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N. Bi



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    O01 - Prognostic and Predictive Biomarkers I (ID 94)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O01.02 - MicroRNA Signature Predicts Survival in Resectable Small-Cell Lung Cancer (ID 1641)

      10:40 - 10:50  |  Author(s): N. Bi

      • Abstract
      • Slides

      Background
      Small-cell lung cancer (SCLC) is one of the most aggressive types of cancer, yet the molecular mechanisms underlying its devastating clinic outcome remain elusive. In this study, we investigated whether microRNA (miRNA) expression profiles can predict clinical outcomes of SCLC patients.

      Methods
      A total of 82 patients with very limited SCLC, who received surgical resection followed by adjuvant chemotherapy according to the standard of care, were enrolled in this study. All the tumor samples used for miRNA profiling were required to contain at least 60% tumor cells and RNA was isolated from formalin-fixed paraffin-embedded specimens. First, we surveyed 924 miRNAs for their expressions from 42 SCLC patients to discover survival relevant miRNAs and develop prognostic models, which were then validated in an independent cohort of 40 cases. A risk score of miRNA signature for survival prediction was calculated according to a combination of expression level of the miRNA weighted by the regression coefficient derived by univariate Cox regression analysis. Kaplan-Meier overall survival curves were compared using the log-rank test and multivariate Cox regression model was used to test if the miRNA signature was an independent prognostic factor.

      Results
      For all the patients, the median follow up time was 57.2 months. Forty-four patients (53.7%) are still alive. Forty-two patients (51.2%) had recurrent disease and the median time to diagnosis of relapse was 12.3 months. In the training set, we identified that two miRNAs, miR-150 and miR-886-3p, were significantly associated with poor OS. The results compared between NL and SCLC tissues also verified that the miR-150 and miR-886-3p expression levels in SCLC were much lower than in normal lung samples (884±126 vs 2954±1652 for miR-150 and 1873±256 vs 3154±448 for miR-150 ). We then derived a miRNA signature 0.545×miR-150 + 0.617 ×miR-886-3p. Compared with patients with low-risk miRNA signature, patients with high-risk signature had significantly shorter median OS (12.6 months versus not reached, P=0.02). This signature was also demonstrated to be a significant predictor of survival in the validation set. Patients with high risk miRNA signatures had poor overall survival (P=0.005) and progression-free survival (P=0.017) compared to those with low-risk scores. It retained statistical significance in a model adjusting for age, gender and smoking status (HR 0.27, 95% CI 0.10-0.72, P=0.008), which suggesting that the miRNA signature may be an independent predictor of survival.

      Conclusion
      In this study, we developed a prognostic miR-150/miR-886-3p signature and validated in an independent dataset for resectable SCLC. Our results indicated that microRNAs may serve as promising molecular prognostic markers as well as new therapeutic targets for SCLC. Larger sample size studies are needed to further validate our findings.

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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-045 - Serum microRNA as a predictive marker for radiation pneumonitis in patients with inoperable/unresectablenon-small cell lung cancer (NSCLC) (ID 2795)

      09:30 - 09:30  |  Author(s): N. Bi

      • Abstract

      Background
      Radiation pneumonitis (RP) is a major dose-limiting toxicity after thoracic radiotherapy (RT), with no good models available to accurately predict the individual risk.MicroRNAs (miRNAs) are found to be stable in serum and other body fluids,with exciting potential as novel non-invasive biomarkers. This study is to investigate serum microRNAs associated with RP grade ≥ 2 in inoperable/unresectable NSCLC patients treated with definitive RT.

      Methods
      134 patients with inoperable/unresectable NSCLC treated with definitive RT (18-month minimum follow-up) were eligible. Serum samples were collected prospectively before treatment. 100 patients who had enough serum and reliable miRNA profile quality were included in this study. MiRNA profiling was performed using real-time PCR-based array, containing a panel of 84 miRNAs detectable in human bodily fluids. Spiked-in cel-miR-39 was used for normalization. The primary endpoint was symptomatic RP (grade 2 and higher). 2-sample mean comparisons were used between the RP and non-RP subgroups.Stepwise Logistic regression model building was used to build a miRNA signature. Receiver operator characteristic (ROC) analysis was used to assess the predictive ability of single-marker and signature of RP.

      Results
      Of 100 patients enrolled, 17 (17.0%) patients developed symptomatic RP. Patients received a median of 70 Gy (34-85.6Gy) of RT with a mean lung dose (MLD) of 16.9 Gy (2.1-25.5 Gy). Serum miRNA profiling identified pre-treatment expressions of 9miRNAs were significantly associated with risk of RP (p<0.05). Significant correlations were not found for any clinical or dosimetric parameters including age, gender, stage, MLD (p>0.05). Stepwise regression modeling identified only has-miR-191 as significant predictors of symptomatic RP (HR=4.94, 95%CI:1.46-16.66, p=0.01). Using ROC curves, we found has-miR-191 was independent predictors of symptomatic RP (p=0.01). A model of combining has-miR-191 and MLD had AUC of 0.72 (p=0.004) comparing to 0.64 of MLD alone (p=0.08).

      Conclusion
      In our preliminary analysis, baseline serum has-miR-191 may help predictingsymptomaticRP. However, analysis on larger and independent datasets will be required to verify our findings.

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    P1.08 - Poster Session 1 - Radiotherapy (ID 195)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P1.08-026 - Functional dosimetric metrics based on the ventilation and perfusion SPECT-CT during the course of radiotherapy and association with radiation-induced lung toxicity in patients with non-small-cell lung cancer (ID 3325)

      09:30 - 09:30  |  Author(s): N. Bi

      • Abstract

      Background
      To investigate volume changes in single photon emission computed tomography (SPECT) ventilation (V) and perfusion (Q) - weighted functional lung (FL), and dose-volume histogram of functional lung (FDVH) from V or Q SPECT and factors associated with radiation-induced lung toxicity (RILT) during the course of radiotherapy (RT) in patients with non-small-cell lung cancer (NSCLC).

      Methods
      Seventy NSCLC patients treated with definitive RT were enrolled prospectively. V and Q SPECT-computed tomography (CT) were performed prior to and during RT at approximately 45 Gy. FL was created from the whole lung (WL) in V and Q SPECT using a threshold of 30% of the maximum uptake of normal lung. Patients had dose calculated on CT scan to provide a standard dose-volume histogram (DVH). V and Q SPECT scans provided FDVH and functional dosimetric parameters. From the FDVH; the percent of FL receiving from 5 to 60 Gy and the mean doses of functional lungs (FMLD) were computed. Differences of volume and volume change of WL and FL between pre-RT and during-RT were compared. Differences of functional and standard dosimetric parameters between the patients with and without RILT were compared. Clinical fibrosis and pneumonitis were graded according to Common Terminology Criteria for Adverse Events version 3.0, grade 2 and above were considered to be clinically significant.

      Results
      The accumulative incidence of ≥ grade 2 clinical fibrosis and pneumonitis were 23.4%. The volume of lung measured by using CT or V and Q SPECT did not change significantly during radiotherapy (All p>0.05). The difference of lung volume between standard CT or V and Q SPECT was not significant in patients with RILT and without RILT (All p>0.05). However, the volume of V and Q both functional lung changed -12.4% (95% CI, -29.6% to 4.9%) in patients with RILT and 13.3% (95% CI, 2.7% to 23.9%) in patients without RILT during RT (p=0.02). The difference of mean lung dose (MLD) measured by using CT or V and Q SPECT was not significant in patients with RILT and without RILT (All p>0.05). However, the MLD was significantly higher in patients with RILT in during-RT than pre-RT CT (17.1 Gy and 15.4 Gy, p=0.01); the FMLD was significantly higher in patients with RILT in during-RT than pre-RT V and Q SPECT (16.7 Gy and 13.0 Gy, p=0.03). The V20-V55 by using during-RT CT were higher in the patients with RILT than without RILT (V20:29.0% and 22.0%, p=0.06; V25: 26.4 % and 19.0 % p=0.04; V30: 23.7 % and 16.6 %, p=0.03; V35: 21.1 % and 14.6 %, p=0.03; V40: 18.9 % and 12.6 %, p=0.02; V45: 16.4 % and 10.9 %, p=0.03; V50: 14.3 % and 9.1 % p=0.03; V55: 11.6 % and 7.5 %, p=0.04). The V5-V60 by using during-RT V and Q SPECT was higher in patients with RILT than without RILT, but not statistically significant.

      Conclusion
      Functional DVH metrics of V and Q SPECT and during-RT CT based DVH may be more significant in their association with RILT than pre-CT. However, these results need to be validated.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-041 - Serum miRNA signature predicts survival in patients with unresectable/inoperable non-small cell lung cancer treated with definitive radiation therapy (ID 2785)

      09:30 - 09:30  |  Author(s): N. Bi

      • Abstract

      Background
      The expression profiles of serum micro RNAs (miRNAs) are known to predict overall survival (OS) of metastatic and operable non-small cell lung cancer (NSCLC). We hypothesized that circulating miRNAs is also correlated with survival in unresectable/inoperable NSCLC treated with radiation therapy (RT).

      Methods
      134 patients with inoperable/unresectable NSCLC treated with definitive RT (18-month minimum follow-up) were eligible. Serum samples were collected prospectively before RT commencement. 100 patients with enough serum and reliable miRNA profile quality were randomly divided into training and validation sets (50 patients each). MiRNA profiling was performed using real-time PCR-based array, containing a panel of 84 miRNAs detectable in human bodily fluids. Spiked-in cel-miR-39 was used for normalization. Stepwise regression Cox model building was used to build a miRNA signature on the training set, which was then assessed on the validation set both alone and with clinical factors.

      Results
      The median age was 67 years; 76% were stages III and 79% received chemoradiation; the median physical dose was 70 Gy. Stepwise regression modeling identified five miRNAs as jointly significant predictors. Using coefficients from Cox model fit, the miRNA signature was 0.53*log(hsa-miR-15b)+0.21*log(hsa-miR-34a)-0.27*log(hsa-miR-221)-0.27*log(hsa-miR-224) -0.07*log(hsa-miR-130b). This signature was a significant predictor of OS in the validation set (p=0.011). It retained statistical significance in a model also containing terms for GTV Volume and KPS, the only two significant clinical factors in univariate analysis in the validation set (p=0.012). Using computational methods (TargetScan6.2) for miRNA target prediction, the putative targets of these five miRNAs are known to modulate apoptosis, cell cycle control, DNA damage response and repair process (including nucleotide excision repair and DNA translesion synthesis), angiogenesis and epithelial-mesenchymal transition.

      Conclusion
      In this study, we developed a prognostic miRNA signature consisting of five miRNAs and validated in an independent dataset for unresectable/inoperable NSCLC treated with RT. This circulating miRNA signature may be used as a non-invasive biomarker, which may have prognostic or therapeutic implications for the future management of locally advance NSCLC patients. Larger sample size studies are needed to further validate our findings.