Clinical utility of tumor genomic profiling in patients with high plasma circulating tumor DNA burden or metabolically active tumors

Abstract

Background: This retrospective study was undertaken to determine if the plasma circulating tumor DNA (ctDNA) level and tumor biological features in patients with advanced solid tumors affected the detection of genomic alterations (GAs) by a plasma ctDNA assay.

Method: Cell-free DNA (cfDNA) extracted from frozen plasma (N = 35) or fresh whole blood (N = 90) samples were subjected to a 62-gene hybrid capture-based next-generation sequencing assay FoundationACT. Concordance was analyzed for 51 matched FoundationACT and FoundationOne (tissue) cases. The maximum somatic allele frequency (MSAF) was used to estimate the amount of tumor fraction of cfDNA in each sample. The detection of GAs was correlated with the amount of cfDNA, MSAF, total tumor anatomic burden (dimensional sum), and total tumor metabolic burden (SUVmax sum) of the largest ten tumor lesions on PET/CT scans.

Results: FoundationACT detected GAs in 69 of 81 (85%) cases with MSAF > 0. Forty-two of 51 (82%) cases had ≥ 1 concordance GAs matched with FoundationOne, and 22 (52%) matched to the National Comprehensive Cancer Network (NCCN)-recommended molecular targets. FoundationACT also detected 8 unique molecular targets, which changed the therapy in 7 (88%) patients who did not have tumor rebiopsy or sufficient tumor DNA for genomic profiling assay. In all samples (N = 81), GAs were detected in plasma cfDNA from cancer patients with high MSAF quantity (P = 0.0006) or high tumor metabolic burden (P = 0.0006) regardless of cfDNA quantity (P = 0.2362).

Conclusion: This study supports the utility of using plasma-based genomic assays in cancer patients with high plasma MSAF level or high tumor metabolic burden.

Trial registration: ClinicalTrials.gov NCT02620527.

Keywords: Cell-free DNA (cfDNA); Circulating tumor DNA (ctDNA); Genomic alterations (GAs); Maximum somatic allele frequency (MSAF); Maximum standardized uptake value (SUVmax); Next-generation sequencing (NGS); Plasma; Positron emission tomography (PET) scan.

Fig. 1

Study schema. This study included 125 consecutive patients with locally advanced or metastatic solid tumors who underwent FoundationACT testing between November 17, 2015, and April 17, 2017. Among 90 patients with available FoundationACT reports, 81 patients had no interval treatment and ¹⁸F-FDG PET/CT scans performed at our institution within 45 days of blood sampling for imaging quantification analyses. The concordance rate of GA detection between 51 matched FoundationACT and FoundationOne cases was calculated and further analyzed for NCCN-recommended molecular targets in 42 patients

Fig. 2

Genomic alterations (GAs) and concordance of NCCN-recommended molecular targets detected by both FoundationACT and FoundationOne assays in 42 patients with advanced solid tumors. GAs in base substitutions (A), insertions or deletions (B), amplifications (C) or rearrangements (D) detected in patients with detectable ctDNA (i.e., MSAF > 0) are shown. Concordant/shared GAs are in blue, GA found only in tissue are in red, and GA found only in ctDNA are in pink. Genes that were only included in tissue (FoundationOne) were shaded in gray. Red color highlights the NCCN-recommended test genes, and red box highlights the NCCN-recommended molecular targets

Fig. 3

MSAF is a valid tool for quantifying the tumor fraction of cfDNA. A representative case showing MSAF was a better tool than cfDNA and SUVmax to correlate with clinical response when the patient had non-infectious, immune-related pneumonitis. A Schema of the clinical course. B Radiographic evaluation: a 67-year-old Caucasian male, former four pack-year smoking history (quit 20 years ago), presented with refractory, lung squamous cell carcinoma (i). The patient developed non-productive cough and shortness of breath after three doses of nivolumab monotherapy and was found to have biopsy-proven, new tumor formation in right lower lobe as well as grade 3 pneumonitis in bilateral lung fields (ii) [46]. However, notable tumor shrinkage at several pre-existing tumors was observed. Blood drawn at 10 weeks later before the initiation of high dose steroids revealed non-detectable ctDNA (i.e., MSAF zero) (iii). Despite discontinuation of nivolumab and use of steroids for over 2 months for symptomatic pneumonitis, continued tumor response to a complete remission was evident by radiographic assessment by ~ 3 months (iv), which has been maintained at 9 months (v) and a recent 3-year follow-up (data not shown). C Quantitative analysis of biomarkers and clinical responses were summarized in table

Fig. 4

Factors affect the detection of GAs in FACT assay. Comparison of MSAF, tumor anatomic burden, and tumor metabolic burden in relation to the detection of GAs (0 vs ≥ 1) in patients with fresh blood samples (a, c, and e) and all sample group (b, d, and f). Each bar demonstrates a mean ± SD. P < 0.05 by two-sample t test is considered statistically significant