Impact of<i>ABC</i>single nucleotide polymorphisms upon the efficacy and toxicity of induction chemotherapy in acute myeloid leukemia

Megías‐Vericat, Juan Eduardo; Montesinos, Pau; Herrero, Marí­a José; Moscardó, Federico; Bosó, Virginia; Rojas, Luis; Martínez‐Cuadrón, David; Hervás, David; Boluda, Blanca; García-Robles, Ana; Rodríguez‐Veiga, Rebeca; Martín-Cerezuela, María; Cervera, José; Sendra, Luis; Sanz, Jaime; Miguel, Antonio; Lorenzo, Ignacio; Poveda, José Luís; Sanz, Miguel Á.; Aliño, Salvador F.

doi:10.1080/10428194.2016.1231405

Cited by 33 publications

(28 citation statements)

References 38 publications

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“…7,[9][10][11][12] Through a linkage of clinical trial data and administrative data resources, we plan to evaluate the utility of cardiac-directed interventions on the progression and potential resolution of cardiac dysfunction. Finally, additional work is ongoing to discover and validate germline genetic variants that may predispose to anthracycline-associated cardiotoxicity and influence treatment efficacy through drug metabolism or other pharmacogenomics pathways, [27][28][29][30][31] as well as to investigate the increased risk of cardiotoxicity in black patients. A more complete understanding of the development of cardiotoxicity and effective interventions will inform evidence-based strategies to improve both the cardiovascular and oncologic outcomes for children with cancer.…”

Section: Discussionmentioning

confidence: 99%

Occurrence of Treatment-Related Cardiotoxicity and Its Impact on Outcomes Among Children Treated in the AAML0531 Clinical Trial: A Report From the Children’s Oncology Group

Getz

Sung

et al. 2019

JCO

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Purpose Late cardiotoxicity after pediatric acute myeloid leukemia therapy causes substantial morbidity and mortality. The impact of early-onset cardiotoxicity on treatment outcomes is less well understood. Thus, we evaluated the risk factors for incident early cardiotoxicity and the impacts of cardiotoxicity on event-free survival (EFS) and overall survival (OS). Methods Cardiotoxicity was ascertained through adverse event monitoring over the course of follow-up among 1,022 pediatric patients with acute myeloid leukemia treated in the Children’s Oncology Group trial AAML0531. It was defined as grade 2 or higher left ventricular systolic dysfunction on the basis of Common Terminology Criteria for Adverse Events (version 3) definitions. Results Approximately 12% of patients experienced cardiotoxicity over a 5-year follow-up, with more than 70% of incident events occurring during on-protocol therapy. Documented cardiotoxicity during on-protocol therapy was significantly associated with subsequent off-protocol toxicity. Overall, the incidence was higher among noninfants and black patients, and in the setting of a bloodstream infection. Both EFS (hazard ratio [HR], 1.6; 95% CI, 1.2 to 2.1; P = .004) and OS (HR, 1.6; 95% CI, 1.2 to 2.2, P = .005) were significantly worse in patients with documented cardiotoxicity. Impacts on EFS were equivalent whether the incident cardiotoxicity event occurred in the absence (HR, 1.6; 95% CI, 1.1 to 2.2; P = .017) or presence of infection (HR, 1.6; 95% CI, 1.0 to 2.7; P = .069) compared with patients without documented cardiotoxicity. However, the reduction in OS was more pronounced for cardiotoxicity not associated with infection (HR, 1.7; 95% CI, 1.2 to 2.5; P = .004) than for infection-associated cardiotoxicity (HR, 1.3; 95% CI, 0.7 to 2.4; P = .387). Conclusion Early treatment-related cardiotoxicity may be associated with decreased EFS and OS. Cardioprotective strategies are urgently needed to improve relapse risk and both short- and long-term mortality outcomes.

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Section: Discussionmentioning

confidence: 99%

Occurrence of Treatment-Related Cardiotoxicity and Its Impact on Outcomes Among Children Treated in the AAML0531 Clinical Trial: A Report From the Children’s Oncology Group

Getz

Sung

et al. 2019

JCO

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“…As consequence, a total of 35 SNPs were selected for genotyping. Although it has reported that some SNPs might affect chemotherapy efficacy in cancer patients, the evidence is not sufficient to address the role of these SNPs in survival, if only chemotherapy‐treated patients were included, unless these SNPs are also indeed involved in chemotherapy efficacy. Therefore, we first compared associations of the SNPs with survival between chemotherapy‐treated and untreated patients.…”

Section: Resultsmentioning

confidence: 99%

Functional genetic variants of XRCC4 and ERCC1 predict survival of gastric cancer patients treated with chemotherapy by regulating the gene expression

Cheng

Qiu

Wang

et al. 2017

Molecular Carcinogenesis

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DNA repair protects genomic integrity and may modulate chemotherapy efficacy. Few large-scale studies have evaluated predictive roles of genetic variants of DNA repair genes in survival of Chinese gastric cancer (GCa) patients treated with chemotherapy. Here, we assessed the roles of 35 single nucleotide polymorphisms (SNPs) in DNA repair genes in survival of 1002 GCa patients, of whom 694 received chemotherapy and 308 did not. Among patients receiving chemotherapy, the ERCC1 rs2298881A allele was associated with a better survival [hazards ratio (HR) = 0.82, 95% confidence interval (CI) = 0.69-0.98; P = 0.03], whereas two XRCC4 SNPs were associated with a worse survival (HR = 1.26, 95% CI = 1.03-1.54 for the rs10040363G allele, P = 0.02; and HR = 1.30, 95% CI = 1.06-1.59 for the rs2075685T allele, P = 0.01). These three SNPs were unique survival predictors for patients treated with chemotherapy (P < 0.05 for all) but not for patients without chemotherapy (P > 0.05 for all), suggesting that they modulated chemotherapy efficacy. Patients who received chemotherapy and had haplotypes with at least one death-risk allele in XRCC4 had a poor survival, and the trend for an increase in the number of death-risk alleles adversely affecting the survival was also observed in an allelic dose-dependent manner (P = 0.001). Further functional analysis revealed that the death-risk alleles up-regulated the gene expression, leading to a worse survival as suggested by our meta-analysis pooling both mRNA microarray data from the GEO database and published data (ERCC1: HR = 1.31 [1.08-1.58]; P = 0.006). These functional genetic variants may independently or jointly affect survival in chemotherapy-treated GCa patients by modulating the gene expression in the tumors.

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“…The way in which a cancer patient responds to drug treatment is dependent on many variables and among these, the individual genotype is an essential factor for influencing drug behaviour. Because of the importance of DNA repair process in determining drug sensitivity and resistance, in various cancer types, the role of polymorphisms in DNA repair genes have been explored to explain inter‐individual differences in the treatment response or survival . Many studies focused their attention on the role of PARP1 polymorphisms and their relation with increased risk for various cancer types .…”

Section: Discussionmentioning

confidence: 99%

Association of PARP1 polymorphisms with response to chemotherapy in patients with high‐risk neuroblastoma

Avitabile

Lasorsa

Cantalupo

et al. 2020

J Cellular Molecular Medi

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The genetic aetiology and the molecular mechanisms that characterize high-risk neuroblastoma are still little understood. The majority of high-risk neuroblastoma patients do not take advantage of current induction therapy. So far, one of the main reasons liable for cancer therapeutic failure is the acquisition of resistance to cytotoxic anticancer drugs, because of the DNA repair system of tumour cells. PARP1 is one of the main DNA damage sensors involved in the DNA repair system and genomic stability. We observed that high PARP1 mRNA level is associated with unfavourable prognosis in 3 public gene expression NB patients' datasets and in 20 neuroblastomas analysed by qRT-PCR. Among 4983 SNPs in PARP1, we selected two potential functional SNPs. We investigated the association of rs907187, in PARP1 promoter, and rs2048426 in non-coding region with response chemotherapy in 121 Italian patients with high-risk NB. Results showed that minor G allele of rs907187 associated with induction response of patients (P = .02) and with decrease PARP1 mRNA levels in NB cell line (P = .003). Furthermore, rs907187 was predicted to alter the binding site of E2F1 transcription factor. Specifically, allele G had low binding affinity with E2F1 whose expression positively correlates with PARP1 expression and associated with poor prognosis of patients with NB. By contrast, we did not find genetic association for the SNP rs2048426. These data reveal rs907187 as a novel potential risk variant associated with the failure of induction therapy for high-risk NB. K E Y W O R D Schemotherapy, neuroblastoma, oncology, PARP1, pharmacogenomics, SNP | 4073 AVITABILE ET AL.

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Impact ofABCsingle nucleotide polymorphisms upon the efficacy and toxicity of induction chemotherapy in acute myeloid leukemia

Cited by 33 publications

References 38 publications

Occurrence of Treatment-Related Cardiotoxicity and Its Impact on Outcomes Among Children Treated in the AAML0531 Clinical Trial: A Report From the Children’s Oncology Group

Occurrence of Treatment-Related Cardiotoxicity and Its Impact on Outcomes Among Children Treated in the AAML0531 Clinical Trial: A Report From the Children’s Oncology Group

Functional genetic variants of XRCC4 and ERCC1 predict survival of gastric cancer patients treated with chemotherapy by regulating the gene expression

Association of PARP1 polymorphisms with response to chemotherapy in patients with high‐risk neuroblastoma

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