Clinical Implementation of Integrated Genomic Profiling in Patients with Advanced Cancers.

Borad MJ1,2,3, Egan JB4, Condjella RM5, Liang WS6, Fonseca R7,5,4, Ritacca NR5, McCullough AE8, Barrett MT5,6, Hunt KS7, Champion MD4,9, Patel MD10, Young SW10, Silva AC10, Ho TH7,5,4, Halfdanarson TR7,5,4, McWilliams RR4,11, Lazaridis KN4, Ramanathan RK7,5, Baker A6, Aldrich J6, Kurdoglu A6, Izatt T6, Christoforides A6, Cherni I6, Nasser S6, Reiman R6, Cuyugan L6, McDonald J6, Adkins J6, Mastrian SD6, Valdez R8, Jaroszewski DE12, Von Hoff DD6, Craig DW6, Stewart AK7,5,4, Carpten JD6, Bryce AH7,5,4.

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Abstract

DNA focused panel sequencing has been rapidly adopted to assess therapeutic targets in advanced/refractory cancer. Integrated Genomic Profiling (IGP) utilising DNA/RNA with tumour/normal comparisons in a Clinical Laboratory Improvement Amendments (CLIA) compliant setting enables a single assay to provide: therapeutic target prioritisation, novel target discovery/application and comprehensive germline assessment. A prospective study in 35 advanced/refractory cancer patients was conducted using CLIA-compliant IGP. Feasibility was assessed by estimating time to results (TTR), prioritising/assigning putative therapeutic targets, assessing drug access, ascertaining germline alterations, and assessing patient preferences/perspectives on data use/reporting. Therapeutic targets were identified using biointelligence/pathway analyses and interpreted by a Genomic Tumour Board. Seventy-five percent of cases harboured 1-3 therapeutically targetable mutations/case (median 79 mutations of potential functional significance/case). Median time to CLIA-validated results was 116 days with CLIA-validation of targets achieved in 21/22 patients. IGP directed treatment was instituted in 13 patients utilising on/off label FDA approved drugs (n = 9), clinical trials (n = 3) and single patient IND (n = 1). Preliminary clinical efficacy was noted in five patients (two partial response, three stable disease). Although barriers to broader application exist, including the need for wider availability of therapies, IGP in a CLIA-framework is feasible and valuable in selection/prioritisation of anti-cancer therapeutic targets.