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U. Pastorino
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OA06 - Prognostic & Predictive Biomarkers (ID 452)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:F. Shepherd, Y. Yatabe
- Coordinates: 12/05/2016, 14:20 - 15:50, Strauss 1
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OA06.02 - Mutational Load Predicts Survival in LDCT Screening-Detected Lung Cancers (ID 5577)
14:30 - 14:40 | Author(s): U. Pastorino
- Abstract
- Presentation
Background:
The issue of overdiagnosis in low-dose computed tomography (LDCT) screening trials for lung cancer has to be addressed by the development of complementary biomarkers able to improve detection of aggressive disease. We previously identified a 24 plasma miRNA signature endowed with good performance in terms of sensitivity and specificity in subjects enrolled in independent LDCT screening trials. However, the relationship between circulating miRNAs in plasma and the molecular heterogeneity of the patients’ tumors needs to be considered. Linking tumor genomics to circulating miRNA profiles represent an attractive approach. In fact a plasma miRNA assay able to classify molecular subclasses of tumors could constitute a sort of “liquid biopsy” endowed with not only diagnostic but also prognostic and, potentially, therapeutic value.
Methods:
We evaluated the mutation profile by targeted Next-Generation Sequencing (NGS) analysis (Cancer Hotspot Panel v.2) in 94 Low Dose Computed Tomography (LDCT) screening-detected lung tumors resected from subjects participating in 3 screening trials for lung cancer. Mutation profile was associated with clinicopathologic, survival features and with a plasma MSC risk level of patients. The mutational profile obtained was compared with the mutations of a selected dataset of clinically detected lung tumors through The Cancer Genome Atlas (TCGA).
Results:
We showed alterations in the main genetic drivers in 79% of screening lung tumors whereas 21% of tumor samples had no alteration within these amplicons. Significant associations between TP53, squamous histology and smoking intensity as well as KRAS mutations with worse OS were detected. EGFR alterations were present in 4 tumors from heavy smokers. The 5-year overall survival (OS) of screening patients with and without mutations in the tumors was 64% and 100%, respectively (p=0.019). By combining the mutational status with the MSC risk profile, patients were stratified into 3 groups with 5-year OS ranging from 41% to 96% (p<0.0001) and the prognostic value was significant even when controlling for stage (p=0.017). A similar mutational profile and mutation frequency was observed in screening- and in clinical (TCGA) tumors, whereas difference in 5-year OS between subjects with and without mutations was exclusively detected in screening patients.
Conclusion:
The mutation profile of screening-detected tumors, while similar to that of clinically-detected tumors, was a strong predictor of OS. The combination of tumor mutational status with a circulating miRNA-based risk classifier predicts tumor aggressiveness and clinical outcome and may find rapid application in LDCT screening programs by reducing the number of unnecessary interventions and helping plan targeted treatment
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-017 - Circulating miRNAs in Lung Cancer Are Associated to Pro-Tumorigenic and Immunosuppressive Microenvironment (ID 5449)
14:30 - 14:30 | Author(s): U. Pastorino
- Abstract
Background:
We previously reported the identification of diagnostic miRNA signatures in plasma samples of lung cancer patients detected by low dose computed tomography (LDCT) screening. Circulating miRNAs are released into the bloodstream by different mechanisms such as passive leakage from damaged cells or active secretion through extracellular-vesicles or protein complexes
Methods:
To evaluate the potential origin and the release of the 24 miRNAs of the diagnostic signature we analyzed their expression by real-time or digital PCR in both cells and conditioned medium (CM) from cancer cell and different cell types of the lung microenvironment. Lung tissues and cell-blocks were analyzed by miRNAs in situ hybridization (ISH). Modulation of miRNAs after in vitro treatments known to induce changes associated with cancer progression, in different cell types was assessed and correlated to changes observed in circulating miRNAs signatures.
Results:
24-miRNAs analysis showed higher abundance in specific cellular components such as mir-145 in fibroblasts, mir-126 in endothelial cells, mir-133a in skeletal muscle cells or mir-451 and 142-3p in hematopoietic cells. Generally, tumor cells showed lower levels of miRNAs compared to bronchial epithelial cells. MiRNAs specific localization in lung tissue was confirmed by ISH. We observed that mir-451 is specifically expressed in lung interstitial alveolar walls while mir-126 by endothelial cells outside the tumor bulk; miR-145 is characteristic of fibroblast and muscle cells and miR-142-3p of hematopoietic cells, fibroblast and muscle whereas mir-21 is over-expressed in the tumor. The analysis of miRNAs in CM showed that miRNAs secretion is correlated with cellular expression for most cell types (Pearson correlation range: 0.41-0.80). Interestingly, platelets and granulocytes were the components that mostly secreted miRNAs. In vitro experiments showed that endothelial cells under hypoxic condition up-regulate mir-126 and that mir-145 was up-regulated and secreted in lung cancer-associated compared to normal fibroblasts. Interestingly, during conversion of T lymphocytes into T regulatory cells up-regulation of mir-15b, mir-19b and mir-320 was observed whereas mir-15b and mir-197 were up-regulated in the conversion of macrophages into M2 phenotype. Modulation of miRNAs in immune and stromal cells was consistent with up-regulation of the same miRNAs observed in plasma samples.
Conclusion:
Our findings on the origin of circulating miRNAs support the conclusion that plasma miRNAs are heterogeneous and secreted by different cellular components of lung microenvironment rather than by tumor cells. In particular, we demonstrated that a pro-tumorigenic and immunosuppressive microenvironment contributes to the de-regulation of miRNAs observed in plasma of lung cancer patients.
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P3.03 - Poster Session with Presenters Present (ID 473)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.03-042 - Study Comparing Volume and TNM in Predicting Clinical Outcome in Malignant Pleural Mesothelioma (ID 6018)
14:30 - 14:30 | Author(s): U. Pastorino
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is a rare cancer with relatively poor outcome. Only stage (TNM) and histotype can be considered prognostic factors, but TNM still results inaccurate and difficult to be classified. Several studies investigated the use of tumor volume (TV) for response assessment, but its role as predictor of survival is unclear. A cut-off of 600 cm[3 ]seemed to divide patients (pts) with different prognosis. Our objective is to assess the association between baseline TV, stage/TNM and overall survival (OS).
Methods:
We retrospectively selected 49 MPM pts treated from August 2002 to January 2012. All pts had a digitally available baseline chest computed tomography (CT), performed before any treatment and up to 3 months after histological diagnosis. CT staging was carried out by two thoracic radiologists according to TNM staging system (7[th] Edition). Pleural disease volume mesaurements were obtained by a computer system. Major prognostic variables (age, sex, histology, TV, stage/TNM, treatment) were collected. Pts were divided in 2 groups according to baseline TV (large volume >600cm[3]; small volume <=600cm[3]). Association of volume groups, stage, T, N, M separately and OS was tested using Cox models adjusted by age, sex, histology and surgery.
Results:
Thirty-three pts were men, 16 women; median age was 62 years (range 25-78). Forty pts had epithelioid MPM, 7 mixed histology, 2 unknown histology. Four pts were diagnosed in early stage (I-II) and 45 in advanced stage (III-IV). The mean baseline TV was 494.15 cm[3 ](range 17.91- 2,329.03). Pts with small volume had a slight but not statistically significant tendency to survive longer than pts with large volume (3-year OS=32% vs 21%, respectively). The HR was 1.5 (95% CI=0.6-3.7) for large volume pts, 4.3 (p=0.08;95%CI=0.8-22.1) and 7.5 (p=0.02;95%CI=1.4-39.9) for stage III and IV, 7.0 (p=0.001;95%CI=2.3-21) and 5.4 (p=0.005;95%CI=1.7-17.4) for T3 and T4, respectively. Regarding N and M, not statistically significant results were observed.
Conclusion:
Coherently with the available literature, we report an association between baseline TV and prognosis; however it seems weak and barely near to statistical significancy. On the contrary, stage, in particular T3, showed a stronger association with prognosis. Considering the small sample and the wide 95% CI, our results should be interpreted with caution; nevertheless they open a critical question on the TV prognostic role and suggest a greater relevance of adjacent organs infiltration in predicting prognosis. Further collaborative studies are needed.
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SC24 - Management of Indeterminate Pulmonary Nodules (ID 348)
- Event: WCLC 2016
- Type: Science Session
- Track: Pulmonology
- Presentations: 1
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SC24.05 - Indication and Techniques of Surgery (ID 6704)
12:10 - 12:30 | Author(s): U. Pastorino
- Abstract
- Presentation
Abstract not provided
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