scholarly journals Tumour Content Ratio Matters for Detecting Epidermal Growth Factor Receptor Mutation by Cobas Test in Small Biopsies; a Retrospective Study

2020 ◽  
Author(s):  
Mariko Kogo ◽  
Daichi Fujimoto ◽  
Kazutaka Hosoya ◽  
Kazuma Nagata ◽  
Atsushi Nakagawa ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Egfr Mutation ◽  
False Negative ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Content Ratio ◽  
Positive Rate ◽  
Epidermal Growth ◽  
Tumour Cellularity ◽  
Egfr Mutated

Abstract Background Recent studies indicate the benefit of treatment with osimertinib over that with conventional epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) for untreated EGFR -mutated non-small cell lung cancer (NSCLC). Cobas ver2 is the only companion diagnostic method for detecting EGFR mutations with osimertinib treatment. We clinically experience false negative cases with this test, but its actual sensitivity is unknown. Moreover, no study has suggested the importance of tumour dissection, and most facilities do not routinely perform them on small biopsies. The purpose of this study was to evaluate the sensitivity of cobas in clinical practice and clarify the role of dissection as a component of the cobas testing. Methods We examined 132 patients with EGFR -mutated NSCLC diagnosed by bronchoscopy and confirmed with PCR clamp. Patients were tested with cobas and the EGFR -positive rate was calculated. Samples with undetected EGFR mutations were retested after tumour dissection and the rate of samples whose EGFR mutation was corrected to positive was assessed. To evaluate tumour cellularity, the tumour content ratio was assessed by calculating tumour cell count over the total cell count on the slide. Results The positive rate of EGFR mutation identification was 76% with cobas, although EGFR mutation-negative patients retained responses to TKI therapy equivalent to positive patients did; however, the tumour content ratio of negative samples was significantly lower than that of positive samples. Twenty-nine negative samples underwent dissection and 24% were corrected to positive. Moreover, 53% of the samples with a tumour content ratio below 10% was negative for cobas, but 33% of these turned positive after dissection. Conclusions Cobas had a high false negative rate in clinical practice, and tumour content ratio might be associated with this rate. Dissection could improve the sensitivity of cobas, especially in samples with low tumour cellularity.

scholarly journals Tumour Content Ratio Matters for Detecting Epidermal Growth Factor Receptor Mutation by Cobas Test in Small Biopsies; a Retrospective Study

2019 ◽  
Author(s):  
Mariko Kogo ◽  
Daichi Fujimoto ◽  
Kazutaka Hosoya ◽  
Kazuma Nagata ◽  
Atsushi Nakagawa ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Egfr Mutation ◽  
False Negative ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Content Ratio ◽  
Positive Rate ◽  
Epidermal Growth ◽  
Tumour Cellularity ◽  
Egfr Mutated

Abstract Background Recent studies indicate the benefit of treatment with osimertinib over that with conventional epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) for untreated EGFR -mutated non-small cell lung cancer (NSCLC). Cobas ver2 is the only companion diagnostic method for detecting EGFR mutations with osimertinib treatment. We clinically experience false negative cases with this test, but its actual sensitivity is unknown. Moreover, no study has suggested the importance of tumour dissection, and most facilities do not routinely perform them on small biopsies. The purpose of this study was to evaluate the sensitivity of cobas in clinical practice and clarify the role of dissection as a component of the cobas testing Materials and Methods We examined 132 patients with EGFR -mutated NSCLC diagnosed by bronchoscopy and confirmed with PCR clamp. Patients were tested with cobas and the EGFR -positive rate was calculated. Samples with undetected EGFR mutations were retested after tumour dissection and the rate of samples whose EGFR mutation was corrected to positive was assessed. To evaluate tumour cellularity, the tumour content ratio was assessed by calculating tumour cell count over the total cell count on the slide. Results The positive rate of EGFR mutation identification was 76% with cobas, although EGFR mutation-negative patients retained responses to TKI therapy equivalent to positive patients did; however, the tumour content ratio of negative samples was significantly lower than that of positive samples. Twenty-nine negative samples underwent dissection and 24% were corrected to positive. Moreover, 53% of the samples with a tumour content ratio below 10% was negative for cobas, but 33% of these turned positive after dissection. Conclusion Cobas had a high false negative rate in clinical practice, and tumour content ratio might be associated with this rate. Dissection could improve the sensitivity of cobas, especially in samples with low tumour cellularity.

scholarly journals Tumour Content Ratio Matters for Detecting Epidermal Growth Factor Receptor Mutation by Cobas Test in Small Biopsies; a Retrospective Study

2020 ◽  
Author(s):  
Mariko Kogo ◽  
Daichi Fujimoto ◽  
Kazutaka Hosoya ◽  
Kazuma Nagata ◽  
Atsushi Nakagawa ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Egfr Mutation ◽  
False Negative ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Content Ratio ◽  
Positive Rate ◽  
Epidermal Growth ◽  
Tumour Cellularity ◽  
Egfr Mutated

Abstract Background Recent studies indicate the benefit of treatment with osimertinib over that with conventional epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) for untreated EGFR -mutated non-small cell lung cancer (NSCLC). Cobas ver2 is the only companion diagnostic method for detecting EGFR mutations with osimertinib treatment. We clinically experience false negative cases with this test, but its actual sensitivity is unknown. Moreover, no study has suggested the importance of tumour dissection, and most facilities do not routinely perform them on small biopsies. The purpose of this study was to evaluate the sensitivity of cobas in clinical practice and clarify the role of dissection as a component of the cobas testing. Methods We examined 132 patients with EGFR -mutated NSCLC diagnosed by bronchoscopy and confirmed with PCR clamp. Patients were tested with cobas and the EGFR -positive rate was calculated. Samples with undetected EGFR mutations were retested after tumour dissection and the rate of samples whose EGFR mutation was corrected to positive was assessed. To evaluate tumour cellularity, the tumour content ratio was assessed by calculating tumour cell count over the total cell count on the slide. Results The positive rate of EGFR mutation identification was 76% with cobas, although EGFR mutation-negative patients retained responses to TKI therapy equivalent to positive patients did; however, the tumour content ratio of negative samples was significantly lower than that of positive samples. Twenty-nine negative samples underwent dissection and 24% were corrected to positive. Moreover, 53% of the samples with a tumour content ratio below 10% was negative for cobas, but 33% of these turned positive after dissection. Conclusions Cobas had a high false negative rate in clinical practice, and tumour content ratio might be associated with this rate. Dissection could improve the sensitivity of cobas, especially in samples with low tumour cellularity.

scholarly journals Frequency of EGFR Mutation and EML4-ALK fusion gene in Arab Patients with Adenocarcinoma of the Lung

2015 ◽  
Vol 6 (2) ◽  
pp. 19-23
Author(s):  
Hanan Ezzat Shafik ◽  
Mohamed Ashour
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Egfr Mutation ◽  
Fusion Gene ◽  
Receptor Gene ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Anaplastic Lymphoma ◽  
Epidermal Growth

Abstract Introduction: Improvement in the clinical outcome of lung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis. The frequency of epidermal growth factor receptor (EGFR) mutations is ethnicity-dependent, with a higher proportion in Asian populations than in whites, while the incidence of EML4-ALK (echinoderm microtubule-associated-protein like 4-anaplastic lymphoma kinase) fusion gene ranged from 1.6% to 16.4% in patients with NSCLC and these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. This study was conducted to determine the frequency of EGFR mutation and EML4-ALK fusion gene in our population and to determine the effect of different clinicopathological features on the expression of those mutations in patients with lung adenocarcinoma. Results: EGFR mutations were detected in approximately 33% of our patients in this series; the most frequently detected mutation was exon 19 deletion. EML4-ALK fusion gene was detected in 7.3% of patients. Conclusion: Our population exhibited the incidence of EGFR mutation approximately similar to that reported in East Asia and Japanese patients, higher than that recorded in USA, and Australia. However, more studies with larger patients’ numbers are needed to verify this finding.

Detection of clinically significant mutations in the epidermal growth factor receptor missed by direct sequencing using a highly sensitive DNA endonuclease

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10054-10054
Author(s):  
A. M. Borras ◽  
Y. Kuang ◽  
A. M. Rogers ◽  
A. J. Holmes ◽  
M. Gallegos Ruiz ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Mutation Detection ◽  
Egfr Mutation ◽  
Direct Sequencing ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Dna Endonuclease ◽  
Epidermal Growth ◽  
Clinically Significant ◽  
Sensitive Method

10054 Background: Mutations in the epidermal growth factor receptor (EGFR) are associated with sensitivity and resistance to EGFR inhibitors gefitinib and erlotinib in patients with non-small cell lung carcinoma (NSCLC). Direct sequencing is currently used for mutation detection but sensitivity is limited and requires dissection to obtain a relatively pure population of tumor cells. We examined a DNA endonuclease, SURVEYOR, which cleaves mismatched heteroduplexed DNA, as a more sensitive method for EGFR mutation screening and compared it to direct sequencing. Methods: EGFR exons 18–21 from tumor DNA were amplified using PCR, digested with SURVEYOR, and the products analyzed by HPLC. Specimens that produced digestion products were re-analyzed by size separation or by denaturing HPLC followed by fractionation and sequencing. Tumor specimens from 191 NSCLC patients were analyzed: 61 frozen tumors specimens; 91 dissected formalin fixed paraffin embedded (FFPE) and 39 un-dissected FFPE tumor specimens from patients treated with gefitinib or erlotinib in whom clinical outcome was available. 173 specimens were independently analyzed by direct sequencing. Results: We detected 48 EGFR mutations by sequencing and 61 using SURVEYOR. All EGFR mutations identified by sequencing, including those using un-dissected tumor specimens, were detected by SURVEYOR and none were missed (sensitivity: 100%, negative predictive value: 100%). 13 mutations were detected by SURVEYOR not detected by sequencing. This included 5 mutations (4 exon 19 deletions; 1 L858R) in 7 (71%) patients who clinically had a PR to gefitinib or erlotinib but who were wild type by sequencing. In 4 patients, 2 with clinical acquired resistance to gefitinib, a T790M mutation was found which was undetected by sequencing. Conclusions: SURVEYOR analysis is a more sensitive method for EGFR mutation detection than direct sequencing. It can be used to detect EGFR mutations from un-dissected tumor specimens and can detect clinically significant activating or resistance associated EGFR mutations not detected by direct sequencing. [Table: see text]

Impact of HER2 aberrations on EGFR-TKI treatment outcomes in lung tumors harboring EGFR mutations: A HER2-CS STUDY subset analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9056-9056 ◽  
Author(s):  
Hiroe Kayatani ◽  
Keisuke Aoe ◽  
Kadoaki Ohashi ◽  
Hiroshige Yoshioka ◽  
Akihiro Bessho ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Her2 Protein ◽  
Epidermal Growth ◽  
Tki Treatment ◽  
Egfr Mutant ◽  
Egfr Mutated ◽  
Egfr Tki ◽  
Egfr Tkis

9056 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a key treatment for EGFR-mutated non-small-cell lung carcinoma (NSCLC). To date, a biomarker to predict whether NSCLC will exhibit a short- or long-term response to first- or second-generation EGFR-TKIs has not been established for clinical use. Human epidermal growth factor receptor-2 (HER2) aberrations are mechanisms for acquired resistance to EGFR-TKIs; however, their impact on EGFR-TKI therapy outcomes in EGFR-mutant NSCLC has not yet been systematically evaluated. Methods: Patients with advanced NSCLC were prospectively registered from more than 35 institutes (HER2-CS STUDY UMIN 000017003). EGFR mutations or anaplastic lymphoma kinase gene translocations were assessed at each institution using a commercially approved test. HER2 protein expression levels were determined by immunohistochemistry (IHC) using the Ventana I-VIEW PATHWAY anti-HER-2/neu (4B5). The IHC status scoring system applied to gastric cancer was used. Results: Of 1,126 screened patients with NSCLC, 354 (31.8%) had EGFR-mutated tumors, and the HER2 protein statuses were as follows: IHC0 (n = 71, 26%), IHC1+ (n = 148, 53%), IHC2+ (n = 51, 18%), and IHC3+ (n = 7, 3%). The patients’ demographics were almost identical in those with lung tumors harboring EGFR mutations and HER2-IHC2+/3+ (group P) or EGFR mutations and HER2-IHC0/1 (group N). The EGFR-TKI response rates were not different between these groups (Table). However, group P showed significantly shorter time to EGFR-TKI treatment failure than group N (median 19.1 vs. 13.3 months; log rank p = 0.038). Conclusions: These data from a large prospective cohort show that HER2 protein expression in EGFR-mutant NSCLC may have a negative impact on the effect of EGFR-TKIs. A clinical trial of EGFR/HER2-TKIs (e.g., afatinib) is warranted for this population. [Table: see text]

scholarly journals The Role of Mutation Status of the Epidermal Growth Factor Receptor Gene In Advanced Non–Small Cell Lung Cancer

Medicina ◽  
2012 ◽  
Vol 48 (4) ◽  
pp. 25 ◽  
Author(s):  
Neringa Vagulienė ◽  
Marius Žemaitis ◽  
Valdas Šarauskas ◽  
Astra Vitkauskienė ◽  
Skaidrius Miliauskas
Keyword(s):  
Lung Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Egfr Mutation ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Positive Group ◽  
Epidermal Growth ◽  
Never Smokers

Objective. The aim of this study was to examine the prevalence of epidermal growth factor receptor (EGFR) gene mutations among patients with advanced nonsquamous non–small cell lung cancer (NSCLC) treated in our institution and to evaluate the associations between EGFR mutations and clinicopathological characteristics. Materials and Methods. A total of 103 patients with NSCLC were examined from April 2010 to September 2011. The patients were screened for EGFR mutations in exons 19 and 21 using sequence analysis. Results. EGFR mutations were detected in 10 patients (9.71%): 23.1% of women and 5.2% of men (P<0.05), 31.8% of never-smokers and 4.7% of smokers (P<0.05), and 12.3% of patients with adenocarcinomas and 6.25% of patients with large cell carcinomas (P>0.05). Eight mutations (80.0%) were found in exon 21: 7 patients had the L858R mutation and 1 patient had the L861G mutation. Two mutations (20.0%) were found in exon 19: 1 patient had the L747-A748 deletion and 1 patient had the L747-A750insE deletion. The overall response rate was significantly greater in the EGFR mutation-positive group than in the EGFR mutation-negative or control groups (P<0.05). The median progression-free survival in the EGFR mutation-negative group and the control group that received systemic standard chemotherapy was 5.6 months (95% CI, 4.3 to 7.0) and 5.3 months (95% CI, 4.9 to 5.7), respectively, but it was not achieved in the EGFR mutation-positive group that received EGFR tyrosine kinase inhibitors (P<0.05). Conclusions. The frequency of EGFR mutations in our patients with nonsquamous NSCLC was found to be similar to that reported in Europe. EGFR mutations were more frequent in women and never-smokers

Epidermal Growth Factor Receptor Mutations and Gene Amplification in Non–Small-Cell Lung Cancer: Molecular Analysis of the IDEAL/INTACT Gefitinib Trials

2005 ◽  
Vol 23 (31) ◽  
pp. 8081-8092 ◽  
Author(s):  
Daphne W. Bell ◽  
Thomas J. Lynch ◽  
Sara M. Haserlat ◽  
Patricia L. Harris ◽  
Ross A. Okimoto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Molecular Markers ◽  
Egfr Mutation ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Epidermal Growth ◽  
The Ideal

Purpose Most cases of non–small-cell lung cancer (NSCLC) with dramatic responses to gefitinib have specific activating mutations in the epidermal growth factor receptor (EGFR), but the predictive value of these mutations has not been defined in large clinical trials. The goal of this study was to determine the contribution of molecular alterations in EGFR to response and survival within the phase II (IDEAL) and phase III (INTACT) trials of gefitinib. Patients and Methods We analyzed the frequency of EGFR mutations in lung cancer specimens from both the IDEAL and INTACT trials and compared it with EGFR gene amplification, another genetic abnormality in NSCLC. Results EGFR mutations correlated with previously identified clinical features of gefitinib response, including adenocarcinoma histology, absence of smoking history, female sex, and Asian ethnicity. No such association was seen in patients whose tumors had EGFR amplification, suggesting that these molecular markers identify different biologic subsets of NSCLC. In the IDEAL trials, responses to gefitinib were seen in six of 13 tumors (46%) with an EGFR mutation, two of seven tumors (29%) with amplification, and five of 56 tumors (9%) with neither mutation nor amplification (P = .001 for either EGFR mutation or amplification v neither abnormality). Analysis of the INTACT trials did not show a statistically significant difference in response to gefitinib plus chemotherapy according to EGFR genotype. Conclusion EGFR mutations and, to a lesser extent, amplification appear to identify distinct subsets of NSCLC with an increased response to gefitinib. The combination of gefitinib with chemotherapy does not improve survival in patients with these molecular markers.

Prospective analysis of the epidermal growth factor receptor gene mutations in non-small cell lung cancer in Japan

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7077-7077 ◽  
Author(s):  
N. Morikawa ◽  
A. Inoue ◽  
T. Suzuki ◽  
T. Fukuhara ◽  
S. Suzuki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Egfr Mutation ◽  
Response Rate ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Epidermal Growth ◽  
Nsclc Patients

7077 Background: Previous clinical trials have revealed that gefitinib is more likely to be effective in non-small cell lung cancer (NSCLC) with activating somatic mutations of epidermal growth factor receptor (EGFR). Most of those reports evaluated NSCLC patients who had post-operative recurrence and then received gefitinib retrospectively using their surgical specimens. However, many NSCLC patients are inoperable at diagnosis. Thus we conducted this study to examine EGFR mutation status by diagnostic tumor samples before gefitinib treatment and investigate the correlation between EGFR mutation and the efficacy of gefitinib. Methods: We prospectively evaluated various tumor samples obtained from NSCLC patients who had never received gefitinib for EGFR mutations in exon 18–23. For patients treated with gefitinib after the examination of EGFR mutations, the response to gefitinib was also evaluated. Results: From June 2004 to November 2005, 91 patients with advanced or post-operative recurrent NSCLC enrolled onto this study and 104 tumor samples were obtained from transbronchial biopsies, effusions, as well as surgical specimens. Thirty-two mutations including deletions in exon 19 in 23 patients and L858R in 9 patients were detected among those 91 patients; 30 in 81 adenocaricinoma, 1 in 2 adenosquamous cell carcinoma, and 1 in 5 large cell carcinoma. The mutations were found more frequently in female (51.9%) than male (12.8%), in never smoker (52.0%) than smoker (14.6%). Response rate of gefitinib in patients with EGFR mutations was 65.0% (13 of 20) compared to 37.5% (3 of 8) in patients without mutations. Among 7 patients with EGFR mutations who were examined multiple tumor samples, 3 had the discrepancy of EGFR gene status between different samples obtained at different time points, suggesting genetic heterogeneity of their tumors. The EGFR status of the most recent samples is likely to be correlated to the response to gefitinib. Conclusions: The EGFR mutation analysis was possible not only from surgical specimens but also from daily available diagnostic samples. For patients with EGFR mutations, gefitinib could achieve a promising high response rate. We propose to examine the most recent tumor samples to predict the sensitivity to gefitinib reliably. No significant financial relationships to disclose.

Clinicopathological features in correlation with epidermal growth factor receptor gene mutations in non-small cell lung cancer (NSCLC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21148-21148 ◽  
Author(s):  
F. Tanaka ◽  
S. Matsumoto ◽  
T. Takuwa ◽  
N. Kondo ◽  
Y. Okumura ◽  
...  
Keyword(s):  
Egfr Mutation ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Fdg Uptake ◽  
Epidermal Growth ◽  
The Mean ◽  
Egfr Mutated ◽  
Egfr Tkis

21148 Background: Mutations in the epidermal growth factor receptor (EGFR) gene are found in 10–30% of non-small cell lung cancer, and are useful to predict the efficacy of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib and erlotinib. However, it is sometimes difficult to examine such mutations. Thus, prediction of presence or absence of EGFR mutations, correlated with clinical response to EGFR-TKIs, based on clinicopathological characteristics may be important in clinical practice. Methods: We retrospectively assessed EGFR-mutation status in correlation with clinical features including FDG-PET findings and pathological features including presence or absence of bronchioalveolar component (BAC) in adenocarcinoma (Ad) case. A total of 72 consecutive patients (24 females; mean age, 65 years; 40 Ad cases) who received thoracotomy from August 2005 through October 2006 were reviewed Results: Sixteen cases (22%) had EGFR-mutations (8 cases each in exon 19 and exon 21). The incidence of EGFR-mutation was significantly higher in female (42%) or never-smoker (60%) than in male (13%) or smoker (15%). EGFR-mutation was almost exclusively found in Ad; among Ad cases, there was no significant difference in the incidence of EGFR-mutation between BAC-positive (47%) and BAC-negative cases (29%; p=0.33). Among 61 cases who received FDG-PET scan prior to thoracotomy, only 15% of EGFR- mutated cases had higher FDG-uptake, whereas 47% of EGFR-wild cases had higher FDG-uptake (p=0.36); the sensitivity and specificity of lower FDG-uptake to predict the presence of EGFR-mutations were 71% and 53%, respectively. The positive predictive value (PPV) of lower- FDG-uptake for the presence of EGFR-mutations was only 29%, but the negative predictive value (NPV) was as high as 85%. The mean standardized uptake value (SUV) of FDG for EGFR-wild patients and EGFR-mutated patients were 5.7 and 3.3, respectively (p=0.11). The mean SUV for tumors mutated in exon 19 seemed to be lower than that for tumors mutated in exon 21 (1.8 versus4.6). Conclusions: Higher FDG-uptake combined with clinical features (male and smoker) may help to exclude patients with EGFR-wild tumors who may not respond to EGFR-TKIs treatment. No significant financial relationships to disclose.

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