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J. Alcaraz
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P1.05 - Early Stage NSCLC (ID 691)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.05-019 - Effects of Tumor Stroma and Inflammation on Survival of Stage I-IIp Lung Cancer (ID 8443)
09:30 - 09:30 | Author(s): J. Alcaraz
- Abstract
Background:
In lung cancer (LC) TNM classification allows an estimation of patient prognosis, but a third of patients with initial stages will relapse within three years. Molecular markers may increase prognostic accuracy and identify subgroups with high risk of progression.
Method:
Stromal (fibrous stroma and α-actin) and inflammation markers (IL1β, TNF-α and COX-2) were examined by immunohistochemistry in tumor tissue from a cohort of 222 patients with early-stage (I-IIp) LC recruited in Spain for the International Association for the Study of Lung Cancer TNM-16 staging project.
Result:
The diagnosis was non-small cell lung carcinoma (NSCLC) in 199 patients (106 adenocarcinoma and 93 squamous cell carcinoma) who were the target for this study. The participants had a mean age of 69 (SD 9) years, frequent respiratory (108, 54.3%) and cardiac (84, 42.2%) comorbidities, and were staged as IA (53, 26.5%); IB (56, 28.1%); IIA (41, 20.6%); IIB (40, 20.1%) or ≥III (9, 4.5%). After three years 94 patients had died (47.2%). In the bivariate analysis, 3-year mortality showed statistically significant associations with more advanced stage (p <0.001) and a higher proportion of fibrous stroma in the tumor (p = 0.014); and a marginal relationship with cardiac comorbidity (p= 0.07) and higher IL1β levels (p = 0.098). Sensitivity and specificity of fibrous stroma and IL1β were calculated and optimal cut-off points established according to Youden’s index. Using these cut-offs, fibrous stroma in >8% of the tumor sample and IL1β H-score levels above 1356 were significantly related to mortality. In Cox proportional hazards models, adjusting by stage and cardiac morbidity, patients with fibrous stroma levels above 8% had higher 3 year-mortality [HR= 2.03, 95% CI (1.1-3.7), p= 0.021]; and similar results were obtained in patients with IL1β levels above 1356 [HR= 2.05, 95% CI (1.1-3.7), p= 0.019]. Combining both markers, patients with both markers above their established cut-offs had a significantly higher risk of 3 year mortality [HR= 2.95% CI (1.1-3.6), p= 0.022].
Conclusion:
An overrepresentation of fibrous stroma and IL1β in the tumor sample is independently associated with 3 year mortality in NSCLC, confirming that the tumor stroma influences survival in LC. Funded by PII Oncology SEPAR and FIS 12-02040
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P3.03 - Chemotherapy/Targeted Therapy (ID 719)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.03-023 - Nintedanib Selectively Inhibits the Activation and Tumor-Promoting Effects of Fibroblasts from Lung Adenocarcinoma Patients (ID 9981)
09:30 - 09:30 | Author(s): J. Alcaraz
- Abstract
Background:
There is growing awareness that tumor-associated fibroblasts (TAFs) play critical roles in both tumor progression and response to therapies in solid tumors including non-small cell lung cancer (NSCLC). Nintedanib (NTD) is a multi-kinase inhibitor of VEGF, FGF and PDGF receptors that has been recently approved to treat advanced lung adenocarcinoma (ADC) patients in combination with docetaxel. The main goal of this study was to assess how TAFs contribute to the selective therapeutic effects of NTD in lung ADC.
Method:
Because TAFs are largely activated in vivo, patient derived lung TAFs from ADC and squamous cell carcinoma (SCC) patients as well as paired control fibroblasts from non-malignant pulmonary tissue were activated with TGF- β1 in the presence of increasing concentrations of NTD. Conditioned medium was also collected and used to stimulate the growth and invasion of several cancer cell lines. A panel of activation markers indicative of fibrosis were analyzed in TAFs, including alpha-smooth muscle actin, collagen-I/III and P4HA2.
Result:
Nintedanib dose-dependently inhibited the TGF-β1-induced expression of all activation markers in both ADC-TAFs and control fibroblasts derived from uninvolved lung parenchyma, whereas such inhibiton was very modest in SCC-TAFs, suggesting that TAF activation is regulated by different mechanisms in ADC and SCC. Remarkably, nintedanib abrogated the stimulation of growth and invasion in a panel of carcinoma cell lines induced by the conditioned medium from activated TAFs in ADC but not SCC. These results reveal that the pro-tumorigenic effects of ADC-TAFs in vitro are markedly reduced in the presence of NTD.
Conclusion:
These results reveal that nintedanib is an effective inhibitor of fibrosis and its associated tumor-promoting effects in ADC, and that the poor antifibrotic response of SCC-TAFs to nintedanib may contribute to the differential clinical benefit observed in both subtypes. Our findings also support that preclinical models based on carcinoma-TAF interactions may help defining the mechanisms of the poor antifibrotic response of SCC-TAFs to nintedanib and testing new combined therapies to further expand the therapeutic effects of this drug in solid tumors.
