Günümüzde akciğer kanseri erkeklerde en sık rastlanan ve ölümle sonuçlanan kanser tipleri arasında birinci sırayı almaktadır. Hastalığın tedavisine yönelik çalışmalarda en güncel ve önemli ivme insan genom yapısının belirlenmesi ve tümör biyolojisinin anlaşılması ile olmuştur. Farmakogenomik, tümör bağımlı gen mutasyonlarını inceleyerek ilacın hangi hastada hangi oranda daha etkili olacağını belirler. Farmakogenomik’e dayanan yöntemler ile direkt hastalığa yönelik kişiye spesifik tedavi yöntemleri uygulanarak en az yan etki ile hastayı iyileştirme yoluna gidilmektedir. Bunun yanında kişilerdeki gen mutasyonları detaylı incelenerek tümöre karşı ilaç duyarlılığının belirlenebilmesi tedavi seçiminde ve sonucunda çok önemli rol oynamıştır. Bu derleme kapsamında akciğer kanserinin tedavisinde hastaya özel tedavi yöntemine dayalı farmakogenomik uygulamaları ve hastalığın seyrine etkisi araştırılmıştır
1. Vogel F. Moderne probleme der humangenetik.
Ergeb Inn Med Kinderheilkd, 1959; 12: 52–125.
2. Meyer UA. Pharmacogenetics five decades of
therapeutic lessons from genetic diversity. Nat Rev
Genet, 2004; 5: 669-76.
3. Haydaroğlu A. Akciğer Kanserleri Tanı ve Tedavi.
Ege Üniversitesi Basımevi, İzmir, 2000.
4. Yener NA, Apa DD, Akciğer Kanserinde Morfolojik
Tanı ve Sınıflama. Trd Sem, 2014; 2: 281-9.
5. Huang YT, Heist RS, Chirieac LR, Lin X, Skaug V,
Zienolddiny S, et al. Genome-wide analysis of
survival in early-stage non-small-cell lung cancer.
J Clin Oncol, 2009; 27: 2660-7.
6. Zhang Y, Martens JW, Yu JX, Jiang J, Sieuwerts
AM, Smid M, et al. Copy number alterations that
predict metastatic capability of human breast
cancer. Cancer Res, 2009; 69: 3795-801.
7. Turner N, Pearson A, Sharpe R, Lambros M, Geyer F,
Lopez-Garcia MA, et al. FGFR1 amplification drives
endocrine therapy resistance and is a therapeutic
target in breast cancer. Cancer Res, 2010; 70(5):
2085-94.
8. Herbest RS, Lilenbaum R. Gemcitabine and
vinorelbine cpmbinations in the treatment of nonsmall cell lung-cancer. J. Clin Oncol, 1999; 13:
1609.
9. Krug LM, Rubinstein L, Sadephi A, Group LCS.
Phase II trials of vinorelbine and doc-etaxel in the
treatment of advanced non-small cell lung cancer.
Semin Oncol, 1999; 26: 24-6.
10. Sandler AB, Nemunaitis J, Denham C. Phase III trail
of gemcitabine plus cisplatin versus cisplatin alone
in patients with locally advanced or metastatic
non-small cell lung cancer. J Clin Oncol, 2000; 18:
120-2.
11. Gazdar AF. Personalized medicine and inhibition of
EGFR signaling in lung cancer. N Engl J Med, 2009;
361: 1018-20.
12. Kratz JR, He J, Van Den Eeden SK, Zhu Z-H, Gao W,
Pham P, et al. A practical molecular assay to predict
survival in resected non- squamous, non-smallcell lung cancer: development and international
validation studies. Lancet, 2012; 379: 823-32.
14. Sharma SV, Bell DW, Settleman J, Haber DA.
Epidermal growth factor mutations in lung cancer.
Nat Rev Cancer, 2007; 7(3): 161-81.
15. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula
S, Okimoto RA, Brannigan BW, et al. Activating
mutations in the epidermal growth factor receptor
underlying responsiveness of non-small-cell lung
cancer to gefitinib. N Engl J Med, 2004; 350: 2129-
39.
16. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H,
Gabriel S, et al. EGFR mutations in lung cancer:
correlation with clinical responses to gefitinib
therapy. Science, 2004; 304: 1497-500.
17. Shan Y, Eastwood MP, Zhang X. 2012. Oncogenic
mutations counteract intrinsic disorder in the EGFR
kinase and promote receptor dimerisation. Cell,
2012; 149: 860-70.
18. Kilic D, Findikcioglu A, Alver G, Akbulut H, Hatipoglu
A. The diagnostic significance and the assessment
of the value of vascular endothelial growth factor
as a marker for success of chemical pleurodesis in
malignant pleural effusion. J Biomed Eng, 2011; 4:
214-21.
19. Hirsch FR, Scagliotti GV, Langer CJ, Varella-Garcia
M, Franklin WA. Epidermal growth factor family
of receptorsin preneoplasia and lung cancer:
perspectives for targeted therapies. Lung Cancer,
2003; 1: 29-42.
20. Rosell R, Carcereny E, Gervais R, Vergnenegre A,
Massuti B, Felip E, et al. Erlotinib versus Standard
chemotherapy as first-line treatment for European
patients with advanced EGFR mutation-positive
non-smallcell lung cancer (EURTAC): a multicentre,
open-label, randomised Phase 3 trial. Lancet
Oncol, 2012; 13: 239-46.
21. Bria E, Miella M, Cuppone F, Novello S, Ceribelli
A, Vaccaro V, et al. Outcome of advanced NSCLC
patients harboring sensitizing EGFR mutations
randomized to EGFR tyrosine kinase inhibitors or
chemotherapy as first-line treatment: a metaanalysis. Ann Oncol, 2011; 22(10): 2277-85.
22. Lee JS, Park K, Kim S. A randomized phase III
study of gefitinib (IRESSA™) versus standard
chemotherapy (gemcitabine plus cisplatin) as firstline treatment for never-smokers with advanced or
metastatic adenocarcinoma of the lung. J Thorac
Oncol, 2009; 4(9): S283.
23. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto
I, Tsurutani J, et al. Gefitinib versus cisplatin plus
docetaxel in patients with non-small-cell lung
cancer harbouring mutations of the epidermal
growth factor receptor (WJTOG3405): an open
label, randomised phase 3 trial. Lancet Oncol,
2010; 11: 121-28.
24. Zhou C, Wu YL, Chen G. Efficacy results from the
randomised phase III OPTIMAL (CTONG 0802) study
comparing first-line erlotinib versus carboplatin
(CBDCA) plus gemcitabine (GEM), in Chinese
advanced non-small-cell lung cancer (NSCLC)
patients (pts) with EGFR activating mutations.
ESMO 2010 late-breaking abstracts. Ann Oncol,
2010; 21: 86.
25. Maemondo M, Inoue A, Kobayashi K. Gefitinib or
chemotherapy for non-small-cell lung cancer with
mutated EGFR. N Engl J Med, 2010; 362: 2380-88.
26. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon
B, Maki RG, et al. Anaplastic lym- phoma kinase
inhibition in non-small-cell lung cancer. N Engl J
Med, 2010; 363: 1693-703.
27. Kim DW, Ahn MJ, Shi Y, De Pas TM, Yang PC, Riely
GJ. Results of a global phase II study with crizotinib
in advanced ALK-positive non-small cell lung cancer
(NSCLC). J Clin Oncol, 2012; 30: 7533.
28. Kim ES, Salgia R. MET pathway as a therapeutic
target. J Thorac Oncol, 2009; 4: 444-7.
29. Shaw AT, Camidge DR, Engelman JA, Solomon
BJ, Kwak EL, Clark JW, et al. Clinical activity of
crizotinib in adavanced non-small cell lung cancer
(NSCLC) harboring ROS1 gene rearrangement. J
Clin Oncol, 2012; 30(8): 863-7010.
30. Misale S, Yaeger R, Hobor S, Scala E, Janakiraman
M, Liska D, et al. Emergence of KRAS mutations
and acquired resistance to anti-EGFR therapy in
colorectal cancer. Nature, 2012; 486: 532-36.
31. Stewart EL, Tan SZ, Liu G, Tsao MS. Known and
putative mechanisms of resistance to EGFR
targeted therapies in NSCLC patients with EGFR
mutations-a review. Transl Lung Cancer Res, 2015;
4(1): 67-81.
32. Kobayashi S, Boggon TJ, Dayaram T. EGFR mutation
and resistance of non-small-cell lung cancer to
gefitinib. N Engl J Med, 2005; 352: 786-92.
33. Pao W, Miller VA, Politi KA, Riely GJ, Somwar
R, Zakowski MF, et al. Acquired resistance of
lung adenocarcinomas to gefitinib or erlotinib is
associated with a second mutation in the EGFR
kinase domain. PLoS Med, 2005; 2: 73.
34. Weiss J, Sos ML, Seidel D, Peifer M, Zander T,
Heuckmann JM, et al. Frequent and focal FGFR1
amplification associates with therapeutically
tractable FGFR1 dependency in squamous cell lung
cancer. Sci Transl Med, 2010; 2: 62-93.
35. Hammerman PS, Sos ML, RamoS AH, Xu C, Dutt A,
Zhou W, et al. Mutations in the DDR2 kinase gene
identify a novel therapeutic target in squamous
cell lung cancer. Cancer Discov, 2011; 1: 78-89.
36. Seo AN, Jin Y, Lee HJ. FGFR1 amplification is
associated with poor prognosis and smoking in nonsmall-cell lung cancer. Virchows Archiv, 2014; 465:
547-58.
37. Jiang T, Gao G, Fan G, Li M, Zhou C. FGFR1
amplification in lung squamous cell carcinoma:
a systematic review with meta-analysis. Lung
Cancer, 2015; 87(1): 1-7.
38. Reis-Filho JS, Simpson PT, Turner NC, Lambros MB,
Jones C, Mackay A. FGFR1 emerges as a potential
therapeutic target for lobular breast carcinomas.
Clin Cancer Res, 2006; 12: 6652-62.
39. Turner N, Pearson A, Sharpe R, Lambros M, Geyer F,
Lopez-Garcia MA, et al. FGFR1 amplification drives
endocrine therapy resistance and is a therapeutic
target in breast cancer. Cancer Res, 2010; 70(5):
2085-94.
40. Bergethon K, Shaw A, Ou SH, Katayama R,
Lovely CM, McDonald NT, Massion PP, et al. ROS1
rearrangements define a unique molecular class of
lung cancers. J Clin Oncol, 2012; 30(8): 63-70.
41. Mino-Kenudson M, Chirieac LR, Law K, Hornick JL,
Lindeman N, Mark EJ, et al. A novel highly sensitive
antibody allows for the routine detection of ALKrearranged lung adenocarcinomas by standard immunohistochemistry. Clin Cancer Res, 2010; 16:
1561-71.
42. Ohashi K, Sequist LV, Arcila ME, Moran T, Chmielecki
J, Lin YL, et al. Lung cancers with acquired
resistance to EGFR inhibitors occasionally harbor
BRAF gene mutations but lack mutations in KRAS,
NRAS, or MEK1. Proc Natl Acad Sci, 2012; 109:
2127-33.
43. Miao L, Wang Y, Zhu S, Shi M, Li Y, Ding J, et al.
Identification of novel driver mutations of the
discoidin domain receptor 2 (DDR2) gene in
squamous cell lung cancer of Chinese patients.
BMC Cancer, 2014; 24(14): 369.
Pharmacogenomics in Lung Cancer Treatment
Year 2017,
Volume: 74 Issue: 2, 175 - 184, 01.06.2017
Lung carcinoma is the most common cause of cancer-related death in men among other cancer types in last years. The most recent and significant step in the treatment of the disease is the determination of the human genome structure and understanding of tumor biology. Pharmacogenomics examines tumordependent gene mutations to determine in which patient the drug will be more effective. Personalized treatments that are specified directly to disease by using pharmacogenomics methods are applied to cure patients with minimum side effects. Also, determining sensitivity of drug against tumor by examining gene mutations in patients plays a crucial role in selection and outcome of treatment. Patient-specific pharmacogenetic applications in lung carcinoma treatment and their effects on prognostic of disease were reviewed in this study
1. Vogel F. Moderne probleme der humangenetik.
Ergeb Inn Med Kinderheilkd, 1959; 12: 52–125.
2. Meyer UA. Pharmacogenetics five decades of
therapeutic lessons from genetic diversity. Nat Rev
Genet, 2004; 5: 669-76.
3. Haydaroğlu A. Akciğer Kanserleri Tanı ve Tedavi.
Ege Üniversitesi Basımevi, İzmir, 2000.
4. Yener NA, Apa DD, Akciğer Kanserinde Morfolojik
Tanı ve Sınıflama. Trd Sem, 2014; 2: 281-9.
5. Huang YT, Heist RS, Chirieac LR, Lin X, Skaug V,
Zienolddiny S, et al. Genome-wide analysis of
survival in early-stage non-small-cell lung cancer.
J Clin Oncol, 2009; 27: 2660-7.
6. Zhang Y, Martens JW, Yu JX, Jiang J, Sieuwerts
AM, Smid M, et al. Copy number alterations that
predict metastatic capability of human breast
cancer. Cancer Res, 2009; 69: 3795-801.
7. Turner N, Pearson A, Sharpe R, Lambros M, Geyer F,
Lopez-Garcia MA, et al. FGFR1 amplification drives
endocrine therapy resistance and is a therapeutic
target in breast cancer. Cancer Res, 2010; 70(5):
2085-94.
8. Herbest RS, Lilenbaum R. Gemcitabine and
vinorelbine cpmbinations in the treatment of nonsmall cell lung-cancer. J. Clin Oncol, 1999; 13:
1609.
9. Krug LM, Rubinstein L, Sadephi A, Group LCS.
Phase II trials of vinorelbine and doc-etaxel in the
treatment of advanced non-small cell lung cancer.
Semin Oncol, 1999; 26: 24-6.
10. Sandler AB, Nemunaitis J, Denham C. Phase III trail
of gemcitabine plus cisplatin versus cisplatin alone
in patients with locally advanced or metastatic
non-small cell lung cancer. J Clin Oncol, 2000; 18:
120-2.
11. Gazdar AF. Personalized medicine and inhibition of
EGFR signaling in lung cancer. N Engl J Med, 2009;
361: 1018-20.
12. Kratz JR, He J, Van Den Eeden SK, Zhu Z-H, Gao W,
Pham P, et al. A practical molecular assay to predict
survival in resected non- squamous, non-smallcell lung cancer: development and international
validation studies. Lancet, 2012; 379: 823-32.
14. Sharma SV, Bell DW, Settleman J, Haber DA.
Epidermal growth factor mutations in lung cancer.
Nat Rev Cancer, 2007; 7(3): 161-81.
15. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula
S, Okimoto RA, Brannigan BW, et al. Activating
mutations in the epidermal growth factor receptor
underlying responsiveness of non-small-cell lung
cancer to gefitinib. N Engl J Med, 2004; 350: 2129-
39.
16. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H,
Gabriel S, et al. EGFR mutations in lung cancer:
correlation with clinical responses to gefitinib
therapy. Science, 2004; 304: 1497-500.
17. Shan Y, Eastwood MP, Zhang X. 2012. Oncogenic
mutations counteract intrinsic disorder in the EGFR
kinase and promote receptor dimerisation. Cell,
2012; 149: 860-70.
18. Kilic D, Findikcioglu A, Alver G, Akbulut H, Hatipoglu
A. The diagnostic significance and the assessment
of the value of vascular endothelial growth factor
as a marker for success of chemical pleurodesis in
malignant pleural effusion. J Biomed Eng, 2011; 4:
214-21.
19. Hirsch FR, Scagliotti GV, Langer CJ, Varella-Garcia
M, Franklin WA. Epidermal growth factor family
of receptorsin preneoplasia and lung cancer:
perspectives for targeted therapies. Lung Cancer,
2003; 1: 29-42.
20. Rosell R, Carcereny E, Gervais R, Vergnenegre A,
Massuti B, Felip E, et al. Erlotinib versus Standard
chemotherapy as first-line treatment for European
patients with advanced EGFR mutation-positive
non-smallcell lung cancer (EURTAC): a multicentre,
open-label, randomised Phase 3 trial. Lancet
Oncol, 2012; 13: 239-46.
21. Bria E, Miella M, Cuppone F, Novello S, Ceribelli
A, Vaccaro V, et al. Outcome of advanced NSCLC
patients harboring sensitizing EGFR mutations
randomized to EGFR tyrosine kinase inhibitors or
chemotherapy as first-line treatment: a metaanalysis. Ann Oncol, 2011; 22(10): 2277-85.
22. Lee JS, Park K, Kim S. A randomized phase III
study of gefitinib (IRESSA™) versus standard
chemotherapy (gemcitabine plus cisplatin) as firstline treatment for never-smokers with advanced or
metastatic adenocarcinoma of the lung. J Thorac
Oncol, 2009; 4(9): S283.
23. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto
I, Tsurutani J, et al. Gefitinib versus cisplatin plus
docetaxel in patients with non-small-cell lung
cancer harbouring mutations of the epidermal
growth factor receptor (WJTOG3405): an open
label, randomised phase 3 trial. Lancet Oncol,
2010; 11: 121-28.
24. Zhou C, Wu YL, Chen G. Efficacy results from the
randomised phase III OPTIMAL (CTONG 0802) study
comparing first-line erlotinib versus carboplatin
(CBDCA) plus gemcitabine (GEM), in Chinese
advanced non-small-cell lung cancer (NSCLC)
patients (pts) with EGFR activating mutations.
ESMO 2010 late-breaking abstracts. Ann Oncol,
2010; 21: 86.
25. Maemondo M, Inoue A, Kobayashi K. Gefitinib or
chemotherapy for non-small-cell lung cancer with
mutated EGFR. N Engl J Med, 2010; 362: 2380-88.
26. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon
B, Maki RG, et al. Anaplastic lym- phoma kinase
inhibition in non-small-cell lung cancer. N Engl J
Med, 2010; 363: 1693-703.
27. Kim DW, Ahn MJ, Shi Y, De Pas TM, Yang PC, Riely
GJ. Results of a global phase II study with crizotinib
in advanced ALK-positive non-small cell lung cancer
(NSCLC). J Clin Oncol, 2012; 30: 7533.
28. Kim ES, Salgia R. MET pathway as a therapeutic
target. J Thorac Oncol, 2009; 4: 444-7.
29. Shaw AT, Camidge DR, Engelman JA, Solomon
BJ, Kwak EL, Clark JW, et al. Clinical activity of
crizotinib in adavanced non-small cell lung cancer
(NSCLC) harboring ROS1 gene rearrangement. J
Clin Oncol, 2012; 30(8): 863-7010.
30. Misale S, Yaeger R, Hobor S, Scala E, Janakiraman
M, Liska D, et al. Emergence of KRAS mutations
and acquired resistance to anti-EGFR therapy in
colorectal cancer. Nature, 2012; 486: 532-36.
31. Stewart EL, Tan SZ, Liu G, Tsao MS. Known and
putative mechanisms of resistance to EGFR
targeted therapies in NSCLC patients with EGFR
mutations-a review. Transl Lung Cancer Res, 2015;
4(1): 67-81.
32. Kobayashi S, Boggon TJ, Dayaram T. EGFR mutation
and resistance of non-small-cell lung cancer to
gefitinib. N Engl J Med, 2005; 352: 786-92.
33. Pao W, Miller VA, Politi KA, Riely GJ, Somwar
R, Zakowski MF, et al. Acquired resistance of
lung adenocarcinomas to gefitinib or erlotinib is
associated with a second mutation in the EGFR
kinase domain. PLoS Med, 2005; 2: 73.
34. Weiss J, Sos ML, Seidel D, Peifer M, Zander T,
Heuckmann JM, et al. Frequent and focal FGFR1
amplification associates with therapeutically
tractable FGFR1 dependency in squamous cell lung
cancer. Sci Transl Med, 2010; 2: 62-93.
35. Hammerman PS, Sos ML, RamoS AH, Xu C, Dutt A,
Zhou W, et al. Mutations in the DDR2 kinase gene
identify a novel therapeutic target in squamous
cell lung cancer. Cancer Discov, 2011; 1: 78-89.
36. Seo AN, Jin Y, Lee HJ. FGFR1 amplification is
associated with poor prognosis and smoking in nonsmall-cell lung cancer. Virchows Archiv, 2014; 465:
547-58.
37. Jiang T, Gao G, Fan G, Li M, Zhou C. FGFR1
amplification in lung squamous cell carcinoma:
a systematic review with meta-analysis. Lung
Cancer, 2015; 87(1): 1-7.
38. Reis-Filho JS, Simpson PT, Turner NC, Lambros MB,
Jones C, Mackay A. FGFR1 emerges as a potential
therapeutic target for lobular breast carcinomas.
Clin Cancer Res, 2006; 12: 6652-62.
39. Turner N, Pearson A, Sharpe R, Lambros M, Geyer F,
Lopez-Garcia MA, et al. FGFR1 amplification drives
endocrine therapy resistance and is a therapeutic
target in breast cancer. Cancer Res, 2010; 70(5):
2085-94.
40. Bergethon K, Shaw A, Ou SH, Katayama R,
Lovely CM, McDonald NT, Massion PP, et al. ROS1
rearrangements define a unique molecular class of
lung cancers. J Clin Oncol, 2012; 30(8): 63-70.
41. Mino-Kenudson M, Chirieac LR, Law K, Hornick JL,
Lindeman N, Mark EJ, et al. A novel highly sensitive
antibody allows for the routine detection of ALKrearranged lung adenocarcinomas by standard immunohistochemistry. Clin Cancer Res, 2010; 16:
1561-71.
42. Ohashi K, Sequist LV, Arcila ME, Moran T, Chmielecki
J, Lin YL, et al. Lung cancers with acquired
resistance to EGFR inhibitors occasionally harbor
BRAF gene mutations but lack mutations in KRAS,
NRAS, or MEK1. Proc Natl Acad Sci, 2012; 109:
2127-33.
43. Miao L, Wang Y, Zhu S, Shi M, Li Y, Ding J, et al.
Identification of novel driver mutations of the
discoidin domain receptor 2 (DDR2) gene in
squamous cell lung cancer of Chinese patients.
BMC Cancer, 2014; 24(14): 369.