To broaden access to and implementation of precision medicine in the care of patients with pancreatic cancer, the Know Your Tumor (KYT) program was initiated using a turn-key precision medicine system. Patients undergo commercially available multiomic profiling to determine molecularly rationalized clinical trials and off-label therapies. Tumor samples were obtained for 640 patients from 287 academic and community practices covering 44 states. College of American Pathologists/Clinical Laboratory Improvement Amendments-accredited laboratories were used for genomic, proteomic, and phosphoprotein-based molecular profiling. Tumor samples were adequate for next-generation sequencing in 96% and IHC in 91% of patients. A tumor board reviewed the results for every patient and found actionable genomic alterations in 50% of patients (with 27% highly actionable) and actionable proteomic alterations (excluding chemopredictive markers) in 5%. Actionable alterations commonly found were in DNA repair genes ( or mutations, 8.4%) and cell-cycle genes ( or alterations, 8.1%). A subset of samples was assessed for actionable phosphoprotein markers. Among patients with highly actionable biomarkers, those who received matched therapy ( = 17) had a significantly longer median progression-free survival (PFS) than those who received unmatched therapy [ = 18; PFS = 4.1 vs. 1.9 months; HR, 0.47; 95% confidence interval (CI): 0.24-0.94; = 0.03]. A comprehensive precision medicine system can be implemented in community and academic settings, with highly actionable findings observed in over 25% of pancreatic cancers. Patients whose tumors have highly actionable alterations and receive matched therapy demonstrated significantly increased PFS. Our findings support further prospective evaluation of precision oncology in pancreatic cancer. .

Recent improvements in next-generation sequencing (NGS) technology have enabled detection of biomarkers in cell-free DNA in blood and may ultimately replace invasive tissue biopsies. However, a better understanding of the performance of blood-based NGS assays is needed prior to routine clinical use. As part of an IRB-approved molecular profiling registry trial of pancreatic ductal adenocarcinoma (PDA) patients, we facilitated blood-based NGS testing of 34 patients from multiple community-based and high-volume academic oncology practices. 23 of these patients also underwent traditional tumor tissue-based NGS testing. cfDNA was not detected in 9/34 (26%) patients. Overall concordance between blood and tumor tissue NGS assays was low, with only 25% sensitivity of blood-based NGS for tumor tissue NGS. Mutations in KRAS, the major PDA oncogene, were only detected in 10/34 (29%) blood samples, compared to 20/23 (87%) tumor tissue biopsies. The presence of mutations in circulating DNA was associated with reduced overall survival (54% in mutation-positive versus 90% in mutation-negative). Our results suggest that in the setting of previously treated, advanced PDA, liquid biopsies are not yet an adequate substitute for tissue biopsies. Further refinement in defining the optimal patient population and timing of blood sampling may improve the value of a blood-based test.

Objectives Scalable informatics solutions that provide molecularly tailored treatment recommendations to clinicians are needed to streamline precision oncology in care settings. Materials and Methods We developed a cloud-based virtual molecular tumor board (VMTB) platform that included a knowledgebase, scoring model, rules engine, an asynchronous virtual chat room and a reporting tool that generated a treatment plan for each of the 1725 patients based on their molecular profile, previous treatment history, structured trial eligibility criteria, clinically relevant cancer gene-variant assertions, biomarker-treatment associations, and current treatment guidelines. The VMTB systematically allows clinician users to combine expert-curated data and structured data from clinical charts along with molecular testing data to develop consensus on treatments, especially those that require off-label and clinical trial considerations. Results The VMTB was used as part of the cancer care process for a focused subset of 1725 patients referred by advocacy organizations wherein resultant personalized reports were successfully delivered to treating oncologists. Median turnaround time from data receipt to report delivery decreased from 14 days to 4 days over 4 years while the volume of cases increased nearly 2-fold each year. Using a novel scoring model for ranking therapy options, oncologists chose to implement the VMTB-derived therapies over others, except when pursuing immunotherapy options without molecular support. Discussion VMTBs will play an increasingly critical role in precision oncology as the compendium of biomarkers and associated therapy options available to a patient continues to expand. Conclusion Further development of such clinical augmentation tools that systematically combine patient-derived molecular data, real-world evidence from electronic health records and expert curated knowledgebases on biomarkers with computational tools for ranking best treatments can support care pathways at point of care.

214 Background: The activation of the RAS/RAF/MEK/ERK pathway is critical for the proliferation, survival, and tumorigenesis of PDACs. Oncogenic mutations in KRAS (90%) or BRAF (3%) are recurrent genomic alterations, but their co-occurrence is not well described. We reviewed BRAF alterations and clinical outcomes in consecutive PDAC patients (pts). Methods: Perthera, Inc. deploys an IRB-approved registry that was utilized in partnership with PanCAN’s “Know Your Tumor” program. Perthera uses CAP/CLIA accredited multi-Omic profiling, including next generation DNA sequencing (NGS, Foundation Medicine) and proteomics/immunohistochemistry (Neogenomics Inc. and Caris Life Sciences, Inc.). We used a Fisher's exact test with multiple testing correction to compare frequencies of mutations and protein over-/under-expression between BRAF-mutated (n = 21) and BRAF wild type pts (n = 745). Results: Of 766 pancreatic cancer pts, 21 pts were identified with BRAF mutations. 18 pts were diagnosed with PDAC, 1 pancreatoblastoma, 1 pancreatic acinar cell carcinoma, and 1 mixed acinar neuroendocrine carcinoma. Amongst the 18 PDAC pts with BRAF mutations, nine variations were found: V600E (5/18), BRAF fusion (4/18), N486_P490del (3/18), T310I (1/18), K601N (1/18), G596R (1/18), exon 2-10 deletions & S467L (1/18), equivocal amplification of BRAF (1/18), and a BRAF inframe deletion (1/18). KRAS was mutated in 6% of BRAF mutated PDACs, compared to 94% in BRAF wild type PDACs (p < 0.001). Amongst KRAS wild type PDACs, 53% of CDKN2A mutated pts had BRAF mutations vs. only 15% of CDKN2A wild type cases (p < 0.05). Two BRAF mutated pts from the database were given BRAF inhibitors. A sustained response to the combination dabrafenib and trametinib was observed in a BRAF V600E mutated PDAC pt, while no response was seen in a pt with concurrent KRAS G12A & BRAF K601N mutations who received trametinib. Conclusions: BRAF mutations are significantly and inversely correlated with KRAS alterations. The most common BRAF alteration, V600E mutation, was found to be mutually exclusive with the KRAS mutation. Clinical trials targeting BRAF alterations in KRAS wild type pancreatic cancer appears warranted.

No abstract

BACKGROUND: Molecular profiling is increasingly used to match patients with metastatic cancer to targeted therapies, but obtaining a high-quality biopsy specimen from metastatic sites can be difficult. METHODS: Patient samples were received by Perthera to coordinate genomic, proteomic and/or phosphoproteomic testing, using a specimen from either the primary tumour or a metastatic site. The relative frequencies were compared across specimen sites to assess the potential limitations of using a primary tumour sample for clinical decision support. RESULTS: No significant differences were identified at the gene or pathway level when comparing genomic alterations between primary and metastatic lesions. Site-specific trends towards enrichment of MYC amplification in liver lesions, STK11 mutations in lung lesions and ATM and ARID2 mutations in abdominal lesions were seen, but were not statistically significant after falsediscovery rate correction. Comparative analyses of proteomic results revealed significantly elevated expression of ERCC1 and TOP1 in metastatic lesions. CONCLUSIONS: Tumour tissue limitations remain a barrier to precision oncology efforts, and these real-world data suggest that performing molecular testing on a primary tumour specimen could be considered in patients with pancreatic adenocarcinoma who do not have adequate tissue readily available from a metastatic site.

No abstract

Anomalous origin of the left coronary artery from the pulmonary artery is a rare but important cause of congestive heart failure in infancy and of sudden death at all ages. Diagnosis is often missed when based solely on physical examination and noninvasive methods. A 4 year old patient is presented in whom mitral regurgitation was noted by a referring physician and an anomalous left coronary artery was found by Doppler color flow mapping upon referral and verified at cardiac catheterization. Doppler color flow mapping was also used intraoperatively using a gas-sterilized transducer to further clarify the hemodynamics and assess the surgical result. After creation of an intrapulmonary artery tunnel from the ostium of the left coronary artery to the aorta, anterograde coronary artery flow and absence of a residual left to right pulmonary artery shunt were verified during surgery by Doppler flow mapping. Postoperatively, residual mitral regurgitation and patency of the left coronary artery graft have been followed up serially by Doppler flow mapping. Therefore, Doppler color flow mapping is useful in the diagnosis and intraoperative and postoperative management of this important and potentially life-threatening abnormality.