Lung Adenocarcinoma with <i>EGFR</i> Amplification Has Distinct Clinicopathologic and Molecular Features in Never-Smokers

Sholl, Lynette M.; Yeap, Beow Y.; Iafrate, A. John; Holmes-Tisch, Alison J.; Chou, Yi-Ping; Wu, Ming‐Tsang; Goan, Yih‐Gang; Li, Su; Benedettini, Elisa; Yu, Jinpu; Loda, Massimo; Jänne, Pasi A.; Christiani, David C.; Chirieac, Lucian R.

doi:10.1158/0008-5472.can-09-2477

Cited by 109 publications

(78 citation statements)

References 33 publications

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“…The presence of high-level amplification may be heterogeneous within the tumor (Figure 2, B), correlates with more advanced-stage and higher-grade disease (suggesting a role in promoting tumorigenesis), and is associated with increased EGFR protein expression. 32 High expression of total EGFR is not specific to tumors with EGFR-activating mutations and thus is an inadequate predictor of response to EGFR-TKIs. 33 Mutation-specific antibodies against EGFR L858R-mutated protein are highly sensitive and specific ( Figure 3); however, this alteration accounts for less than half of those seen in targetable lung ACA.…”

Section: Egfr Copy Number and Protein Expressionmentioning

confidence: 99%

Biomarkers in Lung Adenocarcinoma: A Decade of Progress

Sholl

2014

Archives of Pathology &Amp; Laboratory Medicine

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Context The analysis of molecular biomarkers in lung adenocarcinoma (ACA) is now a central component of pathologic diagnosis and oncologic care. The identification of an EGFR mutation or ALK rearrangement in advanced-stage lung ACA will dictate a change in first-line treatment from standard chemotherapy to targeted inhibition of these oncogenic alterations. Viable approaches to therapeutic targeting of KRAS-mutated ACA are now under investigation, raising the possibility that this too will become an important predictive marker in this tumor type. The recognized array of less common oncogenic alterations in lung ACA, including in the ROS1, RET, BRAF, and ERBB2 genes, is growing rapidly. The therapeutic implications of these findings are, in many cases, still under investigation. Objective To focus on the major molecular biomarkers in lung ACA, recommended testing strategies, the implications for targeted therapies, and the mechanisms that drive development of resistance. Data Sources Our current understanding of predictive and prognostic markers in lung ACA is derived from a decade of technical advances, clinical trials, and epidemiologic studies. Many of the newest discoveries have emerged from application of high-throughput next-generation sequencing and gene expression analyses in clinically and pathologically defined cohorts of human lung tumors. Conclusions Best practices require a solid understanding of relevant biomarkers for diagnosis and treatment of patients with lung ACA.

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Section: Egfr Copy Number and Protein Expressionmentioning

confidence: 99%

Biomarkers in Lung Adenocarcinoma: A Decade of Progress

Sholl

2014

Archives of Pathology &Amp; Laboratory Medicine

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“…This is of special importance in tumors with heterogeneous morphology that have multiple growth patterns, such as mixed germ cell tumors with heterogeneous histologic components, which have various staining patterns, and lung adenocarcinomas with mixed histology. 7 Conventional tissue array blocks are constructed by punching tissue cores in ''donor'' blocks and transferring them into a ''recipient'' block. The donor blocks require sufficient amounts of tissue, and many surgical pathology specimens, especially from biopsies with limited material, may not be suitable for CTA construction, which means exclusion from investigational studies and further selection bias.…”

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Spiral Array: A New High-Throughput Technology Covers Tissue Heterogeneity

Fukuoka¹,

Hofer²,

Hori³

et al. 2012

Archives of Pathology &Amp; Laboratory Medicine

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Context.—Tissue array is a well-established technique that connects basic research with clinical applications and allows for the validation of many pathobiologic events from gene expression dysregulation to genomic aberrations. However, conventional tissue array has several limitations such as poor representation of tissue heterogeneity, destruction of donor tissue blocks due to coring, and usage of particular specimens that have limited evaluable material (tissue from thin specimens or needle biopsies). Objective.—To show the noninferiority and superiority of the new technique named Spiral Array—which allows for improved representation of the donor tissue while keeping the architectural details of the donor block intact—to that of the conventional tissue array. We compared the morphologic features of both methods. Design.—We created both Spiral Array and conventional tissue array for 25 lung adenocarcinomas and 50 multiple tumors of various organs. The degree of coverage of tissue heterogeneity was examined by observing the range of the staining intensity differences in immunohistochemistry, using cytokeratin 7 and epidermal growth factor receptor (EGFR); the degree of morphologic preservation was tested by level of accurate prediction among 3 pathologists of the histopathologic diagnosis and organ type. Results.—The Spiral Array showed better representations of the range of staining intensity for EGFR (P = .01). The level of accuracy for predicting organ type was significantly higher in Spiral Array than conventional tissue array (P = .047), whereas it was not significantly different between the 2 techniques for the histologic diagnosis. Conclusion.—Our data indicate that Spiral Array has benefits for covering tissue heterogeneity and preserving better morphology.

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“…Patients with EGFR-mutated lung cancers who initially achieve a marked response to EGFR-TKI treatment eventually develop progression of the disease during the course of treatment, which is caused, at least partly, by a secondary mutation, such as T790M (12,13). The results of several clinical trials indicate that EGFR gene copy number is also a response predictor (6), and that an exaggerated form of increased copy number, EGFR amplification, is associated with progression of adenocarcinoma (14,15).…”

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Immunohistochemical Detection of EGFR Mutation Using Mutation-Specific Antibodies in Lung Cancer

Kitamura

Hosoda

Sasaki

et al. 2010

Clinical Cancer Research

106

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Purpose: Patients with mutations of epidermal growth factor receptor (EGFR) receive more benefit from EGFR-tyrosine kinase inhibitor treatment. However, usually such treatment is used to treat advanced lung cancer and only small biopsy samples are available for mutational analysis. We used immunohistochemistry to examine recently developed antibodies specific to major hotspot mutations of L858R and DEL E746-A750.Experimental Design: We used five series of lung cancers: 47 non-small cell lung cancers (NSCLC) to evaluate various types of EGFR mutations, a consecutive series of 238 NSCLCs to study the sensitivity and specificity, 11 NSCLCs with both EGFR mutation and amplification to examine the spatial distribution, 32 patients treated with gefitinib to compare clinical responses, and 15 NSCLCs to explore changes associated with acquired T790M mutation.Results: Each antibody specifically recognized the corresponding mutation but also recognized other types of mutations. Overall specificity and sensitivity were 96% and 47%, respectively. The positive reaction showed heterogeneous distribution that agreed with the expression of the total EGFR molecule, part of which was associated with gene amplification. A clinical response to gefitinib treatment correlated with the reaction, although one of the two patients with a positive reaction responded well despite having the wild-type EGFR. Acquired T790M mutation did not change the reaction to the antibodies.Conclusions: On some characteristics, the positive reaction to mutation-specific antibodies differs from the molecular EGFR mutation. Therefore, this study revealed that not all patients with EGFR mutations can be selected using these mutation-specific antibodies. Clin Cancer Res; 16(13); 3349-55. ©2010 AACR.

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Lung Adenocarcinoma with EGFR Amplification Has Distinct Clinicopathologic and Molecular Features in Never-Smokers

Cited by 109 publications

References 33 publications

Biomarkers in Lung Adenocarcinoma: A Decade of Progress

Biomarkers in Lung Adenocarcinoma: A Decade of Progress

Spiral Array: A New High-Throughput Technology Covers Tissue Heterogeneity

Immunohistochemical Detection of EGFR Mutation Using Mutation-Specific Antibodies in Lung Cancer

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