Abstract C66: Pilot study of CLIA enabled integrated whole genome (WGS)/exome (WES)/transcriptome (RNAseq) next-gen sequencing to identify therapeutically relevant targets in advanced cancer patients.

Background: Next-Generation sequencing has revolutionized genomic assessment of cancer and is being increasingly applied in the clinical setting to guide prognostic and therapeutic decision-making. Time to reporting of results, specimen quantity, analyte quality, and ethical-legal-social issues (ELSI) have constrained initial clinical applications to gene panels and whole exome based strategies. Methods: Patients who consented to participate underwent resections, excisional or core biopsies or bone marrow biopsies, followed by fresh frozen tumor/normal nucleic acid extraction, WGS/WES/RNASeq on the Illumina HiSeq2000 or HiSeq2500, bioinformatics analysis and therapeutic target prioritization by a multi-disciplinary Clinical Genomics Board (CGB). All prioritized targets were CLIA validated using Sanger sequencing, RT-qPCR, FISH or IHC as appropriate. Treatment was delivered using on/off-label FDA approved drugs, available clinical trials and single patient INDs. Results: We have enrolled 34 patients with advanced, treatment-refractory cancers [age(yrs): median 59, range 27-91; male/female (62%/38%); ECOG score: 1(92%), 2(4%), 4(4%); tumor type: pancreatic (26%), biliary (24%), multiple myeloma (6%), other (47%): uterine/cervical, NSCLC, mesothelioma, gastric, renal, bladder, testicular, basal cell, melanoma, laryngeal]. Sequencing data is available on 34 patients (WGS/WES/RNASeq [n=23], WGS/RNASeq [n=2], WGS/WES [n=2], WES/RNASeq [n=3] and WGS only [n=4]). The initial 6 patients were evaluated in a non-CLIA pilot phase and 28 in the CLIA enabled phase. Targets of putative therapeutic relevance (total: 44, targets/patient: range 1-4), were prioritized by the CGB in 22 out of 28 patients (79%) for CLIA validation. Time to initial report was 86 days (range 34-143) and time to CLIA validated results 106 days (range 79-152). CLIA validation was achieved in 21 of 22 patients. Genomic, target directed treatment was ultimately instituted in 10 patients [death prior to intended treatment (n=2), death prior to availability of results (n=3), inability to access treatment (n=1) and decision to pursue alternate therapy (n=6)] and preliminary clinical efficacy was noted in 4 patients (2 PR, 2 SD>4 month). Multiple mechanisms of drug access were utilized (on/off label FDA approved drugs [n=8], clinical trial [n=1] and single patient IND [n=1]). Conclusions: Integrated whole genome analysis in a CLIA setting is feasible. Integration of SNV, copy number and transcriptional data may allow for selection of putative driver genes to enhance targeted therapy decisions. Barriers for future broader implementation include need for shorter time to reporting and availability of therapies. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C66. Citation Format: Mitesh Borad. Pilot study of CLIA enabled integrated whole genome (WGS)/exome (WES)/transcriptome (RNAseq) next-gen sequencing to identify therapeutically relevant targets in advanced cancer patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C66.