Molecular Targets in Lung Cancer: Study of the Evolution of Biomarkers Associated with Treatment with Tyrosine Kinase Inhibitors—Has NF1 Tumor Suppressor a Key Role in Acquired Resistance?
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Patients and Samples
2.2. Extraction of cfDNA from Plasma Samples for EGFR Mutation Analysis
2.3. Molecular Characterization of EGFR in cfDNA
2.4. Extraction of cfDNA from Plasma Samples for NGS Analysis
2.5. Validation and Molecular Characterization of NSCLC in FFPE and cfDNA Samples
2.6. Library Preparation and Sequencing
2.7. Variant Calling and Data Analysis
2.8. Statistical Analysis
3. Results
3.1. EGFR Mutations Detected in Tissue and Plasma Samples
3.1.1. Characteristics of Patient Cohort and Presence of Initial EGFR Mutation
3.1.2. EGFR Mutations Detected in Plasma Samples
3.1.3. Patients Undergoing Rebiopsy
3.1.4. Correlation between Mutations
3.2. Liquid Biopsy as a Disease Monitor. Response to TKIs
3.3. Prognostic Significance of the T790M EGFR Mutation and TKI Treatment
3.4. Validation of EGFR Results in Tissue and Plasma Samples
3.5. NGS Analysis of Patients with Discordant Progression
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Variables | No. | % | Variables | No. | % |
---|---|---|---|---|---|
Patients | 86 | Pathological stage | |||
Male | 35 | 40.70 | I | 2 | 2.33 |
Female | 51 | 59.30 | III | 6 | 6.98 |
Age (yr) | IV | 77 | 89.53 | ||
Mean (range) | 66.45 (36–89) | ND | 1 | 1.16 | |
Histology | Smoking | ||||
Adenocarcinoma | 74 | 86.05 | No | 38 | 44.19 |
Squamous cell carcinoma | 3 | 3.49 | Former smoker | 28 | 32.56 |
Other NSCLC | 9 | 10.47 | Yes | 16 | 18.60 |
ND | 4 | 4.65 |
No. | Initial EGFR Mutation | Rebiopsy 1 | Rebiopsy 2 | LB1 | LB2 | LB3 | LB4 | LB5 | LB6 | LB7 | No. | Initial EGFR Mutation | Rebiopsy 1 | LB1 | LB2 | LB3 | LB4 | LB5 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | Ex19Del | NMD | NMD | 43 | Ex19Del | Ex19Del | ||||||||||||
5 | Ex19Del | T790M | NMD | 44 | L858R | NMD | L858R | NMD | NMD | |||||||||
6 | Ex19Del | Ex19Del | Ex19Del T790M | 46 | L858R | L858R | ||||||||||||
7 | Ex19Del | NMD | NMD | NMD | NMD | NMD | NMD | Ex19Del | Ex19Del | 47 | S768I | NMD | NMD | |||||
8 | Ex19Del | Ex19Del | Ex19Del T790M | 50 | Ex19Del | Ex19Del T790M | ||||||||||||
9 | Ex19Del | NMD | Ex19Del T790M | 52 | L858R | L858R | NMD | NMD | L858R T790M | |||||||||
10 | L858R | L858R | 53 | Ex19Del | NMD | Ex19Del T790M | Ex19Del T790M | |||||||||||
11 | L858R | NMD | L858R | L858R | 54 | L858R T790M | L858R T790M | T790M | T790M | T790M | ||||||||
13 | Ex19Del | NMD | Ex19Del | Ex19Del T790M | 55 | L858R | L858R T790M | NMD | L858R | |||||||||
15 | Ex19Del | Ex19Del T790M | 56 | L858R | L858R | L858R | ||||||||||||
20 | S768I, L858R | S768I | NMD | S768I L858R T790M | 59 | L858R | L858R T790M | L858R | INV | L858R | L858R | |||||||
22 | Ex19Del | Ex19Del | NMD | NMD | NMD | 60 | L858R | NMD | L858R T790M | |||||||||
23 | Ex19Del | NMD | Ex19Del T790M | Ex19Del | Ex19Del T790M | 62 | Ex19Del | NMD | ||||||||||
24 | Ex20Ins | NMD | 63 | Ex19Del | NMD | NMD | NMD | NMD | NMD | |||||||||
27 | L858R | L858R T790M | 65 | Ex19Del | NMD | NMD | NMD | |||||||||||
28 | ND | INV | Ex19Del | Ex19Del | 66 | ND | Ex19Del T790M | Ex19Del | Ex19Del | |||||||||
30 | L858R | L858R | L858R | L858R | INV | INV | 67 | L858R | NMD | |||||||||
31 | L858R | L858R | 69 | G719X S768I | NMD | |||||||||||||
32 | Ex19Del | Ex19Del T790M | 70 | Ex19Del | Ex19Del T790M | Ex19Del | ||||||||||||
33 | L858R | L858R T790M | NMD | NMD | L858R | 73 | Ex19Del | NMD | ||||||||||
34 | Ex19Del | Ex19Del T790M | 74 | ND | Ex19Del | NMD | ||||||||||||
35 | ND | L858R T790M | L858R | NMD | NMD | 79 | Ex19Del | NMD | NMD | NMD | ||||||||
36 | Ex19Del | Ex19Del | 80 | L858R | L858R T790M | L858R | NMD | NMD | ||||||||||
37 | Ex19Del | NMD | NMD | NMD | 81 | Ex19Del | T790M | |||||||||||
38 | L858R | L858R | 82 | L858R | NMD | |||||||||||||
39 | G719X | NMD | NMD | 83 | Ex19Del | Ex19Del T790M | ||||||||||||
40 | L858R | L858R T790M | NMD | L858R | 84 | ND | L858R | L858R | ||||||||||
41 | Ex19Del | NMD | NMD | INV | NMD | NMD | NMD | NMD | NMD | 85 | ND | L858R | ||||||
42 | Ex19Del | Ex19Del T790M | Ex19Del | NMD | NMD | 86 | L858R | L858R T790M |
Ex19Del IM | L858R IM | Ex19Del LB | L858R LB | T790M LB | Ex19Del ReBx | L858R ReBx | T790M ReBx | |
---|---|---|---|---|---|---|---|---|
Ex19Del IM | φ: −0.385 *** | φ: 0.637 *** | φ: −0.385 *** | φ: 0.329 ** | φ: 0.110 ns | φ: −0.217 * | φ: −0.011 ns | |
L858R IM | φ: −0.292 ** | φ: 0.811 *** | φ: 0.107 ns | φ: −0.156 ns | φ: 0.470 *** | φ: 0.300 ** | ||
Ex19Del LB | φ: −0.292 ** | φ: 0.438 *** | φ: 0.308 ** | φ: −0.165 ns | φ: 0.081 ns | |||
L858R LB | φ: 0.107 ns | φ: −0.156 ns | φ: 0.470 *** | φ: 0.216 * | ||||
T790M LB | φ: −0.191 ns | φ: −0.066 ns | φ: −0.097 ns | |||||
Ex19Del ReBx | φ: −0.088 ns | φ: 0.328 ** | ||||||
L858R ReBx | φ: 0.633 *** | |||||||
T790M ReBx |
No. | Months | 1st LB | TKI Treat | Months | Subsequent LBs | TKI Treat | Rebiopsy | Exitus | No. | Months | 1st LB | TKI Treat | Months | Subsequent LBs | TKI Treat | Rebiopsy | Exitus |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | 37.2 | 0 | 1 | 4.2 | 0 | 1 | 5.3 | 44 | 4.9 | 0 | 1 | 50.7 | 1 | 1 | |||
5 | 20.0 | 0 | 3 | T790M | 10.5 | 46 | 5.6 | 1 | 1 | 4.8 | |||||||
7 | 5.7 | 0 | 3 | 27.1 | 1 | 1 | NMD | 2.3 | 47 | 32.9 | 0 | 0 | 31 | 0 | 3 | 11.1 | |
8 | 35.8 | 1 | 1 | 0.2 | 1 | 0 | 0.3 | 50 | 31.7 | 2 | 3 | ||||||
9 | 14.9 | 0 | 1 | 0.2 | 2 | 2 | 22.4 | 52 | 17.1 | 0 | 1 | 21.4 | 2 | 3 | 37.2 | ||
10 | 1.8 | 1 | 1 | 1.0 | 53 | 21.8 | 0 | 1 | 32.5 | 2 | 2 | 3.6 | |||||
11 | 4.0 | 0 | 1 | 5.6 | 1 | 1 | 0.6 | 56 | 8.6 | 1 | 2 | 2.2 | 1 | 2 | 1.4 | ||
13 | 15.7 | 0 | 1 | 14.3 | 2 | 3 | 38.1 | 59 | 26.2 | 1 | 1 | 3.0 | 1 | 2 | L858R T790M | 15.5 | |
15 | 8.0 | 2 | 1 | 0.5 | 60 | 8.9 | 0 | 1 | 3.1 | 2 | 2 | 24.8 | |||||
20 | 11.0 | 0 | 1 | 16.4 | 2 | 2 | 27.2 | 62 | 17.5 | 0 | 2 | 2.2 | |||||
23 | 11.9 | 0 | 1 | 35.9 | 2 | 2 | 6.6 | 63 | 5.3 | 0 | 1 | 22.1 | 0 | 2 | |||
27 | 11.7 | 2 | 3 | 14.5 | 65 | 37.4 | 0 | 1 | 10.2 | 0 | 1 | NMD | 5.0 | ||||
30 | 9.5 | 1 | 1 | 5.0 | 1 | 0 | L858R | 0.7 | 67 | 13.9 | 0 | 1 | 3.7 | ||||
31 | 4.87 | 1 | 2 | 2.0 | 69 | 11.8 | 0 | 1 | 21.8 | ||||||||
32 | 10.0 | 2 | 3 | 7.8 | 70 | 9.2 | 1 | 2 | Ex19Del T790M | 12.2 | |||||||
33 | 38.4 | 1 | 1 | 19.9 | 1 | 2 | L858R T790M | 79 | 62.1 | 0 | 1 | 20.3 | 0 | 1 | |||
36 | 9.2 | 1 | 1 | 3.3 | 80 | 57.1 | 1 | 1 | 0.5 | 0 | 2 | L858R T790M | |||||
37 | 20.5 | 0 | 1 | 0.5 | 0 | 0 | 7.9 | 81 | 21.0 | 2 | 3 | ||||||
38 | 15.1 | 1 | 1 | 3.03 | 82 | 12.2 | 0 | 0 | |||||||||
39 | 2.0 | 0 | 1 | 6.2 | 83 | 16.7 | 2 | 3 | 13.8 | ||||||||
43 | 2.0 | 1 | 1 | 1.3 | 86 | 18.3 | 2 | 2 |
A | Censored | B | Censored | ||||||
---|---|---|---|---|---|---|---|---|---|
Mut Status | N Total | N Exitus | N | % | Mut Status | N Total | N Exitus | N | % |
Wild Type | 28 | 23 | 5 | 17.9% | T790M- | 58 | 45 | 13 | 22.4% |
EGFR+ | 58 | 45 | 13 | 22.4% | T790M+ | 28 | 23 | 5 | 17.9% |
Global | 86 | 68 | 18 | 20.9% | Global | 86 | 68 | 18 | 20.9% |
Censored | ||||
---|---|---|---|---|
Mut Status | N Total | N Exitus | N | % |
No TKIs | 27 | 21 | 6 | 22.2% |
1st–2nd Generation | 24 | 20 | 4 | 16.7% |
3rd Generation | 35 | 27 | 8 | 22.9% |
Global | 86 | 68 | 18 | 20.9% |
No. | Type of Sample | Pan Lung Cancer Panel | cobas EGFR Mutation Test |
---|---|---|---|
Mutation Detected | Mutation Detected | ||
1 | Liquid biopsy | Negative | Negative |
5 | Rebiopsy | T790M | T790M |
7 | Rebiopsy | KRAS G12A/V/R/G13C * | Negative |
22 | Liquid biopsy | Negative | Negative |
30 | Rebiopsy | L858R | L858R |
31 | Liquid biopsy | L858R | L858R |
33 | Rebiopsy | L858R T790M | L858R T790M |
35 | Liquid biopsy | Negative | Negative |
37 | Liquid biopsy | Negative | Negative |
54 | Rebiopsy | L858R T790M | L858R T790M |
56 | Liquid biopsy | Negative | Negative |
65 | Rebiopsy | KRAS G12C * | Negative |
70 | Rebiopsy | Ex19Del T790M | Ex19Del T790M |
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Alen, B.O.; Estévez-Pérez, L.S.; Hermida-Romero, M.T.; Reguera-Arias, A.; García-Campelo, R.; de la Torre-Bravos, M.; Concha, Á. Molecular Targets in Lung Cancer: Study of the Evolution of Biomarkers Associated with Treatment with Tyrosine Kinase Inhibitors—Has NF1 Tumor Suppressor a Key Role in Acquired Resistance? Cancers 2022, 14, 3323. https://doi.org/10.3390/cancers14143323
Alen BO, Estévez-Pérez LS, Hermida-Romero MT, Reguera-Arias A, García-Campelo R, de la Torre-Bravos M, Concha Á. Molecular Targets in Lung Cancer: Study of the Evolution of Biomarkers Associated with Treatment with Tyrosine Kinase Inhibitors—Has NF1 Tumor Suppressor a Key Role in Acquired Resistance? Cancers. 2022; 14(14):3323. https://doi.org/10.3390/cancers14143323
Chicago/Turabian StyleAlen, Begoña O., Lara S. Estévez-Pérez, María Teresa Hermida-Romero, Ana Reguera-Arias, Rosario García-Campelo, Mercedes de la Torre-Bravos, and Ángel Concha. 2022. "Molecular Targets in Lung Cancer: Study of the Evolution of Biomarkers Associated with Treatment with Tyrosine Kinase Inhibitors—Has NF1 Tumor Suppressor a Key Role in Acquired Resistance?" Cancers 14, no. 14: 3323. https://doi.org/10.3390/cancers14143323