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.
Finally, myeloid leukocytic cells accumulate genetic alterations during aging similar to those found in myelodysplasia and acute myeloid leukemia. These myeloid-associated mutations can be detected in both tumor and cfDNA samples and are known as clonal hyperplasia of indeterminate potential (CHIP). CHIP is much more common in the cfDNA. For lung cancer, CHIP-associated gene variants are readily distinguished from lung cancer-associated variants, but that distinction is much more difficult in many other tumor types.
In partnership with the current DNA sequencing contractor, NPOP provides access to a second gene panel for hematologic malignancies or sarcomas, though neither of these classes of malignancies currently have clear indications for routine NGS multigene panel testing. Given the low rate of finding a gene mutation that would change therapy that could not be found with smaller, less expensive gene panels, NPOP requires prior approval for the use of this panel.
Finally, since early 2019, programmed deathligand 1 (PD-L1) immunohistochemistry analysis is available through NPOP in association with NGS testing of the same sample for those solid tumors with US Food and Drug Administration (FDA)-approved indications that include a PD-L1 companion diagnostic. This service was added to facilitate concurrent testing of PD-L1 and DNA sequencing, which speeds availability of molecular data to the health care provider and veteran.
Determining Clinical Significance
The complexity of tumor NGS gene panel test results is far greater than frequently ordered laboratory or molecular testing due to the near infinite number of possible results and varying degrees of consensus of the significance of the results for therapeutic decision making. That complexity is reflected in the length of the test reports, which are often ≥ 20 pages. Starting from the gene variants identified by the DNA sequencing variant-caller bioinformatics pipeline, there is a 2-step process, referred to as annotation, to interpret the clinical significance that is repeated for each variant.
The first step is to assign a pathogenicity value, also known as oncogenicity, using a 5-point Likert scale from pathogenic to benign with variant of unknown significance (VUS) in the middle of the scale. Only variants that are pathogenic or likely pathogenic are considered further. A VUS is usually communicated to the health care provider but should generally not be acted on, while benign and likely benign variants may or may not be included in the report and should never be acted on. NPOP examined the concordance of pathogenicity calls among 3 annotation services: N-of-One/QCI Precision Insights (qiagen.com), IBM Watson for Genomics (WfG), and OncoKB (www.oncokb.org).6 There was moderate-to-poor concordance, indicating lack of consensus about whether a significant fraction of observed gene variants contributes to the patient’s cancer. This variability likely arises due to differences in algorithms and criteria used to assess pathogenicity.
