Investigating the efficacy of osimertinib and crizotinib in phase 3 clinical trials on anti-cancer treatment-induced cardiotoxicity: are real-world studies the way forward?

BACKGROUND.: Oncology clinical trials demonstrate the risk of cardiotoxicity but are not sufficient to reveal the true risk. In this article, we compared the incidence of cardiotoxicity of crizotinib and osimertinib from a real-world study to data reported by phase 3 clinical trials. METHODS.: Data from an ongoing real-world lung cancer study was used as a comparator. Patients were recruited retrospectively with the criteria of being diagnosed with non-small cell lung cancer and having received at least a course of treatment of tyrosine-kinase inhibitor and/or immune check-point inhibitor. Characteristics of the patients who developed cardiotoxicity associated with osimertinib and crizotinib in the real-world lung cancer study were analysed against the inclusion criteria of the corresponding phase 3 clinical trials. Variations of cardiotoxicity incidence among the real-world lung cancer study and clinical trials were investigated. RESULTS.: 18%, n = 37/206, of the patients developed cardiotoxicity. QTc prolongation was the most frequently observed cardiotoxicity (n = 12/37). Osimertinib and crizotinib were the most cardiotoxic agents, each responsible for seven cases of cardiotoxicity. FLAURA, AURA3, PROFILE 1007 and PROFILE 1014 were the included clinical trials for analysis. None of the patients who developed cardiotoxicity in the real-world study would have been eligible to participate in FLAURA and PROFILE 1014 study whereas n = 4/7 and n = 5/7 patients were eligible to participate in AURA3 and PROFILE 1007 trials, respectively. CONCLUSION.: Although phase 3 clinical trials play an important role in understanding the effectiveness and give insights on side-effect profiles, real-world studies can show the real risk of cardiotoxicity more accurately and realistically.

Management of COVID-19 in cancer patients receiving cardiotoxic anti-cancer therapy. Future recommendations for cardio-oncology.

Cardiotoxicity induced by anti-cancer treatment has become a significant threat as the number of cardiotoxic anti-cancer agents is growing. Cancer patients are at an increased risk of contracting coronavirus disease 2019 (COVID-19) because of immune suppression caused by anti-cancer drugs and/or supportive treatment. Deterioration in lung functions due to COVID-19 is responsible for many cardiac events. The presence of COVID-19 and some of its treatment modalities may increase the chance of cardiotoxicity development in cancer patients receiving potentially cardiotoxic agents. This review provides evidence-based information on the cardiotoxicity risk in cancer patients clinically diagnosed with COVID-19 who are receiving potentially cardiotoxic anti-cancer agents. Proposed strategies relating to the management of this patient cohorts are also discussed.

Cancer Immunoprevention and Public Health.

The power of cancer immune surveillance has been documented beyond doubt, and the successful exploitation of immune response to cancer has started a new era in the war against cancer. Cancer biologists have recognized immunoevasion as an emerging hallmark in addition to the six hallmarks of cancer. Besides the natural connection between the immune system and cancer development, most established environmental risk factors are now known to interfere with immune surveillance mechanisms. Genetic variations regulating immunity may also modulate cancer susceptibility, but evidence for this is currently limited. Molecular cross talk linking "immune" and "genomic" surveillance pathways has been characterized. It appears that immune mechanisms may contribute to the effects of common cancer risk factors. We provide an updated overview of evidence for cancer immune surveillance, cancer risk factors interfering with it, and interventions to enhance cancer immune surveillance as tools to complement ongoing vaccine development efforts for cancer immunoprevention. Although there is a lot of support for cancer immunoprevention with simple lifestyle modifications from observational studies, there is an urgent need for clinical trials to establish the effectiveness of this approach for public health benefits.

A childhood acute lymphoblastic leukemia genome-wide association study identifies novel sex-specific risk variants.

Childhood acute lymphoblastic leukemia (ALL) occurs more frequently in males. Reasons behind sex differences in childhood ALL risk are unknown. In the present genome-wide association study (GWAS), we explored the genetic basis of sex differences by comparing genotype frequencies between male and female cases in a case-only study to assess effect-modification by sex.The case-only design included 236 incident cases of childhood ALL consecutively recruited at the Texas Children's Cancer Center in Houston, Texas from 2007 to 2012. All cases were non-Hispanic whites, aged 1 to 10 years, and diagnosed with confirmed B-cell precursor ALL. Genotyping was performed using the Illumina HumanCoreExome BeadChip on the Illumina Infinium platform. Besides the top 100 statistically most significant results, results were also analyzed by the top 100 highest effect size with a nominal statistical significance (P <0.05).The statistically most significant sex-specific association (P = 4 × 10) was with the single nucleotide polymorphism (SNP) rs4813720 (RASSF2), an expression quantitative trait locus (eQTL) for RASSF2 in peripheral blood. rs4813720 is also a strong methylation QTL (meQTL) for a CpG site (cg22485289) within RASSF2 in pregnancy, at birth, childhood, and adolescence. cg22485289 is one of the hypomethylated CpG sites in ALL compared with pre-B cells. Two missense SNPs, rs12722042 and 12722039, in the HLA-DQA1 gene yielded the highest effect sizes (odds ratio [OR] ∼ 14; P <0.01) for sex-specific results. The HLA-DQA1 SNPs belong to DQA1*01 and confirmed the previously reported male-specific association with DQA1*01. This finding supports the proposed infection-related etiology in childhood ALL risk for males. Further analyses revealed that most SNPs (either direct effect or through linkage disequilibrium) were within active enhancers or active promoter regions and had regulatory effects on gene expression levels.Cumulative data suggested that RASSF2 rs4813720, which correlates with increased RASSF2 expression, may counteract the suppressor effect of estrogen-regulated miR-17-92 on RASSF2 resulting in protection in males. Given the amount of sex hormone-related mechanisms suggested by our findings, future studies should examine prenatal or early postnatal programming by sex hormones when hormone levels show a large variation.

HLA-DRB1*15 and pediatric aplastic anemia.

We report a positive association between HLA-DRB1*15 (p= 0.0002) in Turkish patients with pediatric severe aplastic anemia (SAA) and a paradoxically favorable influence of the susceptibility marker on the clinical response to immunosuppressive therapy. These findings point to an immune mechanism mediated by DRB1*15 in SAA which confers responsiveness to treatment.