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BACKGROUND: The BCR::ABL1 is a hallmark of chronic myeloid leukemia (CML) and is also found in acute lymphoblastic leukemia (ALL). Most genomic breaks on the BCR side occur in two regions - Major and minor - leading to p210 and p190 fusion proteins, respectively. METHODS: By multiplex long-distance PCR or next-generation sequencing technology we characterized the BCR::ABL1 genomic fusion in 971 patients (adults and children, with CML and ALL: pediatric ALL: n = 353; pediatric CML: n = 197; adult ALL: n = 166; adult CML: n = 255 patients) and designed "Break-App" web tool to allow visualization and various analyses of the breakpoints. Pearson's Chi-Squared test, Kolmogorov-Smirnov test and logistic regression were used for statistical analyses. RESULTS: Detailed analysis showed a non-random distribution of breaks in both BCR regions, whereas ABL1 breaks were distributed more evenly. However, we found a significant difference in the distribution of breaks between CML and ALL. We found no association of breakpoints with any type of interspersed repeats or DNA motifs. With a few exceptions, the primary structure of the fusions suggests non-homologous end joining being responsible for the BCR and ABL1 gene fusions. Analysis of reciprocal ABL1::BCR fusions in 453 patients showed mostly balanced translocations without major deletions or duplications. CONCLUSIONS: Taken together, our data suggest that physical colocalization and chromatin accessibility, which change with the developmental stage of the cell (hence the difference between ALL and CML), are more critical factors influencing breakpoint localization than presence of specific DNA motifs.
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Puntos de Rotura del Cromosoma , Proteínas de Fusión bcr-abl , Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Proteínas de Fusión bcr-abl/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Adulto , Niño , Masculino , Femenino , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
Recent research showed that precision medicine can identify new treatment strategies for patients with childhood cancers. However, it is unclear which patients will benefit most from precision-guided treatment (PGT). Here we report consecutive data from 384 patients with high-risk pediatric cancer (with an expected cure rate of less than 30%) who had at least 18 months of follow-up on the ZERO Childhood Cancer Precision Medicine Program PRecISion Medicine for Children with Cancer (PRISM) trial. A total of 256 (67%) patients received PGT recommendations and 110 (29%) received a recommended treatment. PGT resulted in a 36% objective response rate and improved 2-year progression-free survival compared with standard of care (26% versus 12%; P = 0.049) or targeted agents not guided by molecular findings (26% versus 5.2%; P = 0.003). PGT based on tier 1 evidence, PGT targeting fusions or commenced before disease progression had the greatest clinical benefit. Our data show that PGT informed by comprehensive molecular profiling significantly improves outcomes for children with high-risk cancers. ClinicalTrials.gov registration: NCT03336931.
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Neoplasias , Medicina de Precisión , Humanos , Medicina de Precisión/métodos , Niño , Neoplasias/genética , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Femenino , Masculino , Adolescente , Preescolar , Lactante , Supervivencia sin Progresión , Resultado del TratamientoRESUMEN
Purpose: Social anxiety disorder (SAD) remains an understudied potential link between the cancer experience and adolescent and young adult (AYA) cancer survivors' poor psychosocial outcomes. We investigated the frequency and duration of, as well as factors associated with, symptoms of SAD among AYAs with cancer. Methods: This longitudinal, mixed-methods study involved online surveys (including a validated screening tool for SAD) at recruitment and 6 months later, and a structured clinical interview. Results: Twenty-eight AYAs (aged 12-30 years, <1-year postdiagnosis, 50% male) completed the first survey (M = 6 months postdiagnosis). About 32% reported clinically significant SAD symptoms. Fourteen completed the follow-up survey (M = 12 months postdiagnosis), of which 9 (62%) reported persistent or worse symptoms of SAD significantly associated with emotional distress, physical appearance concerns, negative social cognitions, and depression. Conclusion: A subset of AYAs with cancer may experience clinically significant SAD symptoms that can affect their psychosocial well-being. Further work on how to best identify and support AYAs with SAD is needed.
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Neoplasias , Humanos , Adolescente , Masculino , Femenino , Adulto Joven , Neoplasias/psicología , Neoplasias/complicaciones , Adulto , Niño , Estudios Longitudinales , Fobia Social/psicología , Ansiedad/psicología , Supervivientes de Cáncer/psicologíaRESUMEN
More than 1000 Australian adolescents and young adults (AYAs) are diagnosed with cancer annually. Many report unmet social well-being needs, which impact their mental health. Australian AYA cancer care providers lack guidance to address these needs well. We aimed to develop guidelines for caring for the social well-being of AYAs with cancer in Australia. Following the Australian National Health and Medical Research Council guidance, we formed a multidisciplinary working group (n = 4 psychosocial researchers, n = 4 psychologists, n = 4 AYA cancer survivors, n = 2 oncologists, n = 2 nurses, and n = 2 social workers), defined the scope of the guidelines, gathered evidence via a systematic review, graded the evidence, and surveyed AYA cancer care providers about the feasibility and acceptability of the guidelines. The guidelines recommend which AYAs should have their social well-being assessed, who should lead that assessment, when assessment should occur with which tools/measures, and how clinicians can address AYAs' social well-being concerns. A key clinician, who is knowledgeable about AYAs' developmental needs, should lead the assessment of social well-being during and after cancer treatment. The AYA Psycho-Oncology Screening Tool is recommended to screen for social well-being needs. The HEADSSS Assessment (Home, Education/Employment, Eating/Exercise, Activities/Peer Relationships, Drug use, Sexuality, Suicidality/Depression, Safety/Spirituality Assessment) can be used for in-depth assessment of social well-being, while the Social Phobia Inventory can be used to assess social anxiety. AYA cancer care providers rated the guidelines as highly acceptable, but discussed many feasibility barriers. These guidelines provide an optimal care pathway for the social well-being of AYAs with cancer. Future research addressing implementation is critical to meet AYAs' social well-being needs.
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Supervivientes de Cáncer , Neoplasias , Adolescente , Humanos , Adulto Joven , Australia , Supervivientes de Cáncer/psicología , Evaluación de Necesidades , Neoplasias/terapia , Neoplasias/psicología , Sexualidad , Revisiones Sistemáticas como AsuntoRESUMEN
For one-third of patients with pediatric cancer enrolled in precision medicine programs, molecular profiling does not result in a therapeutic recommendation. To identify potential strategies for treating these high-risk pediatric patients, we performed in vitro screening of 125 patient-derived samples against a library of 126 anticancer drugs. Tumor cell expansion did not influence drug responses, and 82% of the screens on expanded tumor cells were completed while the patients were still under clinical care. High-throughput drug screening (HTS) confirmed known associations between activating genomic alterations in NTRK, BRAF, and ALK and responses to matching targeted drugs. The in vitro results were further validated in patient-derived xenograft models in vivo and were consistent with clinical responses in treated patients. In addition, effective combinations could be predicted by correlating sensitivity profiles between drugs. Furthermore, molecular integration with HTS identified biomarkers of sensitivity to WEE1 and MEK inhibition. Incorporating HTS into precision medicine programs is a powerful tool to accelerate the improved identification of effective biomarker-driven therapeutic strategies for treating high-risk pediatric cancers. SIGNIFICANCE: Integrating HTS with molecular profiling is a powerful tool for expanding precision medicine to support drug treatment recommendations and broaden the therapeutic options available to high-risk pediatric cancers.
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Antineoplásicos , Neoplasias , Humanos , Niño , Evaluación Preclínica de Medicamentos , Detección Precoz del Cáncer , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Ensayos Analíticos de Alto Rendimiento/métodosRESUMEN
Precision medicine programs aim to utilize novel technologies to identify personalized treatments for children with cancer. Delivering these programs requires interdisciplinary efforts, yet the many groups involved are understudied. This study explored the experiences of a broad range of professionals delivering Australia's first precision medicine trial for children with poor-prognosis cancer: the PRecISion Medicine for Children with Cancer (PRISM) national clinical trial of the Zero Childhood Cancer Program. We conducted semi-structured interviews with 85 PRISM professionals from eight professional groups, including oncologists, surgeons, clinical research associates, scientists, genetic professionals, pathologists, animal care technicians, and nurses. We analyzed interviews thematically. Professionals shared that precision medicine can add complexity to their role and result in less certain outcomes for families. Although many participants described experiencing a greater emotional impact from their work, most expressed very positive views about the impact of precision medicine on their profession and its future potential. Most reported navigating precision medicine without formal training. Each group described unique challenges involved in adapting to precision medicine in their profession. Addressing training gaps and meeting the specific needs of many professional groups involved in precision medicine will be essential to ensure the successful implementation of standard care.
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Gene expression noise is known to promote stochastic drug resistance through the elevated expression of individual genes in rare cancer cells. However, we now demonstrate that chemoresistant neuroblastoma cells emerge at a much higher frequency when the influence of noise is integrated across multiple components of an apoptotic signaling network. Using a JNK activity biosensor with longitudinal high-content and in vivo intravital imaging, we identify a population of stochastic, JNK-impaired, chemoresistant cells that exist because of noise within this signaling network. Furthermore, we reveal that the memory of this initially random state is retained following chemotherapy treatment across a series of in vitro, in vivo, and patient models. Using matched PDX models established at diagnosis and relapse from individual patients, we show that HDAC inhibitor priming cannot erase the memory of this resistant state within relapsed neuroblastomas but improves response in the first-line setting by restoring drug-induced JNK activity within the chemoresistant population of treatment-naïve tumors.
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Resistencia a Antineoplásicos , Neuroblastoma , Humanos , Apoptosis , Transducción de Señal , Inhibidores de Histona DesacetilasasRESUMEN
BACKGROUND: Pediatric acute lymphoblastic leukemia (ALL) therapy is accompanied by treatment-related toxicities (TRTs) and impaired quality of life. In Australia and New Zealand, children with ALL are treated with either Children's Oncology Group (COG) or international Berlin-Frankfurt-Munster (iBFM) Study Group-based therapy. We conducted a prospective registry study to document symptomatic TRTs (venous thrombosis, neurotoxicity, pancreatitis and bone toxicity), compare TRT outcomes to retrospective TRT data, and measure the impact of TRTs on children's general and cancer-related health-related quality of life (HRQoL) and parents' emotional well-being. METHODS: Parents of children with newly diagnosed ALL were invited to participate in the ASSET (Acute Lymphoblastic Leukaemia Subtypes and Side Effects from Treatment) study and a prospective, longitudinal HRQoL study. TRTs were reported prospectively and families completed questionnaires for general (Healthy Utility Index Mark 3) and cancer specific (Pediatric Quality of Life Inventory (PedsQL)-Cancer Module) health related quality of life as well the Emotion Thermometer to assess emotional well-being. RESULTS: Beginning in 2016, 260 pediatric patients with ALL were enrolled on the TRT registry with a median age at diagnosis of 59 months (range 1-213 months), 144 males (55.4%), majority with Pre-B cell immunophenotype, n = 226 (86.9%), 173 patients (66.5%) treated according to COG platform with relatively equal distribution across risk classification sub-groups. From 2018, 79 families participated in the HRQoL study through the first year of treatment. There were 74 TRT recorded, reflecting a 28.5% risk of developing a TRT. Individual TRT incidence was consistent with previous studies, being 7.7% for symptomatic VTE, 11.9% neurotoxicity, 5.4% bone toxicity and 5.0% pancreatitis. Children's HRQoL was significantly lower than population norms throughout the first year of treatment. An improvement in general HRQoL, measured by the HUI3, contrasted with the lack of improvement in cancer-related HRQoL measured by the PedsQL Cancer Module over the first 12 months. There were no persisting differences in the HRQoL impact of COG compared to iBFM therapy. CONCLUSIONS: It is feasible to prospectively monitor TRT incidence and longitudinal HRQoL impacts during ALL therapy. Early phases of ALL therapy, regardless of treatment platform, result in prolonged reductions in cancer-related HRQoL.
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Pancreatitis , Leucemia-Linfoma Linfoblástico de Células Precursoras , Enfermedad Aguda , Niño , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Calidad de Vida , Estudios Retrospectivos , Encuestas y CuestionariosRESUMEN
BACKGROUND: ABL-class fusions including NUP214-ABL1 and EBF1-PDGFRB occur in high risk acute lymphoblastic leukaemia (ALL) with gene expression patterns similar to BCR-ABL-positive ALL. Our aim was to evaluate new DNA-based measurable residual disease (MRD) tests detecting these fusions and IKZF1-deletions in comparison with conventional immunoglobulin/T-cell receptor (Ig/TCR) markers. METHODS: Precise genomic breakpoints were defined from targeted or whole genome next generation sequencing for ABL-fusions and BCR-ABL1. Quantitative PCR assays were designed and used to re-measure MRD in remission bone marrow samples previously tested using Ig/TCR markers. All MRD testing complied with EuroMRD guidelines. RESULTS: ABL-class patients had 46% 5year event-free survival and 79% 5year overall survival. All had sensitive fusion tests giving high concordance between Ig/TCR and ABL-class fusion results (21 patients, n = 257 samples, r2 = 0.9786, P < 0.0001) and Ig/TCR and IKZF1-deletion results (9 patients, n = 143 samples, r2 = 0.9661, P < 0.0001). In contrast, in BCR-ABL1 patients, Ig/TCR and BCR-ABL1 tests were discordant in 32% (40 patients, n = 346 samples, r2 = 0.4703, P < 0.0001) and IKZF1-deletion results were closer to Ig/TCR (25 patients, n = 176, r2 = 0.8631, P < 0.0001). CONCLUSIONS: MRD monitoring based on patient-specific assays detecting gene fusions or recurrent assays for IKZF1-deletions is feasible and provides good alternatives to Ig/TCR tests to monitor MRD in ABL-class ALL.
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Proteínas de Fusión bcr-abl , Leucemia-Linfoma Linfoblástico de Células Precursoras , Niño , Proteínas de Fusión bcr-abl/genética , Humanos , Inmunoglobulinas , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptores de Antígenos de Linfocitos T/genéticaRESUMEN
Drug resistance and treatment failure in pediatric acute lymphoblastic leukemia (ALL) are in part driven by tumor heterogeneity and clonal evolution. Although bulk tumor genomic analyses have provided some insight into these processes, single-cell sequencing has emerged as a powerful technique to profile individual cells in unprecedented detail. Since the introduction of single-cell RNA sequencing, we now have the capability to capture not only transcriptomic, but also genomic, epigenetic, and proteomic variation between single cells separately and in combination. This rapidly evolving field has the potential to transform our understanding of the fundamental biology of pediatric ALL and guide the management of ALL patients to improve their clinical outcome. Here, we discuss the impact single-cell sequencing has had on our understanding of tumor heterogeneity and clonal evolution in ALL and provide examples of how single-cell technology can be integrated into the clinic to inform treatment decisions for children with high-risk disease.
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The measurement of circulating tumor DNA (ctDNA) has gained increasing prominence as a minimally invasive tool for the detection of cancer-specific markers in plasma. In adult cancers, ctDNA detection has shown value for disease-monitoring applications including tumor mutation profiling, risk stratification, relapse prediction, and treatment response evaluation. To date, there are ctDNA tests used as companion diagnostics for adult cancers and it is not understood why the same cannot be said about childhood cancer, despite the marked differences between adult and pediatric oncology. In this review, we discuss the current understanding of ctDNA as a disease monitoring biomarker in the context of pediatric malignancies, including the challenges associated with ctDNA detection in liquid biopsies. The data and conclusions from pediatric cancer studies of ctDNA are summarized, highlighting treatment response, disease monitoring and the detection of subclonal disease as applications of ctDNA. While the data from retrospective studies highlight the potential of ctDNA, large clinical trials are required for ctDNA analysis for routine clinical use in pediatric cancers. We outline the requirements for the standardization of ctDNA detection in pediatric cancers, including sample handling and reproducibility of results. With better understanding of the advantages and limitations of ctDNA and improved detection methods, ctDNA analysis may become the standard of care for patient monitoring in childhood cancers.
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Despite intensive chemotherapy regimens, up to 60% of adults with acute myeloid leukaemia (AML) will relapse and eventually succumb to their disease. Recent studies suggest that leukaemic stem cells (LSCs) drive AML relapse by residing in the bone marrow niche and adapting their metabolic profile. Metabolic adaptation and LSC plasticity are novel hallmarks of leukemogenesis that provide important biological processes required for tumour initiation, progression and therapeutic responses. These findings highlight the importance of targeting metabolic pathways in leukaemia biology which might serve as the Achilles' heel for the treatment of AML relapse. In this review, we highlight the metabolic differences between normal haematopoietic cells, bulk AML cells and LSCs. Specifically, we focus on four major metabolic pathways dysregulated in AML; (i) glycolysis; (ii) mitochondrial metabolism; (iii) amino acid metabolism; and (iv) lipid metabolism. We then outline established and emerging drug interventions that exploit metabolic dependencies of leukaemic cells in the treatment of AML. The metabolic signature of AML cells alters during different biological conditions such as chemotherapy and quiescence. Therefore, targeting the metabolic vulnerabilities of these cells might selectively eradicate them and improve the overall survival of patients with AML.
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Biomarkers which better match anticancer drugs with cancer driver genes hold the promise of improved clinical responses and cure rates. We developed a precision medicine platform of rapid high-throughput drug screening (HTS) and patient-derived xenografting (PDX) of primary tumor tissue, and evaluated its potential for treatment identification among 56 consecutively enrolled high-risk pediatric cancer patients, compared with conventional molecular genomics and transcriptomics. Drug hits were seen in the majority of HTS and PDX screens, which identified therapeutic options for 10 patients for whom no targetable molecular lesions could be found. Screens also provided orthogonal proof of drug efficacy suggested by molecular analyses and negative results for some molecular findings. We identified treatment options across the whole testing platform for 70% of patients. Only molecular therapeutic recommendations were provided to treating oncologists and led to a change in therapy in 53% of patients, of whom 29% had clinical benefit. These data indicate that in vitro and in vivo drug screening of tumor cells could increase therapeutic options and improve clinical outcomes for high-risk pediatric cancer patients.
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Antineoplásicos , Neoplasias , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Niño , Modelos Animales de Enfermedad , Genómica/métodos , Humanos , Neoplasias/patología , Medicina de Precisión/métodos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Purpose: Involvement of adolescent and young adult (AYAs) cancer survivors as consumers in research is increasingly encouraged, yet few studies have identified the feasibility and acceptability of methods used to involve them. We aimed to identify: (1) How feasible and acceptable is a consumer-driven, workshop-based research priority-setting approach? And (2) what research priorities do Australian AYA consumers endorse? Methods: AYA cancer survivors diagnosed 15-30 years old and currently younger than 35 years were invited to participate. The AYAs completed a pre-workshop survey to rank their top three priorities from the United Kingdom-based James Lind Alliance list, participated in a 90-minute focus group, and completed a post-workshop evaluation survey. We assessed the workshop feasibility by reviewing considerations, challenges, and enablers of success in the planning and conduct processes. Acceptability was assessed through participants' evaluation surveys and facilitators' informal reflections. The top three priorities were determined from pre-workshop surveys and focus group data. Results: Six survivors participated (M age = 24.2 years, M = 5 years post-treatment, 83% female). All reported that the workshop was an acceptable way to engage with researchers. Costs and recruitment challenges limited the workshop's feasibility. The AYAs' top priority was: What psychological support package improves psychological well-being, social functioning, and mental health during and after treatment?Discussion: The AYA survivors found our workshop to be an acceptable way to engage in research priority-setting. However, the feasibility of this approach depends on the resources available to researchers. Future research is needed to define the optimal method of engagement: What is most acceptable for AYAs and feasible for researchers?
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Supervivientes de Cáncer , Neoplasias , Adolescente , Adulto , Australia , Supervivientes de Cáncer/psicología , Femenino , Humanos , Masculino , Neoplasias/terapia , Investigación , Encuestas y Cuestionarios , Reino Unido , Adulto JovenRESUMEN
Symptomatic methotrexate-related central neurotoxicity (MTX neurotoxicity) is a severe toxicity experienced during acute lymphoblastic leukemia (ALL) therapy with potential long-term neurologic complications. Risk factors and long-term outcomes require further study. We conducted a systematic, retrospective review of 1,251 consecutive Australian children enrolled on Berlin-Frankfurt-Münster or Children's Oncology Group-based protocols between 1998-2013. Clinical risk predictors for MTX neurotoxicity were analyzed using regression. A genome-wide association study (GWAS) was performed on 48 cases and 537 controls. The incidence of MTX neurotoxicity was 7.6% (n=95 of 1,251), at a median of 4 months from ALL diagnosis and 8 days after intravenous or intrathecal MTX. Grade 3 elevation of serum aspartate aminotransferase (P=0.005, odds ratio 2.31 [range, 1.28-4.16]) in induction/consolidation was associated with MTX neurotoxicity, after accounting for the only established risk factor, age ≥10 years. Cumulative incidence of CNS relapse was increased in children where intrathecal MTX was omitted following symptomatic MTX neurotoxicity (n=48) compared to where intrathecal MTX was continued throughout therapy (n=1,174) (P=0.047). Five-year central nervous system relapse-free survival was 89.2 4.6% when intrathecal MTX was ceased compared to 95.4 0.6% when intrathecal MTX was continued. Recurrence of MTX neurotoxicity was low (12.9%) for patients whose intrathecal MTX was continued after their first episode. The GWAS identified single-nucletide polymorphism associated with MTX neurotoxicity near genes regulating neuronal growth, neuronal differentiation and cytoskeletal organization (P<1x10-6). In conclusion, increased serum aspartate aminotransferase and age ≥10 years at diagnosis were independent risk factors for MTX neurotoxicity. Our data do not support cessation of intrathecal MTX after a first MTX neurotoxicity event.
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Estudio de Asociación del Genoma Completo , Leucemia-Linfoma Linfoblástico de Células Precursoras , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Australia , Niño , Humanos , Inyecciones Espinales , Metotrexato/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Factores de RiesgoRESUMEN
Purpose: Adolescent and young adult (AYA) cancer survivors may be at risk of developing symptoms of social anxiety disorder (SAD) due to disruptions in social participation and functioning following a cancer diagnosis. This study aimed to explore (1) the proportion of Australian AYA-aged survivors of childhood and adolescent cancer who experience symptoms of SAD, (2) how symptoms of SAD are described by survivors as affecting their daily social functioning. Methods: A mixed-methods cross-sectional design was employed, inviting survivors, aged 13-25 years, who had completed treatment between one and ten years ago. Survivors completed a paper-based questionnaire, containing validated measures of SAD, and an optional semistructured interview assessing current social functioning and social anxiety. Results: Twenty-seven survivors aged 13-25 years participated (M = 19.15, 51.9% male, and 7 years post-treatment). Nine (33%) participants reported clinically significant symptoms of SAD. In interviews, survivors reported worries about how others perceived them and fears around meeting new people. Survivors described that this impacted their daily social functioning, leading them to avoid, or endure with distress, feared social situations. Conclusion: This study shows that clinically significant social anxiety may be a concern for a subset of survivors of childhood/adolescent cancer. Identifying which young people are at risk of SAD after cancer and how best to support this vulnerable cohort is critical.
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Neoplasias , Sobrevivientes , Adolescente , Ansiedad/etiología , Australia/epidemiología , Estudios Transversales , Miedo , Femenino , Humanos , Masculino , Neoplasias/complicaciones , Neoplasias/terapia , Adulto JovenRESUMEN
BACKGROUND: Minimal residual disease (MRD) measurement is a cornerstone of contemporary acute lymphoblastic leukaemia (ALL) treatment. The presence of immunoglobulin (Ig) and T cell receptor (TCR) gene recombinations in leukaemic clones allows widespread use of patient-specific, DNA-based MRD assays. In contrast, paediatric solid tumour MRD remains experimental and has focussed on generic assays targeting tumour-specific messenger RNA, methylated DNA or microRNA. METHODS: We examined the feasibility of using whole-genome sequencing (WGS) data to design tumour-specific polymerase chain reaction (PCR)-based MRD tests (WGS-MRD) in 18 children with high-risk relapsed cancer, including ALL, high-risk neuroblastoma (HR-NB) and Ewing sarcoma (EWS) (n = 6 each). RESULTS: Sensitive WGS-MRD assays were generated for each patient and allowed quantitation of 1 tumour cell per 10-4 (0.01%)-10-5 (0.001%) mononuclear cells. In ALL, WGS-MRD and Ig/TCR-MRD were highly concordant. WGS-MRD assays also showed good concordance between quantitative PCR and droplet digital PCR formats. In serial clinical samples, WGS-MRD correlated with disease course. In solid tumours, WGS-MRD assays were more sensitive than RNA-MRD assays. CONCLUSIONS: WGS facilitated the development of patient-specific MRD tests in ALL, HR-NB and EWS with potential clinical utility in monitoring treatment response. WGS data could be used to design patient-specific MRD assays in a broad range of tumours.
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Biomarcadores de Tumor/genética , Reordenamiento Génico , Neoplasia Residual/patología , Neuroblastoma/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Sarcoma de Ewing/patología , Secuenciación Completa del Genoma/métodos , Adolescente , Neoplasias Óseas/sangre , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Proteína Proto-Oncogénica N-Myc/genética , Neoplasia Residual/genética , Neuroblastoma/sangre , Neuroblastoma/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteína Proto-Oncogénica c-fli-1/genética , Receptores de Antígenos de Linfocitos T/genética , Sarcoma de Ewing/sangre , Sarcoma de Ewing/genética , Regulador Transcripcional ERG/genéticaRESUMEN
OBJECTIVES: Survivors of adolescent and young adult (AYA) cancer report deficits in social functioning relative to healthy peers. Identifying factors related to their social functioning is critical to improve their long-term social outcomes. This review addressed: (1) How is social functioning defined and measured among studies of AYAs who have had cancer? (2) What factors have quantitatively/qualitatively are associated with/predictors of social functioning? and (3) What associated factors/predictors of social functioning are modifiable and amenable to intervention? METHODS: A systematic review was conducted to identify publications from 2000 to 2021, meeting these criteria: (1) mean/median age at diagnosis/treatment 13-40, (2) assessed social functioning with a validated measure and included factors associated with/predictive of social functioning and/or qualitatively assessed young people's perceptions of factors related to their social functioning and (3) was peer-reviewed/published in English. RESULTS: Thirty-seven publications were included. Definitions and measures of social functioning varied, and factors related to social functioning varied based on definition. Factors most commonly associated with decreased social functioning included treatment status (receiving or completed treatment), poor physical functioning, depression, negative body image, engaging in social comparisons, social/cultural stigma around cancer, and fatigue. Increased social functioning was most commonly associated with social support and the quality/age-appropriateness of care. CONCLUSIONS: Social functioning is multidimensional construct for AYAs diagnosed with cancer and may not be adequately assessed with measures of adjustment or quality of life. Future studies should clarify how to optimally define and measure social functioning in this population, to ensure their functioning can be protected and promoted long-term.
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Neoplasias , Calidad de Vida , Adolescente , Humanos , Neoplasias/terapia , Ajuste Social , Interacción Social , Apoyo Social , Adulto JovenRESUMEN
The prognosis of recurrent malignant peripheral nerve sheath tumors (MPNST) is dismal, with surgical resection being the only definitive salvage therapy. Treatment with chemoradiation approaches has not significantly improved patient outcomes. Similarly, trials of therapies targeting MPNST genomic drivers have thus far been unsuccessful. Improved understanding of the molecular pathogenesis of MPNST indicates frequent activation of the mitogen-activated protein kinase (MAPK) cell signaling pathway. MEK inhibitors have shown activity in preclinical studies; however, their clinical efficacy has not been reported to date. We describe here a case of sustained complete response to MEK inhibition in an adolescent patient with a recurrent metastatic MPNST with multiple alterations in the MAPK pathway, guided by a precision oncology approach.
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We report on the Australian experience of blinatumomab for treatment of 24 children with relapsed/refractory precursor B-cell acute lymphoblastic leukaemia (B-ALL) and high-risk genetics, resulting in a minimal residual disease (MRD) response rate of 58%, 2-year progression-free survival (PFS) of 39% and 2-year overall survival of 63%. In total, 83% (n = 20/24) proceeded to haematopoietic stem cell transplant, directly after blinatumomab (n = 12) or following additional salvage therapy (n = 8). Four patients successfully received CD19-directed chimeric antigen receptor T-cell therapy despite prior blinatumomab exposure. Inferior 2-year PFS was associated with MRD positivity (20%, n = 15) and in KMT2A-rearranged infants (15%, n = 9). Our findings highlight that not all children with relapsed/refractory B-ALL respond to blinatumomab and factors such as blast genotype may affect prognosis.