Dual Tissue and Plasma Testing Improves Detection of Actionable Variants in Patients With Solid Cancers

ASCO 2022 Presentation
Authors MacKay, Matthew, Nicholas Mitsiades, Young Chae, Andrew Davis, Philip Lammers, James Maher, Dan Theodorescu, Peter Rubin, Timothy Pluard, Langer, Lee, Manghnani, Kabir, Ben-Shachar, Rotem, Kim Blackwell, Chen, James L, Joel Dudley, Guinney, Justin, Wade Iams

Background: Next generation sequencing (NGS) of tumor tissue and plasma (circulating
tumor DNA [ctDNA]) are used clinically to identify actionable genomic alterations, with
implications for treatment selection and disease surveillance. Early studies have observed that
solid tumor tissue and ctDNA testing may capture both overlapping and complementary
alterations. Using the Tempus database, we examined whether dual tissue and ctDNA testing,
“dual testing”, improved identification of actionable variants compared with either modality

Methods: We used Tempus Lens to retrospectively analyze 3153 de-identified stage 4 patients
(breast [N=644], colorectal [N=841], non-small cell lung cancer (NSCLC) [N=1232], and prostate
[N=436]). Each patient had dual testing—Tempus xF (ctDNA, 105 panel genes) and Tempus xT
(tumor tissue, 595-648 panel genes), representing 6306 total samples. Samples were defined
as concurrent if biopsied ≤30 days apart and longitudinal if plasma was collected between
31–365 days after tissue biopsy. All analyses were limited to single nucleotide variants and
insertions/deletions that met the limit of detection criteria for both assays (104 genes). Indication
matched actionable variants were defined by OncoKB Level 1 and 2 evidence, or R1 within both
xF and xT (13 genes).

Results: Of the 3153 patients with dual testing, 37% (1168) had actionable variants identified by
at least one test. 94% (1100/1168) of these patients had variants identified via solid tumor
profiling alone, 73% (856) had variants identified via ctDNA profiling alone, and 64% (745) had
perfectly concordant variants. Thus, dual testing identified additional variants in 36% (423/1168)
of these patients compared to any singular test.
Of the 423 patients who had additional actionable alterations discovered through dual testing,
ctDNA revealed unique alterations—which were not found in solid tissue testing—in 22%
(95/423) of patients. Of these patients, 72% (68/95) had all actionable variants identified solely
from ctDNA. Of the 251 patients with additional alterations identified by concurrent dual testing,
24% (61/251) had unique alterations identified in plasma. Similarly, of the 172 patients with
additional alterations identified by longitudinal dual testing, 20% (34/172) had unique alterations
identified in ctDNA alone.

Conclusions: In the largest study of its kind, we show that dual tumor tissue and ctDNA testing—with
samples collected either concurrently or longitudinally—identified more patients with actionable
alterations than single modality testing alone and therefore should be considered as part of
routine NGS testing. Additional studies to explore the genetic and intra-patient tumor
heterogeneity of these variants as well as the impact of time between tissue and plasma
sampling assessments and implications for timing of therapeutic recommendations are