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EGFR Mutations in US Hispanic Versus Non-Hispanic White Patients With Lung Adenocarcinoma.

Lung cancer is the leading cause of cancer-related deaths in the United States and worldwide. More than two-thirds of all patients with lung cancer are seen with advanced disease, and the overall 5-year survival rate of all lung cancer patients remains less than 15%. (1,2) Platinum-based chemotherapy constitutes the standard first-line treatment for stage IV non-small cell carcinoma of the lung, but 5-year survival remains approximately 2% for these patients. (3-5) First-generation tyrosine kinase inhibitors (TKIs) for epidermal growth factor receptor (EGFR) mutations, including gefitinib and erlotinib, significantly improve progression-free survival in stage IV lung cancer patients whose lung cancers are positive for specific driver mutations in the EGFR gene. (6-11) Most lung cancers that are positive for actionable EGFR mutations are adenocarcinoma cell type. These data recently led to the publication of an evidence-based, multidisciplinary, international Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. (12,13) The guideline provides a robust strategy for the selection of lung cancer patients for clinically validated predictive biomarker testing. According to these guidelines, EGFR molecular testing should be used to select patients for EGFR-targeted TKI therapy, and adenocarcinoma cell type is the basis for selecting lung cancers for biomarker testing.

Approximately 90% of the TKI-responsive EGFR mutations in lung adenocarcinomas are deletions in exon 19 and a point mutation that substitutes an arginine for a leucine at codon 858 (L858R) in exon 21. Point mutations or insertions in exons 18 and 20 are other genetic alterations commonly included. (14,15)

Per the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology guidelines, (13) clinical criteria such as racial/ethnic group, sex, or smoking status are not recommended as a basis for selecting patients for EGFR TKI therapy. That is, these criteria exclude too many patients who might benefit from targeted therapy. However, the frequency of actionable EGFR mutations in racial/ethnic groups is important to assess because of its possible clinical impact on specific communities. The frequency of EGFR mutations is approximately 30% in Asian populations, 15% in whites, and 19% in African Americans. (16,17) However, data on the frequency of EGFR mutations in lung adenocarcinoma among Hispanics in the United States is not currently available, to our knowledge. Of note, the frequency of EGFR mutations in non-small cell carcinoma of the lung has been reported to be 33.2% in Latin American countries overall, which is similar to the Asian population. (18,19) The objective of this study was to determine the prevalence and type of EGFR mutations that occur in adenocarcinomas among the US Hispanic population.

MATERIALS AND METHODS

With approval by the institutional review board (IRB HSC20110421H), lung adenocarcinoma tumor tissue samples from 83 patients (40 patients who self-identified as Hispanic and 43 non-Hispanic white patients) were retrieved from the surgical pathology archives at The University of Texas Health Sciences Center at San Antonio and the Audie L. Murphy Memorial Veterans Affairs Medical Center in San Antonio. Demographic information was collected by medical record review and included sex, age and tumor stage at diagnosis, and smoking status. In 2 cases, a second sample was obtained from the adenocarcinoma, providing a total of 85 samples.

Formalin-fixed, paraffin-embedded tumor tissue was cut in 10im sections onto uncharged glass slides. One slide from each case was reviewed by a board-certified pathologist (JJ) and marked for macrodissection to enrich the sample for tumor cells compared with benign cells. A minimum of 50% tumor cells in the sample was sought. The number of sections used for genomic DNA extraction ranged from 5 to 10 depending on tumor volume. Tissue was deparaffinized using CitriSolv (Thermo Fisher Scientific Inc, Waltham, Massachusetts), followed by treatment in 100% ethanol. Puregene Cell Lysis Buffer (Qiagen, Germantown, Maryland) was applied, and tumor tissue was scraped from the slides and digested with proteinase K. DNA was purified using an EZ1 tissue kit (Qiagen) on an automated workstation according to the manufacturer's instructions. The quantity and quality of genomic DNA were assessed using a spectrophotometer (NanoDrop, Thermo Fisher Scientific Inc, Waltham, Massachusetts), and genomic DNA was stored at -20[degrees]C.

A custom assay to test for the EGFR mutations was designed using the MassARRAY Assay Design 3.0 software (Sequenom, San Diego, California). Molecular testing was performed at The Methodist Hospital, Houston, Texas, using a MassARRAY instrument (Sequenom). Locus-specific polymerase chain reaction and detection primers were selected, and lung tumor DNA was amplified in a multiplex polymerase chain reaction, followed by a single-base extension reaction. The resulting nucleotides were desalted and transferred to a 384-element SpectroCHIP array (Sequenom), and alleles were discriminated by mass spectrometry.

[chi square] Contingency table analysis was used to identify significant associations between mutation status and sex, age at diagnosis, race/ethnicity, smoking status, and tumor stage at diagnosis. Significance was set at P <.05 by Fisher exact test.

RESULTS

In total, 85 lung adenocarcinoma tissue samples collected from 83 patients (40 Hispanic and 43 non-Hispanic white) were available for testing. Of the 40 Hispanic patients, 5 were nonsmokers, 13 were smokers, and 22 had unknown smoking status. Of the 43 non-Hispanic white patients, 8 were nonsmokers, 21 were smokers, and 14 had unknown smoking status. The 14 Hispanic female patients were nonsmokers or had an unknown smoking status. Among 12 non-Hispanic white female patients, 2 were smokers, and 10 were nonsmokers or had unknown smoking history. The median ages at diagnosis were 63 years among Hispanics and 62 years among non-Hispanic whites. The average ages at diagnosis were 65 years for white men and 58 years for white women. The average ages at diagnosis were 68 years for Hispanic men and 59 years for Hispanic women. Women were younger than men at diagnosis of lung adenocarcinoma for both populations.

Fourteen of 83 patients (16.9%) had EGFR mutations in their tumor DNA. Six were Hispanic (15.0%), and 8 were non-Hispanic white (18.6%) (Table). No statistically significant difference in EGFR mutation rates was observed between Hispanic and non-Hispanic white patients in our series (P =.66). Similarly, no significant association between EGFR mutations and sex was identified (P =.70). Smoking history could not be obtained for most of the 83 patients, although 8 of the 11 patients with EGFR mutations for whom smoking history was obtained were nonsmokers. Most of the tumors with EGFR mutations (12 of 14; 85.7%) were acinar with lepidic or papillary subtypes in both populations. EGFR mutations occurred in exon 19 (42.8%), exon 18 (28.6%), exon 20 (28.6%), and exon 21 (14.3%). Two cases had 2 mutations in different exons. In the 2 cases in which 2 samples were obtained, both samples showed identical results.

COMMENT

The frequency of the EGFR mutations in different populations is well documented. (16-19) For example, the mutation rate is higher in Asians and female nonsmokers. (20) However, the EGFR mutation rate in lung adenocarcinomas among the US Hispanic population has not been previously investigated to our knowledge. In this limited study, we demonstrate that the EGFR mutation rate in US Hispanics is not significantly different from that in non-Hispanic whites. Unexpectedly, we discovered that US Hispanics seem to have a lower frequency of actionable EGFR mutations in their lung cancers than those reported in Latin America. Arrieta et al, (18) in a study of 1150 patients in Latin America, found that the frequency of EGFR mutations in non-small cell carcinoma of the lung was 33.2% overall, including 19.3% in Argentina, 24.8% in Colombia, 31.2% in Mexico, and 67.0% in Peru. Of note, these authors' findings may be skewed because of the disproportionate inclusion of nonsmokers and women. The number of Hispanic women was approximately the same as the number of non-Hispanic white women in our study. Smoking history could not be obtained for most of the 83 patients herein, although 8 of the 11 patients with EGFR mutations for whom smoking history was obtained were nonsmokers. Also, we observed EGFR mutations mostly in lepidic, papillary, or acinar subtypes of adenocarcinoma, similar to previous findings. (21)

Most of the genetic alterations identified in our study were deletions in exon 19. Exon 21 mutations occurred in only 14.3% of mutation-positive tumors, with proportionately more mutations in exons 18 and 20. None had the exon 20 T790M mutation associated with acquired resistance to EGFR TKI treatment. (13,22,23) Arrieta et al, (18) in their Latin American patients, showed that 48.4% of mutation-positive patients had exon 19 deletions, and 49.0% had the L858R mutation (exon 21). These findings are consistent with data collected from Asian (60% exon 19 and 40% exon 21) and European (62% exon 19 and 38% exon 21) populations. (24)

In summary, our limited study found that the frequency of EGFR mutations in lung adenocarcinomas among US Hispanics is similar to the frequency among non-Hispanic whites. Hispanics in the United States with lung adenocarcinoma can be expected to benefit clinically from EGFR mutation testing.

We thank Leif Peterson, PhD, for assistance with the statistical analysis.

References

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(8.) Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009; 361(10):947-957.

(9.) Pao W, Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer. 2010; 10(11):760-774.

(10.) Stinchcombe TE, Socinski MA. Gefitinib in advanced non-small cell lung cancer: does it deserve a second chance? Oncologist. 2008; 13(9):933-944.

(11.) Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005; 366(9496):1527-1537.

(12.) Cagle PT, Allen TC. Lung cancer genotype-based therapy and predictive biomarkers: present and future. Arch Pathol Lab Med. 2012; 136(12):1482-1491.

(13.) Lindeman NI, Cagle PT, Beasley MB, et al. Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology [published online ahead of print April 4, 2013]. I Mol Diagn. doi:10.1016/j.jmoldx.2013.03. 001.

(14.) He M, Capelletti M, Nafa K, et al. EGFR exon 19 insertions: a new family of sensitizing EGFR mutations in lung adenocarcinoma. Clin Cancer Res. 2012; 18(6):1790-1797.

(15.) Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications [published correction appears in Lancet Oncol. 2011; 12(13):1182]. Lancet Oncol. 2012; 13(1):e23-e31. http://www.sciencedirect.com/science/article/pii/ S1470204511701292. Accessed June 14, 2013.

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(17.) Cote ML, Haddad R, Edwards DJ, et al. Frequency and type of epidermal growth factor receptor mutations in African Americans with non-small cell lung cancer. J Thorac Oncol. 2011; 6(3):627-630.

(18.) Arrieta O, Cardona AF, Federico Bramuglia G, et al; CLICaP. Genotyping non-small cell lung cancer (NSCLC) in Latin America. J Thorac Oncol. 2011; 6(11):1955-1959.

(19.) Bacchi CE, Ciol H, Queiroga EM, Benine LC, Silva LH, Ojopi EB. Epidermal growth factor receptor and KRAS mutations in Brazilian lung cancer patients. Clinics (Sao Paulo). 2012; 67(5):419-424.

(20.) 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.

(21.) Liu Y, Xu ML, Zhong HH, Heng WJ, Wu BQ. EGFR mutations are more frequent in well-differentiated than in poorly-differentiated lung adenocarcinomas. Pathol Oncol Res. 2008; 14(4):373-379.

(22.) Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005; 352(8):786-792.

(23.) Arcila ME, Nafa K, Chaft JE, et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther. 2013; 12(2):220-229.

(24.) Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. New Engl J Med 2009; 361:958-967.

Wei Zhang, MD; Elizabeth B. McQuitty, MD; Randall Olsen, MD, PhD; Hongxin Fan, MD; Heather Hendrickson, MB(ASCP)CM, MBA; Fermin O. Tio, MD; Keith Newton, MB(ASCP)CM; Philip T. Cagle, MD; Jaishree Jagirdar, MD

Accepted for publication June 6, 2013.

Published as an Early Online Release August 12, 2013.

From the Department of Pathology (Dr Zhang), Molecular Diagnostics Laboratory (Dr Fan), and Department of Pathology (Dr Jagirdar), The University of Texas Health Science Center at San Antonio, and Laboratory Service, Audie L. Murphy Memorial Veterans Affairs Medical Center (Dr Tio), San Antonio; and Department of Pathology and Immunology, Baylor College of Medicine (Dr McQuitty), and Department of Pathology and Genomic Medicine, The Methodist Hospital (Drs Olsen and Cagle, Ms Hendrickson, and Mr Newton), Houston, Texas.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Jaishree Jagirdar, MD, Department of Pathology, University of Texas Health Science Center, Mail Code 7750 7703, Floyd Curl Drive, San Antonio, TX 78229-3900 (e-mail: Jagirdar@ UTHSCSA.edu).
EGFR Mutations in US Hispanic Versus Non-Hispanic White Patients With
Lung Adenocarcinoma

Sex         Age at        Race/Ethnicity     Smoking
         Diagnosis, y                        Status

Female   43             Non-Hispanic white   No
Female   62             Non-Hispanic white   No
Female   46             Non-Hispanic white   No
Male     79             Non-Hispanic white   No
Male     88             Non-Hispanic white   No
Male     63             Non-Hispanic white   Yes
Male     58             Non-Hispanic white   Yes
Male     64             Non-Hispanic white   Yes
Female   63             Hispanic             Unknown
Female   61             Hispanic             No
Male     69             Hispanic             No
Male     83             Hispanic             No
Male     69             Hispanic             Unknown
Male     63             Hispanic             Unknown

Sex              EGFR Mutation

Female   Exon 19 E746_A750del
Female   Exon 19 E746_A750del
Female   Exon 20 S768I
Male     Exon 20 H773 > NYP
Male     Exon 18 E709K, exon 20 S761I
Male     Exon 18 E709K, exon 21 L861Q
Male     Exon 21 L861Q
Male     Exon 18 E709K
Female   Exon 19 del NOS
Female   Exon 19 E746_A750del
Male     Exon 19 del NOS
Male     Exon 18 E709K
Male     Exon 20 H773 > NYP
Male     Exon 19 del NOS

Sex                  Growth Pattern

Female   Acinar and papillary
Female   Acinar
Female   Lepidic and focal acinar and papillary
Male     Acinar, bronchioloalveolar carcinoma
Male     Acinar and papillary
Male     Acinar
Male     Acinar
Male     Acinar
Female   Acinar
Female   Acinar and solid
Male     Lepidic and acinar
Male     Acinar
Male     Solid with signet ring feature
Male     Solid

Abbreviations: EGFR, epidermal growth factor receptor;
NOS, not otherwise specified.
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Author:Zhang, Wei; McQuitty, Elizabeth B.; Olsen, Randall; Fan, Hongxin; Hendrickson, Heather; Tio, Fermin
Publication:Archives of Pathology & Laboratory Medicine
Date:Apr 1, 2014
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