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J. Tsai
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MO21 - Prognostic and Predictive Biomarkers V - EGFR (ID 98)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 2
- Moderators:D.C. Lam, S.M. Lee
- Coordinates: 10/30/2013, 10:30 - 12:00, Bayside Auditorium A, Level 1
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MO21.07 - Monitoring of EGFR TKI sensitizing and resistance mutations in plasma DNA of advanced adenocarcinoma of NSCLC during erlotinib treatment. (ID 2168)
11:10 - 11:15 | Author(s): J. Tsai
- Abstract
- Presentation
Background
EGFR TKI sensitizing mutations in plasma DNA isolated prior to treatment were shown to be a potent predictor for survival outcome of advanced NSCLC (T. Mok, ASCO 2013). Levels of EGFR mutations (pEGFRmut) in plasma during treatment, including sensitizing and resistance mutations, may offer an opportunity to monitor patient’s response to therapy and disease progression. In this study, we measured the levels of pEGFRmut at every 4 weeks during erlotinib treatment and investigated the emergence of the T790M mutation in relationship to disease progression.Methods
Retrospective EGFR mutation testing of plasma samples from an unselected cohort of 227 patients with adenocarcinoma with an allele-specific PCR assay, cobas® EGFR_blood test (in development at Roche Molecular Systems, Inc.). The test is designed to detect 42 mutations in exon 18-21 of the EGFR gene including TKI sensitizing mutations (Exon 19 deletions, L858R, G719X and L861Q), resistance mutation (T790M) and atypical mutations (S768I and Exon 20 Insertions). 2 ml plasma of each patient was used for EGFR_blood PCR test. The genomic equivalent copy number of plasma DNA was determined by comparing to a standard curve of genomic DNA.Results
25 (11%) of 227 unselected patients with adenocarcinoma had a sensitizing EGFR mutation in their plasma prior to the erlotinib treatment. Sequential plasma samples were retrieved for 23 of the 25 pEGFRmut+ patients. 22 (96%) of the 23 pEGFRmut+ patients had lower TKI sensitizing mutations after the first cycle (4 weeks) of erlotinib treatment. The mutated DNA was reduced below the limit of detection for 13 (57%) of the 23 pEGFRmut+ patients during the course of erlotinib treatment. At the time of progression, 6/23 had the same EGFR sensitizing mutations, 9/23 developed T790M mutation with the original mutation and 6/23 patients had no detectable mutation. T790M mutation was not detected in 227 plasma samples taken prior to erlotinib treatment. The figure shows the time course of two representative patients where a T790M resistance mutation emerges. In the 9 patients with T790M mutation, it can be detected in the blood between 15 and 344 days (mean of 98 days) before progression is clinically evident.Figure 1Conclusion
The amounts of EGFR TKI sensitizing mutant DNA in plasma change during the erlotinib treatment. T790M mutation was not detected prior to erlotinib treatment and is detected between 15 and 344 days before disease progression is evident.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO21.08 - Detection of EGFR mutations in plasma and diagnosis biopsies from non-small cell lung cancer patients using allele-specific PCR assays. (ID 2248)
11:15 - 11:20 | Author(s): J. Tsai
- Abstract
- Presentation
Background
EGFR TKI sensitizing mutations from plasma prior to treatment were shown to be a potent predictor for survival outcome of advanced NSCLC (T. Mok, ASCO 2013). In this study, we tested EGFR mutations in the archived plasma from 199 advanced adenocarcinoma. The plasma samples were taken when they progressed on their chemotherapy and before their 2nd erlotinib treatment a mean of 10.5 months after the diagnostic biopsy was obtained. EGFR mutations detected in plasma after chemotherapy and in the tumor DNA from their original diagnostic biopsies were also compared.Methods
Plasma DNA and tumor DNA were tested with two allele-specific PCR assays, cobas® EGFR_ FFPET tissue test and cobas® EGFR_blood test (in development at Roche Molecular Systems, Inc.). Both allele-specific PCR assays detect 41 mutations in exon 18-21 of the EGFR gene including TKI sensitizing mutations (Exon 19 deletions, L858R and G719X), resistance mutation (T790M) and atypical mutations (S768I and Exon 20 Insertions). cobas® EGFR_blood test also detects L861Q. Plasma samples of all 199 adenocarcinoma were collected immediately (less than 2 days) prior to the patient’s erlotinib treatment and stored at -80°C. From 197 (99%) of 199 of the patients tumor DNA was extracted from the diagnostic biopsy.Results
Among 199 advanced adenocarcinoma patients, 24/199 (12%) were EGFR mutation positive in plasma. 28/196 (14%) were EGFR mutation positive in tumor DNA. The comparison of EGFR mutation in plasma and tumor DNA is shown in the table 1. The overall concordance of EGFR mutation status in plasma and tumor biopsy was 91% (179/196). 17/196 (9%) patients had the same EGFR mutations in plasma as in their original diagnosis biopsy and 162/196 (82%) patients were mutation negative in both samples. In this study, different EGFR mutation status in plasma and original biopsy was observed in 17 of 196 (9%) patients. 6 of 17 were EGFR mutation positive in plasma only and 11 of 17 were EGFR positive in tumor DNA only. These differences could reflect alterations in the tumor cells between sampling of biopsy and blood (average of 10.5 months) where the patients are treated with chemotherapy. Another possibility is limitations of assay technology with circulating cell-free DNA in plasma or heterogeneity of tumor.Conclusion
Tumor mutations in the patient’s original diagnostic biopsy can be detected in their plasma when they progress on chemotherapy which may provide another opportunity for mutation testing. Table 1. Comparison of EGFR mutations detected in plasma and diagnostic biopsy. MND=Mutation-Not-Detected.Figure 1Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O01 - Prognostic and Predictive Biomarkers I (ID 94)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:T. Mitsudomi, V. Gregorc
- Coordinates: 10/28/2013, 10:30 - 12:00, Parkside Auditorium, Level 1
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O01.06 - Dynamic change in plasma EGFR mutation DNA in response to first line therapy for advanced stage non-small cell lung cancer (NSCLC) (ID 2496)
11:25 - 11:35 | Author(s): J. Tsai
- Abstract
- Presentation
Background
Diagnostic utility study of EGFR mutation analysis of tumor and plasma from FASTACT 2 confirmed that the plasma EGFR mutation DNA (pEGFRmut) is a sensitive and specific biomarker. (Wu et al, Lancet Oncology 2013; T. Mok, ASCO 2013). Primary objective of this study is to investigate the dynamic change in pEGFRmut during course of treatment. Secondary objective is to study the diagnostic utility of pEGFRmut in patients with distant organ metastasis whom we assumed to have higher level of plasma DNA.Methods
Retrospective EGFR mutation testing of FFPET and plasma from FASTACT 2 were performed with two allele-specific assays, cobas® 4800 EGFR_FFPET test and cobas® EGFR_blood test (in Development). Both tests are designed to detect one or more of the 42 known EGFR mut. One FFPET section was used for tissue test and 2-ml plasma was used for blood test. We studied the plasma samples collected at baseline, post cycle 3 (C3) and at tumor progression according to RECIST criteria (PD).Results
Complete analysis of plasma samples at baseline, C3 and PD was available in 305 of 451 pts(67.6%). Incidence of pEGFRmut positive at baseline, C3 and PD was 35% (106/305),15% (47/305)and 27% (81/305), respectively. 98 of 106 pEGFRmut patients harbor the Exon 19 deletion or L858R at baseline. (C arm 51; CE arm 47). At C3, 21 (41%) pts lose pEGFRmut positivity in C arm comparing to 39 (83%) in CE arm. At PD, 8 of the 21pts in C arm and 18 of the 39 in CE arm regained pEGFRmut positivity. Table 1 summarized the median pEGFRmut copies/PCR. There was a considerable decline at C3 in both C and CE arm. However, pEGFRmut copies/PCR rebounded to high level at PD in C arm only and remained low in CE arm. Correlation of dynamic change in pEGFRmut copies/PCR with clinical tumor response and PFS will be presented at the meeting. We have also identified 93 (out of 224 matched tissue and plasma samples) patients with known distant organ metastasis. Sensitivity of pEGFRmut in this patient subgroup is 91% (41/45), specificity at 98% (47/48) and overall concordance at 95% (88/93). Table 1Median pEGFRmut copies/PCR Baseline C3 PD C (Exon 19) 27.6 2.3 35.8 CE (Exon 19) 43.2 0 2.7 C(Exon 21) 40.9 2.6 63.9 CE (Exon 21) 87.1 0 3.5 Conclusion
This is the first study demonstrating the quantitative dynamic change in pEGFRmut in pts who received C or CE for advanced NSCLC. At RECIST progression, pEGFRmut remained low in patients who received erlotinib but not in patients who received chemotherapy only. pEGFRmut is a potential biomarker for monitoring tumor response.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
