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Targeting EGFR is a validated approach in the treatment of squamous-cell cancers (SCCs), although there are no established biomarkers for predicting response. We have identified a synonymous mutation in EGFR, c.2361G [greater than] A (encoding p.Gln787Gln), in two patients with head and neck SCC (HNSCC) who were exceptional responders to gefitinib, and we showed in patient-derived cultures that the A/A genotype was associated with greater sensitivity to tyrosine kinase inhibitors (TKIs) as compared to the G/A and G/G genotypes. Remarkably, single-copy G [greater than] A nucleotide editing in isogenic models conferred a 70-fold increase in sensitivity due to decreased stability of the EGFR-AS1 long noncoding RNA (lncRNA). In the appropriate context, sensitivity could be recapitulated through EGFR-AS1 knockdown in vitro and in vivo, whereas overexpression was sufficient to induce resistance to TKIs. Reduced EGFR-AS1 levels shifted splicing toward EGFR isoform D, leading to ligand-mediated pathway activation. In co-clinical trials involving patients and patient-derived xenograft (PDX) models, tumor shrinkage was most pronounced in the context of the A/A genotype for EGFR-Q787Q, low expression of EGFR-AS1 and high expression of EGFR isoform D. Our study reveals how a 'silent' mutation influences the levels of a lncRNA, resulting in noncanonical EGFR addiction, and delineates a new predictive biomarker suite for response to EGFR TKIs., Author(s): Daniel S W Tan (corresponding author) [1, 2, 3]; Fui Teen Chong [1]; Hui Sun Leong [1]; Shen Yon Toh [1]; Dawn P Lau [1]; Xue Lin Kwang [1]; [...]

Background and Aim: Thiopurines are recommended for maintenance of steroid‐free remission (SFR) in inflammatory bowel disease (IBD). Thiopurine metabolite monitoring (MM) is increasingly used in the West but remains novel in Singapore, with limited information on its therapeutic and economic benefits. Hence, this study aims to investigate MM's clinical utility and its impact on healthcare resource utilization in Singaporean IBD patients. Methods: A retrospective observational study was conducted at Singapore General Hospital outpatient IBD Centre. Patients with IBD, baseline MM during 2014–2017, and weight‐based thiopurine doses for ≥4 weeks were followed up for 1 year. Actions were taken to optimize therapy, and metabolite levels before and after the first action were documented. Outcomes assessed included SFR, no therapy escalation or surgery, healthcare resource utilization, and direct healthcare costs. Results: Ninety IBD patients (50 Crohn's disease, 40 ulcerative colitis) were included. Among them, 40% had baseline metabolite levels within therapeutic range, 31.1% sub‐therapeutic, 21.1% supra‐therapeutic, and 7.8% shunters. Repeated MM with subsequent dose optimization helped 67.2% of patients achieve therapeutic levels after 1 year. Overall, 87.8% of patients achieved SFR and 90% had no therapy escalation or surgery. Despite greater outpatient visits and laboratory investigations with MM, the median total healthcare costs at 1 year only increased marginally (S$6407.66 [shunters] vs S$5215.20 [supra‐therapeutic] vs S$4970.80 [sub‐therapeutic] vs S$4370.48 [control (within therapeutic range)], P = 0.592). Conclusion: MM guided timely therapy escalation for non‐responders, identification of non‐adherence, and reversal of shunting. Therefore, it is a useful clinical tool to optimize thiopurines without significantly increasing healthcare costs. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors (TKIs) elicit high response rates among individuals with kinase-driven malignancies, including chronic myeloid leukemia (CML) and epidermal growth factor receptor-mutated non-small-cell lung cancer (EGFR NSCLC). However, the [...]

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and debilitating disease with limited therapeutic options. The aim of this clinical study was to evaluate the safety, efficacy and pharmacokinetics of a novel regimen comprised of metronomic oxaliplatin (O), chronomodulated capecitabine (X) and UGT1A1 genotype‐guided dosing of irinotecan (IRI) [OXIRI] as well as its immunomodulatory effects. Thirty‐six patients were enrolled into either dose‐escalation or expansion cohorts. In the dose escalation phase, capecitabine doses (2000, 2650, 3500 and 4500 mg/day) were administered at midnight on days 1 to 14 while oxaliplatin and irinotecan were intravenously infused at fixed doses of 50 and 75 mg/m2 respectively on days 1, 8 in a 21‐day cycle. The maximum tolerated dose of capecitabine was 2650 mg/day and the most common grade 3 adverse events were neutropenia (30.6%) and diarrhea (13.9%). No grade 4 toxicity was observed. UGT1A1‐genotype directed dosing resulted in similar exposure levels of irinotecan, SN‐38 and SN‐38G in all patients. Objective response rate was 22.2%. Median overall survival and progression‐free survival were 8.1 and 5.2 months, respectively. Exploratory immunoprofiling by flow cytometry and quantitative spatial localization analysis of infiltrated immune cells performed on biopsy and plasma samples revealed significant declines in CCL22, CCL2 and TNFα levels at end of first cycle and an active host immune response. Our study showed that OXIRI was well‐tolerated and exhibited good efficacy, with immunomodulatory effects. It may be considered as an alternative to FOLFIRINOX in patients intolerant to the latter. [ABSTRACT FROM AUTHOR]

Aim: This pilot study aimed to compare the pharmacokinetic profiles of oral (PO) and intravenous (IV) ibuprofen for treatment of patent ductus arteriosus (PDA) in preterm neonates. Methods: In a single‐centre, parallel, randomised open‐label trial, neonates ≤35 weeks, weight <1800 g with haemodynamically significant PDA during the first week of life were recruited between June 2017 and February 2019 and randomised to receive either PO or IV ibuprofen at standard dosage of 10, 5 and 5 mg/kg every 24 h for three consecutive days. Plasma concentrations of ibuprofen were quantified using a validated high‐performance liquid chromatography method and pharmacokinetic parameters were calculated. Treatment outcomes were recorded. Results: Eleven neonates participated in the trial, six and five patients receiving PO and IV ibuprofen, respectively. Pharmacokinetic analysis reveals similar ibuprofen exposure levels in treatment groups. Median dose‐ and weight‐normalised Cmax values of PO and IV groups were 2.12 and 2.53 g/mL respectively (P = 0.082) and median AUC0‐24 levels were comparable (PO: 34.6 g*h/mL vs. IV: 50.7.6 g*h/mL, P = 0.25). Conclusion: This exploratory study demonstrates comparable pharmacokinetics of PO and IV formulations of ibuprofen in preterm neonates. Larger prospective studies are required to validate these findings. [ABSTRACT FROM AUTHOR]

Endoxifen is one of the most important metabolites of the prodrug tamoxifen. High interindividual variability in endoxifen steady‐state concentrations (CSS,min ENDX) is observed under tamoxifen standard dosing and patients with breast cancer who do not reach endoxifen concentrations above a proposed therapeutic threshold of 5.97 ng/mL may be at a 26% higher recurrence risk compared with patients with endoxifen concentrations exceeding this value. In this investigation, 10 clinical tamoxifen studies were pooled (1,388 patients) to investigate influential factors on CSS,min ENDX using nonlinear mixed‐effects modeling. Age and body weight were found to significantly impact CSS,min ENDX in addition to CYP2D6 phenotype. Compared with postmenopausal patients, premenopausal patients had a 30% higher risk for subtarget CSS,min ENDX at tamoxifen 20 mg per day. In treatment simulations for distinct patient subpopulations, young overweight patients had a 3.1–13.8‐fold higher risk for subtarget CSS,min ENDX compared with elderly low‐weight patients. Considering ever‐rising obesity rates and the clinical importance of tamoxifen for premenopausal patients, this subpopulation may benefit most from individualized tamoxifen dosing. [ABSTRACT FROM AUTHOR]

Purpose: Prediction of impaired tamoxifen (TAM) to endoxifen metabolism may be relevant to improve breast cancer treatment, e.g., via TAM dose increase. The polymorphic cytochrome P450 2D6 (CYP2D6) strongly determines an individual's capacity for endoxifen formation, however, CYP2D6 phenotype assignments inferred from genotype widely differ between studies. Thus, we modeled plasma endoxifen predictability depending on variable CYP2D6 genotype groupings. Methods: CYP2D6 diplotype and metabolite plasma concentrations were assessed in 908 pre- and post-menopausal estrogen receptor (ER)-positive, TAM treated early breast cancer patients of Caucasian (N = 678), Middle-Eastern Arab (N = 77), and Asian (N = 153) origin. Robust coefficients of determination (R2) were estimated for endoxifen (E) or metabolic ratio endoxifen/desmethyl-TAM (E/DMT) as dependent and different CYP2D6 phenotype assignments as independent variables. Allele activity scores (ASs) were modified with respect to a reduced *10 allele activity. Predictability of endoxifen plasma concentrations above the clinical threshold of 5.9 ng/mL was investigated by receiver operating characteristic (ROC) analysis. Results: CYP2D6 diplotypes (N = 898) were strongly associated with E and E/DMT independent of age (P < 10-15). Across all ethnicities, 68-82% inter-patient variability of E/DMT was explained by CYP2D6 diplotype, while plasma endoxifen was predictable by 39-58%. The previously used codeine specific phenotype classification showed worse prediction for both endpoints particularly in Asians (median R2 < 20%; P < 10-9).Downgrading of *10 activity slightly improved the explanatory value of metabolizer phenotype (P < 0.002). Endoxifen plasma concentrations above the clinical threshold of 5.9 ng/mL were achieved in 82.3% of patients and were predictable (96% sensitivity, 57% specificity) by CYP2D6 diplotypes with AS > 0.5, i.e., omitting PM/PM and PM/IM patients. Conclusion: The CYP2D6 explanatory power for active drug level assessment is maximized by TAM-specific phenotype assignments while a genotype cutoff that separates PM/PM and PM/IM from the remaining patients may improve clinical benefit via increased endoxifen concentrations. [ABSTRACT FROM AUTHOR]