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Lianpeng Chang
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MA16 - Novel Mechanisms for Molecular Profiling (ID 917)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 13:30 - 15:00, Room 203 BD
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MA16.06 - EGFR Clonality and Tumor Mutation Burden (TMB) by Circulating Tumor DNA (ctDNA) Sequencing in Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 13146)
14:05 - 14:10 | Author(s): Lianpeng Chang
- Abstract
- Presentation
Background
TKI has significantly improved survival time of NSCLC pts with sensitive mutation. However, pts present different outcome while receiving TKI treatment. We conduct a prospective multicenter clinical trial to determine whether clonality of sensitive mutation is related to the efficacy of TKI. We also evaluate the consistency of TMB between tissue and blood in this cohort.
a9ded1e5ce5d75814730bb4caaf49419 Method
Paired tumor and plasma samples at diagnosis were obtained from systemic treatment naïve pts with advanced NSCLC. DNA was sequenced by target-capture deep sequencing of 1021 previously annotated genes related to solid tumors. Clonal EGFR mutation was defined if EGFR mutation was in the cluster with the highest mean variated allele frequency with PyClone, and otherwise subclonal EGFR mutation. TMB of tissue (tTMB) and blood (bTMB) analysis interrogated single nucleotide variants, small insertion and deletion, with VAF ≥3 % and ≥0.5 %, respectively. TMB-high pts were identified with ≥9 mut/MB (upper quartile of data from geneplus).
4c3880bb027f159e801041b1021e88e8 Result
During February 2017 to April 2018, 127 advanced NSCLC pts were enrolled from 9 centers. A total of 653 somatic variations were detected in tissues. Mutations occurred most frequently in EGFR (57 %), TP53 (54 %), KRAS (9 %), ALK (8 %). In matched plasma, 405 (62 %) tumor-derived mutations were detected by pan-caner panel sequencing. A total of 90 EGFR mutations were detected in 73 pts, most of which occurred in tyrosine kinase domain (L858R, 41%; Ex19del, 33%). Most EGFR mutation were clonal in tissue and plasma, with a consistence of 83 % in paired samples. In addition, bTMB was significantly correlated to tTMB (Pearson r= 0.85, p-value= 1.8e-30), with a consistence of 89 %. Interestingly, high TMB was observed in a small fraction of patients (8 %) with driver mutations, such as mutations in EGFR, ALK fusion, ERBB2 and PIK3CA.
8eea62084ca7e541d918e823422bd82e Conclusion
Deep sequencing with the pan-cancer panel can effectively detect mutations and evaluate TMB in both tissue and blood with high consistence. EGFR mutations can be clonal or subclonal in both tissue and blood. Prospective multicenter study is ongoing to determine the EGFR clonality as a predictive factor for the TKI efficacy in NSCLC (TRACELib-NSCLC, NCT03059641).
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P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.13-18 - Exploring the Resistance Mechanism of Osimertinib and Monitoring the Treatment Response Using Plasma ctDNA in Chinese NSCLC Patients (ID 13297)
16:45 - 18:00 | Author(s): Lianpeng Chang
- Abstract
Background
Osimertinib (AZD9291; Tagrisso) is a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) known to be effective for patients harboring the EGFR-T790M variant, which is accounts for more than half of the acquired resistance mechanisms to the first generation EGFR-TKIs. However, limited osimertinib resistance-mechanism was reported. Study on potential osimertinib-resistance mechanisms in advanced NSCLC is necessary.
a9ded1e5ce5d75814730bb4caaf49419 Method
This study enrolled eight T790M-positive (tissue validated) patients, treated with osimertinib after first generation EGFR-TKI (Erlotinib, Gefitinib, Icotinib) resistance and progressed rapidly. Serial plasma samples were collected until disease progressed. Plasma DNA was extracted and sequenced by target-capture deep sequencing of 1021 previously annotated genes related to solid tumors. Clonal EGFR T790M mutation was defined if mutation was in the cluster with the highest mean variated allele frequency with PyClone, and otherwise subclonal EGFR T790M mutation. Molecular tumor burden index (mTBI) was calculated with the mean variant allele frequency of mutations in trunk clonal population.
4c3880bb027f159e801041b1021e88e8 Result
The median progression-free survival (PFS) of these eight rapidly-progressed patients was 3.82 months [95% CI 2.05-5.01] .Targeted capture sequencing of pretreatment ctDNA showed all of the eight patients (100%) were EGFR-positive (Exon19del [n=6] and L858R [n=2]), and seven patients (88%) harbored EGFR T790M mutation, except for the only one patient (P006) who showed an extremely low level of ctDNA. During the Osimertinib treatment, five patients (63%) had osimertinib resistance-related mutations: EGFR C797S (in cis position), G724S, KRAS G12D, PIK3CA E542K, EGFR amplification, and ERBB2 amplification. Among them, two patients had more than one resistance mechanisms: patient P034 had EGFR G724S, KRAS G12D and EGFR amplification, simultaneously; patient P013 had amplification in both EGFR and ERBB2. Other potential resistance mechanisms were identified including EGFR T751I and K754E mutations in P002 and ERBB2 S603 in P013. Notably, the only one patient (P004) who had not been detected to have any known osimertinib resistance mechanism but progressed in 3 months, was demonstrated to harbor a subclonal EGFR T790M mutation by analysis of ctDNA clonal structure. Serial ctDNA monitoring showed mTBI increased when disease progressed in 88% (7/8) patients, except P006, whose mutation were negative at second (stable disease) and third (progressed disease) therapeutic evaluations due to the extremely low level of ctDNA.
8eea62084ca7e541d918e823422bd82e Conclusion
This study presented comprehensive the resistance mechanism of osimertinib progressed rapidly in ctDNA including multiple mechanisms co-occurred in same patient. Serial monitoring of plasma ctDNA may be a promising approach to explore resistance mechanism and monitored the treatment response of third generation EGFR-TKI.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.01-68 - Capture-Based Sequencing Depicts Evolution Characteristics of Pulmonary Sarcomatoid Carcinoma (ID 13215)
16:45 - 18:00 | Author(s): Lianpeng Chang
- Abstract
Background
Pulmonary sarcomatoid carcinoma (PSC) is a very rare subset of highly aggressive and poorly differentiated non-small cell lung cancer. Mutation profiling of PSC was reported previously. However, the intratumor heterogeneity and evolution characteristics of PSC remains unknown.
a9ded1e5ce5d75814730bb4caaf49419 Method
This study enrolled 39 patients (pts) with PSC. A median follow-up time was 7 months (ranged from 3 to 33 months). Each tumor sample was divided to cancer tissue and sarcoma tissue by microdissection. Matched distant normal tissues were also collected for removing germline background. Capture-based sequencing was performed using a panel covering 1021 genes related to solid tumors. Somatic mutations were used to analyze intratumor heterogeneity and evolution characteristics. Tumor mutation burden (TMB) analysis interrogated single nucleotide variants, small insertion and deletion, with VAF ≥3 %. TMB-high pts were identified with ≥9 mut/MB (upper quartile of data from geneplus).
4c3880bb027f159e801041b1021e88e8 Result
Capture-based sequencing had been done on 90 tissues, including cancer tissues, sarcoma tissues and matched distant normal tissues from 30 pts. Nine patients were excluded due to insufficient DNA samples. A median effective depth of coverage of 1299 × was obtained in tissue samples. A total number of 608 mutations were detected, including driver mutations in TP53 (73%, 44/60), MET (22%, 12/60), EGFR (20%, 12/60), KRAS (20%, 12/60), and NF1 (17%, 10/60). Interestingly, mutations in MET and KRAS were demonstrated to be mutually exclusive in cancer and sarcoma tissues. Shared mutations between cancer and sarcoma tissues were 43%. The median of TMB of sarcoma and cancer samples were both 8.6 mutations/Mb. High TMB were identified in 40% (12/30 pts) of sarcoma samples and 43% (13/30 pts) of cancer samples, respectively. TMB of sarcoma tissues was significantly correlated to that of cancer tissues (Pearson r= 0.92, p-value<0.01), with a consistence of 90 % Furthermore, the fraction of brunch mutations in cancer tissues was related to the worse OS of PSC (Log-rank, HR=3.2, 95% CI=1.1-9.4, p=0.04).
8eea62084ca7e541d918e823422bd82e Conclusion
Sarcoma tissues shared mutations with cancer tissues. Mutations and TMB analysis could help to guide treatment decisions of PSC in both tyrosine kinase and immune checkpoint inhibitors. Evolution characteristics could serve as potential prognostic factors in PSC.
6f8b794f3246b0c1e1780bb4d4d5dc53
