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C. Bai
Moderator of
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JCES01 - Joint IASLC - Chinese Society for Clinical Oncology - Chinese Alliance Against Lung Cancer Session (ID 413)
- Event: WCLC 2016
- Type: Joint Chinese / English Session
- Track:
- Presentations: 22
- Moderators:F.R. Hirsch, C. Bai
- Coordinates: 12/04/2016, 08:00 - 11:45, Stolz 1
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JCES01.02 - Welcome and Introduction (ID 6810)
08:20 - 08:30 | Author(s): F.R. Hirsch, Y.-. Wu, C. Bai
- Abstract
- Presentation
Abstract not provided
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JCES01.03 - Perspectives on Precision Medicine for Early Stage NSCLC (ID 6812)
11:25 - 11:45 | Author(s): J. Hu
- Abstract
- Presentation
Abstract not provided
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JCES01.04 - Liquid Biopsy in Monitoring Dynamic Changes of Driver Genes in Advanced NSCLC (ID 6813)
08:30 - 08:50 | Author(s): Q. Zhou
- Abstract
- Presentation
Abstract:
Epidermal growth factor receptor (EGFR) activating mutations in the tyrosine kinase domain serve as predictive biomarkers for EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment outcome for patients with advanced non-small cell lung cancer (NSCLC).[1] However, due to the invasive procedures required to obtain tumor tissues, not all patients can provide enough high-quality tissues for EGFR mutation analysis. Circulating free DNA (cfDNA) in plasma provides a noninvasive substitute for tumor tissues. Several studies have reported a concordance rate between tumor and plasma > 90%, even reaching 97%, demonstrating the feasibility of detecting EGFR mutations in cfDNA.[2-4]EGFR mutation status detection in cfDNA has been approved by the European Society for Medical Oncology and by China to be used with EGFR-TKI treatment for NSCLC.[5,6] In addition to providing pretreatment information, plasma-based EGFR mutation detection makes it possible to monitor dynamic changes in this mutation during treatment. Several studies have reported a quantitative change in EGFR mutations during EGFR-TKI treatment by comparing pre- and post-treatment plasma, in which various types of plasma EGFR mutations were found.[7,8] The quantity of the plasma EGFR mutation sometimes decreases, or sometimes decreases slowly or rapidly. Patients whose plasma EGFR mutations decrease rapidly usually exhibit a better response to EGFR-TKI treatment.[8] However, these studies were not based on prospective clinical trials, therefore the number of patients who had serial plasma specimens tested during EGFR-TKI treatments was limited, and very few plasma specimens were collected as part of a pre-planned schedule. The only recent study on plasma EGFR mutation changes based on a prospective clinical trial was reported by Mok et al.[9] In this phase III trial (FASTACT-2), patients received gemcitabine/platinum plus sequential erlotinib or placebo. EGFR mutation-specific cfDNA levels decreased at cycle 3 and increased at the time of disease progression. Positive plasma EGFR mutant DNA at cycle 3 predicted a worse clinical outcome. In this study, the treatment was chemotherapy plus EGFR-TKI or placebo, not EGFR-TKI, and there was no information on the plasma EGFR mutation at other time points except at baseline, cycle 3, and at disease progression. The dynamic changing types of plasma EGFR mutations during the whole course of EGFR-TKI treatment and its correlation with clinical outcomes were not determined. To measure changes of plasma EGFR L858R mutation during EGFR-TKI treatment, and to determine its correlation with the response and resistance to EGFR-TKI, we conducted a study. This study was a pre-planned exploratory analysis of a randomized phase III trial conducted from 2009 to 2014 comparing erlotinib with gefitinib in advanced NSCLC harboring EGFR mutations in tumor (CTONG0901). Serial plasma samples were collected as a pre-planned schedule. This trial was conducted in Guangdong Lung Cancer Institute, China. Totally, 256 patients were enrolled in CTONG0901. One hundred and eight patients harbored L858R mutation in tumors and 80 patients provided serial blood samples as pre-planned scheduled. Patients were randomized to receive erlotinib or gefitinib. Serial plasma L858R in 80 patients was detected using quantitative polymerase chain reaction. Changing types of plasma L858R were analyzed using Ward's Hierarchical Clustering Method. Progression-free survival (PFS) and overall survival (OS) were compared between different types. As a whole, the quantity of L858R decreased and reached the lowest level at the time of best response to EGFR-TKI. In 61 patients, L858R increased to its highest level when disease progressed (Ascend Type), while in 19 patients, L858R maintained a stable level when disease progressed (Stable Type). Median PFS was 11.1 (95%CI, 6.6–15.6) and 7.5 months (95%CI, 1.4–13.6) in patients with Ascend and Stable Types, respectively (P = .023). Median OS was 19.7 (95%CI, 16.5–22.9) and 16.0 months (95%CI, 13.4–18.5), respectively (P = .050). This is the first report finding two different changing types of plasma L858R mutation during EGFR-TKI treatment based on a prospective randomized study. Different changing types were correlated with benefits from EGFR-TKI. The impact of plasma L858R levels at disease progression on subsequent treatment strategy needs further exploration. This study was recently published in Journal of Hematology&Oncology.[10] In summary, liquid biopsy is very promising in monitoring dynamic changes of driver genes in advanced NSCLC, which promotes the development of precision medicine. References 1. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 2009;361(10):947-957. 2. Kimura H, Suminoe M, Kasahara K, et al. Evaluation of epidermal growth factor receptor mutation status in serum DNA as a predictor of response to gefitinib (IRESSA). Br. J. Cancer. 2007;97(6):778-784. 3. Douillard JY, Ostoros G, Cobo M, et al. Gefitinib treatment in EGFR mutated caucasian NSCLC: circulating-free tumor DNA as a surrogate for determination of EGFR status. J. Thorac. Oncol. 2014;9(9):1345-1353. 4. Couraud S, Vaca-Paniagua F, Villar S, et al. Noninvasive diagnosis of actionable mutations by deep sequencing of circulating free DNA in lung cancer from never-smokers: a proof-of-concept study from BioCAST/IFCT-1002. Clin. Cancer Res. 2014;20(17):4613-4624. 5. European Medicines Agency. Summary of Product Characteristics 2014 [EB/OL], 10/14 update. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001016/WC500036358.pdf. 6. Iressa 250mg Leaflet professional China. CN52-086A. 20150203. . 7. Sacher AG, Oxnard GR, Mach SL, et al. Prediction of lung cancer genotype noninvasively using droplet digital PCR (ddPCR) analysis of cell-free plasma DNA (cfDNA). Paper presented at: Journal Of Clinical Oncology 2014. 8. Marchetti A, Palma JF, Felicioni L, et al. Early Prediction of Response to Tyrosine Kinase Inhibitors by Quantification of EGFR Mutations in Plasma of NSCLC Patients. J. Thorac. Oncol. 2015;10(10):1437-1443. 9. Mok T, Wu YL, Lee JS, et al. Detection and Dynamic Changes of EGFR Mutations from Circulating Tumor DNA as a Predictor of Survival Outcomes in NSCLC Patients Treated with First-line Intercalated Erlotinib and Chemotherapy. Clin. Cancer Res. 2015;21(14):3196-3203. 10. Zhou Q, Yang JJ, Chen ZH, et al. Serial cfDNA assessment of response and resistance to EGFR-TKI for patients with EGFR-L858R mutant lung cancer from a prospective clinical trial. Journal of Hematology&Oncology. 2016;9:86.
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JCES01.05 - New Clinical Trials on Gene Alteration in China (ID 6814)
08:50 - 09:10 | Author(s): S. Lu
- Abstract
- Presentation
Abstract not provided
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JCES01.06 - European Perspective Phase I Strategy (ID 6816)
09:10 - 09:30 | Author(s): C. Rolfo
- Abstract
- Presentation
Abstract not provided
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JCES01.07 - North American Perspective (ID 6817)
09:30 - 09:50 | Author(s): P.A. Bunn, Jr.
- Abstract
- Presentation
Abstract not provided
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- Abstract
- Presentation
Background:
To assess the ability of droplet digital PCR and ARMS technology to detect epidermal growth factor receptor (EGFR) T790M mutations from circulating tumor DNA (ctDNA) in advanced non-small cell lung cancer (NSCLC) patients with acquired EGFR-TKI resistance. A sensitive and convenient method for detecting T790M mutation would be desirable to direct patient sequential treatment strategy.
Methods:
To assess the ability of droplet digital PCR and ARMS technology to detect epidermal growth factor receptor (EGFR) T790M mutations from circulating tumor DNA (ctDNA) in advanced non-small cell lung cancer (NSCLC) patients with acquired EGFR-TKI resistance. A sensitive and convenient method for detecting T790M mutation would be desirable to direct patient sequential treatment strategy.To assess the ability of droplet digital PCR and ARMS technology to detect epidermal growth factor receptor (EGFR) T790M mutations from circulating tumor DNA (ctDNA) in advanced non-small cell lung cancer (NSCLC) patients with acquired EGFR-TKI resistance. A sensitive and convenient method for detecting T790M mutation would be desirable to direct patient sequential treatment strategy.
Results:
A total of 108 patients were enrolled in this study. 108 patient plasma samples were detected by ddPCR and 75 were detected by ARMS. And 16 patients experienced re-biopsy were detected T790M status by ARMS method. 43.7% (47/108) had acquired T790M mutation by ddPCR. In 75 patient plasma samples, comparing ddPCR with ARMS, the rates of T790M mutation were 46.7% (35/75) and 25.3% (19/75) by ddPCR and ARMS, respectively. Of all, 16 patients both had tumor and plasma samples, the T790M mutation rates were 56.3% (9/16) by ARMS in tissue and 50.5% (8/16) by ddPCR in plasma ctDNA. Among them, there were two ctDNA T790M mutations by ddPCR but T790M gene negative in tumor tissue by ARMS method. For all patients, the median PFS and OS were 12.3 months and 32.8 months, respectively. The patients with T790M-positive tumors had a longer time to disease progression after treatment with EGFR-TKIs (median, 13.1 months vs 10.8 months; P=0.010) and overall survival (median, 35.3 months vs 30.3 months; P=0.214) compared with those with T790M-negative patients.
Conclusion:
Our study demonstrates dPCR assay provide feasibility and sensitive method in detecting EGFR T790M status in plasma samples from NSCLC patients with acquired EGFR-TKI resistance.And T790M-positive patients have better clinical outcomes to EGFR-TKIs than patients with T790M negative.
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JCES01.10 - Serial Quantitative Assessment of Plasma Circulating Tumor DNA by Digital NGS in Patients with Lung Cancer (ID 7054)
10:20 - 10:30 | Author(s): Y. Zhao, J. Gong, W. Ma, K.C. Banks, H. Wen, E.H. Moore, R.B. Lanman, T. Li
- Abstract
- Presentation
Background:
Next generation sequencing (NGS) has been increasingly used in oncology practice but proven practically difficult when serial tumor specimens are needed. The objectives of this study were to determine feasibility and explore clinical utility of serial NGS analyses of circulating tumor DNA (ctDNA) in patients (pts) with advanced solid tumors undergoing treatment.
Methods:
ctDNA digital NGS was performed by a CLIA-certified lab (70-gene panel with mutant allele fraction (MAF) quantification). ctDNA results were retrospectively analyzed and decreases/increases/stability of molecular tumor load (MTL) defined here as MAFs of truncal driver mutations were correlated with clinical and radiographic response to treatment (response, progression, or stable disease, respectively).
Results:
From Jan 2015 to July 2016, 38 consecutive pts with advanced lung tumors (84% LUAD, 5% LUSC, 5% SCLC, 5% NOS) receiving treatment (Table) had serial ctDNA analyses (median 2, range 2-7). ctDNA alterations were detected at least once in 37 (97.4%) pts. Changes in MTL correlated with or predicted all (95% CI, 82.0-99.8%) radiological and/or clinical responses except for the patient with no genomic alteration detected. MTL results clarified response status when radiographic responses were difficult to assess in 9 (28%) of pts with either complex pleural disease (n=6), pneumonitis during PD-1 inhibitor therapy (2). Two MTL change patterns were observed: 1) clonal changes while receiving targeted therapy, including EGFR (12), ALK (3), MET (2), ERBB2 (2); 2) global changes to PD-1 inhibitors, chemotherapy or radiation. Representative tumor response maps will be presented. Table. Summary of tumor types and cancer treatment.Cancer Type Targeted Therapy Immunotherapy Chemotherapy Radiation TOTAL LUAD 14 8 7 3 32 LUSC 1 1 0 0 2 SCLC 0 0 2 0 2 NOS 1 0 1 0 2 All 16 9 10 3 38
Conclusion:
Serial liquid biopsies and ctDNA digital NGS are feasible and clinically useful in monitoring MTL and genomic alterations during cancer treatment, especially in situations when radiographic responses are equivocal. Prospective evaluation of impact on clinical decision making is warranted.
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- Abstract
- Presentation
Background:
Programmed death-ligand 1 (PD-L1) is known to be over-expressed in non-small cell lung cancer (NSCLC). However, the impact of chemotherapy on the altered status of PD-L1 expression has not been examined for NSCLC. The present study was intended to examine the impact of neoadjuvant chemotherapy on PD-L1 expression and its prognostic significance in lung squamous cell carcinoma (SCC).
Methods:
Matched tumor samples were obtained from SCC patients prior to and after neoadjuvant chemotherapy. The expression of PD-L1 was evaluated by immunohistochemistry. Survival analysis was performed by the Kaplan-Meier method.
Results:
A total of 76 eligible SCC patients were recruited. There were 51 males and 25 females with a median age of 60 (39-72) years. The smoking status was former (n=46) and never (n=34). Prior to neoadjuvant chemotherapy, PD-L1 expression was identified in 52.6% (40/76) of SCC patients while 61.8% (47/76) were positive for PD-L1 expression after neoadjuvant chemotherapy . Nine patients switched from negative to positive while another two patients’ samples showed the reverse of the above result. Multivariate analysis demonstrated that postoperative expression of PD-L1 was an independent prognostic factor for overall survival (HR=0.50, P=0.003), but not for PD-L1 expression prior to neoadjuvant chemotherapy.
Conclusion:
Neoadjuvant chemotherapy may up-regulate the expression of PD-L1. As compared with the status of PD-L1 expression prior to chemotherapy, the postoperative expression of PD-L1 is a better prognostic factor for overall survival in SCC.
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JCES01.12 - Discussant Oral Abstracts (ID 6820)
10:40 - 10:55 | Author(s): J.C. Yang
- Abstract
- Presentation
Abstract not provided
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JCES01.13 - Discussant Posters (ID 6821)
10:55 - 11:10 | Author(s): X. Zhang
- Abstract
- Presentation
Abstract not provided
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- Abstract
Background:
Patients with advanced non-small-cell lung cancer (NSCLC) harboring sensitive epithelial growth factor receptor (EGFR) mutations invariably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Although previous research have identified several mechanisms of resistance, the systematic evaluation using next generation sequencing (NGS) to establish the genomic mutation profiles at the time of acquired resistance has not been conducted.
Methods:
In our single center, we performed NGS of a pre-defined set of 416 cancer-related genes in a cohort of 97 patients with NSCLC harboring TKI-sensitive EGFR mutations at the time of acquired resistance to first-generation EGFR-TKIs between January 2015 to December 2015.
Results:
In 97 samples we found total 345 gene alterations (mean 3.6 mutations per patient, range 1-10). Fifty-six patients (57.7%) still exhibit EGFR-sensitive mutations as pretreatment, 93 patients (95.9%) exhibit at least one mutation except for previous existed EGFR-sensitive mutations. In all the 97 patients, most frequently mutated genes were TP53 (59.8%), T790M (28.9%), TET2 (11.3%), EGFR amplification (10.3%), PIK3CA (8.2%), BIM (8.2%), KRAS (7.2%), APC (7.2%), RB1 (7.2%), HER2 (6.2%), DNMT3A (6.2%) and MET (5.2%).
Conclusion:
NGS in this study uncovered many new genetic alterations potentially associated with EGFR TKI resistance and provided information for the further study of drug resistance and corresponding relevant tactics against the challenge of disease progression.
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- Abstract
Background:
Pulmonary adenoid cystic carcinoma (PACC) is one of the rare malignancies, that primary from glandular tissues of lung. Currently, the treatment of PACC relies on surgery and local radiotherapy. However the therapy for advanced PACC patients is limited. A larger number of studies demonstrated that advanced PACC patients obtained little benefit from chemotherapy. Moreover, only a few case reports revealed PACC patients were appropriate for target therapy. Using high-flux and high-resolution techniques to detect the genomic alterations of PACC could provide theoretical foundation for the precision therapy of PACC.
Methods:
8 PACC patients who received surgical resection between January 2013 to December 2015 were enrolled. The tumor tissues from different locations and blood samples were collected. The oncoscreen[TM] panel by Illumina platform, which utilizing probe hybridization to gathering 287 exon regions and 22 intron regions, were used to detect the gene mutation status of PACC. And the embryonal system mutations were filtered by contrasting the gene mutation status of the leukocytes. The tumor heterogeneity was revealed by comparing the gene mutation status in different areas of the same PACC, and the phylogenetic relationships were analyzed to disclose the evolving and developing progression of PACC.
Results:
There were 69 gene mutations together among 8 patients including 29 samples. Each patient has 8.6 mutations averagely. The high-frequency mutations were PAK3-D219E, FBXW7-D112E, TET2-T418I, KAT6A-E796A, and MET-R1005Q. However, the common mutations in other NSCLC, like EGFR, KRAS, ALK, etc., weren’t happened in this group of PACC. In this study, the spatial heterogeneity was discovered in PACC, not only in the mutation site, but also in the mutant abundance. Moreover, the phylogenetic relationships revealed that the clonal evolution and development existed in PACC.
Conclusion:
The status of genomic alterations in PACC was different from the other non-small cell lung cancer (NSCLC). PACC showed obvious spatial heterogeneity and clonal evolution.
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- Abstract
Background:
Amplification of the mesenchymal-epithelial transition factor (MET) gene plays a vital role in non-small cell lung cancer (NSCLC). The anti-MET therapeutic strategies are still unclear in epidermal growth factor receptor (EGFR) mutant patients and EGFR-naive patients. Aims of our study are to discuss role of MET amplification in Chinese NSCLC patients, and evaluate the antitumor activity of crizotinib (MET inhibitor) in Chinese NSCLC patients with MET gene amplification.
Methods:
From Jun 2015 to Jan 2016, we detected 11 metastatic NSCLC patients with MET amplification by fluorescence in situ hybridization (FISH). MET amplification was defined as gene focal amplification or high polysomy (at least 15% cells with ≥5 copy numbers). Patients with MET de novo amplification received crizotinib, patients with concomitant MET acquired amplification and EGFR mutation received combined therapy of EGFR-tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib, icotinib)and crizotinib. All enrolled subjects received tumor measurement according to RECIST1.1
Results:
The frequency of MET de novo amplification was 54.5%(6/11), and that of concomitant MET acquired amplification and EGFR mutation was 45.5%(5/11) respectively. 4 of 6 patients with MET de novo amplification received crizotinib, 2 patients had partial response (PR), 1 patient had stable disease (SD), 1 patient died due to heart disease. Response rate (RR) of crizotinib was 50%(2/4). Encouraging response was observed in one case, a CT scan performed 31 days after starting crizotinib revealed 42.2% decrease in tumor measurement, until now, a 7-month CT revealed 60.0% decrease. 3 of 5 patients with concomitant MET acquired amplification and EGFR mutation received the combined therapy of EGFR-TKIs and crizotinib. 1 patient achieved PR, 2 patients had SD. RR of combined therapy was 33.3%(1/3). Dramatic response was observed in one case with combined therapy, a 2-month CT revealed 31.0% decrease in tumor measurement.
Conclusion:
According to our study, patients with MET amplification benefited from crizotinib, and RR was inspiring. Patients with concomitant MET acquired amplification and EGFR mutation need combined targeted therapy.
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- Abstract
Background:
A significant portion of patients with non-small cell lung cancer (NSCLC) develop brain metastasis. Patients with brain metastasis suffer from poor prognosis with a median survival of less than 6 months and low quality of life with limited treatment options. First generation EGFR tyrosine kinase inhibitors (EGFR TKIs) have demonstrated significant clinical benefit for patients with EGFR-mutant NSCLC. However, their effect on brain metastasis is limited due to poor drug penetration into the brain. Epitinib is an EGFR TKI designed to improve brain penetration. A Phase I dose escalation study on epitinib has been completed and the recommended Phase 2 dose (RP2D) determined (Y-L Wu, 2016 ASCO). This Phase I dose expansion study was designed to evaluate the efficacy and safety of epitinib in EGFR-mutant NSCLC patients with brain metastasis.
Methods:
This is an ongoing open label, multi-center Phase I dose expansion study. EGFR-mutant NSCLC patients with confirmed brain metastasis, either prior EGFR TKI treated or EGFR TKI treatment naïve, were enrolled to receive oral epitinib 160 mg per day. Patients with extra-cranial disease progression while on treatment with an EGFR TKI were excluded. Tumor response was assessed per RECIST 1.1.
Results:
As of 31 May, 2016, 27 patients (13 EGFR TKI pretreated, 14 EGFR TKI treatment naïve) have been enrolled and treated with epitinib. The most frequent adverse events (AEs) were skin rash (89%), elevated ALT (41%)/AST (37%), hyper-pigmentation (41%) and diarrhea (30%). The most frequent Grade 3/4 AEs were elevations in ALT (19%), gamma-GGT (11%), AST (7%), hyperbilirubinemia (7%) and skin rash (4%). There have been no Grade 5 AEs to date. Among the 24 efficacy evaluable patients (11 TKI pretreated, 13 TKI naïve), 7 (7/24, 29%) achieved a partial response (PR), including 1 unconfirmed PR. All PRs occurred in EGFR TKI treatment naïve patients (7/13, 53.8%). Of the 24 evaluable patients, 8 (5 EGFR TKI treatment naïve, 3 EGFR TKI pretreated) had measurable brain metastasis (lesion diameter>10 mm per RECIST 1.1) with 2 PRs (both EGFR TKI treatment naïve patients, 2/5, 40%).
Conclusion:
Epitinib 160mg per day treatment in EGFR-mutant NSCLC patients with brain metastasis demonstrated clinical activity both extra- and intra-cranial. Epitinib was well tolerated. The data to date appears encouraging and warrants further development of epitinib.
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- Abstract
Background:
Recent studies have identified that the degree of tumor infiltrating lymphocyte (TIL) infiltration and PD-L1 expression in the tumor microenvironment (TME) are significantly correlated with the clinical outcomes of anti-PD-1/PD-L1 therapies. Here we conducted this study to verify the distribution of PD-L1/CD8[+] TIL expression and its clinical significance in non-small cell carcinoma (NSCLC). Potential mechanism predicted for PD-1 blockade was explored in depth as well.
Methods:
Immunohistochemistry was performed to detect PD-L1 and CD8 expression in NSCLC. The Kaplan–Meier (KM) survival curve was used to estimate disease free survival (DFS) and overall survival (OS). Gene Set Enrichment Analysis (GSEA) was used to determine potentially relevant gene expression signatures.
Results:
288 cases with stage I-IIIA NSCLC were evaluated for PD-L1 and CD8+ TIL staining. Dual positive PD-L1 and CD8 (PD-L1+/CD8+) represents a predominant subtype in NSCLC, accounting for 36.5% (105/288), followed by PD-L1-/CD8- (24.3%, 70/288), PD-L1-/CD8+ (26.0%, 75/288) and PD-L1+/CD8- (13.2%, 38/288). Survival analysis of DFS (p=0.031) and OS (p=0.002) showed a significant difference between four subgroups. Furthermore, we analyzed the correlation between expression types of PDL1/CD8 and mutation burden and angtigen presentation. We can identified dual positive PD-L1 and CD8 was significant with increased mutation burden (p<0.001), high frequency of mismatch repair (MMR) related gene mutation. More interestingly, tumor with dual positive PD-L1 and CD8 manifested a remarkable activated angtigen presentation and T cell receptor signature compared with other subgroups.
Conclusion:
Dual positive PD-L1 and CD8 was identified as a predominant subtype in NSCLC and correlates with increased immunogenicity. These findings provide the evidence that combined analysis of PD-L1 and CD8 in NSCLC may be a promising way to predict PD-1 blockade immunotherapy.
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- Abstract
Background:
RET fusion gene is identified as a novel oncogene in a subset of non-small cell lung cancer (NSCLC). However, few data are available about the prevalence, clinicopathologic characteristics, genetic variability and therapeutic options in RET-positive lung adenocarcinoma patients.
Methods:
For 615 patients with lung adenocarcinoma, RET status was detected by reverse transcription-polymerase chain reaction (RT-PCR). Next-generation sequencing (NGS) and FISH were performed in positive cases. Thymidylate synthetase (TS) mRNA level was assayed by RT-PCR. Overall survival (OS) was evaluated by Kaplan-Meier method and compared with log-rank test.
Results:
Twelve RET-positive patients were identified by RT-PCR. However, one patient failed the detection of RET arrangement by FISH and NGS. Totally, 11 patients (1.8%) confirmed with RET rearrangements by three methods , including six females and five males with a median age of 54 years. The presence of RET rearrangement was associated with lepidic predominant lung adenocarcinoma subtype in five of 11 patients. RET rearrangements comprised of nine KIF5B–RET and two CCDC6–RET fusions. Four patients had concurrent gene variability by NGS detection,including EGFR(n=1),MAP2K1 (n=1), CTNNB1 (n=1) and AKT1 (n=1) . No survival difference existed between RET-positive and negative patients (58.1 vs. 52.0 months, P=0.504) . The median progression-free survival of first-line pemetrexed/platinum regimen was 7.5 months for four recurrent cases,and longer than RET-negative patients(7.5 vs.5.0 months, P=0.026). . The level of TS mRNA was lower in RET-positive patients than that in those RET-negative counterparts (239±188×10[-4] vs. 394±457×10[-4],P=0.019) .
Conclusion:
The prevalence of RET fusion is approximately 1.8% in Chinese patients with lung adenocarcinoma. RET arrangement is characterized by lepidic predominance and a lower TS level. RET-rearranged patients may benefit more from pemetrexed-based regimen.
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- Abstract
Background:
ROS1 gene-rearrangement in non-small cell lung cancer (NSCLC) patients has recently been identified as a driver gene and benefited from crizotinib treatment. However, no data is available for ROS1-positivity NSCLC about chemotherapeutic options and prognostic data. We investigated pemetrexed-based treatment efficacy in ROS1 translocation NSCLC patients and determined the expression of thymidylate synthetase (TS) to provide a rationale for the efficacy results.
Methods:
We determined the ROS1 status of 1750 patients with lung adenocarcinoma. Patients’ clinical and therapeutic profile were assessed. In positive cases, thymidylate synthetase (TS) mRNA level was performed by RT-PCR. For comparison, we evaluated the TS mRNA status and pemetrexed-based treatment efficacy from 170 NSCLC patients with anaplastic lymphoma kinase (ALK) translocation(n=46), EGFR mutation (n=50), KRAS mutation (n=32) and wild-type of EGFR/ALK/ROS1/KRAS (n = 42).
Results:
Thirty-four ROS1 translocation patients were identified at two institutions. Among the 34 patients, twelve with advanced stage or recurrence were treated with pemetrexed-based first-line chemotherapy. The median progression-free survivals of pemetrexed-based first-line chemotherapy in ROS1 translocation, ALK translocation, EGFR mutation, KRAS mutation and EGFR/ALK/ROS1/KRAS wild-type patients were 6.8, 6.7, 5.2, 4.2 and 4.5 months, respectively (P=0.003). The TS mRNA level was lower in patients with ROS1-positive than ROS1-negative patients (264±469×10[-4] vs. 469 ± 615×10[-4] , P=0.03), but similar with ALK-positive patients (264±469×10-4 vs. 317±524×10[-4], P=0.64).
Conclusion:
Patients diagnosed with ROS1 translocation lung adenocarcinoma may benefit from pemetrexed-based chemotherapy. TS mRNA level enables the selection of therapeutic options for ROS1translocation patients.
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- Abstract
Background:
According to the 2015 World Health Organization classification of lung tumors, pulmonary Large cell neuroendocrine carcinoma (PLCNC) is grouped with the small cell lung cancer (SCLC) and carcinoid as pulmonary neuroendocrine carcinoma(PNC) for the common features of neuroendocrine characteristics . Molecular profiles and prognosis of primary pulmonary neuroendocrine carcinoma(PNC) are not well investigated currently. We conducted present study to evaluate genomic abnormality and survivals in patients with primary PNC.
Methods:
Tumor samples of PNC after completely resection from Zhejiang Cancer Hospital were collected from 2008 to 2015. Nine driver genes including six mutation (EGFR, KRAS, NRAS, PIK3CA, BRAF, HER2) and three fusions (ALK, ROS1, RET) were evaluated by RT-PCR. Survival analysis was evaluated using the Kaplan-Meier method.
Results:
Totally, 108 patients with pathologic confirmed PNC were enrolled. Samples included 52 PLCNC, 44 small cell lung cancer (SCLC) and 12 carcinoid. Twelve patients were found to harbor genomic aberrations (11.1%). The most frequent gene abnormality was PIK3CA (n=5,4.6%),followed with EGFR (n=3,2.8%), KRAS (n=2,n=1.9%), ALK (n=1,0.9%), RET (n=1,0.9%). No ROS1,BRAF,NRAS and HER2 mutations were observed. The frequencies of gene aberrations in PLCNC, SCLC and carcinoid were 15.4%,6.8% and 8.3%,respectively. Sixty-seven patients were with recurrence or metastasis after surgery, including 32 PLCNC, 33 of SCLC, and two of carcinoid (both were atypical carcinoid). Among the 32 patients with PLCNC,none received molecular targeted treatment,28 received first-line chemotherapy,including 18 of etoposide/platinum regimen and 10 of other platinum-based treatment. The progression free survival in patients with etoposide/platinum regimen was longer than patients with non-etoposide/platinum treatment (4.8 vs.3.4 months,P=0.019) . Survival difference was observed among the PLCNC,SCLC and carcinoid group (37.0 vs. 34.0 vs.not reached, P=0.035), but no difference existed between the PLCNC and SCLC group (P=0.606).
Conclusion:
Common genomic abnormality is rare in PNC patients and most frequently observed in PLCNC. Patients with carcinoid had a superior survival than PLCNC and SCLC.
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- Abstract
Background:
This study aimed to assess the ability of different technology platforms to detect epidermal growth factor receptor (EGFR) mutations including L858R, E19-dels, T790M, and G719X from circulating tumor DNA (ctDNA) in patients with non-small cell lung cancer (NSCLC).
Methods:
Plasma samples were collected from 20 patients with NSCLC including detailed clinical information along with data regarding treatment response. ctDNA was extracted from 10 mL plasma using the QIAamp Circulating Nucleic Acid Kit (Qiagen). Extracted ctDNA was analyzed using two real time-amplification refractory mutation system-quantitative PCR platforms (cobas® EGFR Mutation Test: cobas; and AmoyDx® EGFR 29 Mutations Detection Kit: ADx), one digital platform (Droplet Digital[TM] PCR, ddPCR: Bio-rad), and one next-generation sequencing platform (firefly NGS: Accuragen).
Results:
If a positive result was obtained from any one of the four platforms, the sample was categorized as positive. We identified 15 EGFR mutations in 20 patients with NSCLC using the four platforms, for which 7, 11, 10, and 12 mutations were detected by ADx, cobas, ddPCR, and firefly NGS, respectively. Among the 15 EGFR mutations, six and seven EGFRalterations demonstrated an allele frequency of more or less than 1% (group A or B, respectively), and two exhibited unknown allele frequency. In group A, 5, 5, 5, and 6 EGFR mutations were detected by ADx ,cobas, ddPCR, and firefly NGS, respectively. The positive coincidence rate of any two platforms ranged from 66.7% to 100% and the kappa value varied from 0.787 to 1.000 in group A. In group B, 1, 5, 5, and 6 EGFR mutations were detected and the positive coincidence rate of any two platforms ranged from 16.7% to 100% and the kappa value varied from 0.270 to 1.000. The output of cobas, ddPCR, and firefly NGS were highly correlated, whereas ADx displayed weak concordance with these three platforms in group B. In addition, we identified 75 wild-type loci when EGFR alleles identified as negative by one or more platforms were considered as negative. ADx, cobas, ddPCR, and firefly NGS uncovered 73, 69, 70, and 68 EGFR wild-type loci, respectively. The concordance and negative coincidence rates between any two platforms were over 90%.
Conclusion:
The detection rate and concordance were probably affected by the abundance of EGFR mutations and the sensitivity of different platforms. Three platforms, including cobas, ddPCR, and firefly NGS, exhibited higher positive coincidence and detection rates when the allele frequency was lower than 1%.
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- Abstract
Background:
We aimed to investigate the feasibility of droplet digital PCR (ddPCR) for the detection of epidermal growth factor receptor (EGFR) mutations in circulating free DNA (cfDNA) from cerebrospinal fluid (CSF) and plasma of advanced Lung Adenocarcinoma (ADC) with brain metastases (BM).
Methods:
Fourteen advanced ADC patients with BM carrying activating EGFR mutations in tumour tissues were enrolled in this study, and their matched CSF and plasma samples were collected. EGFR mutations were detected by the Amplification Refractory Mutation System (ARMS) in tumour tissues. EGFR mutations, including 19del, L858R, and T790M were examined in cfDNA isolated from 2milliliter CSF or plasma by ddPCR assay. The clinical response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. Overall survival (OS) and progression free survival (PFS) after the diagnosis of BM were also evaluated.
Results:
Out of 14 patients, eleven were females and three males aged from 34 to 74 years old (median age of 55 years old). In all of cases, CSF cytology were negative. In ddPCR assays, EGFR mutations were detected in CSF of three patients (21.4%; one of 19del and two of L858R), and in plasma of six patients (42.9%; one of 19del, one of L858R, one of T790M, two of L858R&T790M, and one of 19del&T790M). All EGFR T790M mutations were found during or after EGFR-TKIs treatments. The three patients with activating EGFR mutations in CSF achieved partial response (PR) of BM after treated with combination of WBRT and EGFR-TKIs. The median OS and PFS after the diagnosis of BM were 18.0 months and 9.0 months, respectively.Patient Tissue EGFR CSF EGFR Plasma EGFR Systematic Treatment BM Treatment 1 19del WT T790M Erotinib+Chemotherapy WBRT+Gamma knife 2 19del WT 19del Erotinib+Chemotherapy WBRT 3 L858R L858R L858R Gefitinib+Chemotherapy WBRT 4 L858R WT WT Gefitinib+Chemotherapy WBRT 5 19del WT WT Gefitinib+Chemotherapy WBRT 6 L858R WT L858R/T790M Erotinib+Chemotherapy WBRT 7 L858R WT WT Gefitinib WBRT 8 19del 19Del 19Del/T790M Gefitinib WBRT 9 L858R WT WT Erotinib+Chemotherapy NONE 10 19del WT WT Erotinib+Chemotherapy WBRT 11 19del WT WT Icotinib+Chemotherapy WBRT 12 L858R WT L858R/T790M Chemotherapy WBRT 13 L858R L858R WT Icotinib WBRT 14 19del WT WT Gefitinib+Chemotherapy WBRT
Conclusion:
It was feasible to test EGFR mutation in CSF. CSF may serve as liquid biopsy of advanced ADC with BM by enabling measurement of cfDNA within CSF to characterize EGFR mutations.
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- Abstract
Background:
In patients with advanced non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutations, EGFR-tyrosine kinase inhibitors (TKIs) are recommended as first-line treatment due to favorable clinical efficacy. However, acquired resistance inevitably develops after median progression-free survival (PFS) of 9-14 months. Among the mechanisms of acquired resistance, small-cell lung cancer (SCLC) transformation was reported to account for nearly 5%. However, the molecular details underlying this histological change and resistance to EGFR-TKI therapy remain unclear.
Methods:
15 out of 233 (6.4%) patients were confirmed to develop SCLC transformation after failure to EGFR-TKI. We analyzed the clinical parameters of these patients by using chi-square test and Kaplan-Meier analysis. To explore gene alterations that might contribute to SCLC transformation, next generation sequencing (NGS) was performed on four pairs of matched pre- and post-transformation tumor tissue samples. We further performed NGS on 11 matched circulating tumor DNA (ctDNA) to explore the potential mechanism of resistance to EGFR-TKI.
Results:
The median age of SCLC transformed patients was 53 years. 93.3% (14/15) patients harbored EGFR exon19 deletion. The median PFS and overall survival (OS) of SCLC-transformed patients treated with EGFR-TKI compared to those without transformation were 11.7 versus 11.9 months (P=0.473) and 29.4 versus 24.3 months (P=0.664), respectively. All 4 patients developed loss of heterozygosity of TP53/RB1 after transformation. Besides, increased copy number of five proto-oncogenes were identified in post-transformation tissue samples. Three patients developed EGFR T790M mutation in the post-transformation ctDNA rather than their tissue samples.
Conclusion:
SCLC transformation was commonly seen in patients harboring EGFR exon 19 deletion. The clinical outcomes of TKI and OS in SCLC transformed patients were similar to non-transformed patients. The loss of heterozygosity of TP53 and RB1along with increased copy number of proto-oncogenes may lead to the SCLC transformation. The mechanisms of acquired resistance to TKI during SCLC transformation might be the emergence of classic drug resistance mutations, which was undetectable due to the intra-tumor heterogeneity.
Author of
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JCES01 - Joint IASLC - Chinese Society for Clinical Oncology - Chinese Alliance Against Lung Cancer Session (ID 413)
- Event: WCLC 2016
- Type: Joint Chinese / English Session
- Track:
- Presentations: 1
- Moderators:F.R. Hirsch, C. Bai
- Coordinates: 12/04/2016, 08:00 - 11:45, Stolz 1
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JCES01.02 - Welcome and Introduction (ID 6810)
08:20 - 08:30 | Author(s): C. Bai
- Abstract
- Presentation
Abstract not provided
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OA12 - SBRT and Other Issues in Early Stage NSCLC (ID 383)
- Event: WCLC 2016
- Type: Oral Session
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:D. De Ruysscher, M.R. Mueller
- Coordinates: 12/06/2016, 11:00 - 12:30, Strauss 2
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OA12.05 - Noninvasive CT-Based Image Biopsy System (iBiopsy) for Early Stage Lung Adenocarcinoma (ID 6080)
11:45 - 11:55 | Author(s): C. Bai
- Abstract
- Presentation
Background:
CT screening programs frequently detect early stage lung adenocarcinoma. Recent studies show that distinct subtypes of lung adenocarcinoma are associated with different prognosis and suggest that treatment should be tailored to histological subtypes as identified in the new WHO Lung Tumor Classification. To develop this personalized approach, it is important to have reliable tools to diagnose tumors before treatment, preferably non-invasively through image analysis. We have developed a CT-image analysis system (iBiopsy) that uses computerized deep learning and artificial intelligence. To validate the accuracy of a noninvasive CT-based image biopsy system (iBiopsy) in differentiating early stage lung adenocarcinoma subtypes of atypical adenomatous hyperplasia (AAH), adenocaricnoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC).
Methods:
We retrospectively identified 365 eligible patients from Zhongshan Hopsital Fudan University, diagnosed with AAH, AIS, MIA or IAC by surgical pathological diagnosis. The last high definition CT scan prior to the surgery of the lesion was analyzed using the iBiopsy system, blinded to pathological result. Based on a pulmonary nodule image feature set (PNIFS) in combination with classified pattern models, such as R-SVM, all the pulmonary nodules were classified into four groups. For diagnosis efficacy, area under the curve (AUC) of Precision-Recall score (PRS), receiver operating characteristic (ROC) of a classification model were calculated in each group.
Results:
365 patients were included in the analysis. The classification recognition rate of the PNIFS was 80.03%. The average value of PRS is 0.92, the mean of ROC is 0.95, and it is more than 0.80 for the cross validation value.
Conclusion:
iBiopsy system allows the non-invasive imaged based stratification of pulmonary adenocarcinoma nodules into four groups, from AAH to IAC. Our result suggest that iBiopsy system could ultimate facilitate the diagnosis and precision management of pulmonary nodules.
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-042 - Evaluate the Utility of the Computed Bioconductance Measurement in the Diagnosis of Lung Cancer (ID 6382)
14:30 - 14:30 | Author(s): C. Bai
- Abstract
Background:
Transcutaneous Computed Bioconductance (CB) has been shown to be different between malignant and benign lung lesions. We have launched a multicenter study to evaluate the utility of the Computed Bioconductance (CB) measurement following the CT scan in the diagnosis of lung cancer in Chinese population.
Methods:
In this multicenter study, we analyzed the result of a non-randomized prospective trail enrolling 123 patients with suspicious lung lesions studied by CT and CB. The pulmonary nodules or lesions confirmed by CT scan are greater than 4mm and smaller than 50mm. A CB test by BSP-E2-1000-A (Prolung Biotech Wuxi Co., Wuxi, China) was operated within these patients prior to an abnormal CT, then the tissue biopsy or surgical specimen would be conducted within 14 days. The detailed protocol could be found on ClinicalTrails.gov identifier NCT02726633.
Results:
Among the current 123 enrolling patients, 34（28%） cases were diagnosed of benign lesion, and 83 (67%) cases were diagnosed of malignant lesion depend on pathological diagnosis, 6 (5%) cases were eliminated due to patient refusal of biopsy. In malignant group, 32 (39%) cases were in stage I; 17 (20%) cased were in stage II and IIIA; 30 (36%) cases were in stage IIIB and IV. In addition, 10 (12%) cases were with EGFR mutation and all were adenocarcinoma. In benign group, 2 (6%) cases were diagnosed of tuberculosis and most other were inflammation and fibrosis lesion. The sex ratio was 45/78 (female vs. male). In addition, body mass index, lung functions test, serum tumor biomarker, nodule position and appearance, medical, treatment and smoking history were collected in the study. Among all cases, 31 had concomitant PET performed and standardized uptake value were collected.
Conclusion:
In this enrolling study, a pre-biopsy assessment of malignant probability with a CT-detected lung lesion, the method which combined CT and CB was evaluated at first time. This non-invasive risk-stratification technology could improve the diagnostic efficacy of lung cancer.
