Key message
Background
Methods
Patients
Rebiopsy and genetic analysis
Data collection
Ethical considerations
Statistical analysis
Results
Patients
Variable | Rebiopsy | ||
---|---|---|---|
(+) | (−) | ||
T790M mutation | |||
Positive (n = 29) | Negative (n = 17) | Unknown (n = 7) | |
Sex | |||
Male | 11 | 3 | 3 |
Female | 18 | 14 | 4 |
Age (years) median (range) | 74 (42 - 86) | 72 (38 - 89) | 70 (59 - 82) |
Histology | |||
Adenocarcinoma | 27 | 17 | 7 |
others | 2 | 0 | 0 |
EGFR mutation at initial diagnosis | |||
Exon 19 deletion | 21 | 6 | 1 |
L858R | 8 | 9 | 5 |
L861Q | 0 | 1 | 0 |
Exon 20 insertion | 0 | 1 | 0 |
Compound mutation | 0 | 0 | 1 |
Smoking status | |||
Never | 18 | 13 | 3 |
Past | 8 | 1 | 2 |
Current | 3 | 3 | 2 |
ECOG performance status | |||
0 | 20 | 12 | 3 |
1 | 8 | 5 | 2 |
2 | 1 | 0 | 1 |
3 | 0 | 0 | 1 |
Stage at initial diagnosis | |||
IA - IIIC | 10 | 3 | 3 |
IVA - IVB | 19 | 14 | 4 |
Surgical treatment | |||
No | 13 | 6 | 3 |
Yes | 16 | 11 | 4 |
Radical Radiotherapy | |||
No | 27 | 16 | 6 |
Yes | 2 | 1 | 1 |
Chemotherapy during treatment | |||
No | 8 | 6 | 6 |
Yes | 21 | 11 | 1 |
Reason for termination of TKIs | |||
Ongoing | 1 | 5 | 3 |
Adverse events | 0 | 1 | 3 |
Tumor growth | 14 | 3 | 0 |
New lesions | 14 | 8 | 1 |
“CEA at progression” / “nadir CEA”; median (range) | 3.1 (1.1–170) | 2.5 (1.3–7.88) | 2.0 (0.5–3.57) |
nadir CEA (ng/mL); median (range) | 3.0 (0.8–36.9) | 2.2 (1.0–78.9) | 45.6 (1.4–198) |
Medical Drugs at TKI naïve line | |||
Gefitinib | 11 | 2 | 0 |
Erlotinib | 16 | 10 | 6 |
Afatinib | 2 | 5 | 1 |
Rebiopsy outcomes
1st | 2nd | 3rd | 4th | Total | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Tissue biopsy (Individual test) | |||||||||||
T790M positive | 21 | 2 | 0 | 1 | 24 | ||||||
With original mutation | 26 | 5 | 3 | 3 | 37 | ||||||
Total | 31 | 6 | 3 | 3 | 43 | ||||||
Tissue biopsy (Cumulative test) | |||||||||||
T790M positive | 21 | 23 | 23 | 24 | 24 | ||||||
Cumulative sensitivity | 0.81 | 0.79 | 0.77 | 0.77 | 0.77 | ||||||
Total | 31 | 37 | 40 | 43 | 43 | ||||||
1st | 2nd | 3rd | 4th | 5th | 6th | 7th | 8th | 9th | 10th | Total | |
Liquid biopsy (Individual test) | |||||||||||
T790M positive | 3 | 4 | 1 | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 11 |
With original mutation | 13 | 5 | 4 | 1 | 1 | 2 | 1 | 1 | 0 | 0 | 28 |
Total | 37 | 17 | 11 | 7 | 7 | 7 | 5 | 4 | 2 | 1 | 98 |
Liquid biopsy (Cumulative test) | |||||||||||
T790M positive | 3 | 7 | 8 | 8 | 8 | 9 | 10 | 11 | 11 | 11 | 11 |
Cumulative sensitivity | 0.13 | 0.21 | 0.2 | 0.18 | 0.17 | 0.17 | 0.18 | 0.19 | 0.19 | 0.19 | 0.19 |
Total | 37 | 54 | 65 | 72 | 79 | 86 | 91 | 95 | 97 | 98 | 98 |
Variable | T790M mutation | ||
---|---|---|---|
Positive patients (n = 29) | Negative patients (n = 17) | Total patients (n = 46) | |
Tissue biopsy (included cytology) count | 31 | 12 | 43 |
T790M positive count | 24 (77.4) | – | 24 (55.8) |
With Original mutation | 22 | – | 22 |
Without Original mutation | 2 | – | 2 |
T790M negative count | 7 (22.6) | 12 | 19 (44.2) |
With Original mutation | 5 | 10 | 15 |
Without Original mutation | 2 | 2 | 4 |
Liquid biopsy count | 58 | 40 | 98 |
T790M positive count | 11 (19.0) | – | 11 (11.2) |
With Original mutation | 10 | – | 10 |
Without Original mutation | 1 | – | 1 |
T790M negative count | 47 (81.0) | 40 | 87 (88.8) |
With Original mutation | 9 | 11 | 20 |
Without Original mutation | 38 | 29 | 67 |
Total rebiopsy count | 89 | 52 | 141 |
Positive clinical factors in patients harboring the T790M substitution
Variables | Univariate Analyses | Multivariate Analysis | ||||
---|---|---|---|---|---|---|
OR | 95%CI | P-value | OR | 95%CI | P-value | |
Mutation site at initial diagnosis; Exon 19 Deletion vs. L858R | 0.17 | 0.05–0.51 | 0.002 | 0.04 | 0.004–0.34 | 0.003 |
Reason for termination of TKIs; | 2.26 | 1.25–4.11 | 0.007 | 3.65 | 1.39–9.59 | 0.008 |
Ongoing | Reference | Reference | ||||
AEs | 1 | – | – | 1 | – | – |
Tumor growth | 37.3 | 3.30–421.6 | 0.003 | 33.8 | 1.60–713.3 | 0.024 |
New lesions | 12.4 | 1.32–117.0 | 0.027 | 44.9 | 2.13–950.9 | 0.014 |
Medical Drugs at TKI-naïve line | 0.24 | 0.08–0.72 | 0.01 | 0.09 | 0.01–0.62 | 0.014 |
Gefitinib | Reference | Reference | ||||
Erlotinib | 0.18 | 0.035–0.95 | 0.044 | 0.49 | 0.02–0.99 | 0.049 |
Afatinib | 0.06 | 0.007–0.55 | 0.012 | 0.01 | 0.0002–0.53 | 0.02 |
Chemotherapy; absent vs. present | 2.63 | 0.84–8.22 | 0.09 | NI | ||
“Serum level of CEA at progression” divided by “Serum nadir level of CEA” | 1.16 | 0.97–1.39 | 0.11 | 1.22 | 0.77–1.93 | 0.4 |
Serum nadir level of CEA (ng/mL) | 0.97 | 0.95–1.01 | 0.14 | NI |
Positive factors associated with the T790M substitution upon rebiopsy
Variable | T790M mutation | ||
---|---|---|---|
Positive (n = 35) | Negative (n = 54) | Total | |
Original mutation | |||
Absent | 3 | 40 | 43 |
Present | 32 | 14 | 46 |
Type of Biopsy; | |||
Liquid | 11 | 47 | 58 |
Tissue | 24 | 7 | 31 |
Detection of New tumor lesion; | |||
< 4 | 11 | 39 | 50 |
4 ≤ | 24 | 15 | 39 |
Number of Tissue biopsy | |||
Median (Range) | 1 (0–4) | 0 (0–3) | 0 (0–4) |
Detection of New metastatic organ, n = 88 | |||
0 | 12 | 39 | 51 |
1 | 12 | 10 | 22 |
2 | 4 | 4 | 8 |
3 | 3 | 1 | 4 |
4 | 3 | 0 | 3 |
Number of tumor lesion | |||
< 6 | 6 | 29 | 35 |
6 ≤ | 29 | 25 | 54 |
Brain metastases, n = 88 | |||
Absent | 16 | 43 | 59 |
Present | 18 | 11 | 29 |
Bone metastases, n = 88 | |||
Absent | 26 | 42 | 68 |
Present | 8 | 12 | 20 |
Number of Liquid biopsy | |||
Median (Range) | 0 (0–8) | 2 (0–9) | 1 (0–9) |
Enlargement of Tumor size | |||
< 12 mm | 15 | 39 | 54 |
12 mm ≤ | 20 | 15 | 35 |
New brain metastases, n = 88 | |||
Absent | 25 | 50 | 75 |
Present | 9 | 4 | 13 |
Mutation site at initial diagnosis | |||
Exon19 Deletion | 24 | 47 | 71 |
L858R | 11 | 7 | 18 |
Minor site metastases, n = 88 | |||
Absent | 27 | 51 | 78 |
Present | 7 | 3 | 10 |
New hepatic metastases, n = 88 | |||
Absent | 28 | 51 | 79 |
Present | 6 | 3 | 9 |
New minor site metastases, n = 88 | |||
Absent | 29 | 52 | 81 |
Present | 5 | 2 | 7 |
Hepatic metastases, n = 88 | |||
Absent | 27 | 49 | 76 |
Present | 7 | 5 | 12 |
Variables | Univariate Analyses | Multivariate Analysis | ||||
---|---|---|---|---|---|---|
OR | 95%CI | P-value | OR | 95%CI | P-value | |
Original mutation; absent vs. present | 30.5 | 8.05–115.3 | < 0.001 | 41.5 | 6.53–264.3 | < 0.001 |
Type of Biopsy; Liquid vs. Tissue | 14.6 | 5.04–42.6 | < 0.001 | NI | ||
Detection of New tumor lesion; < 4 vs 4 ≤ | 5.67 | 2.24–14.4 | < 0.001 | NI | ||
Number of Tissue biopsy | 5.72 | 2.30–14.2 | < 0.001 | NI | ||
Detection of New metastatic organ; 0 → 4 | 2.35 | 1.39–3.97 | 0.001 | NI | ||
Number of tumor lesion; < 6 vs 6 ≤ | 5.61 | 2.0–15.7 | 0.001 | NI | ||
Brain metastases; absent vs. present | 4.40 | 1.71–11.3 | 0.002 | 27.8 | 3.13–247.8 | 0.003 |
Bone metastases; absent vs. present | 3.94 | 1.55–9.98 | 0.004 | NI | ||
Number of Liquid biopsy | 0.69 | 0.52–0.90 | 0.006 | NI | ||
Enlargement of Tumor size; < 12 mm vs 12 mm ≤ | 3.47 | 1.42–8.49 | 0.007 | 24.5 | 2.65–226.7 | 0.005 |
New brain metastases; absent vs. present | 4.5 | 1.26–16.1 | 0.02 | NI | ||
Mutation site at initial diagnosis; Exon19 Deletion vs. L858R | 3.08 | 1.06–8.95 | 0.04 | 3.90 | 0.63–24.3 | 0.145 |
Minor site metastases; absent vs. present | 4.20 | 1.07–16.5 | 0.04 | 21.3 | 1.40–325.6 | 0.03 |
New hepatic metastases; absent vs. present | 3.64 | 0.85–15.7 | 0.08 | NI | ||
New minor site metastases; absent vs. present | 4.48 | 0.82–24.6 | 0.08 | NI | ||
Hepatic metastases; absent vs. present | 2.54 | 0.99–1.09 | 0.141 | NI |
Positive factors associated with the T790M substitution upon liquid biopsy
Variable | T790M mutation | ||
---|---|---|---|
Positive (n = 11) | Negative (n = 47) | Total | |
Original mutation | |||
Absent | 1 | 38 | 39 |
Present | 10 | 9 | 19 |
Bone metastases | |||
Absent | 1 | 39 | 40 |
Present | 10 | 8 | 18 |
Enlargement of Tumor size | |||
< 12 mm | 7 | 7 | 14 |
12 mm ≤ | 4 | 40 | 44 |
Brain metastases | |||
Absent | 4 | 38 | 42 |
Present | 7 | 9 | 16 |
Detection of New tumor lesion | |||
< 4 | 4 | 38 | 42 |
4 ≤ | 7 | 9 | 16 |
Detection of New metastatic organ | |||
0 | 6 | 36 | 42 |
1 | 2 | 7 | 9 |
2 | 0 | 3 | 3 |
3 | 1 | 1 | 2 |
4 | 2 | 0 | 2 |
New minor site metastases | |||
Absent | 8 | 45 | 53 |
Present | 3 | 2 | 5 |
Hepatic metastases | |||
Absent | 8 | 44 | 52 |
Present | 3 | 3 | 6 |
Minor site metastases | |||
Absent | 8 | 44 | 52 |
Present | 3 | 3 | 6 |
Mutation site at initial diagnosis | |||
Exon19 Deletion | 4 | 41 | 45 |
L858R | 7 | 6 | 13 |
New hepatic metastases | |||
Absent | 9 | 45 | 54 |
Present | 2 | 2 | 4 |
Variables | Univariate Analyses | Multivariate Analysis | ||||
---|---|---|---|---|---|---|
OR | 95%CI | P-value | OR | 95%CI | P-value | |
Original mutation; absent vs. present | 42.2 | 4.77–373.6 | 0.001 | NI | ||
Bone metastases; absent vs. present | 48.8 | 5.45–436.4 | 0.001 | 77.9 | 5.32–1140 | 0.001 |
Enlargement of Tumor size; < 12 mm vs 12 mm ≤ | 0.10 | 0.02–0.43 | 0.002 | NI | ||
Brain metastases; absent vs. present | 7.39 | 1.77–30.8 | 0.006 | NI | ||
Detection of New tumor lesion; < 4 vs 4 ≤ | 7.39 | 1.77–30.8 | 0.006 | 14.5 | 1.38–151.2 | 0.026 |
Detection of New metastatic organ; 0 → 4 | 1.98 | 1.09–3.59 | 0.024 | NI | ||
New minor site metastases; absent vs. present | 8.44 | 1.21–58.8 | 0.031 | NI | ||
Hepatic metastases; absent vs. present | 5.50 | 0.94–32.2 | 0.059 | NI | ||
Minor site metastases; absent vs. present | 5.50 | 0.94–32.2 | 0.059 | NI | ||
Mutation site at initial diagnosis; Exon19 Deletion vs. L858R | 3.91 | 0.87–17.5 | 0.075 | 1.15 | 0.13–10.1 | 0.897 |
New hepatic metastases; absent vs. present | 5.00 | 0.62–40.3 | 0.131 | NI |