Main Article Content
Objective: In Lung cancer (LC), which is one of the most deadly cancers, longer survival has been achieved with targeted agents. For this reason, it is important to find the patients who are suitable for targeted therapies. Next-generation sequencing (NGS) is a method that allows multiple genetic variants to be detected simultaneously by performing massive parallel DNA sequencing at the same time. We wanted to reveal the clinical effects and benefits of genetic variant analysis with NGS for our patients.
Material and Methods: Patients with stage 4 non-squamous and not otherwise specified (NOS) Non-small cell LC who underwent genetic variant analysis with NGS were included in the study, retrospectively.
Results: Total of the 51 patients, 41 (80.4%) were male and the median age was 64 (35-85) years. According to TNM, 21 (41.2%) patients were stage 4A, 30 (58.8%) patients were stage 4B and 39 (76.5%) patients had adenocarcinoma and 12 (23.5%) had NOS histology. NGS analyzes were performed in median 14 days (8-43) and determined 24 pathogenic variants in 17 (%25) patients: 9EGFR (%17,6), 6PIKC3A (%11,7), 5KRAS (%9,8), 2PTEN (%3,9), 1BRAF (%1,9), 1MET (%1,6) (7 of them concomitantly). Cytotoxic chemotherapy was recommended in 41, anti-EGFR agents in 8 (afatinib in 4, erlotinib in 4 patients) patients and anti-BRAF+MEK inhibitor agent (dabrafenib+trametinib) in 1 patient.
Conclusion: With the NGS, in just two weeks, both target and resistance genetic variants of our patients were detected at the same time and individualized treatments were applied. In this way, both time and cost were saved.
2. Oser MG, Niederst MJ, Sequist LV, Engelman JA. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol. 2015; 16(4): 165–172.
3. Siegel RL, Miller KD, Jemal A. Cancer Statics, 2015. CA Cancer J Clin. 2015; 65: 5–29
4. Lu M, Su Y. Immunotherapy in non‐small cell lung cancer: The past, the present, and the future. Thorac Cancer. 2019; 10(4): 585–586.
5. Rivero JD, Enewold L, Thomas A. Metastatic lung cancer in the age of targeted therapy: improving long-term survival. Transl Lung Cancer Res. 2016; 5(6): 727–730.
6. Chan BA, Hughes BGM. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl Lung Cancer Res. 2015; 4(1): 36–54.
7. Mayekar MK, Bivona TG. Current Landscape of Targeted Therapy in Lung Cancer. Clin Pharmacol Ther. 2017; 102(5):757-764
8. Lindeman NI, Cagle PT, Aisner DL, Arcila ME, Beasley MB, Bernicker EH, et al. Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2018; 142(3):321-346.
9. Shim HS, Choi YL, Kim L, Chang S, Kim WS, Roh MS, et al. The Korean Cardiopulmonary Pathology Study Group, and The Korean Molecular Pathology Study Group. Molecular Testing of Lung Cancers. J Pathol Transl Med. 2017; 51(3): 242–254.
10. Garinet S, Laurent-Puig P, Blons H, Oudart JP. Current and Future Molecular Testing in NSCLC, What Can We Expect from New Sequencing Technologies? J Clin Med. 2018; 7(6): 144.
11. Kruglyak KM, Lin E, Ong FS. Next-Generation Sequencing and Applications to the Diagnosis and Treatment of Lung Cancer. Adv Exp Med Biol. 2016; 890:123-36.
12. Bernicker EH, Allen TC, Cagle PT. Update on emerging biomarkers in lung cancer. J Thorac Dis. 2019; 11(Suppl 1): 81–88.
13. Mehrad M, Roy S, Bittar HT, Dacic S. Next-Generation Sequencing Approach to Non-Small Cell Lung Carcinoma Yields More Actionable Alterations. Arch Pathol Lab Med. 2018; 142(3):353-357
14. Friedlaender A, Banna G, Malapelle U, Pisapia P, Addeo A. Next Generation Sequencing and Genetic Alterations in Squamous Cell Lung Carcinoma: Where Are We Today? Front Oncol. 2019; 9: 166.
15. Wapiszewski R, Pawlak SD, Adamkiewicz K. Anti-EGFR Agents: Current Status, Forecasts and Future Directions. Targ Oncol. 2016; 11: 739–752
16. Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018; 553(7689):446-454
17. Dearden S, Stevens J, Wu YL, Blowers D. Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol. 2013; 24(9): 2371–2376.
18. Nurwidya F,Takahashi F, Takahashi K. Gefitinib in the treatment of nonsmall cell lung cancer with activating epidermal growth factor receptor mutation. J Nat Sci Biol Med. 2016; 7(2): 119–123.
19. Kanthala S, Pallerla S, Jois S. Current and future targeted therapies for non-small-cell lung cancers with aberrant EGF receptors. Future Oncol. 2015; 11(5): 865–878.
20. Takeda M, Nakagawa K. First- and Second-Generation EGFR-TKIs Are All Replaced to Osimertinib in Chemo-Naive EGFR Mutation-Positive Non-Small Cell Lung Cancer? Int J Mol Sci. 2019; 20(1): 146.
21. Wang J, Wang B, Chu H, Yao Y. Intrinsic resistance to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer with activating EGFR mutations. Onco Targets Ther. 2016; 9: 3711-26
22. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B1, Lee KH, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018; 378(2):113-125.
23. Ramalingam SS, Gray JE, Ohe Y, Cho BC, Vansteenkiste J, Zhou C, et al. Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Final overall survival analysis. Annals of Oncology (2019) 30 (suppl_5): 851-934.
24. Román M, Baraibar I, López I, Nadal E, Rolfo C, Vicent S, et al. KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target. Mol Cancer. 2018; 19;17(1):33
25. Adderley H, Blackhall FH, Lindsay CR. KRAS-mutant non-small cell lung cancer: Converging small molecules and immune checkpoint inhibition. EBioMedicine. 2019; 41: 711–716.
26. Cantley CL. The phosphoinositide 3-kinase pathway. Science. 2002; 296, 1655–1657
27. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004; 304(5670):554.
28. Wu SG, Chang YL, Yu CJ, Yang PC, Shih JY. The Role of PIK3CA Mutations among Lung Adenocarcinoma Patients with Primary and Acquired Resistance to EGFR Tyrosine Kinase Inhibition. Sci Rep. 2016; 6: 35249.
29. Scheffler M, Bos M, Gardizi M, König K, Michels S, Fassunke J, et al. PIK3CA mutations in non-small cell lung cancer (NSCLC): genetic heterogeneity, prognostic impact and incidence of prior malignancies. Oncotarget. 2015; 6(2):1315-26.
30. Papa A, Pandolfi PP. The PTEN–PI3K Axis in Cancer. Biomolecules. 2019; 9(4): 153
31. Gkountakos A, Sartori G, Falcone I, Piro G, Ciuffreda L, Carbone C, PTEN in Lung Cancer: Dealing with the Problem, Building on New Knowledge and Turning the Game Around. Cancers (Basel). 2019; 11(8): 1141.
32. Ku BM, Heo MH, Kim JH, Cho BC, Cho EK, Min YJ, et al. Molecular Screening of Small Biopsy Samples Using Next-Generation Sequencing in Korean Patients with Advanced Non-small Cell Lung Cancer: Korean Lung Cancer Consortium (KLCC-13-01). J. Pathol. Transl. Med. 2018; 52: 148–156
33. Zhu Z, Yu T, Chai Y. Multiple primary lung cancer displaying different EGFR and PTEN molecular profiles. Oncotarget 2016; 7: 81969–81971
34. Sun H, Ma H, Wang J, Xia L, Zhu G, Wang Z , et al. Phosphatase and tensin homolog deleted on chromosome 10 degradation induced by NEDD4 promotes acquired erlotinib resistance in non-small-cell lung cancer. Tumour Biol. 2017; 39(7): 1010428317709639. doi: 10.1177/1010428317709639.
35. Lin Q, Zhang H, Ding H, Qian J, Lizaso A, Lin J, et al. The association between BRAF mutation class and clinical features in BRAF-mutant Chinese non-small cell lung cancer patients J Transl Med. 2019; 17: 298.
36. Alvarez JGB, Otterson GA. Agents to treat BRAF-mutant lung cancer. Drugs Context. 2019; 8: 212566.
37. Planchard D, Smit EF, Groen HJM, Mazieres J, Besse B, Helland Å, et al. Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017; 18(10): 1307-1316
38. Gong J, Pan K, Fakih M, Pal S, Salgia R. Value-based genomics. Oncotarget. 2018; 20; 9(21): 15792–15815
39. Pennell NA, Mutebi A, Zhou ZY, Ricculli ML, Tang W, Wang H, et al. Economic impact of next generation sequencing vs sequential single-gene testing modalities to detect genomic alterations in metastatic non-small cell lung cancer using a decision analytic model. Journal of Clinical Oncology 2018; 36(15): 9031-9031.
40. Besser J, Carleton HA, Gerner-Smidt P, Lindsey RB, Trees E. Next-Generation Sequencing Technologies and their Application to the Study and Control of Bacterial Infections. Clin Microbiol Infect. 2018; 24(4): 335–341.