Tumor Sequencing Research Articles

An initiative to increase referrals for germline testing after tumor sequencing.

413 Background: Tumor sequencing (TS) represents an opportunity to detect hereditary cancer syndromes (HCS), as HCS may be identified or suspected from TS results. Detecting HCS can affect patient treatment and allow genetic testing of relatives. Our institution noted low numbers of referrals for germline genetic testing (GGT) following TS. A quality improvement project assessed current practices and barriers for referring patients with TS findings suspicious for HCS, with the goal of building an initiative to increase referrals for this indication. Methods: Oncologists’ input was sought via two Qualtrics surveys and semi-structured interviews. We asked about demographics, familiarity with TS reports and guidelines about when to recommend follow-up GGT, TS result review workflows, cancer genetics referral practices, preferences for receiving education/updates on cancer genetics, and perceived ability to contact genetics providers. A current state process map and root cause analysis were developed based on findings. Results: Responses identified several barriers to GGT referral based on TS results. Provider-related issues included uncertainty about what TS findings necessitate referral, discrepancies in results return workflows, low priority of GGT in the care plan, absence of guidance from genetics providers, and being uncertain how to consult providers with expertise in GGT. System-level concerns included lack of integration of lab results into the electronic medical record and difficulties scheduling cancer genetics appointments. Patients may also decline referral. Provider-level concerns were seen as the most readily addressable. We used survey/interview findings to design an initiative. Most oncologists prefer to receive information on this topic from cancer genetics clinic providers (79%) and identified email (79%) and presentations at tumor boards (71%) as preferred methods for delivery. A brief presentation, tip sheet, and frequently asked questions document focused on addressing topics identified by our survey/interviews were developed. Provider education is being delivered at tumor boards with written resources provided by email. Conclusions: There are many reasons why patients with potential germline findings on TS may not be referred for GGT despite its value in patient care. We developed an educational initiative for oncologists based on survey/interview findings with the aim of increasing referrals for GGT following TS. Referral trends will be monitored to assess effectiveness of this initiative.

Analyzing Precision Medicine Utilization with Real-World Data: A Scoping Review.

Precision medicine (PM), specifically genetic-based testing, is currently used in over 140,000 individual tests to inform the clinical management of disease. Though several databases (e.g., the NIH Genetic Testing Registry) demonstrate the availability of these sequencing-based tests, we do not currently understand the extent to which these tests are used. There exists a need to synthesize the body of real-world data (RWD) describing the use of sequencing-based tests to inform their appropriate use. To accomplish this, we performed a scoping review to examine what RWD sources have been used in studies of PM utilization between January 2015 and August 2021 to characterize the use of genome sequencing (GS), exome sequencing (ES), tumor sequencing (TS), next-generation sequencing-based panels (NGS), gene expression profiling (GEP), and pharmacogenomics (PGx) panels. We abstracted variables describing the use of these types of tests and performed a descriptive statistical analysis. We identified 440 articles in our search and included 72 articles in our study. Publications based on registry databases were the most common, followed by studies based on private insurer administrative claims. Slightly more than one-third (38%) used integrated datasets. Two thirds (67%) of the studies focused on the use of tests for oncological clinical applications. We summarize the RWD sources used in peer-reviewed literature on the use of PM. Our findings will help improve future study design by encouraging the use of centralized databases and registries to track the implementation and use of PM.

Assessment of Tumor Sequencing as a Replacement for Lynch Syndrome Screening and Current Molecular Tests for Patients With Colorectal Cancer

Universal tumor screening for Lynch syndrome (LS) in colorectal cancer (CRC) is recommended and involves up to 6 sequential tests. Somatic gene testing is performed on stage IV CRCs for treatment determination. The diagnostic workup for patients with CRC could be simplified and improved using a single up-front tumor next-generation sequencing test if it has higher sensitivity and specificity than the current screening protocol. To determine whether up-front tumor sequencing (TS) could replace the current multiple sequential test approach for universal tumor screening for LS. Tumor DNA from 419 consecutive CRC cases undergoing standard universal tumor screening and germline genetic testing when indicated as part of the multicenter, population-based Ohio Colorectal Cancer Prevention Initiative from October 2015 through February 2016 (the prospective cohort) and 46 patients with CRC known to have LS due to a germline mutation in a mismatch repair gene from January 2013 through September 2015 (the validation cohort) underwent blinded TS. Sensitivity of TS compared with microsatellite instability (MSI) testing and immunohistochemical (IHC) staining for the detection of LS. In the 465 patients, mean age at diagnosis was 59.9 years (range, 20-96 years), and 241 (51.8%) were female. Tumor sequencing identified all 46 known LS cases from the validation cohort and an additional 12 LS cases from the 419-member prospective cohort. Testing with MSI or IHC, followed by BRAF p.V600E testing missed 5 and 6 cases of LS, respectively. Tumor sequencing alone had better sensitivity (100%; 95% CI, 93.8%-100%) than IHC plus BRAF (89.7%; 95% CI, 78.8%-96.1%; P = .04) and MSI plus BRAF (91.4%; 95% CI, 81.0%-97.1%; P = .07). Tumor sequencing had equal specificity (95.3%; 95% CI, 92.6%-97.2%) to IHC plus BRAF (94.6%; 95% CI, 91.9%-96.6%; P > .99) and MSI plus BRAF (94.8%; 95% CI, 92.2%-96.8%; P = .88). Tumor sequencing identified 284 cases with KRAS, NRAS, or BRAF mutations that could affect therapy for stage IV CRC, avoiding another test. Finally, TS identified 8 patients with germline DPYD mutations that confer toxicity to fluorouracil chemotherapy, which could also be useful for treatment selection. Up-front TS in CRC is simpler and has superior sensitivity to current multitest approaches to LS screening, while simultaneously providing critical information for treatment selection.

Tumor relevant germline findings in targeted tumor sequencing using matched normal DNA of 1,570 unselected cases.

1509 Background: Tumor Sequencing (TS) can reveal presumed pathogenic germline variants (PPGV) that may be tumor-relevant (TR) and associated with tumorigenesis. Identification of PPGV may have sig...