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K. Yoshimura
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P1.05 - Poster Session with Presenters Present (ID 457)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Early Stage NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.05-011 - Comparative Analysis of TTF-1 Copy Number Alterations and Protein Expression in Patients with Non-Small Cell Lung Cancer (ID 5133)
14:30 - 15:45 | Author(s): K. Yoshimura
- Abstract
Background:
TTF-1 (also known as NKX2-1) is located at chromosome 14q13.3. TTF-1 is a master regulator for the development of normal lung, and is also both a lineage oncogene and a suppressor gene in non-small cell lung cancer (NSCLC). TTF-1 expression is associated with a favorable prognosis. In contrast, the clinical significance of increased TTF-1 gene dosage has yet to be fully elucidated. We explored the relationship of TTF-1 copy number alterations with TTF-1 protein expression as well as patients’ prognoses in a relatively large cohort.
Methods:
We assessed TTF-1 gene copy number and protein expression in microarrayed 636 NSCLC, including 421 adenocarcinomas and 173 squamous cell carcinomas (SCCs), and 42 other histologies, using fluorescent in situ hybridization and immunohistochemistry. TTF-1 copy number alterations were divided into three categories; amplification (TTF-1/CEP14 ≥2), polysomy (TTF-1/CEP14 <2 and TTF-1 signals ≥4 copies per nucleus), and disomy (the others). Their associations with clinical data were retrospectively analyzed.
Results:
Among the entire cohort, TTF-1 amplification and polysomy were observed in 5.6% (36/636) and 8.3% (53/636), respectively. Tumors with copy number alterations (amplification and polysomy) were detected in 14.5% (61/421) among adenocarcinomas, 9.3% (17/173) among squamous cell carcinomas, and 26.2% (11/42) among other histologies (P = 0.012). TTF-1 expression was almost exclusively observed in adenocarcinomas (P < 0.001). In the adenocarcinoma cohort, the frequency was 6.7% (28/421) for TTF-1 amplification and 7.8% (33/421) for polysomy. TTF-1 positivity was 84.8% (357/421). A multivariate Cox hazards model analysis demonstrated that TTF-1 amplification was an independent worse prognostic factor (hazard ratio (HR), 3.84; 95% confidence interval (CI), 2.18-6.71) for overall survival, but TTF-1 expression was adversely an independent better prognostic factor (HR, 0.49; 95% CI, 0.28-0.85). In the SCC cohort, there were few cases of TTF-1 amplification (1.7%, 3/173), polysomy (8.1%, 14/173), and TTF-1 expression (3.7%, 10/273). Interestingly, any case of adenocarcinoma and SCC with TTF-1 amplification harbored positive TTF-1 expression.
Conclusion:
Both TTF-1 amplification and TTF-1 expression were more common in adenocarcinoma. However, they had distinct prognostic roles: TTF-1 amplification was an independent poor prognostic factor in adenocarcinoma, whereas TTF-1 expression was a favorable prognostic factor.
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P1.05-020 - Opposing Prognostic Roles of CD73 and A2A Adenosine Receptor in Non-Small-Cell Lung Cancer (ID 5139)
14:30 - 15:45 | Author(s): K. Yoshimura
- Abstract
Background:
CD73 (otherwise known as ecto-5’-nucleotidase) is an important molecule in the adenosine pathway because it generates adenosine by enzymatically dephosphorylating extracellular AMP, which results in immunosuppressed niche within the tumor microenvironment. A2A adenosine receptor (A2AR) acts as a predominant receptor for adenosine in immune cells and can also be expressed in lung tumor cells. However, the clinical impact of the adenosine pathway in non-small-cell lung cancer (NSCLC) has yet to be uncovered, although the pathway has been shown to have a pivotal role in the regulation of anti-tumor immunity and is considered as one of the promising future treatment targets.
Methods:
We investigated CD73 and A2AR protein expression profiles using immunohistochemistry in tissue microarrays containing 642 resected NSCLC specimens. The expression levels were assessed using the H-score method that ranged from 0 to 300, and cutoffs were determined using the minimum P-value method for overall survival (OS). The associations between their expression levels and clinicopathological and molecular characteristics as well as patients’ prognoses were retrospectively analyzed.
Results:
The median age of patients was 68 years old (range, 23–88) and 440 (68.5%) patients were male. 438 (68.2%) patients had smoking history and 420 (65.4%) patients had adenocarcinoma histology. Significantly higher expression of both CD73 and A2AR was observed in female than male, in never smokers than ever smokers, and in adenocarcinomas than squamous cell carcinomas. Among adenocarcinomas, both high CD73 and A2AR expression were significantly associated with TTF-1 positivity and EGFR mutations. ALK-positive adenocarcinomas showed significantly higher expression levels of CD73 than ALK-negative tumors. High CD73 expression was an independent indicator of a poor prognosis for NSCLC patients in multivariate Cox regression analyses for OS (hazard ratio (HR), 2.19; 95% confidence interval (CI), 1.38–3.47) and disease-specific survival (DSS) (HR, 2.97; 95% CI, 1.78–4.95). Contrary, high A2AR expression was an independent favorable predictor of prognosis for OS (HR, 0.69; 95% CI, 0.49–0.97) and DSS (HR, 0.51; 95% CI, 0.33–0.79). Among adenocarcinomas, high CD73 expression was an independent poor prognostic marker for OS (HR, 2.73; 95% CI, 1.61–4.63) and DSS (HR, 4.57; 95% CI, 2.54–8.23), whereas high A2AR expression was an independent favorable prognostic marker for DSS (HR, 0.56; 95% CI, 0.32–0.98).
Conclusion:
Both CD73 and A2AR expression was associated with TTF-1-positive and EGFR-mutant adenocarcinoma. Nonetheless, they had opposing prognostic significance in resected NSCLC.
