Literature DB >> 24729716

Primary concomitant EGFR T790M mutation predicted worse prognosis in non-small cell lung cancer patients.

Hang Li1, Haichuan Hu1, Rui Wang1, Yunjian Pan1, Lei Wang1, Yuan Li2, Yang Zhang1, Ting Ye1, Yiliang Zhang1, Bin Li1, Lei Shen2, Yihua Sun1, Haiquan Chen1.   

Abstract

PURPOSE: We performed this analysis to improve the understanding of the clinicopathological characteristics and clinical outcome of non-small cell lung cancer (NSCLC) patients harboring the primary epidermal growth factor receptor (EGFR) T790M mutation along with activating EGFR mutation.
METHODS: Resected tumors from 1903 NSCLC patients were analyzed for mutation in EGFR, as well as KRAS (Kirsten rat sarcoma viral oncogene homolog), BRAF (v-raf murine sarcoma viral oncogene homolog B), HER2 (human epidermal growth factor 2), PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha), and EML4 (echinoderm microtubule associated protein like 4)-ALK (anaplastic lymphoma receptor tyrosine kinase) fusion. Fluorescence in situ hybridization was performed to define EGFR and c-MET (met proto-oncogene gene amplification. Expression of PIK3CA and p-Akt (phosphorylated protein kinase B) were tested using immunohistochemistry. Clinical and pathological data, including sex, age at diagnosis, stage, tumor differentiation, smoking history, histological subtype, relapse-free and overall survival, were further analyzed.
RESULTS: In all, 16 NSCLC patients were found to harbor primary EGFR T790M mutation, including 14 adenocarcinomas and two adenosquamous carcinomas, accounting for 2.04% of all the EGFR mutant cases and 0.84% of the total. No c-MET amplification was found to coexist with primary EGFR T790M. Fewer EGFR copy-number variations were found in samples harboring EGFR T790M mutations compared with those in patients with exon 19 deletions and L858R. Overall survival was significantly shorter for patients harboring EGFR T790M mutation than it was for patients with exon 19 deletions (logrank P=0.008). When taking patients harboring EGFR L858R or exon 19 deletions as one group, the overall survival was also significantly longer than that in patients with T790M mutation (logrank P=0.012). There was no significant difference in relapse-free survival among three subgroups of patients.
CONCLUSION: Our study described the clinicopathological and molecular characteristics of NSCLC patients harboring primary EGFR T790M mutations. Its value of being a predictor for worse prognosis was established. Primary EGFR T790M mutation is a rare event in NSCLC cases, but the therapeutic strategies for this subtype of patients should be precisely considered.

Entities:  

Keywords:  EGFR tyrosine kinase inhibitor; acquired resistance; clinicopathological profile; driver mutation; survival

Year:  2014        PMID： 24729716      PMCID： PMC3979794          DOI： 10.2147/OTT.S60122

Source DB:  PubMed          Journal:  Onco Targets Ther        ISSN： 1178-6930            Impact factor:   4.147


Introduction

The presence of mutations in the kinase domain of epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC) patients has been regarded as a predictive marker of good response to tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Nearly 90% of these mutations occur as either multinucleotide in-frame deletions in exon 19 or as single missense mutations that result in substitution of arginine for leucine at position 858 (L858R) in exon 21. However, after a median of approximately 10 months from the onset of TKI treatment, some patients whose tumors were initially sensitive to EGFR-TKIs have eventually developed acquired resistance.1–3 Test of biopsied tumor after disease progression has shown that half of these TKI-resistant cases contained a second site mutation in the EGFR kinase domain.4–6 The most common alteration involves a C-T (cytosine to thymine) change at nucleotide 2369 in exon 20, which results in substitution of methionine for threonine at position 790 (T790M). Cell lines with EGFR T790M mutation have been shown to have a proliferative advantage over wild type (WT) EGFR due to its increased kinase activity and downstream signaling.7 Mulloy et al8 showed the EGFR T790M/L858R double mutant exhibits a substantial increase in phosphorylation compared with the EGFR L858R mutant alone. Nevertheless, Oxnard et al9 and Arcila et al10 also observed lower growth rate in cell lines harboring both the EGFR exon 19 deletion and T790M mutation compared with cells harboring only the exon 19 deletion. Considering that the current in vitro results have been inconsistent, the impact of primary EGFR T790M mutation on the prognosis of NSCLC patients needs to be studied. Bell et al11 reported a family with multiple cases of NSCLC associated with germline EGFR T790M mutation, where four of the six available samples from two patients showed an activating EGFR mutation (L858R, in-frame deletions in exon 19 or G719A). But in another series, EGFR T790M mutation was never found among 237 NSCLC family probands.7 Thus, the finding of an NSCLC patient with primary concomitant T790M mutation in the kinase domain of EGFR was rare event in the available series. Not much is known about this subset of cases. Here we report the clinicopathological characteristics and clinical outcome of NSCLC patients whose tumor harbored T790M along with an activating EGFR kinase domain mutation, with the aim of identifying the molecular profile of this subset of NSCLC patients.

Materials and methods

Patients and specimen collection

We consecutively enrolled patients with newly diagnosed primary NSCLC between October 2007 and October 2012. All patients provided written informed consent and underwent radical surgery. Eligible patients for this study had to meet the following criteria: review of pathological diagnosis of NSCLC by morphological features and immunohistochemistry staining, confirmed by two pathologists (L Shen and Y Li); sufficient tumor tissue and corresponding normal tissue available for analysis; and patient had not received neoadjuvant treatment. This study was approved by the institutional review board of Shanghai Cancer Center, Fudan University, Shanghai, People’s Republic of China.

Mutation analysis

After the surgery, samples were divided into two parts: one part was fixed using formalin and embedded with paraffin to make pathological sections; the other part was snap-frozen in liquid nitrogen at the time of resection and stored in liquid nitrogen. Ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) were extracted from tumors and distant histological normal lung, after frozen specimens were dissected into TRIzol® (Life Technologies Corp, Carslbad, CA, USA). Total RNA samples were reverse transcribed into complementary DNA (cDNA). EGFR (exons 18 to 21), KRAS (Kirsten rat sarcoma viral oncogene homolog) (exons 2 to 3), HER2 (human epidermal growth factor 2) (exons 18 to 21), BRAF (v-raf murine sarcoma viral oncogene homolog B) (exons 11 to 15), PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) (exon 9 and exon 20) were amplified by polymerase chain reaction (PCR) (Eppendorf Mastercycler® nexus; Eppendorf, Hamburg, Germany) using complementary (c) DNA. For detection of EML4 (echinoderm microtubule associated protein like 4)–ALK (anaplastic lymphoma receptor tyrosine kinase) fusions (multiple 5′ primers, including EML4 E2F, EML4 E13F, EML4 E18F and fixed 3′ primer located to ALK E20R, were designed to amplify all known fusions variants, as previously described).12 cDNA PCR products were assessed using the Sanger direct sequencing method13 in the forward and reverse directions. All mutations were verified by analysis of an independent PCR isolate. When combined EGFR mutations were found in the cDNA PCR product, separated genotyping of each exon was performed using DNA PCR product.

Fluorescence in situ hybridization

Fluorescence in situ hybridization (FISH) testing (ThermoBrite StatSpin®; Abbott Molecular, Abbott Park, IL, USA) was performed on the corresponding formalin-fixed paraffin-embedded specimens matching the frozen specimens used for the RNA/DNA extraction, for all patients. We used the Vysis LSI EGFR SpectrumOrange/CEP 7 SpectrumGreen Probe (Abbott Laboratories, Abbott Park, IL, USA), and c-met/CEN7q FISH Probe (Abnova Corp, Taipei, Taiwan) to assess the EGFR and c-MET (met proto-oncogene) gene copy number variations. At least 50 cells were assessed for each case by two pathologists and were classified in line with the published criteria, as disomy low polysomy (<4 copies in >40% of cells), high polysomy (≥4 copies in >40% of cells), or gene amplification (homogenously staining regions with ≥ 15 copies in ≥ 10% of cells or a gene/chromosome ratio ≥2:1 per cell).14,15

Immunohistochemistry

Corresponding paraffin-embedded tissue sections were analyzed for the protein expression of PIK3CA (1:400 dilution) (PI3 Kinase p110 [C73F8] Rabbit mAb #4249; Cell Signaling Technology, Inc., Danvers, MA, USA) and p-Akt (phosphorylated protein kinase B) (1:50 dilution) (Phospho-Akt [Ser473] [736E11] Rabbit mAb #3787; Cell Signaling Technology, Inc.). Immunostaining was evaluated by two blinded observers. Immunoreactivity to any antibody was scored positive if more than 10% cells showed membranous staining of any intensity15

Clinical and pathological variables

Clinical and pathological data collected for the analyses included sex, age at diagnosis, smoking history, pathological TNM stage, tumor differentiation, and histological type. If a sample was confirmed to be lung adenocarcinoma (immunohistochemistry staining showed thyroid t ranscription factor [TTF]-1 and cytokeratin [CK]7 positive), the histological subtypes, according to the new International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) multidisciplinary classification were collected.16 Pathological TNM stages were evaluated in accordance with the seventh edition of the lung cancer staging classification system.17 Patients were interrogated about disease recurrence and survival information, either in clinic or by telephone every 3 months after the date of diagnosis. Relapse-free survival (RFS) was defined as the time elapsed between diagnosis and the date of relapse or last follow-up visit. Overall survival (OS) was calculated from the date of diagnosis to date of death or last follow-up visit.

Statistical analysis

We used percentages for qualitative variables, and mean and standard deviation for quantitative variables. Pearson test or Fisher’s exact tests were used to assess the association between two categorical variables. RFS and OS were compared using the Kaplan–Meier method and logrank test. Cox regression was performed for multivariate analysis of survival. All the statistical analyses were performed using SPSS for Windows (version 16.0) (SPSS Inc., Chicago, IL, USA). P values were two tailed for all the tests, and statistical significance was set as P<0.05.

Results

Prevalence of EGFR T790M mutation in NSCLC

In all, 1,903 patients were eligible for this analysis, including 1,213 adenocarcinomas, 539 squamous carcinomas, 57 adenosquamous carcinomas, 27 large cell carcinomas, and 67 other NSCLC subtypes. A total of 783 patients were found to harbor EGFR mutation, accounting for 41.2% of all the NSCLC cases. Patients harboring EGFR T790M accounted for 2.04% of all the EGFR mutant cases and 0.84% of the total. There were 14 adenocarcinoma patients who were found to harbor a primary concomitant EGFR T790M mutation, accounting for 1.1% of all lung adenocarcinoma cases. Two patients with adenosquamous carcinoma harbored a EGFR T790M mutation, accounting for 3.5% of all adenosquamous cases. Ten patients harbored an EGFR T790M mutation and L858R mutation concurrently. Five patients harbored EGFR T790M mutation and exon 19 in-frame deletions concurrently. One patient harbored EGFR T790M, G719S mutations, and PIK3CA E542K mutation concurrently. None of the 16 patients had any other oncogenic driver mutations, including KRAS, HER2, BRAF, and EML4-ALK fusions.

Clinicopathological characteristics of NSCLC patients harboring EGFR T790M

Primary EGFR T790M mutation occurred in 13 females and three males, ranging in age at diagnosis from 45 to 66 (mean age: 59.3) years. Of these, 93.7% (15 of 16) patients had never smoked. Three tumors were poorly differentiated; the other 13 tumors were moderately differentiated. The number of patients in pathological TNM stages I–IV was 8, 2, 5, and 1, respectively. Among the 16 patients, two had adenosquamous carcinomas, and the other 14 had adenocarcinomas. The majority subtype of adenocarcinoma was acinar (n=6), followed by papillary (n=4), micropapillary (n=2), solid and adenocarcinoma in situ. Details of the 16 patients harboring the EGFR T790M mutation are listed in Table 1. There were 54 patients with a tumor harboring EGFR L858R or exon 19 deletions consecutively enrolled. These samples underwent FISH to detect EGFR gene copy number variations. We compared the clinicopathological characteristics between these patients and patients harboring EGFR T790M (Table 2).
Table 1

Clinicopathological and molecular characteristics of 16 patients harboring primary EGFR T790M mutation

NoSexAgeSmoking historyHistologyAD subtypeDiffpTNMEGFR mutation typeEGFR copy numberOther driver mutationTreatment
1F53NeverADAcinarModerateIaDel E746-A750, T790MAmplification––
2F66NeverADMPModerateIVL858R, T790M––Gefitinib
3F62NeverADAcinarModerateIbL858R, T790M–––
4F66NeverADPModerateIIbDel E746-A750, T790M––Erlotinib
5F64NeverADAcinarModerateIIaL858R, T790M–––
6M45NeverAS–PoorIbL858R, T790MHigh polysomy––
7M62SmokerADAcinarModerateIIIbL858R, T790MAmplification–Gemcitabine + cisplatin
8F62NeverAS–PoorIIIaDel l747-T751, T790MHigh polysomy–Gemcitabine + cisplatin
9F65NeverADAcinarModerateIbL858R, T790M–––
10F66NeverADSolidPoorIIIaG719S, T790MHigh polysomyPIK3CA E542KGemcitabine + cisplatin
11F54NeverADAcinarModerateIIIaL858R, T790MHigh polysomy–Paclitaxel + cisplatin
12F57NeverADMPModerateIaDel L747-T751, T790M–––
13M57NeverADPModerateIaDel l747-T751, T790M–––
14F58NeverADPModerateIaL858R, T790M–––
15F58NeverADAISModerateIaL858R, T790M–––
16F53NeverADPModerateIIIaL858R, T790M––Gemcitabine + cisplatin

Abbreviations: AD, adenocarcinoma; AIS, adenocarcinoma in situ; AS, adenosquamous carcinoma; Diff, differentiation; EGFR, epidermal growth factor receptor; F, female; M, male; MP, micropapillary predominant; P, papillary predominant; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; pTNM, pathological TNM stage.

Table 2

Comparison of clinicopathological and molecular characteristics between NSCLC patients harboring EGFR T790M mutations and those with classic activating mutations

VariablesT790M(n=16)Exon 19 del(n=28)PaL858R(n=26)Pb
Age (years)
 Mean59.358.561.9
 SD610.20.7346.80.452
Sex
 Female131714
 Male3110.195120.102
Smoking history
 Ever198
 Never15190.067180.119
Differentiation
 Poor359
 Moderate/Well13231170.316
Stage
 I8109
 II275
 III51012
 IV110.68100.389
Histologic subtypes
 AIS10–21
 MIA01–1–
 Lepidic04–1–
 Papillary460.707100.730
 Acinar6130.82670.305
 Solid140.65050.399
 Micropapillary20–0–
EGFR FISH
 Positive61417
 Negative10140.42390.078

Notes:

Comparison between T790M and exon 19 deletions;

comparison between T790M and L858R.

Abbreviations: AIS, adenocarcinoma in situ; EGFR, epidermal growth factor receptor; FISH, fluorescence in situ hybridization; MIA, minimally invasive adenocarcinoma; NSCLC, non-small cell lung cancer; SD, standard deviation.

Clinical outcome

A total of 94 patients with only EGFR L858R mutation and 120 patients with only exon 19 in-frame deletions were consecutively enrolled from May 2009 to October 2012 (Table S1). The follow-up phase of these patients corresponded with that of the 16 patients harboring primary EGFR T790M. We analyzed the RFS and OS data of these three subgroups of patients. The median follow-up phase was 28.6 months for all the patients and 20.2 months for patients with EGFR T790M mutation. Two patients harboring EGFR T790M mutation had received EGFR-TKI treatment: one received gefitinib and had an occurrence of brain metastasis in the sixth month; the other received erlotinib to control the metastasis to the liver. The metastasis in the latter patient was assessed as progressive disease after 2 months of EGFR-TKI treatment. OS was significantly shorter for patients harboring EGFR T790M mutation than it was in patients with exon 19 deletions (logrank P=0.008). The OS was also shorter in patients with EGFR T790M mutation than that in patients harboring an L858R point mutation (logrank P=0.09). When taking patients with EGFR L858R or exon 19 deletions as one group, the OS was significantly longer than that in patients with T790M mutation (logrank P=0.012). There was no significant difference in RFS among three subgroups patients harboring different kinds of EGFR mutations (T790M versus exon 19 deletions [logrank P=0.387]; T790M versus L858R [logrank P=0.951]) (Figures 1 and 2).
Figure 1

Overall survival in patients harboring different kinds of EGFR mutation subtypes.

Abbreviation: EGFR, epidermal growth factor receptor.

Figure 2

Relapse-free survival in patients harboring different kinds of EGFR mutation subtypes.

Abbreviation: EGFR, epidermal growth factor receptor.

We also performed a multivariate analysis of survival significance of patients harboring a primary EGFR T790M mutation. Cox regression showed sex, age at diagnosis, smoking history, tumor differentiation, pathological type, EGFR gene copy number variations, and EGFR-TKI therapy had no significant influence on the OS or RFS of these patients.

EGFR gene copy number variations, c-MET amplification, PIK3CA, p-Akt expression in NSCLC with EGFR T790M mutation

Among the 16 patients harboring EGFR T790M, no c-MET amplification was found. Six of the 16 samples (37.5%) were EGFR–FISH positive, including two (12.5%) with gene amplification and four (25%) with high polysomy. We compared the frequency of EGFR gene copy number variationsm in the 16 patients harboring EGFR T790M mutation with that in 54 patients, 28 with EGFR exon 19 deletions and 26 with EGFR L858R. A lower frequency of FISH-positive cases was found in samples harboring EGFR T790M mutation compared with those with exon 19 deletions or L858R (Table 2). Positive PIK3CA and p-Akt expression were observed in four (25%) and eight (50%) of the 16 patients, respectively (Figure 3). A total of 108 NSCLC patients without any mutation were consecutively enrolled from May 2009 to October 2012. We compared PIK3CA and p-Akt expression between these patients and the patients harboring EGFR T790M (Table 3).
Figure 3

Case number of PIK3CA, p-Akt-positive expression and EGFR, c-MET gene copy number variations.

Abbreviations: c-MET, met proto-oncogene; EGFR, epidermal growth factor receptor; FISH, fluorescence in situ hybridization; p-Akt, phosphorylated protein kinase B; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha.

Table 3

Comparison of PIK3CA, p-Akt expression between patients harboring EGFR T790M mutation and those without any mutation

PIK3CA
p-Akt
+−P+−P
EGFR T790M41670.40933750.156
NSCLCa41288

Note:

Non-small cell lung cancer patients harboring no mutation.

Abbreviations: EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; p-Akt, phosphorylated protein kinase B; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha.

Discussion

Compared with classic activating EGFR mutations, such as L858R and exon 19 in-frame deletions, the clinicopathological and molecular characteristics of NSCLC patients harboring primary T790M mutations remain poorly defined. Somatic EGFR T790M is known to occur as a “secondary mutation” in more than 50% of patients in whom acquired resistance to EGFR-TKIs develops.5,6 Germline EGFR T790M mutation is rare and considered to be associated with genetic susceptibility to lung cancer, and may underlie familial predisposition to the disease.11 As far as we know, our study represents the largest investigation for the prevalence, clinicopathological features, molecular correlations, and clinical outcome in pretreated East Asian NSCLC patients harboring EGFR T790M mutation. We determined that primary EGFR T790M mutation was a rare event in NSCLC patients, and it was mutually exclusive with other well-identified molecular alterations, except for one PIK3CA E542K mutation. Prudkin et al18 identified two (0.83%) cases harboring the EGFR T790M mutation from 240 patients with lung adenocarcinomas who had never received treatment with EGFR TKIs. Inukai et al19 found one (0.54%) EGFR T790M mutation in 185 NSCLC patients without EGFR-TKI treatment, using mutant-enriched PCR analysis, but the findings could not be confirmed by direct sequencing. Considering the extremely low prevalence of primary EGFR T790M mutation in NSCLC patients, screening of this mutation in a large cohort is necessary to define the clinicopathological features and molecular correlations. Gefitinib-sensitizing EGFR mutations, such as L858R and exon 19 in-frame deletions, selectively activate antiapoptosis signaling pathways.20 Thus, they can enhance the proliferation and the resistance of apoptosis of tumor cell and have been considered to be oncogenic. In our series, primary EGFR T790M mutation was found concomitant with either L858R or exon 19 deletions in 15 (93.8%) samples. And no single EGFR T790M mutation was found. Also, baseline EGFR T790M was proved to be associated with germline molecular alterations.21 This may indicate that primary T790M mutation alone cannot induce oncogenesis. It can occur before EGFR-TKI treatment because of tumor cell heterogeneity. A valuable result we found is that patients harboring primary EGFR T790M mutation had significantly shorter OS than that did patients harboring EGFR exon 19 deletions. And the patients harboring EGFR L858R seem to have a longer OS than did the patients with EGFR T790M. It was proven that EGFR T790M may in fact provide a proliferative advantage by increasing kinase activity and downstream signaling.7,22 Our findings indicate that primary EGFR T790M mutation might be a predictor for poor prognosis. However, considering the different postoperative treatment strategies these patients received, this finding should be verified. That the RFS was not different among these mutation subtypes may be partly owing to the relatively short follow-up time. c-MET amplification was considered to be a mechanism for acquired resistance to EGFR-TKIs. This molecular change had been found in samples with gefitinib or erlotinib resistance in vivo or in vitro.23 c-MET amplification has also occasionally been found to coexist with EGFR T790M mutation.24 Therefore, we detected this kind of molecular change, using FISH, in the 16 samples harboring EGFR T790M, with an attempt to define the association between these two kinds of TKI-resistant-related molecular changes. But we found no c-MET amplification in them. This result may indicate that concurrence of the two kinds of molecular change is a rare event in patients who have not undergone EGFR-TKI treatment. Some former studies using FISH have proposed EGFR gene copy number variations as an important predictor of response to EGFR-TKIs.14,25,26 In our study, we found a lower frequency of EGFR gene copy number variations in patients harboring EGFR T790M than in patients harboring exon 19 deletions and L858R. This result may confirm that primary EGFR T790M mutation, as a molecular marker, can induce initial resistance to EGFR-TKIs. To our knowledge, well-defined EGFR-TKI resistance mechanisms share the same potential concept: they enable the cancer cell to maintain its intracellular growth signaling pathways, especially the phosphatidylinositol 3-kinase (PI3K)–protein kinase B (AKT) pathway.20,27–30 In our series, we found 50% of samples had an overexpressed level of p-Akt, but a corresponding overexpression were not found in the upstream protein PIK3CA. Our results may indicate primary EGFR T790M mutation can induce p-Akt expression through other mechanism, which are yet to be revealed. In summary, our study of a large cohort described the clinicopathological and molecular characteristics of NSCLC patients harboring primary EGFR T790M mutations. Its value of being a predictor for worse prognosis was established. Primary EGFR T790M mutation is indeed a rare molecular change in NSCLC cases, but the therapeutic strategies for this subtype of patients should be carefully considered. Details of NSCLC patients harboring EGFR L858R mutation or exon 19 deletions Abbreviations: AD, adenocarcinoma; AIS, adenocarcinoma in situ; del, deletion; EGFR, epidermal growth factor receptor; Ima, invasive mucinous adenocarcinoma; pTNM, pathological TNM stage; NSCLC, non-small cell lung cancer; MIA, minimally invasive adenocarcinoma.
Table S1

Details of NSCLC patients harboring EGFR L858R mutation or exon 19 deletions

SexSmoking historyHistologyAD subtypepTNMEGFR mutation type
FemaleEverAdenocarcinomaAcinarIA19 del
MaleEverAdenocarcinomaPapillaryIIIA19 del
MaleNeverAdenocarcinomaLepidicIIIA19 del
FemaleNeverAdenocarcinomaAcinarIIIA19 del
FemaleNeverAdenocarcinomaAcinarIA19 del
MaleEverAdenocarcinomaAcinarIA19 del
MaleEverAdenocarcinomaAcinarIIA19 del
MaleEverAdenocarcinomaPapillaryIA19 del
MaleEverAdenocarcinomaLepidicIA19 del
MaleEverAdenocarcinomaSolidIIA19 del
FemaleNeverAdenocarcinomaSolidIA19 del
FemaleNeverAdenocarcinomaAcinarIB19 del
FemaleNeverAdenocarcinomaAcinarIA19 del
FemaleNeverAdenocarcinomaAcinarIIA19 del
FemaleNeverAdenocarcinomaSolidIIIB19 del
MaleEverAdenocarcinomaPapillaryIIIA19 del
FemaleNeverAdenocarcinomaAcinarIIA19 del
FemaleNeverAdenocarcinomaLepidicIA19 del
FemaleNeverAdenocarcinomaImaIB19 del
FemaleNeverAdenocarcinomaAcinarIIA19 del
FemaleNeverAdenocarcinomaMicropapillaryIA19 del
FemaleNeverAdenocarcinomaSolidIIIA19 del
MaleEverAdenocarcinomaSolidIB19 del
FemaleNeverAdenocarcinomaLepidicIIIA19 del
MaleNeverAdenocarcinomaPapillaryIA19 del
FemaleNeverAdenocarcinomaAcinarIA19 del
FemaleNeverAdenocarcinomaSolidIIIA19 del
FemaleNeverAdenocarcinomaSolidIIIA19 del
FemaleNeverAdenocarcinomaPapillaryIIIB19 del
FemaleEverAdenocarcinomaAcinarIIA19 del
FemaleNeverAdenocarcinomaSolidIB19 del
MaleNeverAdenocarcinomaPapillaryIA19 del
FemaleNeverAdenocarcinomaAcinarIA19 del
FemaleNeverAdenocarcinomaAcinarIIIA19 del
FemaleNeverAdenocarcinomaAcinarIA19 del
FemaleNeverAdenocarcinomaPapillaryIB19 del
FemaleNeverAdenocarcinomaPapillaryIB19 del
FemaleNeverAdenocarcinomaAcinarIA19 del
FemaleNeverAdenocarcinomaLepidicIB19 del
MaleEverAdenocarcinomaPapillaryIIIA19 del
FemaleNeverAdenocarcinomaAcinarIA19 del
FemaleNeverAdenocarcinomaPapillaryIIIA19 del
MaleEverAdenocarcinomaAcinarIB19 del
FemaleNeverAdenocarcinomaSolidIB19 del
MaleNeverAdenocarcinomaAcinarIA19 del
FemaleNeverAdenocarcinomaAcinarIB19 del
FemaleNeverAdenocarcinomaAcinarIIIA19 del
MaleNeverAdenocarcinomaPapillaryIIA19 del
FemaleNeverAdenocarcinomaSolidIIA19 del
FemaleNeverAdenocarcinomaAcinarIB19 del
FemaleNeverAdenocarcinomaAcinarIA19 del
MaleEverAdenocarcinomaAcinarIIIA19 del
FemaleNeverAdenocarcinomaAcinarIB19 del
MaleNeverAdenocarcinomaAcinarIB19 del
MaleNeverAdenocarcinomaPapillaryIIIA19 del
MaleNeverAdenocarcinomaAcinarIIIA19 del
FemaleNeverAdenocarcinomaImaIB19 del
FemaleNeverAdenocarcinomaAcinarIIA19 del
MaleEverAdenocarcinomaAcinarIV19 del
FemaleNeverAdenocarcinomaLepidicIA19 del
FemaleNeverAdenocarcinomaPapillaryIIIA19 del
MaleEverAdenocarcinomaAcinarIA19 del
FemaleNeverAdenocarcinomaLepidicIB19 del
MaleNeverAdenocarcinomaAcinarIB19 del
MaleEverAdenocarcinomaAcinarIIIA19 del
FemaleNeverAdenocarcinomaAcinarIIIA19 del
MaleEverAdenocarcinomaPapillaryIA19 del
MaleEverAdenocarcinomaAcinarIIIA19 del
FemaleNeverAdenocarcinomaAcinarIB19 del
FemaleNeverAdenocarcinomaPapillaryIB19 del
FemaleNeverAdenocarcinomaAcinarIA19 del
FemaleNeverAdenocarcinomaAcinarIIIA19 del
FemaleNeverAdenocarcinomaSolidIIIA19 del
FemaleNeverAdenocarcinomaAcinarIA19 del
MaleEverAdenocarcinomaAcinarIB19 del
MaleEverAdenocarcinomaAcinarIIIA19 del
FemaleNeverAdenocarcinomaAcinarIIIA19 del
FemaleNeverAdenocarcinomaAcinarIA19 del
FemaleNeverAdenocarcinomaPapillaryIB19 del
FemaleNeverAdenocarcinomaAcinarIIIA19 del
MaleEverAdenocarcinomaAcinarIIIA19 del
FemaleNeverAdenocarcinomaAcinarIB19 del
MaleEverAdenocarcinomaSolidIIA19 del
MaleEverAdenocarcinomaPapillaryIIA19 del
MaleEverAdenocarcinomaSolidIA19 del
MaleEverAdenocarcinomaAcinarIB19 del
MaleNeverAdenocarcinomaAcinarIIA19 del
FemaleNeverAdenocarcinomaAcinarIB19 del
FemaleNeverAdenocarcinomaLepidicIB19 del
FemaleNeverAdenocarcinomaPapillaryIIIA19 del
FemaleNeverAdenocarcinomaPapillaryIIIA19 del
FemaleNeverAdenocarcinomaSolidIIA19 del
MaleEverAdenocarcinomaAcinarIIIA19 del
FemaleNeverAdenocarcinomaSolidIIIA19 del
FemaleNeverAdenocarcinomaMIAIA19 del
FemaleNeverAdenocarcinomaAcinarIA19 del
FemaleNeverAdenocarcinomaMicropapillaryIIA19 del
FemaleNeverAdenocarcinomaAcinarIB19 del
FemaleNeverAdenocarcinomaAcinarIIIA19 del
MaleEverAdenocarcinomaPapillaryIB19 del
FemaleNeverAdenocarcinomaAcinarIB19 del
MaleEverAdenocarcinomaAcinarIIIA19 del
FemaleNeverAdenocarcinomaLepidicIA19 del
FemaleNeverAdenocarcinomaSolidIIIA19 del
MaleEverAdenocarcinomaAcinarIIIA19 del
FemaleNeverAdenocarcinomaAcinarIA19 del
FemaleNeverAdenocarcinomaAcinarIA19 del
FemaleNeverAdenocarcinomaLepidicIA19 del
FemaleNeverAdenocarcinomaAcinarIB19 del
FemaleNeverAdenocarcinomaLepidicIA19 del
FemaleNeverAdenocarcinomaAcinarIB19 del
FemaleNeverAdenocarcinomaLepidicIA19 del
FemaleNeverAdenocarcinomaAcinarIB19 del
MaleEverAdenocarcinomaPapillaryIIIA19 del
FemaleNeverAdenocarcinomaAcinarIA19 del
MaleNeverAdenocarcinomaMicropapillaryIIIA19 del
FemaleNeverAdenocarcinomaAcinarIA19 del
FemaleNeverAdenocarcinomaAISIA19 del
FemaleNeverAdenocarcinomaAcinarIIIA19 del
MaleEverAdenocarcinomaPapillaryIB19 del
MaleEverAdenocarcinomaAcinarIAL858R
FemaleNeverAdenocarcinomaAcinarIIIAL858R
MaleEverAdenocarcinomaPapillaryIAL858R
MaleNeverAdenocarcinomaPapillaryIIIAL858R
MaleEverAdenocarcinomaSolidIIIAL858R
FemaleNeverAdenocarcinomaAISIAL858R
FemaleNeverAdenocarcinomaPapillaryIBL858R
FemaleNeverAdenocarcinomaAcinarIIIAL858R
FemaleNeverAdenocarcinomaPapillaryIAL858R
MaleEverAdenocarcinomaPapillaryIAL858R
FemaleNeverAdenocarcinomaAcinarIIIAL858R
FemaleNeverAdenocarcinomaAcinarIBL858R
FemaleNeverAdenocarcinomaPapillaryIAL858R
FemaleNeverAdenocarcinomaSolidIIAL858R
MaleNeverAdenocarcinomaPapillaryIIBL858R
FemaleNeverAdenocarcinomaAcinarIAL858R
FemaleNeverAdenocarcinomaPapillaryIIAL858R
FemaleNeverAdenocarcinomaPapillaryIIIAL858R
FemaleNeverAdenocarcinomaAcinarIAL858R
MaleEverAdenocarcinomaAcinarIIAL858R
FemaleNeverAdenocarcinomaAcinarIIIAL858R
FemaleNeverAdenocarcinomaAcinarIAL858R
FemaleNeverAdenocarcinomaAcinarIIIAL858R
MaleEverAdenocarcinomaSolidIIIAL858R
MaleEverAdenocarcinomaLepidicIAL858R
MaleEverAdenocarcinomaAcinarIIIAL858R
MaleNeverAdenocarcinomaAcinarIAL858R
MaleNeverAdenocarcinomaAcinarIAL858R
FemaleNeverAdenocarcinomaMIAIAL858R
FemaleNeverAdenocarcinomaAcinarIBL858R
FemaleNeverAdenocarcinomaAcinarIBL858R
FemaleNeverAdenocarcinomaAcinarIAL858R
FemaleNeverAdenocarcinomaAcinarIAL858R
FemaleNeverAdenocarcinomaAcinarIAL858R
FemaleNeverAdenocarcinomaAcinarIIIBL858R
FemaleNeverAdenocarcinomaLepidicIAL858R
MaleNeverAdenocarcinomaMicropapillaryIIIAL858R
FemaleNeverAdenocarcinomaPapillaryIIIAL858R
MaleEverAdenocarcinomaAcinarIIIAL858R
MaleNeverAdenocarcinomaAcinarIBL858R
FemaleNeverAdenocarcinomaLepidicIBL858R
FemaleNeverAdenocarcinomaAcinarIBL858R
FemaleNeverAdenocarcinomaImaIIIAL858R
MaleEverAdenocarcinomaAcinarIIIAL858R
FemaleNeverAdenocarcinomaAcinarIIIAL858R
MaleEverAdenocarcinomaPapillaryIIIAL858R
MaleNeverAdenocarcinomaLepidicIBL858R
MaleEverAdenocarcinomaSolidIAL858R
MaleEverAdenocarcinomaSolidIVL858R
FemaleNeverAdenocarcinomaAcinarIAL858R
FemaleNeverAdenocarcinomaAcinarIBL858R
FemaleNeverAdenocarcinomaAcinarIIIAL858R
FemaleNeverAdenocarcinomaPapillaryIAL858R
MaleNeverAdenocarcinomaAcinarIAL858R
MaleEverAdenocarcinomaPapillaryIIAL858R
FemaleNeverAdenocarcinomaAcinarIBL858R
FemaleNeverAdenocarcinomaAcinarIAL858R
FemaleNeverAdenocarcinomaAcinarIAL858R
FemaleNeverAdenocarcinomaMicropapillaryIAL858R
FemaleNeverAdenocarcinomaPapillaryIIIAL858R
FemaleNeverAdenocarcinomaAcinarIIIAL858R
FemaleNeverAdenocarcinomaAcinarIAL858R
FemaleNeverAdenocarcinomaAcinarIBL858R
FemaleNeverAdenocarcinomaSolidIIIAL858R
FemaleNeverAdenocarcinomaAcinarIIIAL858R
MaleEverAdenocarcinomaAcinarIIIAL858R
FemaleNeverAdenocarcinomaAcinarIAL858R
FemaleNeverAdenocarcinomaLepidicIAL858R
MaleNeverAdenocarcinomaMIAIAL858R
FemaleNeverAdenocarcinomaAcinarIBL858R
FemaleNeverAdenocarcinomaAcinarIAL858R
MaleEverAdenocarcinomaAcinarIAL858R
MaleEverAdenocarcinomaPapillaryIIIAL858R
FemaleNeverAdenocarcinomaAcinarIBL858R
MaleNeverAdenocarcinomaAcinarIIAL858R
FemaleNeverAdenocarcinomaAcinarIBL858R
FemaleNeverAdenocarcinomaSolidIIIAL858R
FemaleNeverAdenocarcinomaAcinarIBL858R
FemaleNeverAdenocarcinomaPapillaryIAL858R
MaleNeverAdenocarcinomaPapillaryIBL858R
FemaleNeverAdenocarcinomaAcinarIBL858R
FemaleNeverAdenocarcinomaAcinarIAL858R
FemaleNeverAdenocarcinomaLepidicIAL858R
FemaleNeverAdenocarcinomaAcinarIIAL858R
FemaleNeverAdenocarcinomaAcinarIAL858R
FemaleNeverAdenocarcinomaLepidicIBL858R
MaleEverAdenocarcinomaSolidIIBL858R
FemaleNeverAdenocarcinomaAcinarIAL858R
FemaleNeverAdenocarcinomaAcinarIIIAL858R
FemaleNeverAdenocarcinomaLepidicIAL858R
FemaleNeverAdenocarcinomaPapillaryIAL858R
FemaleNeverAdenocarcinomaPapillaryIIAL858R
MaleEverAdenocarcinomaAcinarIIBL858R
FemaleNeverAdenocarcinomaSolidIIIAL858R

Abbreviations: AD, adenocarcinoma; AIS, adenocarcinoma in situ; del, deletion; EGFR, epidermal growth factor receptor; Ima, invasive mucinous adenocarcinoma; pTNM, pathological TNM stage; NSCLC, non-small cell lung cancer; MIA, minimally invasive adenocarcinoma.

  30 in total

1.  Oncogenic activity of epidermal growth factor receptor kinase mutant alleles is enhanced by the T790M drug resistance mutation.

Authors:  Nadia Godin-Heymann; Ianthe Bryant; Miguel N Rivera; Lindsey Ulkus; Daphne W Bell; David J Riese; Jeffrey Settleman; Daniel A Haber
Journal:  Cancer Res       Date:  2007-08-01       Impact factor: 12.701

2.  Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR.

Authors:  Daphne W Bell; Ira Gore; Ross A Okimoto; Nadia Godin-Heymann; Raffaella Sordella; Roseann Mulloy; Sreenath V Sharma; Brian W Brannigan; Gayatry Mohapatra; Jeff Settleman; Daniel A Haber
Journal:  Nat Genet       Date:  2005-10-30       Impact factor: 38.330

3.  Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib.

Authors:  David M Jackman; Beow Y Yeap; Lecia V Sequist; Neal Lindeman; Alison J Holmes; Victoria A Joshi; Daphne W Bell; Mark S Huberman; Balazs Halmos; Michael S Rabin; Daniel A Haber; Thomas J Lynch; Matthew Meyerson; Bruce E Johnson; Pasi A Jänne
Journal:  Clin Cancer Res       Date:  2006-07-01       Impact factor: 12.531

4.  Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib.

Authors:  Takayuki Kosaka; Yasushi Yatabe; Hideki Endoh; Kimihide Yoshida; Toyoaki Hida; Masahiro Tsuboi; Hirohito Tada; Hiroyuki Kuwano; Tetsuya Mitsudomi
Journal:  Clin Cancer Res       Date:  2006-10-01       Impact factor: 12.531

5.  Comprehensive analysis of epidermal growth factor receptor gene status in lung adenocarcinoma.

Authors:  Chenguang Li; Yihua Sun; Zhaoyuan Fang; Xiangkun Han; Rong Fang; Yang Zhang; Yunjian Pan; Wenjing Zhang; Yan Ren; Hongbin Ji; Haiquan Chen
Journal:  J Thorac Oncol       Date:  2011-06       Impact factor: 15.609

6.  Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255.

Authors:  Sean Tracy; Toru Mukohara; Mark Hansen; Matthew Meyerson; Bruce E Johnson; Pasi A Jänne
Journal:  Cancer Res       Date:  2004-10-15       Impact factor: 12.701

7.  Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay.

Authors:  Maria E Arcila; Geoffrey R Oxnard; Khedoudja Nafa; Gregory J Riely; Stephen B Solomon; Maureen F Zakowski; Mark G Kris; William Pao; Vincent A Miller; Marc Ladanyi
Journal:  Clin Cancer Res       Date:  2011-01-19       Impact factor: 12.531

8.  Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer.

Authors:  Federico Cappuzzo; Fred R Hirsch; Elisa Rossi; Stefania Bartolini; Giovanni L Ceresoli; Lynne Bemis; Jerry Haney; Samir Witta; Kathleen Danenberg; Irene Domenichini; Vienna Ludovini; Elisabetta Magrini; Vanesa Gregorc; Claudio Doglioni; Angelo Sidoni; Maurizio Tonato; Wilbur A Franklin; Lucio Crino; Paul A Bunn; Marileila Varella-Garcia
Journal:  J Natl Cancer Inst       Date:  2005-05-04       Impact factor: 13.506

9.  The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours.

Authors:  Peter Goldstraw; John Crowley; Kari Chansky; Dorothy J Giroux; Patti A Groome; Ramon Rami-Porta; Pieter E Postmus; Valerie Rusch; Leslie Sobin
Journal:  J Thorac Oncol       Date:  2007-08       Impact factor: 15.609

10.  Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib.

Authors:  Gregory J Riely; William Pao; Duykhanh Pham; Allan R Li; Naiyer Rizvi; Ennapadam S Venkatraman; Maureen F Zakowski; Mark G Kris; Marc Ladanyi; Vincent A Miller
Journal:  Clin Cancer Res       Date:  2006-02-01       Impact factor: 12.531
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  16 in total

1.  Coexpression of c-Met and Notch-1 correlates with poor prognosis in resected non-small-cell lung cancer.

Authors:  Ximing Wang; Na Song; Ye Zhang; Ying Cai; Yunpeng Liu; Xiujuan Qu; Zhi Li; Danni Li; Kezuo Hou; Jian Kang; Xuejun Hu
Journal:  Tumour Biol       Date:  2015-04-14

2.  Genomic Signature of Driver Genes Identified by Target Next-Generation Sequencing in Chinese Non-Small Cell Lung Cancer.

Authors:  Shiwang Wen; Lei Dai; Lei Wang; Wenjian Wang; Duoguang Wu; Kefeng Wang; Zhanghai He; Aodi Wang; Hui Chen; Peng Zhang; Xiaowei Dong; Yu-An Dong; Kai Wang; Ming Yao; Minghui Wang
Journal:  Oncologist       Date:  2019-03-22

3.  Biomarkers in Non-Small Cell Lung Cancers: Indian Consensus Guidelines for Molecular Testing.

Authors:  Kumar Prabhash; Suresh H Advani; Ullas Batra; Bivas Biswas; Anuradha Chougule; Mithua Ghosh; Vamshi Krishna Muddu; T P Sahoo; Ashok K Vaid
Journal:  Adv Ther       Date:  2019-03-12       Impact factor: 3.845

4.  Multiplex Ultrasensitive Genotyping of Patients with Non-Small Cell Lung Cancer for Epidermal Growth Factor Receptor (EGFR) Mutations by Means of Picodroplet Digital PCR.

Authors:  Masaru Watanabe; Tomoya Kawaguchi; Shun-Ichi Isa; Masahiko Ando; Akihiro Tamiya; Akihito Kubo; Hideo Saka; Sadanori Takeo; Hirofumi Adachi; Tsutomu Tagawa; Osamu Kawashima; Motohiro Yamashita; Kazuhiko Kataoka; Yukito Ichinose; Yukiyasu Takeuchi; Katsuya Watanabe; Akihide Matsumura; Yasuhiro Koh
Journal:  EBioMedicine       Date:  2017-06-07       Impact factor: 8.143

Review 5.  A systematic review and meta-analysis of individual patient data on the impact of the BIM deletion polymorphism on treatment outcomes in epidermal growth factor receptor mutant lung cancer.

Authors:  Sheila X Soh; Fahad J Siddiqui; John C Allen; Go Woon Kim; Jae Cheol Lee; Yasushi Yatabe; Manabu Soda; Hiroyuki Mano; Ross A Soo; Tan-Min Chin; Hiromichi Ebi; Seiji Yano; Keitaro Matsuo; Xiaomin Niu; Shun Lu; Kazutoshi Isobe; Jih-Hsiang Lee; James C Yang; Mingchuan Zhao; Caicun Zhou; June-Koo Lee; Se-Hoon Lee; Ji Yun Lee; Myung-Ju Ahn; Tira J Tan; Daniel S Tan; Eng-Huat Tan; S Tiong Ong; Wan-Teck Lim
Journal:  Oncotarget       Date:  2017-06-20

Review 6.  The safety and efficacy of osimertinib for the treatment of EGFR T790M mutation positive non-small-cell lung cancer.

Authors:  Xin Gao; Xiuning Le; Daniel B Costa
Journal:  Expert Rev Anticancer Ther       Date:  2016-03-21       Impact factor: 4.512

Review 7.  Tumor heterogeneity and resistance to EGFR-targeted therapy in advanced nonsmall cell lung cancer: challenges and perspectives.

Authors:  Xinghua Cheng; Haiquan Chen
Journal:  Onco Targets Ther       Date:  2014-09-23       Impact factor: 4.147

Review 8.  Osimertinib making a breakthrough in lung cancer targeted therapy.

Authors:  Haijun Zhang
Journal:  Onco Targets Ther       Date:  2016-09-06       Impact factor: 4.147

9.  Clinical analysis of sixty-four patients with T1aN2M0 stage non-small cell lung cancer who had undergone resection.

Authors:  Jian Xiong; Rui Wang; Yihua Sun; Haiquan Chen
Journal:  Thorac Cancer       Date:  2015-10-06       Impact factor: 3.500

10.  Uncommon EGFR mutations in cytological specimens of 1,874 newly diagnosed Indonesian lung cancer patients.

Authors:  Elisna Syahruddin; Laksmi Wulandari; Nunuk Sri Muktiati; Ana Rima; Noni Soeroso; Sabrina Ermayanti; Michael Levi; Heriawaty Hidajat; Grace Widjajahakim; Ahmad Rusdan Handoyo Utomo
Journal:  Lung Cancer (Auckl)       Date:  2018-03-23
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