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3579 Background: BRAFV600E ( BRAF) mutations (mts) portend poor prognosis in mCRC and patients (pts) may die before ascertainment. Since 2014, Vancouver Coastal Health (VCH) has performed reflex hereditary screening of CRCs with BRAF and mismatch repair (MMR) immunohistochemistry (IHC). We evaluated this BRAF mt population-based cohort ( BRAFPOP) to establish the true prognosis of BRAF mts in mCRC. Methods: We reviewed all mCRCs from VCH between 4/2014 and 5/2018 for BRAF by IHC (VE1 antibody). Overall survival (OS) from stage IV diagnosis was compared to mCRCs with next generation sequencing (NGS) determined BRAF mts ( BRAFNGS) from BC Cancer & MD Anderson. BRAFNGS OS did not differ by center (p = 0.77). Results: See table for BRAF cohort baseline characteristic comparison. BRAFPOP pts had worse OS than BRAFNGS pts (HR 2.5, 95% CI 1.6 – 3.9, P < 0.0001). Median OS for all BRAF mt pts was 17.9 mos. Both groups had worse OS than wild type pts (P < 0.0001). 52 (81%) of BRAFPOP pts were referred to oncology, 40 (63%) received chemotherapy, and 12 (19%) had NGS BRAF testing. BRAFPOP pts who had NGS testing with BRAF mts had OS comparable to other BRAFNGS pts (P = 0.89) and better OS than BRAFPOP pts that never had NGS testing (HR 0.37, 95% CI 0.18-0.76, P = 0.030). Pts with BRAF mts and MMR deficiency (dMMR) (n = 40) had worse OS than MMR proficiency (pMMR, n = 202) (1.6, 95% CI 1.0-2.5, P = 0.011). This was driven by BRAFPOP dMMR pts (HR 1.9, 95% CI 0.9-4.0, P = 0.036) as no difference was seen by MMR in BRAFNGS pts (HR 1.3, 95% CI 0.8-2.2, P = 0.30). Conclusions: Current estimates of prognosis for mCRC with BRAF mts likely underestimate its impact due to referral bias for NGS testing. BRAF mts with dMMR are associated with worse prognosis than pMMR. This appears driven by BRAFPOP pts. [Table: see text] more...

9080 Background: EGFR T790M testing is standard of care for EGFR mutant (EGFRm) NSCLC progressing on 1st/2nd generation TKIs to select patients for osimertinib. Circulating free DNA (cfDNA) levels are measured prior to circulating tumour DNA (ctDNA) testing using droplet digital PCR (ddPCR) to measure activating/resistant EGFR mutations. We reviewed cfDNA levels and ctDNA mutational status to determine the influence on patient outcome. Methods: Following extraction of cfDNA from plasma using the QIAamp Circulating Nucleic Acid Kit, cfDNA levels are measured with a Qubit 2.0 Fluorometer. Custom ddPCR assays were used to test for the appropriate EGFR activating mutation and the EGFR T790M resistance mutation using the Bio-Rad QX200 system. The custom designed ddPCR assays have a limit of detection of < 0.1% variant allele fraction. All patients undergoing ctDNA testing from February-December 2018 were identified. Baseline characteristics and follow up data were collected retrospectively. OS was calculated from date of metastatic diagnosis to death/last follow-up. Results: 142 patients with EGFR mutant adenocarcinoma had EGFR ctDNA testing: results 52% indeterminant, 32% T790M, 16% activating EGFRm only. At the time of testing: median age 66, 64% female, 57% never smokers 53% Asian; systemic treatment (tx) 62% first line only, 25% two lines and 13% ≥ three lines. First TKI therapy: 32% afatanib, 66% gefitinib, 2% erlotinib. Median cfDNA concentration was 5.65 ng/ml (range 0.50-217.72). The 5 yr OS was 72% below cfDNA median and 25% above the median. Tx after ctDNA testing for below and above cfDNA median: 52 vs 33% original TKI, 34 vs 55% osimertinib, 14 vs 12% other systemic tx. Multivariate analysis shows that even accounting for age, sex and ctDNA mutation result, cfDNA concentration remains an independent predictor of outcome (HR 2.36, 95% CI 1.08-5.18, p = 0.032). Conclusions: cfDNA concentration can predict patient outcome in patients with EGFR mutant NSCLC progressing on TKI regardless of ctDNA testing results. Clinicians may consider switching to chemotherapy for patients with high cfDNA and without detectable EGFR T790M ctDNA to avoid missing the window for therapy instead of awaiting repeat EGFR T790M testing more...

e13021 Background: Multi-gene panel tumour testing (TT) has been available in British Columbia since mid-2016 for metastatic non-small cell lung cancer (NSCLC), colorectal cancer (CRC), melanoma (MEL), low-grade glioma (LGG), and gastro-intestinal stromal tumours (GIST). TT can detect somatic driver mutations and potential pathogenic germline variants (pPGVs) associated with hereditary cancer susceptibility. We reviewed the frequency of pPGVs identified by TT and examined referral rates to the Hereditary Cancer Program (HCP) for confirmatory germline testing (GT) and therapeutic implications of PGV findings. Methods: All patients (pts) undergoing TT testing from October 1, 2016 to December 31, 2018 were identified. Diagnosis, age, gender, family history and treatment data were obtained. TT was performed by next-generation sequencing for all/selected regions of the following genes: AKT1, ALK, BRAF, BRCA1, BRCA2, CCND1, CCND3, CIC, EGFR, ERBB2, ERBB3, FUBP1, HRAS, IDH1, IDH2, KIT, KRAS, MAP2K1, MET, NRAS, PDGFRA, PIK3CA, PTEN, ROS1, SDHA, SDHB, SDHC, SDHD. Results: Among 2937 TTs, pPGVs were identified in 83 pts (2.8%) [Table 1]. 50 pts (57%) were referred to HCP, 41 had germline testing, and 14 PGV were confirmed. PGVs were most commonly identified in BRCA1/2 and SDHA and these findings did not influence oncologic treatments. Conclusions: TT detected pPGVs in 2.8% of unselected pts with metastatic cancers. Among 41 pts undergoing germline testing, 34% who would not have otherwise met testing criteria, had a confirmed PGV. Referral rates were low due to lack of patient and clinician awareness and poor health status. Although PGV findings did not directly impact treatment, TT identified 14 new families with hereditary cancer who can benefit from early detection and screening. Future directions include expansion of TT to include additional hereditary cancer susceptibility genes and development of digital tools for pts and clinicians. [Table: see text] more...

e13113 Background: The Personalized OncoGenomics (POG) project at the BC Cancer Agency utilizes tumor-normal whole genome sequencing (WGS) to understand key driver pathways and guide personalized treatment decisions. Analysis of the germline data can reveal variants; these may be presumed pathogenic, presumed benign or of unknown significance (VUS). We have developed a process for evaluating and returning presumed pathogenic variants in known cancer susceptibility genes to patients, for counseling and validation in a clinical-accredited laboratory. Methods: Patients receive germline cancer related information as part of the consent process for participation in the POG program. A sub-committee comprised of medical geneticists, bioinformaticians, pathologists, oncologists and an ethicist review the germline results. Any variants suspicious of being an artifact undergo a technical validation step. Presumed pathogenic findings of known cancer susceptibility genes are returned to the patient by their treating oncologist and patients are referred to the Hereditary Cancer Program (HCP), for genetic counseling and clinical confirmation. Results: From June 2012 - January 2017 – 466 patients have consented to the project. To date, 39 cases (8.4%) had at least one variant that was deemed pathogenic, 86 cases had at least one VUS in a known cancer susceptibility gene. 11 out of 23 cases (47.8%) with high penetrance mutations were already known to HCP. All VUS were reviewed by the sub-committee taking in to consideration the VUS and clinical context. 8 of the subjects with pathogenic results and 3 with VUS were known to HCP before POG data was generated. A VUS in 7 cases (1.5%) was returned after review. Conclusions: The number of pathogenic variants in known cancer susceptibility genes is consistent with published oncology results. We created a process to manage clinically relevant germline findings discovered during the course of genomic research to ensure appropriate care for patients. Genetic counseling within HCP and validation of variants in the clinically accredited Cancer Genetics Laboratory enables seamless return of research generated clinically relevant germline results to affected subjects. Clinical trial information: NCT02155621. more...

1582Background: ctDNA is a potentially superior means of classifying tumor genotype but predictors of Con with atDNA are not well established. We conducted a prospective multicenter study to determ... more...

TPS11136 Background: Lung cancer is the most common cause of cancer-related deaths in North America. A number of pharmaceutical firms currently have therapies that target ALK-driven lung cancers in... more...

8096 Background: ALK gene rearrangement (ALK+) has been found in 3-5% of advanced non-small cell lung cancer patients. FISH is considered the “gold standard” for identification of ALK+ tumors, but its cost-effectiveness and adoption as a screening assay has been debated. Recent reports suggested that ALK IHC may serve as an alternative screening or possibly a diagnostic method. In this context, CALK was initiated to assess the feasibility of implementing ALK IHC and/or FISH assays across Canadian hospitals. Methods: FISH-confirmed 22 ALK+ and 6 ALK- tumors were used as study samples. Unstained sections and scanned images of HE-stained slides from each tumor block were distributed to participating centres. IHC protocols with best signal to noise ratio using the 5A4 (Novocastra) or ALK-1 (Dako) antibodies were developed for various auto-stainers and implemented to suit the existing conditions of the participating centres. A common FISH protocol using the ALK break-apart probe (Abbott Molecular, Chicago, IL) was developed based on published reports. H-score was used to assess IHC. FISH signals were scored in 100 tumor cells/case by 2-3 pre-trained persons. A second round IHC study using newly distributed slides was completed by 8 centres. Results: Independent IHC scores from 12 centres and FISH scores from 11 centres were collected and analysed. The intraclass correlation coefficients (ICC) between centres for IHC and FISH were 0.84 and 0.68, respectively. Following the analysis of initial IHC results, a second round study resulted in improved ICC of 0.94. One of 23 tumors revealed IHC-/FISH+ discrepancy, with the FISH revealing unusual signal configurations that suggested an atypical rearrangement. However, the sensitivity and specificity of FISH results across centres using the 15 aberrant signals cut-off ranged from 86.7-100% and 100%, respectively. Conclusions: Standardization across multiple centres for ALK testing by IHC and FISH can be achieved. IHC detected all FISH+ ALK tumors, except for one discrepant case with atypical FISH finding of unknown clinical implication. The study was supported by a Pfizer Canada grant. more...

e18017 Background: Gefitinib was licensed in Canada for the first line treatment of advanced non-small cell lung carcinoma (NSCLC) patients with EGFR tyrosine kinase mutation. Methods: A Pan-Canadi... more...