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H. Bai
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MINI 16 - EGFR Mutant Lung Cancer 2 (ID 130)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:G.J. Riely, M.C. Garassino
- Coordinates: 9/08/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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MINI16.12 - Lung Adenocarcinoma Transformation into Small-Cell Lung Cancer after Treatment: Clinical Evidence and the Exploratory Mechanism (ID 2485)
16:45 - 18:15 | Author(s): H. Bai
- Abstract
- Presentation
Background:
The phenomenon of small cell lung cancer(SCLC) transformation in EGFR mutated adenocarcinoma had been previously identified as a resistant mechanism. However, this phenomenon was only reported in single case and a repeat biopsy patient cohort. Moreover, the underlying molecular mechanism remains unclear. Previous study found that the inactivation of TP53 and Rb1 could efficiently transform neuroendocrine and alveolar type 2 cells into SCLC. We inferred that TP53 and Rb1 might also play an important role in SCLC transformation. So we use the sh-RNA mediated depletion of RB1 adenocarcinoma cell line, that also have TP53 inactivation in nature, to investigate the molecular mechanism of SCLC transformation.
Methods:
Both primary and metastatic tissue were analyzed on 3 SCLC transformation patients by whole genome sequencing (WGS). We knock down RB1 in TP53 inactivation cell lines, PC-9, HCC-827 and H1975. Western blot and immunohistochemistry (IHC) were used to confirm RB1 knock down and expression of neuroendocrine (NE) markers. Trans well cell invasion assay and softer agar clone formation test were investigated the change of invasion and migration. CCK8 kit was used to evaluate relative viability of cells after RB1 knock down. Cell cycle and apoptosis were determined by folw cytometry. And we use balb/c mice for cell line tumorgenesis.
Results:
① Pathological analysis of the 3 patients’ primary lesion and the consistent EGFR mutation status confirmed the phenomenon of SCLC transformation. WGS showed the copy number variation of primary tumor and transformed metastasis was distinct. RB1 is lost in 100% of the three transformed cases but occur in one patient’s primary tissue in extremely low frequency(<5%). ② PC-9, HCC827 and H1975 cell line showed up-regulation of NE markers after sh-RNA mediated RB1 depletion, which presented more capable of invasion and migration. Cell folw cytometry showed more cells was in G2 and S phase after RB1 knock down. The expression of Bik and puma that belong to Bcl-2 family was up-regulated after RB1 inactivation compared with the control group.
Conclusion:
The NE differentiation and changes in invasion, migration, apoptosis and cell cycle indicated that the loss of TP53 and RB1 promote the process of SCLC transformation. TP53 and RB1 deficiency may be a necessary event for SCLC transformation to emerge, but is still insufficient to induce SCLC transformation.
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MINI 24 - Epidemiology, Early Detection, Biology (ID 140)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:J. Creaney, M. Carbone
- Coordinates: 9/08/2015, 16:45 - 18:15, 102+104+106
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MINI24.12 - Assessment of PD-L1, TGF-β Expression and Tumor-Infiltrating CD8+ T Cells in Advanced Thymic Epithelial Tumors (ID 2373)
16:45 - 18:15 | Author(s): H. Bai
- Abstract
- Presentation
Background:
“Avoiding immune destruction” is one of the emerging hallmarks of cancer, as proposed by Weinburg and Hanahan. High expressions of immunosuppresive proteins strongly links to prognosis and cancer treatment. This study aimed to exam the expressions of immunosuppressors programmed death receptor ligand-1 (PD-L1) and transforming growth factor –β (TGF-β), and CD8+ tumor-infiltrating lymphocytes (TILs) in pre-treatment specimens from patients with advanced thymic epithelial tumors (TETs) including advanced thymic carcinoma and advanced invasive thymoma. To our knowledge, this is the first report to demonstrate the expression of PD-L1, TGF-β and CD8 and their clinical relevance in advanced TETs in Chinese population.
Methods:
Retrospective analysis was performed using tumor specimens from 20 patients with stage IV thymic carcinoma and 13 patients with stage III/IV invasive thymoma. Tissue biopsies were obtained before the first-line chemotherapy with (or without radiotherapy). The expression level of PD-L1, TGF-β and the prevalence of CD8+ TILs were assessed using immunohistochemistry (IHC). Their prognostic value for predicting overall survival (OS) and progression-free survival (PFS) were statistically analyzed using the SPSS software.
Results:
Higher expression levels of PD-L1 and TGF-β were detected in advanced thymic carcinoma than in advanced invasive thymoma (65.0% vs. 46.2%, 65.0% vs. 15.4%, respectively). Low level of CD8+ TILs was presented in 45.0% cases with advanced thymic carcinoma. In advanced thymic carcinoma, higher TGF-β expression was strongly associated with worse OS, with a p-value almost reaching statistical significance (p = 0.052). Median OS of patients with TGF-β high and low expression was 29.5 ms (95%CI: 18.6-40.4) and 62.9 ms (95%CI: 15.6-110.1), respectively. Higher PD-L1 expressions significantly predicted worse PFS after firs-line chemotherapy with (or without) radiotherapy (p =0.043). Median PFS was not estimable in PD-L1 low expression group. Mean PFS of patients with PD-L1 high and low expression was 13.3ms (95%CI: 8.0-18.6) and 23.5ms (95%CI: 13.9-33.2), respectively. An additional radiation treatment was particularly needed for CD8 low expression patients, in which first-line treatment with “chemotherapy + radiotherapy” significantly prolonged PFS compared to “chemotherapy-alone” (median PFS = 6.8ms, 95%CI: 0.0-2.7 vs. 3.5ms, 95%CI: NE, p = 0.015).
Conclusion:
Our results documented the clinical relevance of PD-L1, TGF-β, and CD8 in advanced TETs, with the prognostic value of predicting OS and PFS, as well as a potential association of immune conditions with therapeutic benefits.
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MINI 27 - Biology and Other Issues in SCLC (ID 152)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:P.A. Bunn, Jr, J. Sage
- Coordinates: 9/09/2015, 16:45 - 18:15, 605+607
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MINI27.06 - Acquired Resistance Mechanisms in Small Cell Lung Cancer Mediated by the Cancer Stem Cell Marker Calcium Channel α2δ1 Subunit (ID 2473)
16:45 - 18:15 | Author(s): H. Bai
- Abstract
- Presentation
Background:
As a subtype of lung cancer, small cell lung cancer (SCLC) remains a severe threat to human health. Although it is initially a chemosensitive disease, development of acquired resistance is a major problem. Studies in recent years revealed that cancer stem cell (CSC) could play a role in this process. However, the CSC specific marker and the detailed signal pathway associated with acquired resistance in SCLC is unknown yet. It was recently reported that the voltage-dependent calcium channel α2δ1 subunit positive cells is a CSC marker in hepatic cell cancer and that 1B50-1 is the specific monoclonal antibody of the α2δ1 subunit. In present study, we attempted to disclose that α2δ1 could play a role in acquired resistance of SCLC. Also we investigated possible molecular mechanism of α2δ1 mediated resistance in SCLC and finally provided the potential strategies overcoming the resistance.
Methods:
We screened for positive expression of 1B50-1and CD133 in SCLC cell lines and in patient-derived xenograft (PDX) models, and we used flow cytometry to verify the properties of CSCs. We recorded the expression of 1B50-1 before and after chemotherapy in PDXs in chemosensitive and resistant models to determine if α2δ1 subunit-positive cells were related to acquired resistance. We used exome and transcriptome sequencing to explore the expression of genes related to stem cell properties and drug resistance. We used Western blotting to verify the key molecules and pathways in the process of drug resistance. On the basis of these results, we explored the mechanisms of acquired drug resistance that are mediated by the α2δ1 subunit.
Results:
We observed a difference in the positive expression levels of 1B50-1 and CD133 in SCLC cell lines (H1048, H69, and H209) and PDX models. Both 1B50-1-positive and CD133-positive cells exhibited stem cell-like properties such as the capacity to self-renew in vitro, tumorigenesis in vivo, the potential for differentiation, and high expression levels of genes related to CSCs and drug resistance. Chemotherapy could induce the enrichment of 1B50-1-positive cells but not CD133-positive cells in PDXs. Also, high rates of 1B50-1-positive cells corresponded to high levels of resistance. Together, these findings indicated that the expression of 1B50-1 is related to chemoresistance. Exome and transcriptome sequencing revealed that the expressions of multiple pathway related genes in pathways, including MAPK, CAMs, TGFβ, and Notch, were increased in 1B50-1-positive H1048 cells. Western blotting revealed the activation of the Erk protein in the MAPK pathway and the over-expression of the Erk protein in 1B50-1-positive H1048 cells. The specific α2δ1 antibody 1B50-1 improved response to chemotherapy and delayed relapse when combined with chemotherapy or used y as maintenance therapy.
Conclusion:
The α2δ1 subunit positive SCLC cells (1B50-1+) displayed CSC properties, and were associated with acquired resistance. The Erk protein in the MAPK pathway was highly expressed in the 1B50-1-positive H1048 cell line, and might be the key molecule involved in resistance mediated by the α2δ1 subunit. The α2δ1 subunit-specific antibody 1B50-1 could improve response to chemotherapy and delay relapse when combined with chemotherapy or when used as sequential therapy.
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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)
10:45 - 12:15 | Author(s): H. Bai
- 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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ORAL 25 - Biology and Other Issues in SCLC (ID 125)
- Event: WCLC 2015
- Type: Oral Session
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:J. Sage, L. Montuenga
- Coordinates: 9/08/2015, 10:45 - 12:15, 605+607
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ORAL25.03 - Establishment of Lung Cancer Xenograft Models Derived from Bronchoscopy Biopsy and Investigating Mechanism of Refractory Small Cell Lung Cancer (ID 3097)
10:45 - 12:15 | Author(s): H. Bai
- Abstract
- Presentation
Background:
There were mainly two kinds of lung cancer xenograft models, xenograft models derived from stable cell lines and patient derived xenograft (PDX) models which adopted tissues resected by surgeries. However, these animal models may not reflect biological and genetic characteristics of advanced lung cancer, especially small cell lung cancer (SCLC). We utilized bronchoscopy-guided biopsy tumor tissues of advanced lung cancer to establish xenograft models and analyzed fidelity of histopathology, genetic profile and chemotherapeutic efficacy with their parental tumors. At last the molecular mechanism of drug resistance in refractory SCLC was studied.
Methods:
Primary pulmonary tumor tissues taken from bronchoscopy were implanted to NOD-SCID (nonobese diabetic-severe combined immunodeficiency disease) mice subcutaneously for model establishment and consecutive passage. The histopathology and genetic profile in samples of bronchoscopy-guided biopsy tumor tissues-derived xenograft (BDX) models and their parental tumors were detected. Parental fidelity of BDXs’ chemotherapeutic response was detected by chemosensitivity in vivo. Next generation sequencing (NGS) of target gene was taken in SCLC BDXs to analyze high-fidelity with their parental samples. Based on bioinformatic analysis, molecular mechanism of sensitive and refractory SCLC was discussed.
Results:
66 BDXs from 188 patients (35%) were successfully established. Successful rate of BDXs in SCLC was significantly higher than that in squamous cell cancer (SCC) (50.72% vs. 32.00%, p=0.005) and in adenocarcinoma (ADC) (50.72% vs. 16.22%, p=0.025). The growth rate of passage 1 BDXs in SCLC was slower than it in SCC or ADC (P<0.0001). Almost all BDXs kept similar histology, pathological marker and driver-gene mutations with their corresponding patients’ tissues. The gene mutations of which frequency was more than 10% in patient’s SCLC were kept consistent in BDXs with same genotype and frequency. Gene mutations which regulated mitogen activated protein kinase (MAPK) pathway as KRAS, KIT, MET were only detected in refractory SCLC and corresponding BDXs rather than sensitive disease. In further functional verification, the percentage of positive pERK was 100% (5/5) in refractory BDXs, but 20% (1/5) in sensitive BDXs (p=0.0476).
Conclusion:
BDXs which were successfully established with high-fidelity of histopathology, genetic profile and chemotherapeutic response could be utilized as animal models in research of unresectable lung cancer. MAPK pathway related gene mutations found in both BDXs and primary tumor tissues may be associated with resistance in refractory SCLC. PERK was promising to be used as molecular markers in genotype and prediction of chemotherapy-resistance for SCLC.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-002 - PD-L1 Expression and FGFR1 Amplification in Chinese Stage III/IV Lung Squamous Carcinoma (ID 2478)
09:30 - 17:00 | Author(s): H. Bai
- Abstract
Background:
This study aims to explore status of PD-L1 expression and FGFR1 amplification in stage IIIB/IV SQC, further to analyze their correlation with clinicpothological characteristics, efficacy of gemcitabine based chemotherapy and prognosis of SQC patients.
Methods:
128 stage III/IV SQC patients were enrolled into this study from May 1[st] 2009 to May 31[st] 2014, all of which had complete clinical profile. 78 patients received gemcitabine-based chemotherapy. Immunohistochemistry (IHC) was used to detect PD-L1 expression, fluorescence in situ hybridization was applied to detect FGFR1 amplification. SPSS17.0 was used for statistical analysis.
Results:
80 (62.5%) SQC had IHC positive PD-L1 expression. PD-L1expression was significantly higher in male and smoker population than female and non-smoker, respectively. (gender: 65.5% VS. 22.2%, P=0.011; smoke histology 67.0% VS. 44.0%, P=0.039). PD-L1 expression had no significant relationship with objective response rate (ORR) and disease control rate(DCR) for gemcitabine-based chemotherapy(54.8% VS.59.7%, P =0.434 and P=0.840). However, the overall survival (OS) of PD-L1 negative SQC was significantly longer than PD-L1 positive group (29.8 vs. 20.1 months, P=0.001). 32 cases showed FGFR1 FISH positive (32/128, 25.0%), and stage III patients presented lower rate compared with stage IV SQC (17.1% vs. 36.5%, P=0.013). FGFR1 amplification had no relationship with ORR and DCR in patients treated with gemcitabine-base chemotherapy(32.3% VS.30.6%. P=0.663 and P=0.659). No correlation between PD-L1 expression and FGFR1 amplification was found (P=0.916).
Conclusion:
PD-L1 expression could act as a prognosis factor in Chinese stage III/IV SQC patients. PD-L1 expression and FGFR1 amplification might be irrelevant.
