Epidermal Growth Factor Receptor Mutation and Lung Cancers, Current Evidence, a Brief Review

Research Article

Austin J Radiat Oncol & Cancer. 2015; 1(3): 1012.

Epidermal Growth Factor Receptor Mutation and Lung Cancers, Current Evidence, a Brief Review

Yen-Chien Lee*

Department of Oncology, Tainan Hospital, Ministry of Health and Welfare, Tainan

*Corresponding author: Yen-Chien Lee, Department of Oncology, Tainan Hospital, Ministry of Health and Welfare, ROC.No. 125, Jhongshan Rd, Tainan City 70043, Tainan

Received: June 22, 2015; Accepted: September 15, 2015; Published: October 01, 2015

Abstract

With the advances of target therapies, lung cancer patients overall survival had extended from previous 6 months to 2.5 years. Some patients even survived over 5 years more. It is important nowadays for general physicians have some knowledge of this topic. A brief review was conducted.

Keywords: EGFR; Progression free survival; Overall-survival

Abbreviations

PFS: Progression Free Survival; OS: Overall-Survival

Epidemiology

EGFR mutations, EGFR gene copy number, and EGFR protein expression are three EGFR-related biomarkers [1-3]. EGFR mutations are present in the first four exons and about 90% of these mutations are either short in-frame deletions in exon 19, or point mutations that result in a substitution of arginine for leucine at amino acid 858 (L858R) [4-6].

Among severe Asian regions, EGFR mutation had been detected about 51.4% overall, but lowest in Indian 22.2% [7]. In Western population, around 15% (13.1-17.8%) EGFR mutation, 27.6% (465/1,683) KRAS mutations, and around 5% (4.4-7.1%) ALK rearrangements were identified [8,9]. Also, EGFR mutations and ALK rearrangement were mutually exclusive [8,9] but not with KRAS. In BR.21 trial, 3 patients had both EGFR and KRAS mutation [10]. EGFR mutation has only being reported 9.8% in Germany samples [11]. African Americans has been reported harboring EGFR mutation as low as 2% [12] but 21% mutation has been reported [13] in North African patients.

Among non-adenocarcinoma of the lung, 8.4% was associated with EGFR mutations [14].

EGFR mutant type

In recent studies, four published meta-analysis of EGFR mutant analysis had showed that TKIs treatment compared with chemotherapy has been associated with better PFS but not OS [15- 18]. Only 1 of 4 paper used fixed effect model in meta-analysis (Table 1). Due to over all comparisons were not based on randomization and the extracted data used for this analysis could not be considered randomization. Also, most of the published articles provided the crossover rate only for the entire group of enrolled patients with out wild type or mutation subgroup data. The effect of treatment crossover on the out comes could not be examined in IPASS study, 64.3% EGFR mutation received EGFR TKIs post discontinuation [19]. As for OPTIMAL and CTONG-0802 trials, OS cannot be reached due to not mature yet. However, in their regimen, they used carboplatin instead of cisplatin [20] which has been long considered being a standard regimen.

Table 1: Baseline characteristics of the meta-analysis





  

    
Study

    
End of search date

    
Published year

    
Treatment

    
Study selected

      
meta-methods

  

  

    
Gao G et al (15)

    
1966 to June 10, 2011

    
2012

    
1st line

    
Randomized, random-effect

  

  

    
Xu C etl al (16)

    
Dec 31,2011

    
2012

    
1st line

    
Randomized, random-effect

  

  

    
Lee CK et al (17)

    
Jan 1,2004 to June6, 2012

    
2013

    
1st, 2nd and 3rd

    
Randomized, fixed-effect

  

  

    
Lee JK et al (18)

    
Dec 16,2013

    
2014

    
1st, 2nd and maintaneous

    
Randomized,

      
Random effect

  










Table 1:  Baseline characteristics of the meta-analysis

Difference in exon 19, 21 mutation sequence has also been associated with different median PFS [21]. Exon 19 deletion has been associated with a better PFS than L858R mutation [19-20] but not OS [22]. Even among exon 19 deletion, deletions encompassing the entire amino acid string from L747 though E749 had better PFS but not OS than deletion at other sites [23]. Uncommon EGFR mutations were associated with poor OS than common mutation under TKI therapy [24,25]. Milella M et al., reported that those with higher EGFR gene copy number had a poorer PFS and OS than EGF Rmutation [26] after receiving TKI. On contrary, Lee Y et al., reported higher EGFR gene copy number and skin rash had been associated with better response rate and PFS compared with no amplification [27]. KRA Summation combined with EGFR mutations had been associated with a poor response [28].

On the other hand, there were around 10% (8.75%-13.9%) discordance in EGFR mutation heterogeneity between the primary Chinese lung cancer tissue and the metastasis sites [29,30] and 15.7 discordance in Japan [31]. About a third of combined EGFR-mutated and wild-type were detected in a study of 85 patients [32]. So, direct sequencing or any methods might misclassify of EGFR mutation as WT.

The most common toxicity of TKIs is rash and the most serious toxicity is interstitial lung disease, which occurs in about 1% of patients and is fatal in 30% who develop this toxicity. In NCIC CTG BR19 Study of adjuvant setting of gefitinib, the most common serious adverse event was dyspneam (13% vs 7% of patients on gefitinib and placebo, respectively). Other serious adverse events were less frequent and occurred in = 5% of patients, with the exception of infection and pain. Three of five deaths (60%) in the gefitinib arm were considered drug related.

EGFR wild type

As for wild type, TKI has been associated with better PFS in maintenance therapy but not 1st line or 2nd and 3rd line (Table 2). Wild type didn’t have good response nor poor response to TKI in OS (Table 3).

Table 2: Progression free survival.





  

    
EGFRmut+

    
Placebo/N

    
HR (95% CI)

  

  

    
1stline

    
 

    
 

  

  

    
Xu C etl al (16)

    
0/5

    
0.36 (0.31,0.43)

  

  

    
Lee CK et al (17)

    
1/12

    
0.43 (0.38,0.49)

  

  

    
Gao G et al (15)

    
0/6

    
0.37 (0.27,0.52)

  

  

    
Maintenance

    
 

    
 

  

  

    
Lee CK et al (17)

    
3/3

    
0.34 (0.20,0.60)

  

  

    
2nd line

    
 

    
 

  

  

    
Lee CK et al (17)

    
0/4

    
0.34(0.20,0.60)

  

  

    
EGFRmut-

    
 

    
 

  

  

    
1st line

    
 

    
 

  

  

    
Lee CK et al (17)

    
1/7

    
1.06 (0.94,1.19)

  

  

    
Lee JK et al (18)

    
0/4

    
1.53 (0.87,2.69)

  

  

    
Maintenance

    
 

    
 

  

  

    
Lee CK et al (17)

    
3/3

    
0.81 (0.68,0.97)

  

  

    
2nd line

    
 

    
 

  

  

    
Lee CK et al (17)

    
0/5

    
1.23 (1.05,1.46)

  

  

    
Lee JK et al (18)

    
0/6

    
1.34 (1.09,1.65)

  










Table 2:  Progression free survival.

Table 3: Overall survival.





  

    
EGFRmut+

    
Placebo/N

    
HR (95% CI)

  

  

    
1stline

    
 

    
 

  

  

    
Xu C etl al (16)

    
0/3

    
1.00 (0.79,1.27)

  

  

    
Lee CK et al (17)

    
1/11

    
1.01 (0.87,1.18)

  

  

    
Gao G et al (15)

    
0/5

    
0.97 (0.77,1.15)

  

  

    
Maintenance

    
 

    
 

  

  

    
Lee CK et al (17)

    
2/1

    
0.78(0.33,1.84)

  

  

    
2nd line

    
 

    
 

  

  

    
Lee CK et al (17)

    
2/5

    
0.74 (0.45,1.19)

  

  

    
EGFRmut-

    
 

    
 

  

  

    
1st line

    
 

    
 

  

  

    
Lee CK et al (17)

    
1/6

    
1.00 (0.88,1.14)

  

  

    
Lee JK et al (18)

    
0/4

    
1.05 (0.91, 1.23)*

  

  

    
Maintenance

    
 

    
 

  

  

    
Lee CK et al (17)

    
2/2

    
0.84 (0.69,1.04)

  

  

    
2nd line

    
 

    
 

  

  

    
Lee CK et al (17)

    
2/5

    
0.93 (0.79,1.10)

  

  

    
Lee JK et al (18)

    
0/5

    
1.05 (0.93,1.19)*

  










Table 3:  Overall survival.

Others TKIs

Other drugs including in phase III trial were icotinib. However, mutation status were not planed initially at randomization [33]. Afatinib has been shown to improved PFS in mutant type compared with Gemcitabine and cisplatin group (11.0 months vs 5.6 months) in LUX-Lung 6 study [34]. The OS result was still pending.

Survival benefit, mutation type better or wild type better

After brain metastasis, EGFR mutation didn’t associated with better PFS or OS compared with wild type [35]. EGFR mutation has been associated with better PFS after treatment with TKI but not OS as well [33]. In stage IV lung cancer patients, EGFR mutations compared with wild type were more associated with lung, brain and bone metastasis. Bone metastasis was associated with poor OS [36]. Even more complicated, difference in transcriptional subgroups in EGFR mutated and EGFR wild types were associated with different OS [37].

Marks JL et al [38] tried to clarify the role of EGFR and KRAS mutation in prognosis but failed due to small sample size. Whether EGFR mutation is a poor prognosis factor for poor OS in the era of TKI remains largely unknown.

EGFR resistant mechanism

Mutant EGFR patients often develop acquired resistance to EGFR TKI after a median of 10 to 16 months [39].

Among 155 EGFR-mutant lung cancers with resistant to TKI, 63% had CGFR T790M mutation, whereas HER2 amplifications (13%, 3/24), MET amplification (5%, 4/75), small cell transformation (3%) occur less frequently [40]. Besides, LEE GK et al., [41] had reported a preexisting EGFR T790M mutation in 25% of patients with EGFRmutant lung cancer in their 124 treatment-naive patients. Another reported around 5-11% of harboring EGFR T790M mutation prior to the therapy [42].

Cell line models resistant mechanisms were beyond the description of this paper. Interesting readers could review the following paper [43].

BR.21 trial had demonstrated better OS which later lead to the prove of TKI for 2nd and 3rd line of standard treatment. However, no OS were identified of TKI therapy with either wild type or mutant type EGFR [17]. Increased EGFR copy number by FISH has also been associated with a better OS and KRAS mutation seems associated with poor response of OS though the power was not enough [10]. Would it possible that EGFR gene copy by FISH be the biomarker of better OS? Maybe higher EGFR gene copy number should be the issue.

In conclusion, TKIs therapy in EGFR mutation could lead to prolong PFS in 1st, 2nd and maintenance therapy but not OS. Further clarified the role of EGFR gene copy number and protein expression in the era of TKIs might be need.

References

  1. Tsao MS, Sakurada A, Cutz JC, Zhu CQ, Kamel-Reid S, Squire J et al. Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med 2005; 353: 133-144.
  2. Hirsch FR, Varella-Garcia M, Bunn PA, Jr., Franklin WA, Dziadziuszko R, Thatcher N et al. Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 2006; 24: 5034-5042.
  3. Douillard JY, Shepherd FA, Hirsh V, Mok T, Socinski MA, Gervais R et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol 2010; 28: 744-752.
  4. 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: 2129-2139.
  5. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304: 1497-1500.
  6. Kosaka T, Yatabe Y, Endoh H, Kuwano H, Takahashi T, Mitsudomi T. Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res 2004; 64: 8919-8923.
  7. Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, Khoa MT et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 2014; 9: 154-162.
  8. Gainor JF, Varghese AM, Ou SH, Kabraji S, Awad MM, Katayama R et al. ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res 2013; 19: 4273-4281.
  9. Martinez P, Hernandez-Losa J, Montero MA, Cedres S, Castellvi J, Martinez-Marti A et al. Fluorescence in situ hybridization and immunohistochemistry as diagnostic methods for ALK positive non-small cell lung cancer patients. PLoS One 2013; 8: e52261.
  10. Zhu CQ, da Cunha Santos G, Ding K, Sakurada A, Cutz JC, Liu N et al. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 2008; 26: 4268-4275.
  11. Gahr S, Stoehr R, Geissinger E, Ficker JH, Brueckl WM, Gschwendtner A et al. EGFR mutational status in a large series of Caucasian European NSCLC patients: data from daily practice. Br J Cancer 2013; 109: 1821-1828.
  12. Leidner RS, Fu P, Clifford B, Hamdan A, Jin C, Eisenberg R et al. Genetic abnormalities of the EGFR pathway in African American Patients with non-small-cell lung cancer. J Clin Oncol 2009; 27: 5620-5626.
  13. Errihani H, Inrhaoun H, Boukir A, Kettani F, Gamra L, Mestari A et al. Frequency and type of epidermal growth factor receptor mutations in moroccan patients with lung adenocarcinoma. J Thorac Oncol 2013; 8: 1212-1214.
  14. Cho SH, Park LC, Ji JH, Park S, Hwang DW, Lee JY et al. Efficacy of EGFR tyrosine kinase inhibitors for non-adenocarcinoma NSCLC patients with EGFR mutation. Cancer Chemother Pharmacol 2012; 70: 315-320.
  15. Gao G, Ren S, Li A, Xu J, Xu Q, Su C et al. Epidermal growth factor receptor-tyrosine kinase inhibitor therapy is effective as first-line treatment of advanced non-small-cell lung cancer with mutated EGFR: A meta-analysis from six phase III randomized controlled trials. Int J Cancer 2012; 131: E822-829.
  16. Xu C, Zhou Q, Wu YL. Can EGFR-TKIs be used in first line treatment for advanced non-small cell lung cancer based on selection according to clinical factors? - A literature-based meta-analysis. J Hematol Oncol 2012; 5: 62.
  17. Lee CK, Brown C, Gralla RJ, Hirsh V, Thongprasert S, Tsai CM et al. Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: a meta-analysis. J Natl Cancer Inst 2013; 105: 595-605.
  18. Lee JK, Hahn S, Kim DW, Suh KJ, Keam B, Kim TM et al. Epidermal growth factor receptor tyrosine kinase inhibitors vs conventional chemotherapy in non-small cell lung cancer harboring wild-type epidermal growth factor receptor: a meta-analysis. JAMA 2014; 311: 1430-1437.
  19. Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 2011; 29: 2866-2874.
  20. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011; 12: 735-742.
  21. Lee VH, Tin VP, Choy TS, Lam KO, Choi CW, Chung LP et al. Association of exon 19 and 21 EGFR mutation patterns with treatment outcome after first-line tyrosine kinase inhibitor in metastatic non-small-cell lung cancer. J Thorac Oncol 2013; 8: 1148-1155.
  22. Won YW, Han JY, Lee GK, Park SY, Lim KY, Yoon KA et al. Comparison of clinical outcome of patients with non-small-cell lung cancer harbouring epidermal growth factor receptor exon 19 or exon 21 mutations. J Clin Pathol 2011; 64: 947-952.
  23. Chung KP, Wu SG, Wu JY, Yang JC, Yu CJ, Wei PF et al. Clinical outcomes in non-small cell lung cancers harboring different exon 19 deletions in EGFR. Clin Cancer Res 2012; 18: 3470-3477.
  24. Watanabe S, Minegishi Y, Yoshizawa H, Maemondo M, Inoue A, Sugawara S et al. Effectiveness of gefitinib against non-small-cell lung cancer with the uncommon EGFR mutations G719X and L861Q. J Thorac Oncol 2014; 9: 189-194.
  25. Wu JY, Yu CJ, Chang YC, Yang CH, Shih JY, Yang PC. Effectiveness of tyrosine kinase inhibitors on "uncommon" epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin Cancer Res 2011; 17: 3812-3821.
  26. Milella M, Nuzzo C, Bria E, Sperduti I, Visca P, Buttitta F et al. EGFR molecular profiling in advanced NSCLC: a prospective phase II study in molecularly/clinically selected patients pretreated with chemotherapy. J Thorac Oncol 2012; 7: 672-680.
  27. Lee Y, Shim HS, Park MS, Kim JH, Ha SJ, Kim SH et al. High EGFR gene copy number and skin rash as predictive markers for EGFR tyrosine kinase inhibitors in patients with advanced squamous cell lung carcinoma. Clin Cancer Res 2012; 18: 1760-1768.
  28. Takeda M, Okamoto I, Fujita Y, Arao T, Ito H, Fukuoka M et al. De novo resistance to epidermal growth factor receptor-tyrosine kinase inhibitors in EGFR mutation-positive patients with non-small cell lung cancer. J Thorac Oncol 2010; 5: 399-400.
  29. Sun L, Zhang Q, Luan H, Zhan Z, Wang C, Sun B. Comparison of KRAS and EGFR gene status between primary non-small cell lung cancer and local lymph node metastases: implications for clinical practice. J Exp Clin Cancer Res 2011; 30: 30.
  30. Shin DY, Na, II, Kim CH, Park S, Baek H, Yang SH. EGFR mutation and brain metastasis in pulmonary adenocarcinomas. J Thorac Oncol 2014; 9: 195-199.
  31. Shimizu K, Yukawa T, Hirami Y, Okita R, Saisho S, Maeda A et al. Heterogeneity of the EGFR mutation status between the primary tumor and metastatic lymph node and the sensitivity to EGFR tyrosine kinase inhibitor in non-small cell lung cancer. Target Oncol 2013; 8: 237-242.
  32. Bai H, Wang Z, Wang Y, Zhuo M, Zhou Q, Duan J et al. Detection and clinical significance of intratumoral EGFR mutational heterogeneity in Chinese patients with advanced non-small cell lung cancer. PLoS One 2013; 8: e54170.
  33. Shi Y, Zhang L, Liu X, Zhou C, Zhang L, Zhang S et al. Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol 2013; 14: 953-961.
  34. Li DW, Liu WQ, Wang HM, Ying S, Cui L, Zhao FF. The Chinese language version of the abbreviated Burn Specific Health Scale: a validation study. Burns 2014; 40: 1001-1006.
  35. Luo D, Ye X, Hu Z, Peng K, Song Y, Yin X et al. EGFR mutation status and its impact on survival of Chinese non-small cell lung cancer patients with brain metastases. Tumour Biol 2014; 35: 2437-2444.
  36. Fujimoto D, Ueda H, Shimizu R, Kato R, Otoshi T, Kawamura T et al. Features and prognostic impact of distant metastasis in patients with stage IV lung adenocarcinoma harboring EGFR mutations: importance of bone metastasis. Clin Exp Metastasis 2014; 31: 543-551.
  37. Planck M, Isaksson S, Veerla S, Staaf J. Identification of transcriptional subgroups in EGFR-mutated and EGFR/KRAS wild-type lung adenocarcinoma reveals gene signatures associated with patient outcome. Clin Cancer Res 2013; 19: 5116-5126.
  38. Marks JL, Broderick S, Zhou Q, Chitale D, Li AR, Zakowski MF et al. Prognostic and therapeutic implications of EGFR and KRAS mutations in resected lung adenocarcinoma. J Thorac Oncol 2008; 3: 111-116.
  39. Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009; 361: 958-967.
  40. Diaz R, Nguewa PA, Parrondo R, Perez-Stable C, Manrique I, Redrado M et al. Antitumor and antiangiogenic effect of the dual EGFR and HER-2 tyrosine kinase inhibitor lapatinib in a lung cancer model. BMC Cancer 2010; 10: 188.
  41. Lee Y, Lee GK, Lee YS, Zhang W, Hwang JA, Nam BH et al. Clinical outcome according to the level of preexisting epidermal growth factor receptor T790M mutation in patients with lung cancer harboring sensitive epidermal growth factor receptor mutations. Cancer 2014; 120: 2090-2098.
  42. Oh JE, An CH, Yoo NJ, Lee SH. Detection of low-level EGFR T790M mutation in lung cancer tissues. APMIS 2011; 119: 403-411.
  43. Suda K, Mizuuchi H, Maehara Y, Mitsudomi T. Acquired resistance mechanisms to tyrosine kinase inhibitors in lung cancer with activating epidermal growth factor receptor mutation--diversity, ductility, and destiny. Cancer Metastasis Rev 2012; 31: 807-814.

Citation: Yen-Chien Lee. Epidermal Growth Factor Receptor Mutation and Lung Cancers, Current Evidence, a Brief Review. Austin J Radiat Oncol & Cancer. 2015; 1(3): 1012. ISSN:2471-0385