressed in mature blood cell fractions. CONCLUSION: Our data suggest that simultaneous low MEL1/EL1 expression in AML is abnormal and that favorable disease is highly associated with this abnormal phenotype.
Subject(s)
Carrier Proteins/analysis , DNA-Binding Proteins/analysis , Leukemia, Myeloid, Acute/etiology , Proto-Oncogenes , Transcription Factors , Adolescent , Adult , Base Sequence , Bone Marrow/chemistry , Carrier Proteins/genetics , DNA-Binding Proteins/genetics , Female , Hematopoietic Stem Cells/chemistry , Humans , Karyotyping , Leukemia, Myeloid, Acute/metabolism , MDS1 and EVI1 Complex Locus Protein , Male , Middle Aged , Molecular Sequence Data , RNA, Messenger/analysisABSTRACT
The CCAAT/enhancer binding protein alpha is an essential transcription factor for granulocytic differentiation. Recent studies reported N- and C-terminal CEBPA mutations in approximately 7% of acute myeloid leukaemia (AML) patients. C-terminal mutations are usually in-frame and occur in the basic-leucine zipper (bZIP) domain, resulting in deficient DNA binding. Using a rapid PCR approach, we screened for bZIP mutations and determined the prognostic value of these mutations in a cohort of 277 de novo AMLs. In addition, we set out to quantify CEBPA mRNA levels by 'real-time' PCR using TaqMan technology. In-frame insertions were observed in 12 (4.3%) cases. All cases with mutations carried an intermediate-risk karyotype and all but one belonged to M1 or M2 FAB class. Further sequence analysis revealed that CEBPA C-terminal mutations are associated with frameshift mutations in the N-terminus of CEBPA. These two mutations were always found in different alleles. Event-free survival (EFS) and overall survival (OS) of patients with CEBPA mutations were significantly increased (P=0.02 and 0.03, respectively) in comparison to the patients lacking these mutations. Mutations were associated with a significantly reduced hazard ratio for death (OS: HR=0.35, P=0.04) and failure (EFS: no CR, death in CR or relapse, HR=0.37, P=0.03). This favourable hazard ratio was maintained after adjustment for cytogenetic risk, FLT3-ITD and CEBPA expression levels in multivariable analysis. In contrast, low CEBPA expression in AML with intermediate-risk karyotype (n=6) seemed to be associated with poor prognosis (not significant). By including this newly developed PCR assay, we define a subgroup of good-risk patients within the heterogeneous intermediate-risk group of AML.
Subject(s)
CCAAT-Enhancer-Binding Protein-alpha/genetics , Gene Expression Regulation, Leukemic , Leukemia, Myeloid/genetics , Neoplasm Proteins/genetics , Acute Disease , Adolescent , Adult , Alleles , Amino Acid Sequence , Binding Sites , CCAAT-Enhancer-Binding Protein-alpha/biosynthesis , CCAAT-Enhancer-Binding Protein-alpha/deficiency , DNA Mutational Analysis , DNA, Complementary/genetics , DNA, Neoplasm/genetics , Disease-Free Survival , Female , Frameshift Mutation , Humans , Karyotyping , Leucine Zippers/genetics , Leukemia, Myeloid/metabolism , Leukemia, Myeloid/mortality , Life Tables , Male , Middle Aged , Molecular Sequence Data , Mutagenesis, Insertional , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/deficiency , Neoplastic Stem Cells/metabolism , Prognosis , Protein Structure, Tertiary , RNA, Messenger/biosynthesis , RNA, Neoplasm/biosynthesis , Remission Induction , Risk , Risk Factors , Sequence Alignment , Sequence Homology, Amino Acid , Survival AnalysisSubject(s)
Antineoplastic Agents/adverse effects , Chromosome Aberrations/chemically induced , Etoposide/adverse effects , Hematopoietic Stem Cells/drug effects , Myeloid-Lymphoid Leukemia Protein/genetics , Animals , Antigens, CD34/drug effects , Antigens, CD34/immunology , Base Sequence , Cell Adhesion/drug effects , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Gene Expression Profiling , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/immunology , Humans , Lipids/biosynthesis , Mice , Mice, Inbred NOD , Mice, SCID , Microscopy, Confocal , Molecular Sequence Data , Oligonucleotide Array Sequence Analysis/methods , Polymerase Chain Reaction/methodsABSTRACT
Genetic abnormalities leading to infant leukemias already occur during fetal development and often involve rearrangements of the mixed-lineage leukemia (MLL) gene. These rearrangements resemble the aberrations observed in therapy-related leukemias following treatment with topoisomerase II (topoII)-inhibiting agents such as etoposide. Since flavonoids are potent topoII inhibitors, we examined the role of three widely consumed dietary flavonoids (quercetin, genistein and kaempferol) on the development of MLL rearrangements in primary human CD34(+) cells. Using the neutral Comet assay, we demonstrated a dose-dependent double-strand break (DSB) formation after exposure to flavonoids. An incorrect repair of these DSBs resulted in chromosomal translocations that co-localized with those identified in infant leukemias. Most of these translocations were formed by microhomology-mediated end joining. Moreover, in all but one translocation, SINE/Alu or LINE/L1 repetitive elements were present in at least one side of the breakpoint junction. Beside MLL translocations, fluorescence in situ hybridization analysis demonstrated monosomy or trisomy of MLL in 8-10% of the quercetin-exposed CD34(+) cells. Our study demonstrates that biologically relevant concentrations of flavonoids can induce MLL abnormalities in primary hematopoietic progenitor cells. This is particularly alarming knowing that the differences in metabolism and excretion rate between mother and fetus can lead to a higher flavonoid concentration on the fetal side. Therefore, it is important to raise public awareness and set guidelines for marketing flavonoid supplements to reduce the risk of infant leukemias.
Subject(s)
Antigens, CD34/biosynthesis , Dietary Supplements/adverse effects , Flavonoids/adverse effects , Leukocytes, Mononuclear/metabolism , Myeloid-Lymphoid Leukemia Protein/genetics , Translocation, Genetic , Cells, Cultured , DNA Breaks, Double-Stranded , Etoposide/adverse effects , Genistein/adverse effects , Histone-Lysine N-Methyltransferase , Humans , Kaempferols/adverse effects , Leukemia/chemically induced , Leukemia/genetics , Leukocytes, Mononuclear/drug effects , Quercetin/adverse effectsABSTRACT
Recurrent chromosomal rearrangements are associated with the development of acute myeloid leukemia (AML). The frequent inversion of chromosome 16 creates the CBFB-MYH11 fusion gene that encodes the fusion protein CBFbeta-SMMHC. This fusion protein inhibits the core-binding factor (CBF), resulting in a block of hematopoietic differentiation, and induces leukemia upon the acquisition of additional mutations. A recent genetic screen identified Plag1 and Plagl2 as CBF beta-SMMHC candidate cooperating proteins. In this study, we demonstrate that Plag1 and Plagl2 independently cooperate with CBF beta-SMMHC in vivo to efficiently trigger leukemia with short latency in the mouse. In addition, Plag1 and Plagl2 increased proliferation by inducing G1 to S transition that resulted in the expansion of hematopoietic progenitors and increased cell renewal in vitro. Finally, PLAG1 and PLAGL2 expression was increased in 20% of human AML samples. Interestingly, PLAGL2 was preferentially increased in samples with chromosome 16 inversion, suggesting that PLAG1 and PLAGL2 may also contribute to human AML. Overall, this study shows that Plag1 and Plagl2 are novel leukemia oncogenes that act by expanding hematopoietic progenitors expressing CbF beta-SMMHC.
Subject(s)
DNA-Binding Proteins/genetics , Leukemia, Myeloid/genetics , Oncogene Proteins, Fusion/genetics , RNA-Binding Proteins/genetics , Transcription Factors/genetics , Acute Disease , Adolescent , Adult , Animals , DNA-Binding Proteins/metabolism , Female , G1 Phase/immunology , Gene Expression Regulation, Leukemic , Hematopoietic Stem Cells/cytology , Humans , Leukemia, Myeloid/physiopathology , Male , Mice , Mice, Mutant Strains , Middle Aged , Mutagenesis, Insertional , Oncogene Proteins, Fusion/metabolism , RNA-Binding Proteins/metabolism , Retroviridae/genetics , S Phase/immunology , Transcription Factors/metabolismSubject(s)
Estrogens/pharmacology , Leukemia/chemically induced , Translocation, Genetic , Child , Humans , Leukemia/geneticsABSTRACT
The proto-oncogene EVI1 encodes a DNA binding protein and is located on chromosome 3q26. The gene is aberrantly expressed in acute myeloid leukemia (AML) patients carrying 3q26 abnormalities. Two mRNAs are transcribed from this locus: EVI1 and a fusion of EVI1 with MDS1 (MDS1-EVI1), a gene located 5' of EVI1. The purpose of this study was to investigate which of the 2 gene products is involved in transformation in human AML. To discriminate between EVI1 and MDS1-EVI1 transcripts, distinct real-time quantitative polymerase chain reaction (PCR) assays were developed. Patients with 3q26 abnormalities often showed high EVI1 and MDS1-EVI1 expression. In a cohort of 319 AML patients, 4 subgroups could be distinguished: EVI1(+) and MDS1-EVI1(-) (6 patients; group I), EVI1(+) and MDS1-EVI1(+) (26 patients; group II), EVI1(-) and MDS1-EVI1(+) (12 patients; group III), and EVI1(-) and MDS1-EVI1(-) (275 patients; group IV). The only 4 patients with a 3q26 aberration belonged to groups I and II. Interestingly, high EVI1 and not MDS1-EVI1 expression was associated with unfavorable karyotypes (eg, -7/7q-) or complex karyotypes. Moreover, a significant correlation was observed between EVI1 expression and 11q23 aberrations (mixed lineage leukemia [MLL] gene involvement). Patients from groups I and II had significantly shorter overall and event-free survival than patients in groups III and IV. Our data demonstrate that high EVI1 expression is an independent poor prognostic marker within the intermediate- risk karyotypic group.