Genetic evolution of EGFR and the clonal origin of adenocarcinomas exhibiting various degrees of bronchioloalveolar carcinoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22050-e22050
Author(s):  
W. Zhong ◽  
X. Yang ◽  
A. Guo ◽  
J. Su ◽  
X. Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Distant Metastases ◽  
Genetic Alterations ◽  
Bronchioloalveolar Carcinoma ◽  
Egfr Mutations ◽  
Lung Field ◽  
Wild Type ◽  
Activating Mutations ◽  
Single Clone

e22050 Background: EGFR mutations may accumulate during multistage progression of bronchioloalveolar carcinoma (BAC), leading to heterogeneity within the tumor. Moreover, intrapulmonary emersions are the predominant sites of BAC progression in the absence of other distant metastases. In cases of emerging bilateral lung lesions during the follow-up to complete resection, the issue of how to differentiate between lesions originating from multifocal BACs or distant metastases/local recurrence is an important and unresolved issue. This study was performed to determine whether sequential adenocarcinoma with BAC features emerges in the lung field arises from a single clone or multiple clones in the same individual. Methods: Samples of adenocarcinomas exhibiting various degrees of BAC were obtained by thoracotomy. Sequential specimens were obtained on detection of novel lesions in the lung field. Genomic DNA was extracted from the specimens, and the presence of activating mutations in EGFR was analyzed by direct sequencing. Our pathological findings, sequential imaging, and EGFR sequence data were compared to monitor evidence of cancer evolution. Results: Based on an analysis of EGFR in tumor specimens from 428 lung cancer patients, fifteen cases of sequential BAC-related adenocarcinoma obtained by thoracotomy were identified. Together with alterations in BAC/adenocarcinoma components, the EGFR-TKI untreated series with at least one episode of EGFR-activating mutations represented three typical models: no significant EGFR evolution for a single clone, genetic alterations from mutant to wild-type EGFR for multifocal lesions, and a switch from wild-type to mutant EGFR, which might exhibit uncertain circumstances of cancer progression. Conclusions: Genetic analysis in conjunction with pathological and radiological diagnoses can be used to explore the origin of multifocal BAC. The single clone model indicates subsequent disease progression, whereas genetic alterations from mutations to wild-type EGFR are suggestive of secondary primary carcinoma. When additional lesions emerge after radical resection of BAC-related lung cancer, sequential tumor samples should be obtained for further evaluation. No significant financial relationships to disclose.

Molecular changes in epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) biopsies at time of progression compared to initial biopsy

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22066-e22066
Author(s):  
G. Speranza ◽  
V. Cohen ◽  
J. S. Agulnik ◽  
G. Chong ◽  
F. Meilleur ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Kinase Inhibitors ◽  
Genetic Alterations ◽  
Egfr Mutations ◽  
Missense Mutations ◽  
Molecular Changes ◽  
Mutational Status ◽  
Exon 19 Deletion ◽  
Exon 19

e22066 Background: EGFR mutations predict sensitivity and clinical outcome to tyrosine kinase inhibitors (TKI) in NSCLC. The two most commonly described mutations are Exon 19 deletion and Exon 21 L858R missense mutations. Genetic alterations over time have been described in other tumour types, but studies assessing EGFR genotypic changes with lung cancer progression are lacking. We sought to compare EGFR mutational status from lung tumors at time of recurrence or progression with the primary tumor. Methods: Using the Jewish General Hospital lung cancer database, of all patients diagnosed with NSCLC since 1999, those with biopsies at two different points in time were identified. All tumour samples were genotyped for EGFR exons 19 and 21 mutations using denaturing high performance liquid chromatography (dHPLC). Results: 29 patients were identified. Data for 12 patients, whose time of recurrence or progression varied between 4 months and 6 years, are available at this time. Of 12 patients, one had EGFR exon 19 mutation at time of diagnosis. One patient who initially displayed no EGFR mutation was found to have an exon 19 deletion at time of recurrence. The one with exon 19 at time of initial diagnosis continued to express exon 19 in the second biopsy. Conclusions: To our knowledge, this is the only study assessing changes in molecular genotype using dHPLC between primary and recurrent or progressive lung cancer biopsy specimens. Although sample size is small, it is evident that changes in EGFR mutational status can occur. Further prospective studies are required to determine how commonly molecular changes occur. No significant financial relationships to disclose.

scholarly journals Genome-wide analysis of microRNA signature in lung adenocarcinoma with EGFR exon 19 deletion

2015 ◽  
Author(s):  
Lixia Ju ◽  
Mingquan Han ◽  
Xuefei Li ◽  
Chao Zhao
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Genetic Alterations ◽  
Egfr Mutations ◽  
Wild Type ◽  
Lung Cancer Patients ◽  
Whole Genome Microarray ◽  
Exon 19 Deletion ◽  
The Difference ◽  
Exon 19

AbstractPurposeThe findings of EGFR mutations and the development of targeted therapies have significantly improved the overall survival of lung cancer patients. Still, the prognosis remains poor, so we need to know more about the genetic alterations in lung cancer. MicroRNAs are dysregulated in lung cancer, and microRNAs can regulate EGFR. So it is very important to predict the candidate microRNAs that target mutated EGFR and to investigate the role of these candidate microRNAs in lung cancer.Materials and methodsIn this study, we investigated the difference of microRNAs expression between lung adenocarcinoma cell lines with EGFR exon 19 deletion (H1650 and PC9) and its wild-type (H1299 and A549) using the Phalanx Human Whole Genome Microarray. Then the expression of individual microRNAs was validated by qRT-PCR assays. Moreover, we have detected the microRNAs expression in serum of lung adenocarcinoma patients with EGFR exon 19 deletion and wild-type.ResultsThe expression of 1,732 microRNAs was evaluated, and we found that microRNAs expression was different between these two groups. Hsa-miR-141-3p, hsa-miR-200c-3p, hsa-miR-203, hsa-miR-3182, hsa-miR-934 were up-regulated and hsa-miR-3196 was down-regulated in the EGFR exon 19 deletion group compared with wild-type group. The detection of circulating microRNAs showed that miR-3196 was down-regulated in lung adenocarcinoma patients with EGFR exon 19 deletion compared with wild-type.ConclusionsIt is suggested that microRNAs associate with EGFR exon 19 deletion and miR-3196 can be further explored for potential predictor and targeted biomarker when it is difficult to get the tumors.

scholarly journals Concurrent Genetic Alterations and Other Biomarkers Predict Treatment Efficacy of EGFR-TKIs in EGFR-Mutant Non-Small Cell Lung Cancer: A Review

2020 ◽  
Vol 10 ◽  
Author(s):  
Yijia Guo ◽  
Jun Song ◽  
Yanru Wang ◽  
Letian Huang ◽  
Li Sun ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Treatment Efficacy ◽  
Genetic Alterations ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Egfr Tkis ◽  
Gene Alterations

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) greatly improve the survival and quality of life of non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, many patients exhibit de novo or primary/early resistance. In addition, patients who initially respond to EGFR-TKIs exhibit marked diversity in clinical outcomes. With the development of comprehensive genomic profiling, various mutations and concurrent (i.e., coexisting) genetic alterations have been discovered. Many studies have revealed that concurrent genetic alterations play an important role in the response and resistance of EGFR-mutant NSCLC to EGFR-TKIs. To optimize clinical outcomes, a better understanding of specific concurrent gene alterations and their impact on EGFR-TKI treatment efficacy is necessary. Further exploration of other biomarkers that can predict EGFR-TKI efficacy will help clinicians identify patients who may not respond to TKIs and allow them to choose appropriate treatment strategies. Here, we review the literature on specific gene alterations that coexist with EGFR mutations, including common alterations (intra-EGFR [on target] co-mutation, TP53, PIK3CA, and PTEN) and driver gene alterations (ALK, KRAS, ROS1, and MET). We also summarize data for other biomarkers (e.g., PD-L1 expression and BIM polymorphisms) associated with EGFR-TKI efficacy.

The influence of gastric secretion inhibitors on gefitinib therapy in patients with non-small cell lung cancer harboring epidermal growth factor receptor activating mutations.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18059-e18059 ◽  
Author(s):  
Sho Saeki ◽  
Jiichiro Sasaki ◽  
Junko Morioka ◽  
Ryo Sato ◽  
Shinya Sakata ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Gastric Secretion ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Activating Mutations ◽  
Epidermal Growth

e18059 Background: Gefitinib is orally available, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor used in patients with non-small cell lung cancer (NSCLC), especially harboring EGFR activating mutations. Pharmacokinetic study revealed absorption of gefitinib was affected by the gastric pH. However, cancer patients in advanced stage are frequently administered gastric secretion inhibitors, such as proton pump inhibitors (PPIs) and H2 blockers (H2Bs) for various reasons. We hypothesized that gastric secretion inhibitors might suppress the efficacy of gefitinib therapy in NSCLC patients with EGFR activating mutations. The purpose of this study is to investigate the influence of PPIs/H2Bs on the efficacy of gefitinib therapy in the patients with NSCLC harboring EGFR activating mutations. Methods: From Apr 2004 to Aug 2011, we retrospectively analyzed the correlation between administration of PPIs/H2Bs and efficacy of gefitinib therapy in the patients with NSCLC harboring EGFR mutations. Results: Forty-three patients with EGFR mutations received gefitinib therapy in our hospital. 65.1% (28/43) patients administered PPIs/H2Bs simultaneously. Patients who received PPIs/H2Bs (PPIs/H2Bs group) had similar response rate compared with patients who didn’t receive PPIs/H2Bs (non-PPIs/H2Bs group) (77.8% vs 73.3%, p=1.00). Median progression free survival was 291 days in PPIs/H2Bs group and 353 days in non-PPIs/H2Bs group ( HR 1.23, Log-rank trest, p=0.578), respectively. Median overall survival was 718 days in PPIs/H2Bs group and not reached in non-PPIs/H2Bs group ( HR 1.53, Log-rank trest, p=0.403), respectively. Conclusions: Gastric secretion inhibitors didn’t affect the efficacy of gefitinib treatment in patients with NSCLC harboring EGFR activating mutations.

RELAY study of erlotinib (ERL) + ramucirumab (RAM) or placebo (PL) in EGFR-mutated metastatic non-small cell lung cancer (NSCLC): Biomarker analysis using circulating tumor DNA (ctDNA) in Japanese patients (pts).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9527-9527
Author(s):  
Kazuto Nishio ◽  
Kazuko Sakai ◽  
Takashi Seto ◽  
Makoto Nishio ◽  
Edward B. Garon ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Progression Free Survival ◽  
Japanese Patients ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Phase Iii ◽  
Egfr Mutations ◽  
Time Points ◽  
Activating Mutations ◽  
Biomarker Analysis

9527 Background: The phase III RELAY study (NCT02411448) showed significantly improved progression-free survival (PFS) for RAM+ERL vs PL+ERL in 449 pts with previously untreated EGFR mutation-positive metastatic NSCLC (median PFS 19.4 vs 12.4 mo, HR 0.591 [95% CI 0.461–0.760], p<.0001). To understand baseline genetic mutations and treatment-emergent (TE) resistance mechanisms, this exploratory liquid biopsy substudy examined biomarkers in ctDNA from participating Japanese pts by next-generation sequencing (NGS) and droplet digital PCR (ddPCR). Methods: Plasma samples were collected at baseline, during treatment (Cycle 4, 13, and every 6 cycles to Cycle 53) and post-study treatment discontinuation (30-day follow-up [30d FU]). Mutations were assessed at baseline and 30d FU by NGS (Ion AmpliSeq Colon and Lung Cancer panel). EGFR mutations and MET and ERBB2 copy number (CN) were assessed at all time points by ddPCR. Baseline markers were analyzed in pts with any detectable baseline mutation (to confirm ctDNA presence; NGS N=84, ddPCR N=74). TE mutations were analyzed in pts with any detectable mutation at baseline and 30d FU (NGS N=26, ddPCR N=28). Among these pts, 81% and 57% for NGS and ddPCR, respectively, had progressed by 30d FU. Results: By plasma NGS, baseline EGFR activating mutations (exon 19 deletion or exon 21 [L858R] mutation) were detected in 83.3% of pts. Common co-occurring baseline mutations were TP53 (42.9%), PTEN (7.1%) and KRAS (6.0%). Baseline TP53 mutation rate was higher in men vs women (p=.02). No difference in PFS was detected by baseline TP53 status (interaction predictive p=.45, prognostic p=.33). TE mutations were detected in EGFR (including T790M), FGFR3, KRAS and TP53. Slightly higher rates of TE KRAS (p=.03) and TP53 (p=.07) mutations were detected in RAM+ERL than in PL+ERL. TE total EGFR mutations (p=.65) or TE T790M (p=.69) did not differ by arm. By ddPCR, baseline EGFR activating mutations were detected in all pts. T790M was detected at baseline in 2/37 pts/arm (5.4%) and was TE in 6/11 (55%) RAM+ERL pts and 7/17 (41%) PL+ERL pts. There was a trend (p=.054) for greater ERBB2 CN in RAM+ERL vs PL+ERL at Cycle 4. MET CN decreased slightly at Cycle 4 in both arms (significant in PL+ERL, p=.003). Biomarker levels by ddPCR across all time points will be presented. Conclusions: Though limited by sample size and likely inconsistent tumor shedding, this exploratory study identified potential differences in TP53, KRAS, ERBB2 and MET by demographics, treatment and/or time. Clinical trial information: NCT02411448 .

Concurrent somatic alterations of TP53 and RB1 in Chinese lung adenocarcinoma with or without EGFR mutations.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21526-e21526
Author(s):  
JUN WANG ◽  
Gang Chen ◽  
Bicheng Zhang ◽  
Jianguo Sun ◽  
Jing Liang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Inhibitor ◽  
Genetic Alterations ◽  
Egfr Mutations ◽  
Wild Type ◽  
Mutational Status ◽  
Significant Difference ◽  
Somatic Alterations ◽  
Egfr Mutant ◽  
Mutant Egfr

e21526 Background: Endothelial growth factor receptor (EGFR)-mutant lung adenocarcinoma displays diverse responses to tyrosine kinase inhibitor therapy. Concurrent somatic alterations represent different biological substantial proportion of patients with EGFR mutations and impacts their prognosis. Methods: We conducted this retrospective study to clarify the comprehensive concurrent genetic alterations of TP53 and RB1 and tumor mutational burden (TMB) in 712 EGFR-mutant or EGFR-wild type lung adenocarcinoma by next generation sequencing-based gene panel tests. Results: EGFR was the most frequently mutated gene altered in 58.0% (413/712) of lung adenocarcinoma, followed by TP53 altered in 56.7%, KRAS altered in 13.3%, and RBM10 altered in 11.2% of all patients. Concurrent genetic alteration of TP53 and RB1 is more likely to be found in EGFR-mutant patients than in EGFR-wild type patients, with a frequency of 11.4% (45/413) and 4.3% (13/299), respectively (p = 0.003). However, the frequency of TP53 and RB1 concurrent alteration was similar in lung cancer with sensitive EGFR mutation compared to those with non-sensitive mutation (10.5% versus 11.6%). TP53 mutation was most frequently found in patients with RB1 mutation (58/61), irrespective of EGFR mutational status. Furthermore, significant difference was found regarding median TMB in patients with mutant EGFR compared to those with non-mutant EGFR (3.8 versus 4.3; p < 0.001). Median TMB was higher for patients with TP53 and RB1 concurrent alteration than those without concurrent alteration in all patients (5.4 versus 4.3, p = 0.018). Conclusions: Our data showed that high prevalence of concurrent somatic alterations of TP53 and RB1 genes among lung adenocarcinoma patients with EGFR mutations, which might help understand several key biological processes and develop potential therapeutic strategies.

scholarly journals The EGFR-TMEM167A-p53 Axis Defines the Aggressiveness of Gliomas

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 208
Author(s):  
Berta Segura-Collar ◽  
Ricardo Gargini ◽  
Elena Tovar-Ambel ◽  
Esther Hernández-SanMiguel ◽  
Carolina Epifano ◽  
...  
Keyword(s):  
High Frequency ◽  
Genetic Alterations ◽  
Vesicular Trafficking ◽  
Egfr Mutations ◽  
Growth Factor Signaling ◽  
P53 Mutations ◽  
Wild Type ◽  
Intracellular Vesicles ◽  
Wild Type P53 ◽  
Signaling Activity

Despite the high frequency of EGFR and TP53 genetic alterations in gliomas, little is known about their crosstalk during tumor progression. Here, we described a mutually exclusive distribution between mutations in these two genes. We found that wild-type p53 gliomas are more aggressive than their mutant counterparts, probably because the former accumulate amplifications and/or mutations in EGFR and show a stronger activation of this receptor. In addition, we identified a series of genes associated with vesicular trafficking of EGFR in p53 wild-type gliomas. Among these genes, TMEM167A showed the strongest implication in overall survival in this group of tumors. In agreement with this observation, inhibition of TMEM167A expression impaired the subcutaneous and the intracranial growth of wild-type p53 gliomas, regardless of the presence of EGFR mutations. In the absence of p53 mutations, TMEM167A knockdown reduced the acidification of intracellular vesicles, affecting the autophagy process and impairing EGFR trafficking and signaling. This effect was mimicked by an inhibitor of the vacuolar ATPase. We propose that the increased aggressiveness of wild-type p53 gliomas might be due to the increase in growth factor signaling activity, which depends on the regulation of vesicular trafficking by TMEM167A.

Response to Osimertinib in a Patient With Non-Small Cell Lung Cancer and Two Uncommon EGFR mutations

2020 ◽  
pp. 10-13
Author(s):  
Christoforos Astaras ◽  
Adrienne Bettini ◽  
Daniel C. Betticher
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Genetic Alterations ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Exon 20

In advanced non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) mutations are one of the most frequent oncogenic drivers. They confer a favorable prognosis and strongly predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Over the last decades, several EGFR genetic alterations, common and uncommon mutations, have been described in exons 18−21. Common mutations are exon 19 deletions (most frequently E746-A750) and exon 21 L858R substitution. Uncommon mutations include exon 18 G719X, exon 20 S768l, exon 21 L861Q and many other rare ones. This report describes the case of a 55-year-old woman with a newly diagnosed metastatic lung adenocarcinoma harboring two rare EGFR mutations and showing sustained response to osimertinib.

Randomized phase II study of erlotinib (E) or intercalated E with carboplatin/paclitaxel (CP) in chemotherapy-naive advanced NSCLC: Correlation of biomarker status and clinical benefit

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8026-8026
Author(s):  
F. R. Hirsch ◽  
R. Dziadziuszko ◽  
L. Varella-Garcia ◽  
W. Franklin ◽  
P. Bunn ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kras Mutation ◽  
Phase Ii Study ◽  
Egfr Mutations ◽  
Gene Copy ◽  
Wild Type ◽  
Kras Mutations ◽  
Activating Mutations ◽  
Randomized Phase Ii ◽  
Evaluable Population

8026 Background: E plus chemotherapy showed no additive effects in NSCLC but preclinical studies suggested that intercalation of E and chemotherapy could give synergy. Clinical studies suggested that EGFR mutations could aid in pt selection. KRAS mutation status of tumors was also evaluated. We conducted a randomized phase II study of E and E intercalated with CP in pts with chemonaive NSCLC. Methods: Stage IIIB/IV EGFR+ NSCLC pts were randomized to E 150 mg/d or CP d1 plus E days 2–15 q21 days (ECP). After 4 cycles, E continued until PD. Tumor tissue was evaluated by IHC (EGFR), FISH (EGFR gene copy number), and PCR amplification followed by DNA sequencing (EGFR and KRAS mutations). Results: Among 143 pts randomized 53% EGFR FISH+; 13% activating EGFR mutations and 8% non-activating EGFR mutations (evaluable samples=114); and 22% KRAS mutations (evaluable samples=130). No pt had both EGFR and KRAS mutations. EGFR-activating mutations were higher among females (19% vs 6% males), adenocarcinoma histology (17% vs 0% others), Asians (45% vs 7% non-Asian), and never smokers (29% vs 7% former and 0% current); KRAS mutations were higher in current smokers (41% vs 27% former and 0% never) and adenocarcinoma histology (22% vs 18% squamous). In the E arm, 6-mo PFS probability for the efficacy evaluable population (n=69) was significantly higher in pts with EGFR activating mutations vs no mutations (89% vs 25%, HR=0.17, P=0.001), numerically higher in pts with EGFR FISH+ vs FISH- (40% vs 22%, HR=0.61, P=0.07), and with KRAS wild type vs mutation+ (38% vs 12%, HR=0.56, P=0.10). Response rates, PFS and OS by type of EGFR/KRAS mutation will be presented. In the ECP arm, 6-mo PFS probability for the efficacy evaluable population (n=68) was numerically higher in pts with EGFR activating mutations (42% vs 29%, HR=0.72, P=0.53), numerically higher in pts with wild type KRAS (32% vs 9%, HR=0.57, P=0.08), and numerically lower in pts with EGFR FISH+ vs FISH- (23% vs 30%, HR=0.93, P=0.78). Conclusions: Activating EGFR mutations correlate with increased 6 mo PFS probability in 1st line therapy with E. EGFR FISH + and absence of KRAS mutation trend towards increased 6 mo PFS rate with E. [Table: see text]

Detection of EGFR-activating mutations from plasma DNA as a potent predictor of survival outcomes in FASTACT 2: A randomized phase III study on intercalated combination of erlotinib (E) and chemotherapy (C).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8021-8021 ◽  
Author(s):  
Tony Mok ◽  
Yi Long Wu ◽  
Jin Soo Lee ◽  
Chong-Jen Yu ◽  
Virote Sriuranpong ◽  
...  
Keyword(s):  
Phase Iii ◽  
Egfr Mutations ◽  
Survival Outcomes ◽  
Wild Type ◽  
Plasma Dna ◽  
Predictive Values ◽  
Activating Mutations ◽  
Specific Pcr ◽  
Potent Predictor ◽  
Biomarker Analysis

8021 Background: Biomarker analysis of tumor from FASTACT 2 confirmed predictive power of EGFR mut on the benefit of intercalated combination of E and C as 1st line in advanced NSCLC (T. Mok, ESMO 2012). However, only limited tumor were available. Recent development allowed us to detect EGFR mut in cell-free DNA from plasma (pEGFRmut). In this study, we studied the concordance between pEGFRmut and EGFR mut in tumor (tEGFRmut), and the role of pEGFRmut as predictor of PFS and OS. Methods: Retrospective EGFR mut testing of FFPET and plasma from FASTACT 2 were performed with two allele-specific PCR assays, cobas EGFR_FFPET test and cobas EGFR_blood test (in development). Both tests are designed to detect EGFR activating mut (exon 19 deletions, L858R, G719X). One FFPET section was used for tissue test and 2-ml plasma was used for blood test. Results: Among 268 tumors from 451 enrolled pts, 90% (241/268) were analyzable. 40% (96/241) harbored at least one activating EGFR mut. All 427 plasmas from 451 enrolled pts were analyzable. 32% (136/427) were positive for EGFR activating mut. The concordance of two tests from 224 matched tissue and plasma samples was summarized below. Using tissue as comparator, the sensitivity of plasma test was 76% (68/89) and the specificity of plasma test was 96% (130/135) respectively. Positive and negative predictive values for EGFR activating mut were 93% (68/73) and 86% (130/151) respectively. Median PFS of patients with pEGFRmut treated with intercalated combination versus chemotherapy alone was 13.8 vs. 6.1 m (HR=0.21 p<0.0001), and for pEGFR wild-type, 6.7 vs. 6.0 m (HR=0.80, p=0.06). Median OS of patients with pEGFRmut treated with intercalated combination versus chemotherapy alone was 32.4 vs. 19.0 m (HR=0.51, p=0.0035), and for pEGFR wild-type, 16.1 vs 13.3 m (HR=0.89, p=0.39). Conclusions: cobas EGFR_blood test can be used to reliably detect EGFR mutations in plasma. pEGFRmut is a potent predictor of survival outcomes in FASTACT 2. Clinical trial information: NCT00883779/ MO22201/CTONG0902. [Table: see text]

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