Functional Brain Imaging with Multi-Objective Multi-Modal Evolutionary Optimization

Functional brain imaging is a source of spatio-temporal data mining problems. A new framework hybridizing multi-objective and multi-modal optimization is proposed to formalize these data mining problems, and addressed through Evolutionary Computation (EC). The merits of EC for spatio-temporal data mining are demonstrated as the approach facilitates the modelling of the experts' requirements, and flexibly accommodates their changing goals

The first Canadian experience with the Afirma® gene expression classifier test

Abstract Background Thyroid nodules are common and often benign, although prove to be malignant upon surgical pathology in 5–15% of cases. When assessed with ultrasound-guided fine-needle aspiration (USFNA), 15–30% of the nodules yield an indeterminate result. The Afirma® gene expression classifier (AGEC) was developed to improve management of indeterminate thyroid nodules (ITNs) by classifying them as “benign” or “suspicious.” Objectives were (1) to assess the performance of the AGEC in two Canadian academic medical centres (2), to search for inter-institutional variation and (3) to compare AGEC performance in Canadian versus American institutions. Methods We undertook a retrospective cohort study of patients with indeterminate cytopathology (Bethesda Class III or IV) as per USFNA who underwent AGEC testing. We reviewed patient demographics, cytopathological results, AGEC data and, if the patient underwent surgery, results from their final pathology. Results In total, we included 172 patients with Bethesda Class III or IV thyroid nodules underwent AGEC testing, 109 in Montreal, Quebec and 63 in St. John’s, Newfoundland, in this study. Among the nodules sent for testing, 55% (60/109) in Montreal and 46% (29/63) in St. John’s returned as “benign.” None of these patients underwent surgery. On the other hand, 45% (49/109) nodules in Montreal and 54% (34/63) in St. John’s were found to be “suspicious,” for a total of 83 specimens. Seventy seven of these patients underwent surgery. Both in Montreal and St. John’s, the final pathology yielded malignant thyroid disease in approximately 50% of the specimens categorized as “suspicious.” Since 2013, no patient diagnosed with a benign nodule as per AGEC testing was found to harbor a malignant thyroid nodule on follow-up. Conclusions Molecular analysis is increasingly used in the management of indeterminate thyroid nodules. This study highlights the experience of two Canadian centres with AGEC testing. We found inter-institutional variability in the rate of nodules returning as “benign,” however we found similar rates of confirmed malignancy in nodules returning as “suspicious.” According the literature, results for AGEC testing in two Canadian institutions align with results reported in American centres

Abstract 1009: Comprehensive ctDNA sequencing reveals mechanisms of resistance to rociletinib in EGFR T790M-mutated NSCLC

Abstract Background: First and second-generation EGFR tyrosine kinase inhibitors (TKIs) have benefited patients with EGFR-mutated non-small cell lung cancer (NSCLC), but resistance invariably develops after a median of 9-16 months. In ~60% of patients, resistance is mediated by a second mutation in EGFR, namely T790M. Hence, third-generation EGFR TKIs such as osimertinib and rociletinib were developed to target both activating EGFR mutations as well as T790M. Unfortunately, patients also develop resistance to these therapies through mechanisms that have not yet been thoroughly explored. Since repeat tissue biopsies pose potential complications from invasive procedures, circulating tumor DNA (ctDNA) testing is increasingly used in the clinical setting to identify potentially targetable mechanisms of resistance. Methods: Matched pre-treatment and progression plasma from 57 patients with EGFR-mutated NSCLC treated with rociletinib were profiled using a 70-gene ctDNA targeted next-generation sequencing panel (Guardant360) that detects somatic single nucleotide variants, short insertions and deletions, fusions, and copy number variants. Pre-treatment EGFR ctDNA allele fractions were also determined by BEAMing, a technique based on droplet digital PCR followed by flow cytometry. Pre-treatment tumor EGFR status was assessed by the therascreen EGFR test. Results: In all 57 pre-treatment samples profiled, plasma-based ctDNA analysis detected the initial EGFR driver and T790M resistance mutations that were identified in the matched tumor. Interestingly, we found that 12% (7/57) of patients had evidence of compound EGFR driver mutations at baseline, including E709A-L858R, K860I-L858R, and L718V-L858R. EGFR T790M mutations in plasma were observed subclonally (present on average at 40% of the allele fraction of the driver mutation), suggesting tumor heterogeneity at baseline. The correlation coefficients (r) between Guardant360 and BEAMing for EGFR L858R, Exon19Del, and T790M were 0.90, 0.92, 0.95, respectively. Upon progression on rociletinib, 5% of patients (3/57) developed the EGFR C797S resistance mutation, 5% (3/57) developed focal MET amplification, and 2% (1/57) developed a NTRK1 fusion that were not present in the matched baseline plasma. Additionally, 4 deleterious BRCA1/2 alterations (2 germline and 2 somatic) were identified, with the somatic alterations emerging at progression. In 14% (8/57) of the patients, mutations in genes involved in the RAS/RAF signaling pathway, including KRAS Q61H, KRAS K117N and NF1 Q1822*, emerged or increased at progression. Conclusions: Plasma ctDNA revealed heterogeneity and multiple mechanisms of resistance in rociletinib treated patients. Thus comprehensive ctDNA sequencing allows for the identification of potentially actionable alterations and may help inform the choice of next therapy for patients progressing on a third-generation EGFR TKI. Citation Format: Elena Helman, Andrew D. Simmons, Chris A. Karlovich, Thomas C. Harding, Mitch Raponi, Darya I. Chudova, Daniel A. Simon, Richard B. Lanman, AmirAli Talasaz. Comprehensive ctDNA sequencing reveals mechanisms of resistance to rociletinib in EGFR T790M-mutated NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1009. doi:10.1158/1538-7445.AM2017-1009</jats:p

Does Addition of BRAF

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