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. 2023 Feb 10;12(4):1438. doi: 10.3390/jcm12041438

Table 1.

The correlation between plasma ctDNA/cfDNA EGFR mutations and the efficacy and prognosis of EGFR-TKI targeted therapy in patients with NSCLC.

Reference (Year) Characteristics of Subjects n ctDNA/cfDNA Detection Method Prognostic Relevance
[28]
(2015)

  • ➢ Stage IIIB/IV

  • ➢ Deletion in exon 19 or L858R in exon 21 in the tumor

  • ➢ No prior chemotherapy for metastatic diseases

  • ➢ Treatment: erlotinib or chemotherapy

 97 TaqMan assay

  • ✓ mOS

cfDNA L858R mutation vs. cfDNA exon 19 deletion: 13.7 m (95% CI = 7.1–17.7) vs. 30.0 m (95% CI = 19.3–37.7; p < 0.001)
L858R mutation in tissues and cfDNA vs. L858R mutation in tissues but not in cfDNA: 13.7 m (95% CI = 7.1–17.7) vs. 27.7 m (95% CI = 16.1–46.2) (HR = 2.22; 95% CI = 1.09–4.52; p = 0.03)
[31]
(2016)

  • ➢ Group classification:

Group A: positive for EGFR mutations in both tumor tissues and blood (T+/C+) (n = 264)
Group B: positive for EGFR mutations in blood only (T−/C+) (n = 28)
Group C: positive for EGFR mutations in tissue only (T+/C−) (n = 180)

  • ➢ Treatment: EGFR-TKIs

 472 ARMS,
ddPCR and
NGS

  • ✓ ORR

Group A: 54.6%; Group B: 46.4%; Group C: 53.9%; p = 0.715

  • ✓ mPFS

Group A: 9.5 m (95% CI = 8.8–10.3); Group B: 6.5 m (95% CI = 5.1–7.9 m); Group C: 9.4 m (95% CI = 7.7–11.0 m), p = 0.062

  • ✓ mOS

Group A: 25 m (95% CI = 21.7–28.4 m); Group B: 18.9 m (95% CI = 2.1–35.7 m); Group C: 29.1 m (95% CI = 24.3–34.0 m), p = 0.068
[45]
(2018)

  • ➢ Stage IIIB/IV

  • ➢ Failed with prior EGFR-TKI therapy

  • ➢ Positive for ctDNA T790M mutations

  • ➢ Treatment: osimertinib

 19 Cobas EGFR Mutaion Test v2
or
PANA Mutyper

  • ✓ ORR: 66.7% (10/15)

  • ✓ mPFS: 8.3 m (95% CI = 7.9–8.7)

  • ✓ mDoR: 6.8 m (95% CI = 5.3–8.3)
[46]
(2018)

  • ➢ Stage IV

  • ➢ Activating EGFR mutations (exon 19 deletion and L858R mutation) in tumors

  • ➢ Treatment: first-generation EGFR-TKIs

 57 Qualitative (PANAMutyper) and quantitative (PANAGENE-SQI)

  • ✓ mPFS (qualitative test)

ctDNA detected vs. ctDNA undetected:11.5 m vs. 13.5 m (HR = 1.417; 95% CI = 0.80–2.52; p = 0.234)

  • ✓ mPFS (quantitative test)

ctDNA detected vs. ctDNA undetected: 9.8 m vs. 20.7 m (HR = 2.30; 95% CI = 1.202–4.385; p = 0.012)
[32]
(2018)

  • ➢ Stage IV

  • ➢ Systemic treatment-naïve

  • ➢ EGFR-sensitizing mutations in pre-treatment plasma

  • ➢ Treatment: gefitinib

 183 ddPCR

  • ✓ ORR: 72.1% (132/183)

  • ✓ mPFS: 9.5 m (95% CI = 9.07–11.04)

Clear of EGFR mutations at week 8 vs. EGFR mutations persisted at week 8:11.0 m (95% CI = 9.43–12.85) vs. 2.1 m [95% CI = 1.81–3.65) (HR = 0.14; 95% CI = 0.08–0.23; p < 0.0001)
[47]
(2019)

  • ➢ Stage IIIB/IV

  • ➢ EGFR mutations

  • ➢ Failed with prior EGFR-TKI

  • ➢ T790M mutations detected in plasma

  • ➢ Treatment: osimertinib

 22 dPCR and NGS

  • ✓ Undetectable levels of original EGFR-sensitizing mutations after 3 months of treatment were associated with superior PFS (HR = 0.2; 95% CI = 0.05–0.7)

  • ✓ Re-emergence of original EGFR mutations, either alone (HR = 8.8, 95% CI = 1.1–70.7) or together with T790M mutations (HR = 5.9, 95% CI = 1.2–27.9) was significantly associated with shorter PFS
[30]
(2019)

  • ➢ Stage IIIB/IV

  • ➢ Adenocarcinoma

  • ➢ Newly diagnosed (90.6%) or PD after EGFR-TKI therapy (3.9%) or recurrence after surgery (5.4%)

  • ➢ Treatment: gefitinib or icotinib

 71 ADx-ARMS

  • ✓ ORR

EGFR mutations in tumors (T+): 64.8% (46/71); EGFR mutations in plasma (C+): 69.0% (29/42)

  • ✓ mPFS

T+ vs. C+: 10.0 m vs. 11.0 m (p = 0.175)
C+EGFR wild type vs. C+EGFR mutant type: 8.7 m vs. 11.0 m (p = 0.001)
[48]
(2019)

  • ➢ Clinically suspected advanced lung cancer

  • ➢ Plasma EGFR sensitizing mutations

  • ➢ Treatment: first-generation EGFR-TKIs

 30 NGS or ARMS

  • ✓ mPFS

EGFR-TKIs vs. Best supportive care: 11.0 m (95% CI = 7.746–14.254) vs. 1.0 m (p < 0.001)

  • ✓ mOS

EGFR-TKIs vs. Best supportive care: NR vs. 3.0 m (95% CI = 2.053–3.947; p < 0.001)
[49]
(2019)

  • ➢ Stage III/IV

  • ➢ EGFR T790M-positive tumors

  • ➢ Failed with prior EGFR-TKI therapy

  • ➢ Treatment: osimertinib vs. platinum–pemetrexed

 307 Cobas EGFR Mutation Test v2

  • ✓ mPFS

T790M-negative plasma: 12.5 m with osimertinib (95% CI = 10.9-NR) ; 5.6 m with platinum–pemetrexed (95% CI = 3.2–6.7)
T790M-positive plasma: 8.3 m with osimertinib (95% CI = 6.8–10.5) ; 4.2 m with platinum–pemetrexed (95% CI = 4.1–5.4)
[34]
(2019)

  • ➢ Stage IV

  • ➢ Sensitive EGFR mutations in tumors or plasma

  • ➢ Treatment: icotinib

 66 ddPCR

  • ✓ ORR

T+: 51.51% (34/66); C+: 57.14% (24/42)

  • ✓ DCR

T+: 90.91% (60/66); C+: 92.86% (39/42)
[50]
(2020)

  • ➢ EGFR-T790M-positive tumors

  • ➢ CNS metastases

  • ➢ Failed with prior EGFR-TKI therapy

  • ➢ Paired plasma and CSF samples

  • ➢ Treatment: osimertinib

 12 NGS

  • ✓ ORR: 41.7% (5/12; 95% CI = 15.2–72.3)

  • ✓ DCR: 83.3% (10/12; 95% CI = 51.6–97.9)

  • ✓ mPFS: 8.3m (95% CI = 2.7-NR)


Patients with undetectable plasma EGFR mutations at week 6 had better overall PFS compared to those with detectable mutations (NR vs. 4.5 m; 95% CI = 0.0–1.1; p < 0.05). No significant changes in PFS were observed based on the absence of detectable EGFR-sensitizing mutations in CSF at week 6 (p = 0.68)
[51]
(2020)

  • ➢ Metastatic EGFR-mutated lung cancer

  • ➢ No prior treatment with EGFR-TKIs and/or VEGF inhibitors

  • ➢ Initial detectable ctDNA

  • ➢ Treatment: osimertinib and bevacizumab

 30 ddPCR

  • ✓ mPFS

Clearance vs. no clearance (week6): 16.2 m vs. 9.8 m (p = 0.04)

  • ✓ mOS

Clearance vs. no clearance (week6): NR vs. 10.1 m (p = 0.002)

  • ✓ ORR

No association between detectable EGFR-mutated ctDNA at 6 weeks and ORR (p = 0.60)
[52]
(2020)

  • ➢ Advanced or recurrent NSCLC with known TKI-sensitizing EGFR mutations

  • ➢ Failed with prior first-or second-generation EGFR-TKI therapy

  • ➢ Positive T790M mutation in plasma

  • ➢ Treatment: osimertinib

 53 Cobas EGFR Mutation Test v2 or ddPCR

  • ✓ ORR: 55.1% (27/49; 95% CI = 40.2–69.3%)

  • ✓ mPFS: 8.3 m (95% CI = 6.9–12.6 m)
[53]
(2020)

  • ➢ Failed with prior first-or second-generation EGFR-TKI therapy

  • ➢ Positive T790M mutations in plasma

  • ➢ Treatment: osimertinib

 52 Cobas EGFR Mutation Test v2, ddPCR and NGS

  • ✓ Significant differences in ORR and PFS were observed between the sensitizing EGFR MF-high and sensitizing EGFR MF-low groups at cycle 4 (cutoff: median)

[35]
(2021)

  • ➢ Stage IIIB/IV

  • ➢ Activating EGFR mutations in ctDNA

Group A: EGFR mutation in ctDNA only (n = 11)
Group B: EGFR mutations in ctDNA and tumor DNA (n = 10)

  • ➢ Treatment: afatinib

 21 PNA-based
RT-PCR

  • ✓ ORR: 74% (14/19)

Group A vs. Group B: 80% (8/11) vs. 67% (6/10) (p = 0.35)

  • ✓ PFS: 12.0 m

Group A vs. Group B: 11.5 m vs. 12.8 m (p = 0.70)
[54]
(2021)

  • ➢ Stage IIIB/IV

  • ➢ No prior exposure to EGFR-TKIs

  • ➢ Activating EGFR mutations detected in tumor tissues or cytology specimens and ctDNA

  • ➢ Treatment: osimertinib

 19 Mutyper and
Cobas EGFR Mutation Test v2

  • ✓ ORR: 68% (13/19)

ex19del vs. L858R/L861Q: 91% (10/11) vs. 43% (3/7)

  • ✓ mPFS: 11.1 m (95%CI = 0.0–26.7)

ex19del vs. L858R/L861Q: 21.9 m (95%CI = 5.5–38.3) vs. 5.1 m (95%CI = 2.3–7.9)

  • ✓ mDoR: 17.6 m (95%CI = 3.5–31.7)

[55]
(2021)

  • ➢ Stage III/IV

  • ➢ EGFR mutations in plasma

  • ➢ Treatment: first generation EGFR-TKIs

 54 cSMART assay

  • ✓ ORR: 50.0%

Cutoff value for plasma EGFR mutation abundance: 0.1%
60.0% for the >0.1% group vs. 21.4% for the ≤0.1% group (p = 0.028)

  • ✓ mPFS

>0.1% group vs. ≤0.1% group: 9.5 m vs. 5.0 m (p = 0.0115)
[56]
(2021)

  • ➢ Stage IIIB/IV lung adenocarcinoma

  • ➢ Newly diagnosed or recurrence after surgery

  • ➢ EGFR mutations in tumors

  • ➢ R-superARMS method was used to detect the different values of EGFR mutations in plasma

  • ➢ Treatment: first-generation EGFR-TKI monotherapy or combination therapy with antiangiogenic drugs

41 R-superARMS

  • ✓ Baseline

mOS: EGFR mutations ΔCt* ≤8.11 vs. >8.11: NR vs. 11.0 m (p = 0.024)

  • ✓ 1 month after treatment

mOS: mutation clearance vs. incomplete mutation clearance: NR vs. 10.4 m (p = 0.021)
ΔCt >4.89 vs. 4.89: NR vs. 11.0 m (p = 0.014)
mPFS: mutation clearance vs. incomplete mutation clearance: NR vs. 27.5 m (p = 0.088)
[57]
(2022)

  • ➢ EGFR-mutated NSCLC

  • ➢ Treatment:

  • first-or second-generation EGFR-TKI therapys (n = 14) or osimertinib (n = 14)

 28 NGS

  • ✓ mPFS

CtDNA-clearance vs. ctDNA-non-clearance (week4): 11.4 m vs. 6.9 m (p = 0.091; HR = 0.42; 95% CI = 0.15–1.19)
EGFR clearance vs. EGFR non-clearance (week4): 11.4 m vs. 5.67 m (p = 0.011; HR = 0.23; 95% CI = 0.08–0.72)
Non-clearance vs. EGFR clearance only vs. total-clearance (week4): 11.4 m vs. 9.2 m vs. 5.07 m

  • ✓ ORR

Non-clearance vs. EGFR clearance only vs. total clearance: 22.2% vs. 75.0% vs. 85.7%
[58]
(2022)

  • ➢ Clinically diagnosed advanced peripheral lung cancer

  • ➢ Systemic treatment-naive

  • ➢ Positive pretreatment plasma EGFR-sensitizing variants

  • ➢ Treatment: icotinib

 116 SuperARMS
ddPCR
NGS

  • ✓ ORR: 52.6% (95% CI, 43.1–61.9%)

  • ✓ DCR: 84.5% (95% CI, 76.6–90.5%)

  • ✓ mPFS: 10.3 (95% CI, 8.3–12.2)

  • ✓ mOS: 23.2m (95% CI, 17.7–28.0)
[33]
(2022)

  • ➢ Stage IV

  • ➢ EGFR mutations in tissues

  • ➢ Systemic treatment-naïve

  • ➢ Treatment: gefitinib only or gefitinib with pemetrexed and carboplatin chemotherapy

 158 Cobas EGFR Mutation Test v2

  • ✓ mPFS

CtDNA negative post-treatment initiation vs. ctDNA positive: 14 m (95% CI = 12.0–17.0) vs. 8 m (95% CI = 6.0–10.0) (p < 0.001)

  • ✓ mOS

CtDNA-negative post-treatment initiation vs. ctDNA positive: 27 m (95% CI = 24.0–32.0 vs. 15 m (95% CI = 11.0–19.0) (p < 0.001)

Abbreviations: mOS, median overall survival; 95% CI, 95% confidence index; HR, hazard ratio; T+, EGFR mutations in tissues; C+, EGFR mutations in ctDNA; T−, no EGFR mutations in tissues; C−, no EGFR mutations in ctDNA; ddPCR, droplet digital PCR; NGS, next-generation sequencing; ORR, objective response rate; mPFS, median progression-free survival; DoR, duration of response; dPCR, digital PCR; ADx-ARMS, ADx-amplification refractory mutation system; NR, not reached; ctDNA, circulating tumor DNA; cfDNA, circulating free DNA; ARMS, amplification refractory mutation system; CNS, central nervous system; DCR, disease control rate; CSF, cerebrospinal fluid; VEGF, vascular endothelial growth factor. The*ΔCt value (i.e., mutant cycle threshold (Ct) value—internal control Ct value) was calculated to identify the presence of EGFR mutations, and was automatically calculated from PCR amplification fluorescence plots and the corresponding number of cycles.