Higher Dosage of the Epidermal Growth Factor Receptor Mutant Allele in Lung Adenocarcinoma Correlates with Younger Age, Stage IV at Presentation, and.

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Higher Dosage of the Epidermal Growth Factor Receptor Mutant Allele in Lung Adenocarcinoma Correlates with Younger Age, Stage IV at Presentation, and Poorer Survival Gerard J. Oakley, MD, Simion I. Chiosea, MD Journal of Thoracic Oncology Volume 6, Issue 8, Pages 1407-1412 (August 2011) DOI: 10.1097/JTO.0b013e31821d41af Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 A–C, Representative cases of EGFR exon 21 codon 858 T to G point mutations. The variation in peak heights for mutant and wild-type alleles on sequencing electropherograms (SEs) is shown. Portions of the SE surrounding the point mutation (arrows) were scanned. The top row represents the nucleotide sequence of the dominant polymerase chain reaction product, as recognized by the sequencing software (“GGCKGGC,” where “K” stands for a nucleotide unrecognized by the software due to the colocation of two nucleotides). Each of the four nucleotides was labeled with a unique fluorescent dye (e.g., T = thymidine, A = adenosine). A, Representative case with the mutant allele peak lower than the WA peak (MA < WA). B, Representative case with the mutant allele peak approximately threefold higher than the wild-type allele peak (MA > WA). C, Representative case with the mutant allele peak approximately ninefold higher than the wild-type allele peak (MA > WA). Journal of Thoracic Oncology 2011 6, 1407-1412DOI: (10.1097/JTO.0b013e31821d41af) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Correlation between the EGFR mutant and wild-type allelic ratio as determined by sequencing electropherogram (SE) and the EGFR/CEP7 ratio as determined by fluorescence in situ hybridization (Spearman's bivariate correlation test). The correlation coefficient (ρ) is 0.757 and indicates a high degree of correlation (p = 0.003). Journal of Thoracic Oncology 2011 6, 1407-1412DOI: (10.1097/JTO.0b013e31821d41af) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Correlation of EGFR fluorescence in situ hybridization (FISH) with the semiquantitative evaluation of sequencing electropherograms (SEs). Portions of SE surrounding the deletion points (red arrows) were scanned. The top row was typed in and represents the wild-type sequence, and the second row represents the actual sequence of the dominant polymerase chain reaction product. A, SE of a case with an EGFR exon 19 deletion and without an easily identifiable wild-type allele after the deletion point. These laboratory values belonged to a deceased 44-year-old white nonsmoking woman who presented with stage IIIb (pT2b N2) lung adenocarcinoma and developed recurrence associated with distant metastases 8 months after the initial surgery. B, EGFR FISH corresponding to the SE in 3A (EGFR/CEP7 ratio = 39). C, Mutant allele peaks are higher than the wild-type allele peaks. However, mutant allele specific imbalance is not accompanied by amplification (see panel D). D, The EGFR/CEP7 ratio is 1.1. The presence of four EGFR and CEP7 signals per nucleus indicates tetraploidy. Polysomy and amplification represent two mechanisms of mutant allele specific imbalance that are detectable by FISH. Red signal, Texas red/rhodamine—EGFR probe; green signal, fluorescein isothiocyanate—CEP7 probe; blue signal, 4′,6-diamidino-2-phenylindole—outlining the nuclei. Journal of Thoracic Oncology 2011 6, 1407-1412DOI: (10.1097/JTO.0b013e31821d41af) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Disease-specific survival (DSS) analysis based on the Kaplan-Meier method. A, DSS by stage: stages I–III (events [i.e., death from disease] = 6/55, 24%; estimated mean survival = 53 months, 95% CI 47–60) versus stage IV (events = 4/17, 24%; estimated mean survival = 36 months, 95% CI 24–47). B, DSS and the dosage of the EGFR mutant allele. MA < WA (mutant allele peak height lower than that of the wild-type allele; events = 4/52, 8%; estimated mean survival = 55 months, 95% CI 48–62) versus MA > WA (mutant allele peak height higher than that of the wild-type allele, EGFR mutant allele specific imbalance; events = 6/20, 33%, estimated mean survival = 37 months, 95% CI 29–45). C, To control for stage, the DSS analysis was performed in a subgroup of patients with stage I to III. MA < WA: events = 3/43, 7%; estimated mean survival = 56 months, 95% CI 50–63 versus MA > WA: events = 3/12, 25%, estimated mean survival = 34 months, 95% CI 28–39. D, To control for patient age, the DSS was analyzed in a subgroup of patients younger than 65 years. MA < WA: events = 2/21, 10%; estimated mean survival = 57 months, 95% CI 50–65 versus MA > WA: events = 5/15, 33%, estimated mean survival = 32 months, 95% CI 25–38. Journal of Thoracic Oncology 2011 6, 1407-1412DOI: (10.1097/JTO.0b013e31821d41af) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions