Tyrosine Kinase Inhibitor Treatment In Patients Research Articles

BAP18 acting as a novel peroxisome proliferator-activated receptor α co-regulator contributes to hepatocellular carcinoma progression

Hepatocellular carcinoma (HCC) is a common malignancy worldwide with a poor prognosis. The therapeutic outcomes of HCC patients are urgently needed to be improved, and predictive biomarkers for the optimal treatment selection remains to be further defined. In the present study, our results showed that BPTF-associated protein of 18 KDa (BAP18) was highly expressed in HCC tissues. In cultured HCC cells, BAP18 regulated a subset of down-stream genes involved in different functions, particularly including peroxisome proliferator-activated receptor (PPAR) pathway and lipid metabolism. Furthermore, BAP18 co-activated PPARα-mediated transactivation and facilitated the recruitment of nucleosome acetyltransferase of H4 (NuA4)/tat interacting protein 60 (TIP60) complex, thereby increasing histone H4 acetylation on stearoyl-CoA desaturase 1 (SCD1) loci. In addition, BAP18 promoted HCC cell proliferation, increased intracellular lipid levels and enhanced cell survival under the metabolic stress conditions, such as glucose limitation or tyrosine kinase inhibitors (TKIs) treatment. Importantly, higher BAP18 expression was positively correlated with the postoperative recurrence and the poor disease-free survival in clinical patients receiving sorafenib treatment. Altogether, we discovered that BAP18 plays an oncogenic role in the survival and proliferation of HCC cells, and BAP18 may serve as a predictive biomarker for adjunct TKIs treatment in patients with HCC, and further facilitate the precise treatment.

The Prognostic Value of 18F-FDG PET/CT Metabolic Parameters in Predicting Treatment Response Before EGFR TKI Treatment in Patients with Advanced Lung Adenocarcinoma.

Objectives:This study makes a retrospective examination of exploring the prognostic value of 18fluorine-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) related metabolic-volumetric variables, nutritional status, and immune and inflammatory markers on progression-free survival (PFS) and overall survival (OS) in advanced adenocarcinoma patients with positive epidermal growth factor receptor (EGFR) mutations undergoing EGFR tyrosine kinase inhibitor (TKI) therapy.Methods:A retrospective examination was made of patients diagnosed with lung adenocarcinoma who underwent 18F-FDG PET/CT imaging for staging maximum four weeks before starting treatment, between January 2015 and July 2020. Included in the study were 68 patients identified histopathologically to have locally advanced/metastatic EGFR mutation-positive adenocarcinoma, and who underwent EGFR TKI therapy. The laboratory data of the patients, obtained 15 days before imaging performed for PET/CT staging, were evaluated.Results:Metabolic tumor volume, modified Glasgow prognostic score and locally advanced disease were identified as independent prognostic parameters for PFS (p=0.004, p=0.029, p=0.016, respectively). A univariate Cox regression analysis revealed albumin/alkaline phosphatase and tumor size to be significant parameters for prognosis (p=0.033, p=0.043, respectively). A multivariate Cox regression analysis revealed that none of the parameters were predictive or OS.Conclusion:The parameters of 18F-FDG PET/CT, especially the volumetric parameters, were found to be strong prognostic factors with statistical significance for predicting PFS. We believe that these parameters are important prognostic markers that should be evaluated together in the management and follow-up of patients with EGFR mutation-positive adenocarcinoma.

Importance of the Duration of TKI Treatment in Treatment-Free Remission of Chronic Phase Chronic Myeloid Leukemia: Results of D-Free Trial

Importance of the Duration of TKI Treatment in Treatment-Free Remission of Chronic Phase Chronic Myeloid Leukemia: Results of D-Free Trial

Outcomes of paediatric patients with B-cell acute lymphocytic leukaemia with ABL-class fusion in the pre-tyrosine-kinase inhibitor era: a multicentre, retrospective, cohort study

ABL-class fusion genes other than BCR-ABL1 have been identified in approximately 3% of children with newly diagnosed acute lymphocytic leukaemia, and studies suggest that leukaemic cells carrying ABL-class fusions can be targeted successfully by tyrosine-kinase inhibitors. We aimed to establish the baseline characteristics and outcomes of paediatric patients with ABL-class fusion B-cell acute lymphocytic leukaemia in the pre-tyrosine-kinase inhibitor era. This multicentre, retrospective, cohort study included paediatric patients (aged 1-18 years) with newly diagnosed ABL-class fusion (ABL1 fusion-positive, ABL2 fusion-positive, CSF1R fusion-positive, and PDGFRB fusion-positive) B-cell acute lymphocytic leukaemia enrolled in clinical trials of multidrug chemotherapy done between Oct 3, 2000, and Aug 28, 2018, in which tyrosine-kinase inhibitors had not been given as a first-line treatment. Patients from 14 European, North American, and Asia-Pacific study groups of the Ponte di Legno group were included. No patients were excluded, and patients were followed up by individual study groups. Through the Ponte di Legno group, we collected data on the baseline characteristics of patients, including IKZF1, PAX5, and CDKN2A/B deletion status, and whether haematopoietic stem cell transplantation (HSCT) had been done, as well as treatment outcomes, including complete remission, no response, relapse, early death, and treatment-related mortality, response to prednisone, and minimal residual disease (MRD) at end of induction therapy. 5-year event-free survival and 5-year overall survival were estimated by use of Kaplan-Meier methods, and the 5-year cumulative incidence of relapse was calculated by use of a competing risk model. We identified 122 paediatric patients with newly diagnosed ABL-class fusion B-cell acute lymphocytic leukaemia (77 from European study groups, 25 from North American study groups, and 20 from Asia-Pacific study groups). 64 (52%) of 122 patients were PDGFRB fusion-positive, 40 (33%) were ABL1 fusion-positive, ten (8%) were CSF1R fusion-positive, and eight (7%) were ABL2 fusion-positive. In all 122 patients, 5-year event-free survival was 59·1% (95% CI 50·5-69·1), 5-year overall survival was 76·1% (68·6-84·5), and the 5-year cumulative incidence of relapse was 31·0% (95% CI 22·4-40·1). MRD at the end of induction therapy was high (≥10-2 cells) in 61 (66%) of 93 patients, and most prevalent in patients with ABL2 fusions (six [86%] of 7 patients) and PDGFRB fusion-positive B-cell acute lymphocytic leukaemia (43 [88%] of 49 patients). MRD at the end of induction therapy of 10-2 cells or more was predictive of an unfavourable outcome (hazard ratio of event-free survival in patients with a MRD of ≥10-2vs those with a MRD of <10-2 3·33 [95% CI 1·46-7·56], p=0·0039). Of the 36 (30%) of 119 patients who relapsed, 25 (69%) relapsed within 3 years of diagnosis. The 5-year cumulative incidence of relapse in 41 patients who underwent HSCT (17·8% [95% CI 7·7-31·3]) was lower than in the 43 patients who did not undergo HSCT (45·1% [28·4-60·5], p=0·013), but event-free survival and overall survival did not differ between these two groups. Children with ABL-class fusion B-cell acute lymphocytic leukaemia have poor outcomes when treated with regimens that do not contain a tyrosine-kinase inhibitor, despite the use of high-risk chemotherapy regimens and frequent HSCT upon first remission. Our findings provide a reference for evaluating the potential benefit of first-line tyrosine-kinase inhibitor treatment in patients with ABL-class fusion B-cell acute lymphocytic leukaemia. The Oncode Institute, Pediatric Cancer Foundation Rotterdam, Dutch Cancer Society, Kika Foundation, Deutsche Krebshilfe, Blood Cancer UK, Associazione Italiana per la Ricerca sul Cancro, Cancer Australia, National Cancer Institute, National Institute of Health, and St Baldrick's Foundation.

Complex ALK Fusions Are Associated With Better Prognosis in Advanced Non-Small Cell Lung Cancer.

BackgroundEchinoderm microtubule-associated protein-like 4 (EML4) is the canonical anaplastic lymphoma kinase (ALK) fusion partner in non-small cell lung cancer (NSCLC), and ALK-positive patients showed promising responses to ALK tyrosine kinase inhibitors (TKIs). However, studies that comprehensively investigate ALK TKI treatment in patients with different ALK fusion patterns are still lacking.MethodsNinety-eight ALK-positive patients with advanced NSCLC were retrospectively studied for their response to crizotinib and subsequent treatments. Comprehensive genomic profiling (CGP) was conducted to divide patients into different groups based on their ALK fusion patterns. Non-canonical ALK fusions were validated using RNA-sequencing.Results54.1% of patients had pure canonical EML4-ALK fusions, 19.4% carried only non-canonical ALK fusions, and 26.5% harbored complex ALK fusions with coexisting canonical and non-canonical ALK fusions. The objective response rate and median progression-free survival to crizotinib treatment tended to be better in the complex ALK fusion group. Notably, patients with complex ALK fusions had significantly improved overall survival after crizotinib treatment (p = 0.012), especially when compared with the pure canonical EML4-ALK fusion group (p = 0.010). The complex ALK fusion group also tended to respond better to next-generation ALK TKIs, which were used as later-line therapies. Most identified non-canonical ALK fusions were likely to be expressed in tumors, and some of them formed canonical EML4-ALK transcripts during mRNA maturation.ConclusionOur results suggest NSCLC patients with complex ALK fusions could potentially have better treatment outcomes to ALK TKIs therapy. Also, diagnosis using CGP is of great value to identify novel ALK fusions and predict prognosis.

The Impact of Renal Impairment on Survival Outcomes in Patients With Metastatic Renal Cell Carcinoma Treated With Tyrosine Kinase Inhibitors.

Purpose:It remained unclear whether tyrosine kinase inhibitors (TKIs) related renal impairment had impact on the survival of patients with metastatic renal cell carcinoma (mRCC).Methods:Clinicopathological parameters of patients with mRCC treated with TKIs were retrospectively reviewed. Blood urea nitrogen (BUN), proteinuria and estimated glomerular filtration rate (eGFR) at baseline and during TKIs treatment were recorded. BUN > 7.1mol/L, eGFR <60 ml/min/1.73m2 and/or proteinuria level > 0.3 g/L were defined as renal impairment. eGFR and proteinuria were furtherly classified into different levels. Treatment outcomes were defined as progression-free survival (PFS) and overall survival (OS).Results:At baseline, the presence of abnormal BUN, eGFR and proteinuria level were observed in 25 (22.7%), 27 (25.5%) and 30 (27.3%) patients, which increased to 46 (41.8%), 55 (50.0%) and 64 (58.2%) respectively after TKIs treatment. In the whole cohort (N = 110), survival analysis suggested that only post-treatment renal impairment was related to survival outcomes. Interestingly, sub-analysis showed that post-treatment eGFR level (p = 0.004), proteinuria (p = 0.014) and eGFR decrease >10% (p = 0.012) and elevated proteinuria compared with baseline (p = 0.006) were statistically correlated with OS among patients without RI at baseline (N = 51). On the contrary, deterioration of renal impairment after TKIs treatment in patients with renal impairment at baseline (N = 59) had no relationship with either PFS or OS. Furthermore, eGFR (p = 0.020) and eGFR decrease >10% (p = 0.016) within 1 year after TKIs therapy were potential biomarkers for OS.Conclusion:Dynamic changes of TKI-induced RI during TKIs treatment, especially eGFR and proteinuria level, could be considered as potential biomarkers predicting survival outcomes of mRCC patients.

A sensitive QPCR assay for EGFR mutation in plasma samples of NSCLC patients.

2595 Background: Tyrosine kinase inhibitors (TKI) have improved the overall outlook and quality of life for most of EGFR mutation positive NSCLC patients. However, tumor tissues are often absent or insufficient for testing EGFR mutations to guide EGFR TKIs treatment of patients with nonsmall cell lung cancer (NSCLC). An assay that detects EGFR mutations in the plasma would provide a noninvasive technique to assess suitability for TK inhibitor therapy. The ACCB new EGFR Mutation Kit is a ARMS-PCR test for the qualitative detection of 45 mutations in exons 18, 19, 20, and 21 of the EGFR gene in DNA derived from human plasma from NSCLC patients. Methods: 10 mL tubes of blood were collected from patients who never had been treated by EGFR TKI, and plasma circulating tumor DNA were extracted from plasma by Biomark Circulating DNA Kit. Qubit 2.0 Fluorometer was used to make plasma circulating DNA tumor quantitation. The concentration of final DNA sample is ≦2ng/μl. Total, 272 plasma DNA samples from 246 lung adenocarcinoma, 23 lung squamous carcinoma and 3 lung adenosquamous carcinoma patients were collected. 104 paired tissue EGFR mutations were detected by the same kit. Results: EGFR mutation was detected in 88 from 272 plasma DNA samples, 86 lung adenocarcinoma, 1 lung squamous carcinoma, 1 lung adenosquamous carcinoma, with EGFR mutation rate were 35.0% (86/246), 4.3% (1/23), 33.3% (1/3) respectively. In 61 Ⅰ~Ⅲ and 211 Ⅳ stage NSCLC patients, EGFR mutation rate were 21.3% (13/61) and 35.5% (75/211) respectively. Conclusions: The ACCB new EGFR Mutation Kit is a sensitive, accurate, rapid, and reproducible assay capable of testing DNA extracted from human plasma from NSCLC patients.

EGFR mutation testing in blood for guiding EGFR tyrosine kinase inhibitor treatment in patients with nonsmall cell lung cancer

Epidermal growth factor receptor (EGFR) mutation testing in tumor tissue is now a common practice in selecting non-small cell lung cancer (NSCLC) patients for EGFR tyrosine kinase inhibitor (TKI) treatment. However, tumor tissues are often absent or insufficient for the testing. Blood is a potential substitute providing a noninvasive, easily accessible and repeatedly measureable source of genotypic information. However which is the best blood EGFR mutation testing method remains unclear. We undertake this study to investigate the best blood EGFR mutation testing method for selecting EGFR TKI treatment in patients with NSCLC. This study was registered in PROSPERO (CRD42017055263). PubMed, EMBASE, Cochrane library, and NIHR Health Technology Assessment program will be searched. Studies fulfill the following criteria will be eligible: (1) randomized controlled trials or cohort studies; (2) included patients with NSCLC; (3) reported response, progression-free survival, or overall survival for EGFR TKI by the EGFR mutation status in blood sample. Diagnostic accuracy of blood EGFR mutation tests for predicting response to TKI will be pooled. Tumor response, progression-free survival, and overall survival according to different blood EGFR mutation testing methods will be evaluated and compared. Based published data and combined analysis, this study will quantitatively compare the blood EGFR mutation testing methods according to their accuracy for predicting treatment response and relationship with clinical outcome in NSCLC patients treated with EGFR TKIs. This protocol will determine the best blood EGFR mutation testing method.

Blood as a Substitute for Tumor Tissue in Detecting EGFR Mutations for Guiding EGFR TKIs Treatment of Nonsmall Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Tumor tissues are often absent or insufficient for testing epidermal growth factor receptor (EGFR) mutations to guide EGFR tyrosine kinase inhibitors (TKIs) treatment of patients with nonsmall cell lung cancer (NSCLC). We conducted this systematic review and meta-analysis to assess whether blood can be used as a substitute for tumor tissue in detecting EGFR mutations. MEDLINE, EMBASE, and the Cochrane Library were searched for studies that provided data to estimate the accuracy of blood testing against tissue testing in NSCLC patients and/or those directly compared the efficacy of EGFR TKIs in EGFR mutant and wild-type patients according to sources of specimens. Sensitivity, specificity, and concordance rate were used as measures of the accuracy. Risk ratio (RR) for objective response and hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS) were used as measures for treatment efficacy. We combined the effects by using the fixed-effects model unless there was evidence of heterogeneity, in which case a random-effects mode was used. This systematic review included 25 studies with 2605 patients. The pooled overall sensitivity, specificity, and concordance rate were 0.61, 0.90, and 0.79, respectively. Serum showed lower sensitivity (0.56 vs 0.65) but higher specificity (0.95 vs 0.85) and higher concordance (0.86 vs 0.74) than plasma. EGFR mutations (exon 19 or 21) in blood were significantly associated with objective response (RR: 4.08; 95% confidence interval [CI] 2.48-6.70), PFS (HR: 0.72; 95% CI 0.64-0.80), and OS (HR: 0.71; 95% CI 0.50-0.99). Importantly, the association of the mutations with the 3 clinical outcomes for serum was similar to that for tumor tissue and higher than that for plasma. Blood, in particular serum, is a good substitute when tumor tissue is absent or insufficient for testing EGFR mutations to guide EGFR TKIs treatment in patients with NSCLC. EGFR mutation positivity in blood could be used to recommend EGFR TKIs treatment, but the absence of blood positivity should not necessarily be construed with confirmed negativity.

Patient Preferences for Stopping Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

Abstract 4274 Introduction:After the introduction of tyrosine kinase inhibitors (TKIs), chronic myeloid leukemia (CML) became the first cancer with a medical treatment that affords patients a normal lifespan. First-line treatment includes one of the three approved TKIs with regular molecular monitoring. Several reports have described individuals stopping imatinib and remaining in complete molecular response (CMR). There are currently several ongoing randomized clinical trials evaluating the safety of stopping TKI treatment in patients with a sustained CMR. In 2010 the preliminary results from the STIM (STop IMatinib) trial (Mahon, Lancet Oncology), were published. Results showed that 38% of patients had a sustained CMR after 2 years off TKI treatment and the remaining 62% who relapsed responded to restarting their previous TKI treatment. As this research will potentially influence clinical practice in the near future, we aimed to explore patient reactions, preferences and risk acceptability of stopping TKI treatment. With that in mind we conducted an interview-assisted survey of CML patients seen at a single tertiary care centre. Methods:We included CML patients with cytogenetic and molecular Ph+ chromosome confirmation currently being treated with a TKI. Patients were approached during regular follow-up appointments. A survey was conducted through structured interviews using a standard form. Patients’ preferences were explored through a case-based scenario using Visual Analog Scales ranging from 0 to 100% or 5-point Likert scales ranging from “absolutely stop” (1) to “absolutely not stop” (5). A trained interviewer asked the survey questions and was able to clarify questions that were unclear to the participant. Data was analyzed using proportions for dichotomous variables and medians and interquartile ranges for continuous variables. 95% confidence intervals for the proportions were calculated using the normal approximation interval. Results:Interviews were conducted between June and August 2012 at the London Regional Cancer Program (LRCP) in London, Ontario. 38 out of 40 (95%) CML patients approached completed the survey. Mean age of participants was 51 years old and 47% were male. 37% of participants had not finished high school and another 37% had completed college/university/trade school. Participants had a diagnosis of CML for an average of 50 months prior to enrollment. The majority (21/38 participants, 55%) were taking imatinib, with 11 (29%) on nilotinib and 6 (16%) on dasatinib. 71% (95% CI ± 14%) of the participants said that taking their medications daily was “simple and easy and they were able to remember 100% of the time.” 26% reported daily side effects while 24% reported never experiencing side effects from their TKI. 79% (95% CI ± 13%) of the participants said that they have never considered stopping the drug based on the side effects that they experience. 61% of participants responded that fear of the disease going out of control keeps them taking their TKI (95% CI ± 16%), whereas 34% responded that it is their doctor’s strong recommendation that motivates them (95% CI ± 15%). When asked what risk of relapse after stopping the TKI they would be willing to accept the median response was a 25% relapse rate (interquartile range 20–50). When responding to the same question after informing the participant that all patients have responded to restarting TKIs the median response increased to a 35% relapse rate (interquartile range 20–60). When given a relapse rate of 20% and a likert scale ranging from “absolutely stop” to “absolutely not stop,” the median response was “likely stop” with the 25th and 75th interquartile ranges being “absolutely stop” and “likely not stop” respectively. When the published relapse rate of 60% was given, however, the median was “likely not stop” with the 25th interquartile range at “neutral to stopping” and 75thinterquartile range at “absolutely not stop.” Discussion:This data suggests that the majority of participants perceive little difficulty with taking their TKI regularly and have never considered stopping it. Two major determinants on participant's decisions are fear of the disease going out of control and their physician's influence. Further, with the published rate of relapse after stopping TKI treatment the majority of individuals would choose to continue taking their medications for CML. Disclosures:Lazo-Langner:LeoPharma: Honoraria; Pfizer: Honoraria. Hsia:Novartis: Participant in Advisory Board Other.

Comparison of clinical outcome of patients with non-small-cell lung cancer harbouring epidermal growth factor receptor exon 19 or exon 21 mutations

AimsDeletion of exon 19 of the epidermal growth factor receptor (EGFR) and mutation of exon 21 are the most common EGFR mutations and predict higher response to EGFR tyrosine kinase...

Cetuximab Monotherapy in Patients with Advanced Non-small Cell Lung Cancer After Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy

Therapeutic agents directed against the epidermal growth factor receptor (EGFR) signaling pathway have been effective in the treatment of non-small cell lung cancer (NSCLC). Cetuximab is a monoclonal antibody against the EGFR receptor with antitumor activity in NSCLC. This study evaluated the efficacy of cetuximab monotherapy after prior treatment with an oral EGFR tyrosine kinase inhibitor (TKI). Eligible patients had stage IIIB, IV, or recurrent NSCLC with progression on the oral EGFR TKIs gefitinib or erlotinib. Cetuximab was administered intravenously at 400 mg/m on day 1 and then 250 mg/m weekly until disease progression or unacceptable toxicity. The primary end point was response rate. Eighteen patients were enrolled. Patients were heavily pretreated with chemotherapy and TKIs (average number of treatments = 4.2). The response rate was 0/18 (0%), and 28% of patients had confirmed stable disease. Median progression-free survival was 1.8 months (95% confidence interval, 1.6-5.4 months), and median overall survival was 7.5 months (95% confidence interval, 2.2-19 months). Three patients harbored activating EGFR mutations, and one of them had stable disease for nearly 6 months on cetuximab. Common toxicities were mild and included fatigue, skin rash, and nausea/vomiting. Two patients developed interstitial lung disease, life threatening in one case. Cetuximab monotherapy administered after prior EGFR TKI treatment in patients with advanced NSCLC does not yield clinical responses.