Citations

Abstract Precision oncology is the practice of interpreting the clinical significance of observed molecular changes in patient neoplasms, potentially impacting medical decision making and care. This process is labor-intensive and (among other challenges) involves accurately translating between variation representation conventions from one resource to the next. For example, differences in representations of Copy Number Variation (CNV) from genomic regions, cytogenomic bands, or gene features create challenges in knowledge matching due to lack of standards covering all of these modalities of observed variation.The Global Alliance for Genomics and Health (GA4GH; ga4gh.org) is an international collaborative of genomic data sharing initiatives (Driver Projects) developing genomic data sharing standards within a human rights framework. GA4GH recently published the Variation Representation Specification (VRS; pronounced “verse”), a standard for the computational representation of biomolecular variation. VRS is a terminology, schema, and associated conventions for creating uniquely identifiable and federatable representations of molecular variation. VRS has formal data classes well-suited to differentiating between variation on a single molecule (e.g. tandem duplications) from variation measured at a systemic level (e.g. genome-wide copy number variation). In addition to molecular sequence variation, VRS also supports variation on cytogenetic coordinate systems and genes, making it well-suited to representing variation associated with cancer biomarkers.We demonstrate the use of VRS to model reported gene-associated CNVs from the AACR Project GENIE cohort, to aid in the computational discovery of evidence from clinico-genomic knowledgebases with genomic or cytogenomic CNV representations. We highlight the use case of knowledge matching to the Atlas of Genetics and Cytogenetics in Oncology and Haematology (“the Atlas”; atlasgeneticsoncology.org), a cytogenetics resource historically driven by user website navigation. Using VRS search tools we developed for the Variant Interpretation for Cancer Consortium (VICC; cancervariants.org) GA4GH Driver Project, we found that 64% of GENIE samples with reported CNVs matched clinically relevant knowledge in the Atlas. This work was enabled by programmatic search tools leveraging standard VRS object structures, demonstrating how VRS enables collection of real-world evidence across more resources without manual interpretation or custom normalization methods. We conclude with a survey of open-source tools supporting this analysis as well as search of other clinico-genomic knowledgebases with VRS, including CIViC (civicdb.org), BRCA Exchange (brcaexchange.org), and the Molecular Oncology Almanac (moalmanac.org). Citation Format: Matthew Cannon, Kori Kuzma, James Stevenson, Jiachen Liu, Colin O'Sullivan, Bimal P. Chaudhari, Matthew Brush, Robert R. Freimuth, Tristan Nelson, Michael Baudis, Obi L. Griffith, Malachi Griffith, Lawrence Babb, Melissa S. Cline, Xuelu Liu, Brian Walsh, Alex H. Wagner. Introduction of the GA4GH Variation Representation Specification (VRS) and supporting tools for discovery and exchange of clinical genomic and cytogenomic knowledge in cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1177.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non–Small Cell Lung Cancer (NSCLC) provide recommended management for patients with NSCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. Patients with metastatic lung cancer who are eligible for targeted therapies or immunotherapies are now surviving longer. This selection from the NCCN Guidelines for NSCLC focuses on targeted therapies for patients with metastatic NSCLC and actionable mutations.

Background & Goals: Diet may contribute to symptoms of irritable bowel syndrome (IBS) and luminal production of putative IBS biomarkers including short-chain fatty acids (SCFAs). Study aims were to to assess relationships of habitual fiber or starch intake with fecal SCFAs in patients with IBS and healthy volunteers (HVs). Study: In 18 HVs and 30 patients with IBS (13 constipation-predominant [IBS-C] and 17 diarrhea-predominant [IBS-D]), habitual diet using a food frequency questionnaire; bowel functions using a validated bowel diary; and fecal SCFAs by HPLC-mass spectrometry were assessed. Associations of fiber and starch with SCFAs were analyzed using Spearman (r s ) and Pearson (R) correlations. Relationships between other dietary endpoints, SCFAs, and bowel functions were explored. Results: Habitual fiber or starch intakes were not significantly correlated with SCFAs or bowel functions in all participants or HVs nor with SCFAs in IBS. Starch was negatively correlated (R=−0.53; P=0.04) with complete evacuation in IBS-D. Fiber (r s =0.65; P=0.02) and starch (r s =0.56; P=0.05) were correlated with ease of passage in IBS-C. Stool form, frequency, and ease of passage were positively correlated with total SCFAs (all P<0.05), acetate (all P<0.01), propionate (all P<0.05), and butyrate (form P=0.01; ease of passage P=0.05) among all participants, but not in IBS. Complete evacuation was negatively correlated with propionate (R=−0.34; P=0.04) in all participants. Total (P=0.04) and individual SCFAs (all P<0.05) were positively correlated with stool form in HVs. Conclusions: Habitual fiber and starch intake does not influence fecal SCFAs but may influence bowel functions in IBS. Fecal SCFAs correlate with bowel functions among all participants including HVs.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non–Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines regarding targeted therapies, immunotherapies, and their respective biomarkers.

The NCCN Guidelines for Non–Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates in immunotherapy. For the 2020 update, all of the systemic therapy regimens have been categorized using a new preference stratification system; certain regimens are now recommended as “preferred interventions,” whereas others are categorized as either “other recommended interventions” or “useful under certain circumstances.”

29 Background: CRS-207 is a live, attenuated, double-deleted Listeria monocytogenes (LADD) engineered to stimulate immune response to mesothelin. In a phase I trial of 60 MPM patients, 34% of subjects had tumor reduction (range -1 to -47%) following 2 doses of CRS-207 alone. In KEYNOTE-028 pembro showed activity in PDL1+ (≥1% by IHC) MPM, with an objective response rate (ORR) of 20% (5/25) and stable disease in 52% of subjects who had failed or did not receive chemotherapy. Subsequent studies of pembro have shown similar results in MPM. Results from a pre-clinical murine lung tumor model (CT26hMeso) showed anti-PD-1 enhanced LADD-induced tumor response. The study described here evaluated the efficacy of combination therapy of CRS-207/pembro. Methods: Adults with epithelial/biphasic MPM, ≤2 prior lines, progression on pemetrexed and platinum-based therapy, and no prior immunotherapies were enrolled. CRS-207/pembro were administered IV Q3W for 4 cycles, after which pembro continued Q3W and CRS-207 changed to Q6W. Response was assessed Q6W by modified RECIST for MPM (Byrne and Nowak, 2004). The primary endpoint was ORR; secondary endpoints included DOR, disease control rate (DCR), progression-free survival (PFS) and overall survival. Pre- and on-treatment blood and tumor samples were collected. Shedding and blood clearance of CRS-207 were evaluated. Results: 9/10 subjects were evaluable for response. No responses were observed; DCR was 11% (1/9 with SD) and PFS ranged from 3.4 to 8.9 weeks. Most common treatment related adverse events were chills, pyrexia and nausea. 3/10 subjects evaluated were PDL-1 negative by IHC. Of 6 subjects who underwent clearance and shedding evaluation, CRS-207 was detected in blood in 1 at 18-24 hrs after the first CRS-207 dose and cleared by the next evaluation at Day 4; shedding samples (urine, fecal, and saliva) tested negative. Conclusions: The toxicity profile of CRS-207/pembro combination was consistent with the safety profile of each component alone. No evidence of clinical activity was observed. Based on the results and an overall evaluation of the program, the clinical development of CRS-207 was discontinued. (NCT01675765) (NCT02054806). Clinical trial information: NCT03175172.