Detection of EGFR Mutation Status in Lung Adenocarcinoma Specimens with Different Proportions of Tumor Cells Using Two Methods of Differential Sensitivity

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Detection of EGFR Mutation Status in Lung Adenocarcinoma Specimens with Different Proportions of Tumor Cells Using Two Methods of Differential Sensitivity Hye-Suk Han, MD, Sung-nam Lim, MD, Jin Young An, MD, Ki Man Lee, MD, Kang Hyeon Choe, MD, Ki Hyeong Lee, MD, Seung Taik Kim, MD, Seung-Myoung Son, MD, Song-Yi Choi, MD, Ho-chang Lee, MD, Ok-Jun Lee, MD Journal of Thoracic Oncology Volume 7, Issue 2, Pages 355-364 (February 2012) DOI: 10.1097/JTO.0b013e31823c4c1b Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 The peptide nucleic acid (PNA) clamping system. The PNA oligomer was designed to bind to the bottom strand of the wild-type sequence, spanning mutational hotspots in exons 18–21 of the epidermal growth factor receptor gene. The forward polymerase chain reaction (PCR) primer partially overlapped the PNA binding site. A, A PNA/DNA hybrid with a perfect match prevents annealing of the PCR primer and amplification of wild-type DNA. B, A PNA/DNA hybrid with a single base pair mismatch does not suppress annealing of the PCR primer or amplification of mutant alleles. Journal of Thoracic Oncology 2012 7, 355-364DOI: (10.1097/JTO.0b013e31823c4c1b) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Representative histology, epidermal growth factor receptor (EGFR) mutation status, and response to EGFR tyrosine kinase inhibitors (TKIs) for two patients (cases 9[A] and 32[B]) carrying an EGFR mutation that was detected only by peptide nucleic acid (PNA) clamping, but who responded differently to EGFR TKI therapy, and whose tumors contained different proportions of tumor cells. A, Tumor cells in the cell block of the malignant pleural effusion represented <10% of all nucleated cells (hematoxylin and eosin [H&E]; original magnification, ×400). EGFR status detected by PNA clamping indicated the presence of a leucine to arginine mutation (L858R) in exon 21, whereas direct sequencing indicated a wild-type allele. The objective response to EGFR TKI therapy was partial response. B, Tumor cells in the cell block of the malignant pleural effusion represented >50% of all nucleated cells (H&E; original magnification, ×400). EGFR status detected by PNA clamping indicated an L858R mutation in exon 21, whereas direct sequencing indicated a wild-type allele. However, the objective response to EGFR TKI therapy was progressive disease. (a) A cell block of malignant pleural effusion (H&E), (b) amplification curve derived from PNA clamping, (c) direct sequencing chromatograms, (d) response to EGFR TKI therapy. Journal of Thoracic Oncology 2012 7, 355-364DOI: (10.1097/JTO.0b013e31823c4c1b) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Representative histology, epidermal growth factor receptor (EGFR) mutation status, and response to EGFR tyrosine kinase inhibitors (TKIs) for two patients (cases 9[A] and 32[B]) carrying an EGFR mutation that was detected only by peptide nucleic acid (PNA) clamping, but who responded differently to EGFR TKI therapy, and whose tumors contained different proportions of tumor cells. A, Tumor cells in the cell block of the malignant pleural effusion represented <10% of all nucleated cells (hematoxylin and eosin [H&E]; original magnification, ×400). EGFR status detected by PNA clamping indicated the presence of a leucine to arginine mutation (L858R) in exon 21, whereas direct sequencing indicated a wild-type allele. The objective response to EGFR TKI therapy was partial response. B, Tumor cells in the cell block of the malignant pleural effusion represented >50% of all nucleated cells (H&E; original magnification, ×400). EGFR status detected by PNA clamping indicated an L858R mutation in exon 21, whereas direct sequencing indicated a wild-type allele. However, the objective response to EGFR TKI therapy was progressive disease. (a) A cell block of malignant pleural effusion (H&E), (b) amplification curve derived from PNA clamping, (c) direct sequencing chromatograms, (d) response to EGFR TKI therapy. Journal of Thoracic Oncology 2012 7, 355-364DOI: (10.1097/JTO.0b013e31823c4c1b) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Schema showing appropriate use of different methods for the detection of epidermal growth factor receptor (EGFR) mutation status, depending on the proportion of tumor cells in lung adenocarcinoma samples. A, In clinical samples with a low proportion of tumor cells (10%), a highly sensitive method may be useful. Clinical samples were representative in four patients (cases 2, 8, 9, and 15) who experienced a partial response to EGFR tyrosine kinase inhibitor (TKI) therapy and whose EGFR mutant status was detected only by peptide nucleic acid clamping. B, On the other hand, for clinical samples with a high proportion of tumor cells (50%), EGFR mutation status by direct sequencing may be more representative of the whole tumor. One patient (case 32) experienced progressive disease on treatment with EGFR TKI, and EGFR wild-type status was detected only by direct sequencing. MT-tumor cell, mutant-type tumor cell; WT-tumor cell, wild-type tumor cell. Journal of Thoracic Oncology 2012 7, 355-364DOI: (10.1097/JTO.0b013e31823c4c1b) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions