VA National Precision Oncology Program
Background: The US Department of Veterans Affairs (VA) is the largest integrated health care system in the US. The VA sees about 50,000 new cancer diagnoses each year and provides care for more than 400,000 veterans with cancer. The heterogeneity of molecular testing practice patterns and methods of testing at VA health care facilities and the increasing number and complexity of molecular tests led to the development of national program for precision oncology.
Observations: The National Precision Oncology Program (NPOP) provides tumor sequencing and consultative services for the treatment of veterans with cancer. NPOP is used by nearly all VA oncology practices and has now sequenced > 13,000 samples. The initial focus was on advanced-stage nonsquamous non-small cell lung cancer, which has one of the highest number of mutated genes that result in sensitivity to antineoplastic drugs. Recently, testing was expanded to include metastatic prostate cancer and hematologic malignancies with prior approval. The program also offers cell-free DNA (liquid biopsy) and PD-L1 immunohistochemistry analyses.
Conclusions: The VA NPOP is one of the largest clinical DNA sequencing programs in the US with integrated consultation services and health informatics resources to facilitate patient care, clinical trials, and health outcomes research. The clinical services of NPOP provide cutting-edge oncology services to veterans throughout VA without exacerbating disparities and will be a national resource for research.
The second step of annotation is assignment of the actionability of the variant, using a level of evidence (LoE) scale from 1 (on-label indication) to 4 (absence of clinical evidence; ie, only preclinical or theoretical evidence). Initially, NPOP used an adaptation of the LoE scales from WfG and OncoKB but now mostly uses the recently revised OncoKB LoE. Actionability also includes prediction of resistance to a treatment (LoE level R1 and R2). An example of a resistance gene variant is a KRAS mutation in colorectal cancer, which predicts lack of clinical benefit from anti- EGFR antibodies. It is important to note that a determination of actionability requires 3 inputs: gene, variant, and tumor type. A BRAF V600E mutation in melanoma has different medications with level 1 LoE than does the same mutation in colorectal cancer, for example.
Another complexity in annotation for actionability is tumor type ontogeny—the classification system used for cancer types. WfG uses a subset of the National Cancer Institute Thesaurus (ncithesaurus.nci.nih.gov), OncoKB uses the unique OncoTree (oncotree.mskcc.org), and Foundation Medicine (www.foundationmed icine.com), and N-of-One use propriety classification systems. The WfG and OncoKB tumor types have evolved over time, while it is unclear what changes have been made in the FMI and N-of-One tumor type classification systems. Thus, a gene variant observed in a single patient may be annotated differently by these services because of how the tumor type is mapped onto the services’ tumor type ontogeny. NPOP has been assigning WfG diagnoses since 2017, including historic assignment for prior samples back to the pilot project in 2015. In early 2019, NPOP began requiring test requesters to include International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) diagnoses (histology and site codes) with the sample. ICD-O-3 codes are used in all cancer registry data in North America, including the VA Cancer Registry System. The approximately 50,000 possible diagnoses allow fine precision in diagnoses, which is important for less common and rare cancer types; however, the large number of diagnoses adds complexity. NPOP has created a partial translation table for ICD-O-3 to WfG diagnosis that includes all diagnoses seen to date; this table facilitates continuing provision of WfG diagnosis without manual review as was previously required.
NPOP-Provided Genetic Services
Given these complexities in interpretation of NGS multigene panel results, NPOP provides several services to assist health care providers and other members of the care team. First, the NPOP Interfacility Consult (IFC) is a virtual “phone-a-friend” service that provides asynchronous patient-specific expert recommendations in precision oncology. By far the most requested service is assistance with interpretation of a patient’s DNA sequence results. Other requests include advice on whether to perform NGS testing and what molecular testing to perform. The IFC is integral to the VA Computerized Patient Record System electronic health record. Additional requests have been submitted and answered by e-mail.
The Molecular Oncology Tumor Board is a monthly case-based educational conference supported by the VA Employee Education Service, which provides continuing education credits for attendees. NPOP staff coordinate the conference, and a panel of specialists from around the country provide expert commentary.
In 2016, IBM gifted the services of WfG to VA. WfG’s main functionality is annotation of NGS results. About 5,000 samples were processed from 2017 to 2019; sample processing is expected to resume shortly. The availability of WfG annotations early in NPOP operation was very useful to the implementation of NPOP in general and the NPOP consultation services in particular, resulting in improved thoroughness of opinions provided by NPOP staff.
