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. Author manuscript; available in PMC: 2019 May 15.
Published in final edited form as: Clin Cancer Res. 2017 Dec 21;24(10):2241–2250. doi: 10.1158/1078-0432.CCR-16-3169

Table 4.

Selected Blood-Based Biomarker Studies

Blood based biomarker Reference Disease Stage (Number) Biomarker Collection Time Point Assay Key Results and Application
cfDNA Takai et al., 2015(52) Resectable (108)
LA (44)
Metastatic: (107)		 Pre-treatment KRAS ddPCR, NGS Detection:

  • Resectable: 8.3%

  • LA: 18.2%

  • Metastatic: 58.9%

Predictive:

  • 29.2% (14/48) with targeted sequencing had potential therapeutic target gene
Sausen et al., 2015(50) Resectable (51; 9 longitudinal) Pre-resection, multiple post-resection timepoints KRAS dPCR, NGS Detection:

  • Resectable 43%

Monitoring:

  • mDFS by ctDNA 3.1 months vs 9.6 by CT imaging

Predictive:

  • 38% with clinically applicable mutations

  • 6% with FDA approved agent
Zill et al., 2015(68) 26 hepatobiliary (18 PDAC)
23/26 metastatic		 54 gene NGS sequencing panel - tumor and cfDNA Tumor genome surrogate:

  • 90% of tumor mutations in cfDNA

  • One of 7 most common mutations identified in 89% of samples

  • 7/9 tumor biopsies with insufficient sample for analysis had ctDNA mutations found
Lee et al., 2017(48) Stage 1 (7), Stage 2 (99), Stage 3 (8), Stage 4 (5) Diagnosis, post-resection NGS Detection:

  • Stage 1: 42.9%, Stage 2: 54.5%, Stage 3: 50%, Stage 4: 100%

Prognosis:

  • Post-resection ctDNA associated with poorer OS (mOS 8 months, HR 6.93, p=0.006)
Del Re et al., 2017(69) LA (4), Metastatic (23) Day 0, 14, CT KRAS ddPCR Detection: 70.3%
Predictive:

  • ctDNA increase at d14 vs stable/decrease (mPFS: 2.5 vs 7.5 months, p = 0.03; mOS: 9 vs 11.5 months p = 0.009)

  • All increased ctDNA progressed on next imaging
Exosomes
Madhavan et al. (2015)(70) Pancreas Cancer (131), CP (25), BPT (22), non PC tumor (12), HC (30) Immunoaffinity (anti-CD44v6, anti-Tspan8, anti-EpCAM and anti-CD104)
qRT-PCR: miR-1246, miR-4644, miR-3976 and miR-4306		 Detection:

  • Sensitivity 100%

  • Specificity 80% (93% when non-PC malignancies removed)
San Lucas et al. (2015)(71) Metastatic (2; 1 blood, 1 pleural fluid) 1 pre-treatment, 1 POD ddPCR, WGS Pre-clinical:

  • 56–82% tumor fraction in exosomal DNA by ddPCR

  • 95–99% of targeted genome covered in exosomal DNA
Melo et al. (2015)(72) Discovery: Stage I (2), IIa (19), IIb (117), III (11), IV (41)
Validation: Stage I (2); IIa (15), IIb (35), IV (3)		 Pre-/post-resection, pre-chemotherapy Glypican-1 Detection:

  • Sensitivity: 100%

  • Specificity: 100%

  • AUC 1.0

Prognosis:

  • Mean bead bound GPC1 level:

    • Metastatic 58.5%

    • Nodal 50.5%

    • Local 39.9%

  • Post-resection GPC-1 reduction:

    • Low reduction OS 15.5 months

    • Greater reduction OS 26.2 months
Allenson et al, 2017(73) Discovery: Local (33), LA (15), Metastatic (20), HC (54)
Control:
Validation: Local (39), HC (82)		 Pre-/post-resection, exoDNA and cfDNA KRAS ddPCR Detection:

  • Discovery: exoDNA vs cfDNA

    • Local: 66.7% vs 45.5%

    • LA: 80% vs 30.8%

    • HC: 7.4% vs 14.8%

    • Post-resection 5% vs 0%

  • Validation:

    • Local: 43.6%

HC: 20.7%
CTCs
de Albuquerque et al, 2012(74) Stage II (4); III (2); IV (28), HC (40) Pre-treatment Anti-MUC1 and anti-EPCAM immunocapture followed by RT-PCR of KRT19, MUC1, EPCAM, CEACAM5, BIRC5 Detection:

  • 47.1%

Prognosis:

  • CTC positive vs negative mPFS 66 days vs 138 (p=0.01)
Hong et al, 2012(75) Multiple solid malignancies treated with dasatinib (30, 17% PDAC) Pre-treatment, day 8, day 28 CellSearch Predictive:

  • SD >=6 months/PR vs all others:

  • Day 1 to 28 mean CTC count change, −0.92 vs 1.61 (p=0.123)

Mean CTC count/7.5 mL at day 28, 0.5 vs 3.85, p=0.052)
Yu et al, 2014(53) Metastatic (50) Pre-treatment collagen adhesion matrix cell invasion assay; Gene expression based pharmacogenomic model Predictive:

  • Predicted sensitive/intermediate/resistant

  • mPFS: 10.4/7.8/3.6 months (p<0.0001)

mOS: 17.2/13.8/8.3 months (P<0.0304)
Okubo et al, 2017(76) Borderline Resectable (9), metastatic (56) Pre-treatment, under treatment (mean 3 months) CellSearch Detection:

  • 32.3%

Predictive:

  • 45.4% with PD had CTC detected at 3 months vs 24.1% with SD or PR detected at 3 months

  • 2 PD, 4 SD in increased CTC count patients vs 4 SD, 1PR in decreased CTC patients

AUC: area under the curve, CP: chronic pancreatitis, CT: computed tomography, ddPCR: digital droplet PCR, HC: healthy control, IPMN: intrapapillary mucinous neoplasm, LA: locally advanced, mDFS: mean disease-free survival, NED: no evidence of disease, NET: neuroendocrine tumor, NGS: next generation sequencing, OS: overall survival, PD: progression of disease, PR: partial response, PV: portal venous, SD, stable disease, SV: systemic venous, WES: whole exome sequencing