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S. Ma
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MINI 05 - EGFR Mutant Lung Cancer 1 (ID 103)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:Y. Yatabe, R. Perez-Soler
- Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 2a-3b
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MINI05.02 - Impact of ABCG2 Polymorphisms on the Clinical Outcome of TKIs Therapy in Chinese Advanced Non-Small-Cell Lung Cancer Patients (ID 591)
16:50 - 16:55 | Author(s): S. Ma
- Abstract
- Presentation
Background:
ATP binding cassette superfamily G member 2 (ABCG2) has been demonstrated to be associated with the effect of chemotherapy/targeted therapy in non-small-cell lung cancer (NSCLC) and the single nucleotide polymorphisms (SNPs) of ABCG2 gene are supposed to affect the expression of ABCG2 protein. The purpose of this study was to investigate the correlation between SNPs of ABCG2 and outcome of tyrosine kinase inhibitions (TKIs) therapy in Chinese advanced NSCLC patients.
Methods:
SNP genotyping(34 G/A, 421 C/A, 1143 C/T and -15622 C/T)of ABCG2 gene in 100 patients was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The clinical characteristics of 100 patients were collected. A total of 70 patients were treated with TKIs(gefitinib, erlotinib and icotinib). The association between ABCG2 polymorphisms and clinical characteristics was evaluated. Kaplan-Meier survival curves were plotted for overall survival (OS) and analyzed with the log-rank test. Cox proportional hazards model was applied to evaluate the association between OS and clinical or genomic characteristics and estimated the adjusted HR and its 95 %CI.
Results:
The three polymorphisms of the ABCG2 34 G/A, 421 C/A and 1143 C/T occurred more frequently compared with -15622 C/T in Chinese advanced NSCLC patients. The allele A of 421C>A happened frequently in EGFR mutation positive patients (33.3% vs 9.1%, P=0.038). There was no association between ABCG2 polymorphisms and other clinical characteristics (p> 0.05).The median OS of patients with 34G>A mutant type (GA+AA) was 31.0 (95%CI: 22.9-39.1) months , which was significantly longer than those with wild type (GG) , 18.0 (95%CI: 14.9-21.1) months (p=0.005). No significant difference of OS was found in 421 C/A and 1143 C/T polymorphisms (p> 0.05).
Conclusion:
Our findings demonstrate a strong association between the ABCG2 34G>A polymorphism and the overall survival of NSCLC patients treated with TKI. It may be a possible predictor of the clinical outcome of TKIs therapy in NSCLC patients.
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MINI 33 - Radiotherapy and Complications (ID 164)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
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MINI33.04 - Acute Radiation Pneumonitis in Lung Cancer Treated with Volumetric Modulated Arc Therapy (ID 2634)
18:50 - 18:55 | Author(s): S. Ma
- Abstract
Background:
Thoracic radiotherapy plays an important role in the treatment of lung cancer. However, the safety of thoracic radiotherapy delivery is restricted to the risk of radiation pneumonitis(RP), which is the major dose limiting toxicity for patients undergoing thoracic radiotherapy. Few studies to date have assessed risk factors associated with the development of RP in lung cancer patients treated with volumetric modulated arc therapy (VMAT). This study aimed to report the RP incidence and clinical and dosimetric risk factors associated with RP in lung cancer patients treated with VMAT at a single institution.
Methods:
In this retrospective study, lung cancer patients treated with VMAT from 2013 through 2015 were reviewed. RP was graded according to Common Terminology Criteria for Adverse Events (CTCAE) version.4.0. Clinical factors and dosimetric parameters were evaluated using logistic multivariate regression for estimating the correlation with RP. The results were considered statistically significant when the p-value was<0.05.
Results:
Thoracic radiotherapy with VMAT was administered in 77 lung cancer patients. Of these patients, 58 were men and 19 were women, with a median age of 60 years (range 22-84 years); 25 patients received concurrent chemoradiotherapy, and the median radiation dose was 60Gy (range 45-64Gy). VMAT plans were performed with single arc in 9 patients, double in 55 patients, triple in 4 patients, and the mean (±SD) delivery time was 189.1s±42.0s. VMAT allowed us to respect most planning objectives on target volumes and organs at risk, for PTV V~95% ~= 96.8 ± 6.1%; for lung V~5~ = 41.3 ± 8.7%, V~10~ = 29.9 ± 7.1%, V~20~ = 20.9 ± 5.7%, mean dose=1150.9±277.6Gy. With regard to acute RP after thoracic radiotherapy, 10.4% were grade 1 (G1), 16.9% G2, 9.1% G3, 2.6% G5. The overall incidence rate of symptomatic RP (grade ≥ 2 by CTCAE) was 28.6% in the entire cohort. Based on the clinical data and dosimetric parameters analysis, factors predictive of symptomatic RP were lung volume receiving ≥10Gy (V~10~) [OR: 1.39, 95% CI 1.07–1.80, p=0.014], PS score[OR:5.44, 95% CI 1.29–23.08, p=0.021], concurrent chemotherapy[OR:3.85, 95% CI 1.07–13.86, p=0.039]and CRP changing level[OR:1.06, 95% CI 1.01–1.12, p=0.014].
Conclusion:
VMAT, a novel technique, provides a viable option for the thoracic radiotherapy of lung cancer with acceptable toxicities. However, for patients with higher V~10~, poorer PS score, greater increasing level of CRP and undergoing concurrent chemotherapy, VAMT technique should be administrated with cautions. Several molecular biomarkers have been reported that correlated with the development of RP, which will be tested in our further analysis.
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ORAL 39 - Potential Biomarkers for CT Screening (ID 149)
- Event: WCLC 2015
- Type: Oral Session
- Track: Screening and Early Detection
- Presentations: 2
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ORAL39.01 - Multiplexing Serum Proteins and Circulating Autoantibody for Detection of Lung Cancer (ID 570)
16:45 - 16:56 | Author(s): S. Ma
- Abstract
Background:
Currently, a blood test for lung cancer does not exist. Low-dose spiral computed tomography (CT) has been proposed as an early detection screening tool. However, despite its high sensitivity, the specificity of CT in lung cancer detection is poor. In addition, the necessity for repeated CT scans to determine growth rates over time can expose patients to potentially harmful radiation. Therefore, a minimally-invasive biomarker-based test that could further characterize CT-positive patients based on risk of malignancy would greatly enhance its clinical efficacy.
Methods:
From 2009 through 2013, six hospitals enrolled 1148 patients with lung cancer, 889 blood donors as healthy participants and 36 patients with other lung diseases. The lung cancer associated biomarker panels were identified from the pretreated serum samples and subsequently analyzed in three randomly determined subgroups, the discovery cohort (40 patients with lung cancer, and 45 healthy participants), test cohort (204 patients with lung cancer, and 120 healthy participants), and validation cohort (904 patients with lung cancer, 724 healthy participants, and 36 patients with other lung diseases). Finally the panel of biomarkers were used to predict 12 prospective patients with a suspicious pulmonary nodule by CT images.
Results:
The discovery cohort demonstrated that 4 serum biomarkers (C-reactive protein, prolactin, hepatocyte growth factor, and NY-ESO-1 autoantibody) were significantly higher in patients with lung cancer compared to healthy controls. The 4-biomarker panel was independently investigated in the test cohort and validation cohort. The test characteristics were area under the curve (AUC) of 0.835 (95% CI 0.79-0.873, sensitivity 70.1%, specificity 88.3%) in the test cohort, and 0.818 (95% CI 0.798-0.836, sensitivity 70.0%, specificity 79.6%) in the expanded validation cohort. The 4 biomarkers had no discriminatory power for detecting other benign lung diseases. The performance of the panels in patients with stage I-II lung cancer was AUC of 0.774 (95% CI 0.746-0.801) in the combined test and validation cohorts. Remarkably, analysis model generated by the biomarkers correctly predicted 7 out of 9 prospective patients having lung cancer, and 2 out of 3 patients as benign, which were further verified by the pathologist.
Conclusion:
This study identified four diagnostic biomarkers in serum samples with the potential to distinguish patients with lung cancer from healthy controls. This panel of serum proteins is valuable in suggesting the diagnosis of patients with an indeterminate pulmonary lesion, and potentially in predicting individuals at high risk for lung cancer. Further research is necessary to understand whether these have clinical implications for early detection of lung cancer.
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ORAL39.05 - Identification of miRNAs as Biomarkers for Early Diagnosis of Lung Cancers (ID 808)
17:28 - 17:39 | Author(s): S. Ma
- Abstract
Background:
Current clinical diagnostic methods lack the specificity in detecting lung cancer patients. The issue is critical for stage I & II patients as there are no available biomarkers to indicate which high-risk patients should undergo adjuvant therapy. There is considerable evidence that microRNA plays a very important role in lung carcinogenesis. We postulated that the expression pattern of multiple microRNAs (miRNAs) could aid clinicians in detecting cancer patients thus reducing the mortality of lung cancer.
Methods:
Differential expressed miRNAs were analyzed by miRNA microarrays in 15 paired non-small-cell lung cancer (NSCLC) tumors and distant normal tissues. The identified miRNAs were further validated by qRT-PCR using snap-frozen lung tissue samples collected from independent 22 patients with NSCLC. Classification analyses of miRNA expression data were performed by the Bayesian Compound Covariate predictor (BCCP). The expression levels of miR-141-5p, miR-301a-3p and miR-1244 were also analyzed by qRT-PCR in serum samples collected from 60 patients with lung cancer and 50 healthy controls.
Results:
A total of 41 miRNAs was identified with significantly elevated levels in patients with lung cancer by profiling microRNA array, of which 12 miRNAs were further validated in the independent sample cohort. Multiplexing analysis with the panel of 12 miRNAs generated the highest discriminatory power in separating NSCLC from normal tissues with an AUC of 0.915 (95% CI = 0.894-1.000; P <0.001). Leave-one-out cross-validation revealed the 85% sensitivity and 95% specificity at a cutoff score of 0.5. In addition, serum miR-1244 was significantly upregulated in an independent trial and could distinguish NSCLC from controls with 77.6% sensitivity and 78.7% specificity.
Conclusion:
Our 12-miRNA classifier might have potential clinical utility in discriminating NSCLC from healthy population.
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P1.02 - Poster Session/ Treatment of Localized Disease – NSCLC (ID 209)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.02-033 - Pemetrexed plus Platinum as Adjuvant Therapy in Patients with Resected Lung Adenocarcinoma and Exploratory Biomarkers Analysis (ID 2524)
09:30 - 09:30 | Author(s): S. Ma
- Abstract
Background:
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death around the world. Currently, adjuvant platinum-based chemotherapy is recommended as the standard treatment for patients with completely resected stage IB-IIIA NSCLC. Pemetrexed, a multitargeted antifolate agent, has been shown to have definite activity in non-squamous NSCLC and has proven to be efficacious in the first-line metastatic NSCLC. Hence, the aim of this study was to evaluate the efficacy and toxicity of pemetrexed/ platinum in patients with completely resected lung adenocarcinoma and identify prognostic factors in this setting.
Methods:
A retrospective study was performed in patients with completely resected stage IB-IIIA lung adenocarcinoma who received pemetrexed and a platinum as adjuvant therapy. Generally, pemetrexed 500mg/m2 d1 and cisplatin 30mg/ m2 day1-3 were administrated every 21-28 days for 4 cycles. Study endpoints included overall survival (OS), progression-free survival (PFS) and treated-related toxicities. Immunohistochemical (IHC) was used to examine the protein expression of p53, thymidylate synthase (TS), dihydrofolate reductase (DHFR), Lipocalin 2 and nm23-H1 in surgical resection specimens of 23 patients. The associations between protein expression level and clinical outcome were evaluated using cox proportional hazards model.
Results:
Between Feb. 2012 and Jan.2014, 49 patients were treated with pemetrexed-based chemotherapy. Median age 57(range35-79, years), males 47%; stage IB 41%, II 18%, IIIA 41%; ever smokers 35%; lobectomy 92%, wedge resection 8%. The completion of 4-cycle chemotherapy was 67.3%. Grade 3+ hematologic and gastrointestinal toxicities were observed in 5 (10%) patients and 4 (8%) patients, respectively. The median PFS was 39.63 months (95%CI 26.55-52.71 months), and the median OS was unreachable. 1-, 2- and 3-year survival rates were 95.9%, 93.6%, 83.2%, respectively. 1-, 2- and 3-year PFS rates were 93.9%, 75.3% and 56.8%, respectively. Of 23 patients measured by IHC, 19 expressed TS, 9 expressed p53, 10 expressed DHFR, and none expressed Lipocalin 2 or nm23-H1. No significant correlations of these protein expression and clinical outcome were observed.
Conclusion:
The regimen of pemetrexed/platinum showed lower incidence rates of toxicities and promising treatment outcomes in patients with completely resected stage IB-IIIA lung adenocarcinoma. However,no prognostic biomarker was identified in our study, which may be related to the small sample size.
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P1.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 212)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.03-012 - Combined Effects of SAHA and Cisplatin on Radiation Sensitivity and Cancer Cell Invasion in NSCLC (ID 538)
09:30 - 09:30 | Author(s): S. Ma
- Abstract
Background:
Lung cancer is a leading cause of cancer mortality worldwide. In an effort to improve local control of the disease and to increase survival, concurrent chemoradiotherapy has been explored as a therapeutic option. Of them, cisplatin-based chemoradiotherapy is currently used as first line therapy for non-small-cell lung cancer (NSCLC). However, the chemotherapeutic agents cannot be administered for most patients at full doses safely with radical doses of thoracic radiation, and thus further optimizations of chemotherapy regimen to be given with radiation are needed.
Methods:
We examined the effects of suberoylanilide hydroxamic acid (SAHA) and cisplatin on DNA damage repairs using U2OS reporter cells and in vivo end-joining assay, and determined the combination effects of SAHA and cisplatin on various cell lines, primary tumor tissues and in vivo xenograft in response to irradiation. We also investigated the potential differentiation effect of SAHA and its consequent effect on cancer cell invasion in cisplatin-treated cancer cells.
Results:
Our data demonstrated that SAHA and cisplatin compromised distinct DNA damage repair pathways. Treatment with SAHA enhanced synergistic radiosensitization effects of cisplatin in NSCLC cells, and induced prolonged persistence of γ-H2A.X nuclear foci in irradiated primary NSCLC tumor tissues treated with cisplatin. SAHA combined with cisplatin also significantly increased inhibitory effect of ionizing radiation on tumor growth in mouse xenograft model. In addition, we showed here that SAHA could induce differentiation in stem cell-like cancer cell population, reduce tumorogenesity and decrease the invasion/migration capabilities of human lung cancer H460 cells.
Conclusion:
Our results suggest a potential clinical impact for SAHA as a radiosensitizer and as a part of chemoradiotherapy regimen for NSCLC. The strategy may also benefit those patients with high risk of cancer metastasis.
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-053 - Characterization of Invasive Cancer Cells and Potential Therapeutic Effect of Suberoylanilide Hydroxamic Acid on Human Lung Cancer Metastasis (ID 223)
09:30 - 09:30 | Author(s): S. Ma
- Abstract
Background:
Lung cancer is a worldwide problem andthe leading cause of death among all malignancies. Despite tremendous progresses in diagnosis and treatment, the overall treatment outcomes for lung cancer patients remain poor, and metastatic lung cancer is responsible for more than ninety percent of lung cancer related deaths. However, the details for lung cancer invasion and thereafter metastasis remain unclear. In this study, we characterized the biological features of invasive human lung cancer cells, and investigated the potential therapeutic effects of Suberoylanilide Hydroxamic Acid (SAHA) on invasive cancer cell subpopulation.
Methods:
Boyden-type cell invasion chambers were used for isolation of cancer cell subpopulations with high invasiveness (H-INV) and low invasiveness (L-INV) from human lung cancer H460 cells. The potential enrichment of stem cell-like cancer cells in H-INV cells and the resistances of H-INV cells to chemotherapy and radiation treatment were investigated. We also tested the effects of SAHA on the differentiation of cancer stem cell and its consequences on cancer cell invasion and the sensitivities to radio/chemotherapies in H-INV cells. Furthermore, microarray for message RNA was performed for identification of gene expression profiling for invasive cancer cells.
Results:
Comparing to L-INV cells, H-INV cells are with enrichments of stem cell-like cancer cells, with increased positive staining of putative stem cell markers such as CD24[low]/CD44[+] and OCT3/4, and more tumorigenic. H-INV cells are also more resistant to treatments of chemotherapeutic agents and ionizing radiation. Treatment with SAHA can induce differentiation of stem cell-like cell in H-INV cells, causing reduced cancer cell invasion and increased sensitivity to chemo/radiotherapy in cells. With mRNA microarray assay, we identified 453 genes differentially expressed in H-INV versus L-INV, and five of these genes have been further tested for their significances in paired primary and metastatic lung tumors.
Conclusion:
Our study suggested putative roles of cancer stem cell in lung cancer invasion and migration. Study also showed that invasive lung cancer cells are resistant to most of first-line and second-line chemotherapeutic agents and radiotherapy, indicating novel therapeutic strategies are needed for the treatment of metastatic lung cancer. Of this setting, SAHA may serve as a chemotherapeutic agent for benefiting lung cancer patients. The candidate genes identified in this study may also have clinic impact as potential metastatic predictors for diagnosis and prognosis for human lung cancer.
