This document addresses the use of epidermal growth factor receptor (EGFR) mutation and gene amplification testing for predicting the response to drug therapy in individuals with non-small cell lung cancer (NSCLC), and for all other indications.

Medically Necessary: 

Analysis of mutations in the gene for the epidermal growth factor receptor (EGFR) is considered medically necessary as a technique to predict treatment response to erlotinib (Tarceva^®) or gefitinib (Iressa^®) in individuals with non-small cell, non-squamous cell lung cancer, if the results of the test will be used to select therapy. 

Investigational and Not Medically Necessary:

Analysis of mutations in the gene for epidermal growth factor receptor (EGFR) is considered investigational and not medically necessary for all other uses not specified above.

Analysis of gene amplification for epidermal growth factor receptor (EGFR) is considered investigational and not medically necessary for all indications, including as a technique to predict treatment response to tyrosine kinase inhibitor therapy [e.g., erlotinib (Tarceva^®) or gefitinib (Iressa^®)] in individuals with non-small cell lung cancer (NSCLC).

EGFR mutation analysis

The published literature addressing the use of EGFR mutation analysis consists of EGFR mutational analysis correlated with response to either gefitinib or, to a lesser extent, erlotinib; two tyrosine kinase inhibitor drugs (TKIs) used in the treatment of some lung cancers. Given that individuals with advanced NSCLC have few treatment options, the most likely clinical application of EGFR mutational analysis would be to deselect individuals most unlikely to benefit from targeted therapy with a TKI. Therefore, the negative predictive value (NPV) of tumor response is of greatest clinical importance. Relevant, published studies are reviewed here, with an emphasis on the NPV.

Gefitinib (Iressa^®)

Han and colleagues retrospectively performed EGFR mutational analysis in 90 consecutive subjects with advanced NSCLC who had received gefitinib; all were of Asian ethnicity (Han, 2005). Of these 90 subjects, 17 harbored EGFR mutations (18%), and 11 of these 17 subjects (64.7%) exhibited a partial remission. In contrast, only 10 of 73 subjects (13.7%) without an EGFR mutation exhibited a partial remission. A higher incidence of EGFR mutations has been found in those of East Asian ethnicity, and it is unclear if the results of the analysis could be generalized to a broader population. In a similarly designed study, Mitsudomi and colleagues performed EGFR mutational analysis on 59 subjects with recurrent NSCLC treated with gefitinib (Mitsudomi, 2005). Mutations were identified in 33 subjects (56%). Response was assessable in 50 subjects, and among these, only 2 of 21 subjects without an EGFR mutation exhibited a response to gefitinib.

The IDEAL-1 and IDEAL-2 studies were randomized studies of gefitinib monotherapy versus placebo in individuals with advanced NSCLC who had received prior chemotherapy. Another set of studies, the INTACT-1 and INTACT-2 studies, compared single-agent chemotherapy with and without gefitinib in previously untreated individuals. Bell and colleagues reported the results of EGFR mutational analysis on subsets of individuals from these trials (Bell, 2005). The negative predictive value of mutational analysis for overall response was 90% in the IDEAL studies while the negative predictive value of mutational analyses was 44% in the INTACT studies.

Mok and colleagues conducted a randomized open-label study comparing gefitinib to chemotherapy in previously untreated individuals with pulmonary adenocarcinoma (2009). In this study, 609 subjects were randomized to receive gefitinib and 608 to receive carboplatin-paclitaxel chemotherapy with the primary endpoint of progression free survival (PFS).  At the end of a 12-month follow-up period, overall PFS was 24.0% for the gefitinib group and 6.7% for the chemotherapy group (p < 0.001). In the subgroup that tested positive for an EGFR mutation (n=261), PFS was significantly longer in the gefitinib group than the chemotherapy group (p < 0.001) while the EGFR negative subgroup had  significantly longer PFS when treated with chemotherapy compared to gefitinib (p < 0.001).  The authors concluded that the presence of an EGFR gene mutation in a tumor is a strong predictor of a better outcome with gefitinib than with carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma. 

Erlotinib (Tarceva^®)

The National Institute of Canada Clinical Trials Group Study BR.21 randomized study compared the outcomes of erlotinib monotherapy with placebo as a salvage therapy in 731 subjects with advanced NSCLC. Tsao and colleagues reported the results of EGFR mutational analysis in a subset of 100 subjects who received erlotinib, had successful mutational analysis, and who had evaluable disease (Tsao, 2005). Among the 19 subjects with an EGFR mutation, only 3 achieved a response (16%), while 6 of 81 subjects (7%) without an EGFR mutation had a response. Mutational status appeared to have no significant association with responsiveness (P=0.37).

Another study by Clark and others analyzed tumor samples from individuals who participated in the National Institute of Canada Clinical Trials Group Study BR.21 (Clark, 2006).  Three hundred and twenty five subjects from the study had evaluable tumor samples which were tested for EGFR expression via immunochemistry.  The authors report that the prognostic ability of EGFR expression status testing was not significant at any cut-off point in their study.  They concluded that selection or exclusion of individuals with NSCLC for erlotinib therapy after failure of standard therapy for advanced disease should not be based solely on EGFR expression.

In 2009, the Spanish Lung Cancer Group published the findings of a prospective case series study involving 2105 subjects from 129 institutions with stage IIIB disease with pleural effusion or stage IV disease who were prospectively screened for EGFR mutations (Rosell, 2009). Individuals with tumors carrying EGFR mutations were eligible for erlotinib treatment.  The study was designed to analyze the association between EGFR mutations and the outcome of treatment with erlotinib.  EGFR mutations were found in 350 (16.6%) of all subjects.  EGFR mutations were more frequent in women (69.7%), in subjects who had never smoked (66.6%), and in those with adenocarcinoma (80.9%).  The mutations found were deletions in exon 19 (62.2%) and L858R (37.8%).  Investigators evaluated 296 subjects with tumors carrying an EGFR mutation, 79 did not receive erlotinib treatment (23 declined, 18 died prior to starting treatment, 38 began treatment subsequent to study start date).  Of the 217 subjects who received erlotinib, 197 could be evaluated.  Of the 197 subjects evaluated, 24 had a complete response, 115 had a partial response; 38 had stable disease, and 20 had progressive disease.  Median follow-up was 14 months.  Median progression-free survival (erlotinib as first-, second-, or third-line therapy) was 14.0 months and median overall survival was 27.0 months which is an improvement over lung cancer outcomes in trials reported previously where chemotherapy normally yields a 30% response, a 5-month progression-free survival, and a 12 month median survival.  Multivariate analysis showed a higher probability of response with exon 19 deletion mutation (odds ratio 3.08; 95% CI, 1.63-5.81; p=0.001) and an age between 61 and 70 years (odds ratio, 2.55; 95% CI, 1.32 TO 4.96; P=0.006), but not with other factors.  The authors concluded that screening for EGFR mutation is warranted in women with lung cancer, in those who have never smoked, and in those with non-squamous tumors as a tool to select targeted therapy with erlotinib.

D'Angleo and colleagues conducted a study investigating the correlation of EGFR exon 19 deletions and exon 21 L858R mutations to sex and smoking status in 2,142 lung adenocarcinoma samples from consecutively treated subjects.  EGFR mutations were found in 15% of tumors from former smokers, 6% from current smokers, and 52% from never smokers (p < 0.001 for ever vs. never smokers). EGFR mutations in former or current smokers represented 40% of all those detected. EGFR mutations were found in 19% of tumors from men and 26% of tumors from women (p < 0.001).  EGFR mutations in men represented 31% of all those detected.  The authors conclude that even though the mutation rate is low in men and smokers, they account for a larger portion of those with adenocarcinoma of the lung. Thus, including these populations in routine mutation analysis when being considered for treatment with erlotinib or gefitinib is reasonable and warranted.   

At this time there are no peer-reviewed published studies addressing the clinical utility of EGFR mutation analysis in individuals with conditions other than NSCLC.

Gene Amplification

It has been proposed that the measurement of EGFR amplification in NSCLC tumor tissue can be used for the prediction of response to TKI drug therapy.  The evidence regarding this question is currently mixed.  One study of 102 subjects with advanced NSCLC treated with gefitinib reported that EGFR gene amplification was statistically significantly associated with better drug response, disease control rate, time to progression and survival (Capuzzo, 2005).  In contrast, a study of 199 subjects with early stage NSCLC who had undergone surgical resection found no significant survival difference between subjects with or without EGFR amplification (Dacic, 2006).  Another study by Tsao and colleagues (2005) evaluated 221 subjects with advanced NSCLC treated with erlotinib.  The authors reported that although responsiveness to erlotinib may be associated with EGFR gene amplification (P=0.04), increased survival was not (P=0.10).

The use of EGFR amplification testing for conditions other than NCSLC has been limited. There have been several  small studies that have investigated the use of EGFR amplification status in subjects with glioblastoma, head and neck squamous cell cancer (HNSCC), colon and gastric cancers (Cascinu, 2008; da Cunha Santos, 2010; Geyer, 2010; Laurent-Puig, 2009; Saarilahti , 2010; Srividya, 2010; Van Damme, 2010; Yung, 2010).  Several of these studies have shown some benefit from EGFR amplification testing.  However, at this time the clinical utility of such testing has not been established.

National Comprehensive Cancer Network (NCCN) Guidelines

The National Comprehensive Cancer Network (NCCN) Version 2.2012 guideline for the treatment of NSCLC (2011) includes a category 1 recommendation for EGFR testing for the following NSCLC histologies:  adenocarcinoma, large cell, and NSCLC NOS (not otherwise specified).  NCCN concluded that EGFR mutation testing is not recommended for squamous cell carcinoma of the lung.

American Society of Clinical Oncology (ASCO) Publication Recommendations

The American Society of Clinical Oncology (ASCO) published a guideline update on chemotherapy for stage IV NSCLC (Azzoli, 2009). This guideline includes an updated recommendation that first-line use of gefitinib may be considered for individuals with a known activating EGFR tumor mutation, but for negative or unknown EGFR mutation status, cytotoxic chemotherapy is still preferred.

Summary

While to date there have not been prospective, randomized clinical trials demonstrating improved survival when EGFR mutation status is used to direct therapy with erlotinib, an increasing number of studies have demonstrated an association between EGFR mutation status and clinical response to erlotinib.  However, most are nonconcurrent, prospective or single-arm studies which evaluate the response of EGFR positive and EGFR negative tumors to erlotinib or gefitinib.  As noted above, individuals with EGFR mutation positive tumors are likely to respond favorably to erlotinib while individuals without an EGFR mutation (wild-type tumor) are not and individuals with EGFR positive tumors appear to show better response to erlotinib than standard chemotherapy.  Taken together, these studies have been used to support consensus opinions and clinical guidelines developed by respected clinical authorities.

According to the American Cancer Society, NSCLC accounts for nearly 85% of all lung cancers.  There are multiple sub-types of NSCLC that differ in size, shape, histology and molecular markers (see definitions section).  The more common subtypes include: 1) squamous cell carcinoma, which accounts for about 25% to 30% of all lung cancers; 2) adenocarcinoma, which accounts for about 40% of lung cancers; and 3) large-cell undifferentiated carcinoma, which accounts for about 10% to 15% of lung cancers.

A specific glycoprotein called epidermal growth factor receptor EGFR is a tyrosine kinase that has been identified as a major factor in regulating cellular proliferation, differentiation and survival.  NSCLC cells frequently have over-expressed and activated genes for EGFR, which are believed to contribute to the growth and progression of this type of cancer.  Recent research has focused on the development of EGFR-specific TKIs.

Erlotinib received FDA approval in November of 2004 as salvage therapy for advanced NSCLC, based on the results of a phase III clinical trial that demonstrated a modest survival benefit, 6.7 months median survival compared to 4.7 months in the placebo group. Gefitinib (Iressa) was FDA approved in 2003 through the FDA's accelerated approval process, based on the initially promising results of phase II trials.  The labeled indication was limited to individuals with NSCLC who had failed two or more prior chemotherapy regimens.  However, in December of 2004 results of phase III trials became available, suggesting that gefitinib was not associated with a survival benefit.  In their press release, the FDA noted that in Phase III trials, individuals treated with erlotinib did have a very modest, but statistically significant improvement in survival, implying that this was the preferred agent.  In May of 2005, the FDA revised the labeling of gefitinib to further limit its use to individuals who were currently benefiting from the drug, or who had benefited in the past.

Subsequent subgroup analysis over several clinical trials of both of these drugs suggested that factors predicting response were female sex, never having smoked, Asian descent, or bronchioalveolar (type of adenocarcinoma) cancer (as opposed to other NSCLC subtypes). Several studies have now reported that these characteristics are also associated with increased frequency of specific EGFR gene mutations (Paez 2004).

Another issue related to EGFR and NSCLC is gene amplification, which is defined as the presence of an increased number of copies of a specific gene fragment in a chromosome. This is measured using a laboratory method referred to as in-situ hybridization.  Gene amplification may lead to production of increased numbers of a gene copies, a process referred to as elevated gene expression.  Gene expression is measured by immunohistochemical testing.  EGFR gene amplification testing has been proposed as a predictor of clinical response to TKI drugs.

Both EGFR mutation analysis (PCR amplification and gene sequencing) and EGFR gene amplification (fluorescence in-situ hybridization or FISH) are commercially available (Genzyme Genetics Westborough, MA).  These tests are regulated under the Clinical Laboratory Improvement Amendments (CLIA).  Pre-market approval from the FDA is not required when the assay is performed in a laboratory that observes the CLIA regulations.

Epidermal Growth Factor Receptor (EGFR): A cell receptor that is associated with regulation of cell growth. This type of receptor is referred to as a tyrosine kinase. 

Gene amplification: A genetic variation characterized by the presence of multiple copies of the same genetic code on a chromosome.

Mutation: A permanent, transmissible change in genetic material.

World Health Organization (WHO)/International Association for the Study of Lung Cancer Histologic Classification of Non-Small Cell Lung Carcinomas (NSCLC):

1. Squamous cell carcinoma.
   • Papillary.
   • Clear cell.
   • Small cell.
   • Basaloid.
2. Adenocarcinoma.
   • Acinar.
   • Papillary.
   • Bronchioloalveolar carcinoma.
     • Nonmucinous.
     • Mucinous.
     • Mixed mucinous and nonmucinous or indeterminate cell type.
   • Solid adenocarcinoma with mucin.
   • Adenocarcinoma with mixed subtypes.
   • Variants.
     • Well-differentiated fetal adenocarcinoma.
     • Mucinous (colloid) adenocarcinoma.
     • Mucinous cystadenocarcinoma.
     • Signet ring adenocarcinoma.
     • Clear cell adenocarcinoma.
3. Large cell carcinoma.
   • Variants.
     • Large-cell neuroendocrine carcinoma.
     • Combined large-cell neuroendocrine carcinoma.
     • Basaloid carcinoma.
     • Lymphoepithelioma-like carcinoma.
     • Clear cell carcinoma.
     • Large cell carcinoma with rhabdoid phenotype.
4. Adenosquamous carcinoma.
5. Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements.
   • Carcinomas with spindle and/or giant cells.
   • Spindle cell carcinoma.
   • Giant cell carcinoma.
   • Carcinosarcoma.
   • Pulmonary blastoma.
6. Carcinoid tumor.
   • Typical carcinoid.
   • Atypical carcinoid.
7. Carcinomas of salivary-gland type.
   • Mucoepidermoid carcinoma.
   • Adenoid cystic carcinoma.
   • Others.
8. Unclassified carcinoma.

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member. 

When services may be Medically Necessary when criteria are met:

When services are Investigational and Not Medically Necessary:
For EGFR mutation analysis testing when criteria are not met and for all other uses not specified as medically necessary.

When services are also Investigational and Not Medically Necessary:
When the code(s) describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Peer Reviewed Publications:

1. Asahina H, Yamazaki K, Kinoshita I, et al. A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations. Br J Cancer. 2006; 95(8):998-1004
2. Bell DW, Lynch TJ, Haserlat SM, et al. Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol. 2005; 23(31):8081-8092.
3. Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst. 2005; 97(9):643-655.
4. Cappuzzo F, Ligorio C, Toschi L, et al. EGFR and HER2 gene copy number and response to first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). J Thorac Oncol. 2007a: 2(5):423-429.
5. Cappuzzo F, Ligorio C, Jänne PA, et al. Prospective study of gefitinib in epidermal growth factor receptor fluorescence in situ hybridization-positive/phospho-Akt-positive or never smoker patients with advanced non-small-cell lung cancer: the ONCOBELL trial. J Clin Oncol. 2007b; 25(16):2248-2255.
6. Cascinu S, Berardi R, Salvagni S, et al. A combination of gefitinib and FOLFOX-4 as first-line treatment in advanced colorectal cancer patients. A GISCAD multicentre phase II study including a biological analysis of EGFR overexpression, amplification and NF-kB activation. Br J Cancer. 2008; 98(1):71-76.
7. Clark GM, Zborowski DM, Culbertson JL, et al. Clinical utility of epidermal growth factor receptor expression for selecting patients with advanced non-small cell lung cancer for treatment with erlotinib. J Thorac Oncol. 2006; 1(8):837-846.
8. da Cunha Santos G, Dhani N, Tu D, et al. Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: National Cancer Institute of Canada Clinical Trials Group Study PA.3. Cancer. 2010; 116(24):5599-5607.
9. Dacic S, Flanagan M, Cieply K, et al.  Significance of EGFR protein expression and gene amplification in non-small cell lung carcinoma. Am J Clin Pathol. 2006; 125(6):860-865.
10. D'Angelo SP, Pietanza, C, Johnson ML, et al. Incidence of EGFR exon 19 deletions and L858R in tumor specimens from men and cigarette smokers with lung adenocarcinomas. J Clin Oncol. 2011; 29(15):2066-2070.
11. Douillard JY, Shepherd FA, Hirsh V, 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(5):744-752.
12. Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small cell lung cancer treated chemotherapy alone and in combination with erlotinib. J Clin Oncol. 2005; 23(25):5900-5909.
13. Feld R, Sridhar SS, Shepherd FA, et al. Use of the epidermal growth factor receptor inhibitors gefitinib and erlotinib in the treatment of non-small cell lung cancer: a systematic review. J Thorac Oncol. 2006; 1(4):367-376.
14. Fukuoka M, Wu YL, Thongprasert S, 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(21):2866-2874.
15. Geyer JR, Stewart CF, Kocak M, et al. A phase I and biology study of gefitinib and radiation in children with newly diagnosed brain stem gliomas or supratentorial malignant gliomas. Eur J Cancer. 2010; 46(18):3287-3293.
16. Han SW, Kim TY, Hwang PG, et al. Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol. 2005; 23(11):2493-2501.
17. Hirsch FR, Varella-Garcia M, McCoy J, et al. Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a Southwest Oncology Group Study. J Clin Oncol. 2005; 23(28):6838-6845.
18. Hirsch FR, Varella-Garcia M, Cappuzzo F, et al. Combination of EGFR gene copy number and protein expression predicts outcome for advanced non-small-cell lung cancer patients treated with gefitinib. Ann Oncol. 2007; 18(4):752-760.
19. Huang SF, Liu HP, Li LH, et al. High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan. Clin Cancer Res. 2004; 10(24):8195-8203.
20. Inoue A, Suzuki T, Fukuhara T, et al. Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol. 2006; 24(21):3340-3346.
21. Laurent-Puig P, Cayre A, Manceau G, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009; 27(35):5924-5930.
22. Lynch TJ, Bell DW, Sordella R, 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(21):2129-2139.
23. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non–small-cell lung cancer with mutated EGFR. N Engl J Med. 2010; 362:2380-2388.
24. Mitsudomi T, Morita S, Yatabe Y, 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(2):121–128.
25. Mitsudomi T, Kosaka T, Endoh H, et al. Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol. 2005; 23(11):2513-2520.
26. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009; 361(10):947-957.
27. Mok TS, Wu YL, Yu CJ, et al. Randomized, placebo-controlled, phase II study of sequential erlotinib and chemotherapy as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol. 2009; 27(30):5080-5087.
28. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004; 304(5676):1497-1500.
29. Parra HS, Cavina R, Latteri F, et al. Analysis of epidermal growth factor receptor expression as a predictive factor for response to gefitinib ('Iressa', ZD1839) in non-small-cell lung cancer. Br J Cancer. 2004; 91(2):208-212.
30. Rosell R, Perez-Roca L, Sanchez JJ, et al. Customized treatment in non-small-cell lung cancer based on EGFR mutations and BRCA1 mRNA expression. PLoS One. 2009; 4(5):e5133.
31. Rosell R, Moran T, Queralt C, et al.; The Spanish Lung Group. Screening for epidermal growth factor receptor mutations in lung cancer.  N Engl J Med. 2009; 361(10):958-967.
32. Saarilahti K, Bono P, Kajanti M, et al. Phase II prospective trial of gefitinib given concurrently with cisplatin and radiotherapy in patients with locally advanced head and neck cancer. J Otolaryngol Head Neck Surg. 2010; 39(3):269-276.
33. Sequist LV, Joshi VA, Jänne PA, et al. Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing. Oncologist. 2007; 12(1):90-98.
34. Srividya MR, Thota B, Arivazhagan A, et al. Age-dependent prognostic effects of EGFR/p53 alterations in glioblastoma: study on a prospective cohort of 140 uniformly treated adult patients. J Clin Pathol. 2010; 63(8):687-691.
35. Takano T, Ohe Y, Sakamoto H, et al. Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol. 2005; 23(28):6829-6837.
36. Tan EH, Ramlau R, Pluzanska A, et al. A multicentre phase II gene expression profiling study of putative relationships between tumour biomarkers and clinical response with erlotinib in non-small-cell lung cancer. Ann Oncol. 2010; 21(2):217-222.
37. Tanaka T, Matsuoka M, Sutani A, et al. Frequency of and variables associated with the EGFR mutation and its subtypes. Int J Cancer. 2010; 126(3):651-655.
38. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med. 2005; 353(2):133-144.
39. Van Damme N, Deron P, Van Roy N, Demetter P, et al. Epidermal growth factor receptor and K-RAS status in two cohorts of squamous cell carcinomas. BMC Cancer. 2010; 10:189.
40. van Zandwijk N, Mathy A, Boerrigter L, et al. EGFR and KRAS mutations as criteria for treatment with tyrosine kinase inhibitors: retro- and prospective observations in non-small-cell lung cancer. Ann Oncol. 2007; 18(1):99-103.
41. Wu YL, Zhong WZ, Li LY, et al. Epidermal growth factor receptor mutations and their correlation with gefitinib therapy in patients with non-small cell lung cancer: a meta-analysis based on updated individual patient data from six medical centers in mainland China. J Thorac Oncol. 2007; 2(5):430-439.
42. Yoshida K, Yatabe Y, Park JY, et al. Prospective validation for prediction of gefitinib sensitivity by epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer. J Thorac Oncol. 2007; 2(1):22-28.
43. Yung WK, Vredenburgh JJ, Cloughesy TF, et al. Safety and efficacy of erlotinib in first-relapse glioblastoma: a phase II open-label study. Neuro Oncol. 2010; 12(10):1061-1070.
44. Zhu CQ, da Cunha Santos G, Ding K, et al; National Cancer Institute of Canada Clinical Trials Group Study BR.21. 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(26):4268-4275.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Azzoli CG, Baker S Jr, Temin S, et al. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non–small-cell lung cancer. J Clin Oncol. 2009; 27(36):6251-6266.
2. Blue Cross Blue Shield Association. Epidermal growth factor receptor mutations and tyrosine kinase inhibitor therapy in advanced non-small-cell lung cancer. TEC Assessment, 2007; 22(6).
3. National Comprehensive Cancer Network (NCCN) [website]. Practice Guidelines in Oncology. Non-Small Cell Lung Cancer. v2.2011. Updated October 4, 2011. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#.  Accessed October 11, 2011.

1. American Cancer Association. Lung Cancer - Non-Small Cell. Available at: http://www.cancer.org/Cancer/LungCancer-Non-SmallCell/DetailedGuide/index. Accessed on August 26, 2011.
2. National Cancer Institute. Non-Small Cell Cancer Treatment (PDQ^®). Available at: http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/HealthProfessional/page2. Accessed on August 26, 2011.
3. National Library of Medicine. Medical Encyclopedia: Non-Small Cell Lung cancer. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/007194.htm. Accessed on August 26, 2011.

EGFR
Epidermal Growth Factor Receptor
Erlotinib
Gefitinib
Iressa^®
Tarceva^®
Tyrosine Kinase 

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.