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X. Yang
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ORAL 16 - Clinical Care of Lung Cancer and Advanced Biopsies (ID 115)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:J.W. Neal, Q. Zhou
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 2a-3b
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ORAL16.06 - Quantification of Mutant Alleles in Circulating Tumor DNA from Advanced Non-Small Cell Lung Cancer (ID 2452)
11:39 - 11:50 | Author(s): X. Yang
- Abstract
- Presentation
Background:
The most important advantage of EGFR mutation analysis in circulating tumor DNA(ctDNA) from plasma is quantitative and dynamic evaluation. Here, we investigated the feasibility of droplet digital PCR(ddPCR) for quantitative and dynamic detection of EGFR mutation in ctDNA and next generation sequencing (NGS) for screening a range of resistance-relevant mutations in plasma DNA in the process of disease progression for patients diagnosed with advanced lung adenocarcinoma.
Methods:
Seventy-three patients were enrolled in this study. Tumor tissues were sampled before treatment, and paired plasma DNA samples were collected pre- and post- EGFR-TKI therapy. Sixty-seven of 73 patients obtained blood samples in the time-point of disease progression. All 73 patients presented EGFR mutation in tumor tissues tested by denaturing high performance liquid chromatography（DHPLC）method. We measured the absolute quantities of plasma EGFR mutant and wild-type alleles by ddPCR. Multi-genes testing was performed using NGS in twenty-seven plasma samples from the twelve patients.
Results:
Taking the EGFR mutation in tumor tissue as the standard, the EGFR mutations detection sensitivity in plasma DNA was 74%（54/73）. According to EGFR mutation status in TKI-naïve patients, all 73 patients were divided into two subgroups that carried mutation in both of specimens (B+/T+,n=54) and mutation only in tissues rather than in plasma ctDNA(T+ /B-,n=19) . The B+/T+ group showed superior progression-free survival (PFS, median, 12.6 vs. 6.7 months, P<0.0001) compared to T+ /B- group. The patients with high EGFR mutated abundance in plasma ctDNA (＞5.15%) showed better PFS (median, 15.4 vs 11.1months; P=0.021) compared with those with low EGFR abundance (≤5.15%). EGFR mutation dynamic alteration during EGFR-TKIs therapy was analyzed and showed patients with decreased quantity of EGFR mutated alleles after disease progression（n=29）showed better PFS compared with non-decreased quantity group(n=38) (median, 12.7 vs 7.1 months; P=0.001). However, NGS results came from 12 patients’ matched plasma DNA showed that 66.6% total mutational copies were elevated and 76.5% mutual mutation frequency increased after disease progression. Besides canonical EGFR pathway, mutated genes in plasma DNA were significantly enriched in cell cycle and TGF-β pathways when disease progressed. Quantification of mutant allele fraction by means of either NGS or ddPCR assay showed excellent agreement.
Conclusion:
Droplet digital PCR is a highly sensitive method for EGFR mutation analysis in plasma DNA of patients with advanced lung adenocarcinoma, while NGS shows good performance in multiple genes testing especially novel and uncommon genes. High EGFR sensitive mutated abundance（>5.15%） in plasma samples of TKI-naïve patients can predict better PFS of EGFR-TKI treatment.
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