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M. Rodríguez-Rivera
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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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P2.01-063 - PDL1, JAK2 and PTEN Copy Number Alterations Synergistically Upregulate PD-L1 Expression in NSCLC (ID 5871)
14:30 - 14:30 | Author(s): M. Rodríguez-Rivera
- Abstract
Background:
Predictive biomarkers research in anti-PD-1/PD-L1 immunotherapy treatment is still at an early stage of development. Recently, amplification of PDL1 gene (9p24.1) has been described in NSCLC in correlation with PD-L1 protein expression. In addition, other tumor-constitutive alterations such as JAK2 amplifications (322kb upstream of PDL1) or PTEN deletions are also known to modulate PD-L1 expression. We aimed to determine PDL1, JAK2 and PTEN copy number alterations (CNAs) and subsequent PD-L1 protein expression in NSCLC.
Methods:
A total of 171 NSCLC patients (121 ADC and 50 SCC) were included. Clinical, histopathological and molecular data were collected. In resected early-stage diseases, two distinct histologic areas from FFPE tumoral tissue were included for each patient in 8 tissue microarrays (TMAs). PD-L1 expression analysis was assessed by IHC using PD-L1 #SP142 clone (Ventana) and positive cut off was defined at >1%. Moreover, H-score semi-quantitative approach was used to generate a score from 0 to 300. PDL1, JAK2 and PTEN CNAs were studied by FISH using commercial and non-commercial probes hybridized with respective centromere enumeration probes. Amplifications were defined as mean gene by mean centromere ratio ≥2.0, deletions as mean gene by mean centromere ratio ≤0.8, gains as mean gene ≥2.5, and high gains as mean gene ≥4.0.
Results:
PD-L1 expression was positive in 40 out of 171 cases (23.3%), with an average H-score of 177 and significantly associated with ADC solid histological pattern (p=0.012), KRAS mutations (p=0.001), the presence of TILs (p=0.001), and active smoking status (p=0.031). PDL1 gene CNAs were seen in 68/159 assessable cases (42.8%). We found 14 tumors with PDL1 amplification (8.8%), 21 PDL1 high gains (13%) and 33 PDL1 gains (20.8%). Twelve out of 14 FISH amplified cases had PD-L1 positive expression. Thus, FISH predicted positive PD-L1 IHC result with a low sensitivity (31.6%) but a high specificity (98.6%). Among PD-L1 expressing tumors (n=40), seven cases had JAK2 amplifications (6 of them with PDL1 gene coamplification) and eight showed PTEN deletions (3 of them were PDL1 amplified). Differences in H-score intensity between these groups were observed: JAK2-PDL1 coamplified cases had near 2-fold increase in PD-L1 expression than PDL1 alone (average H-score: 282 vs. 148).
Conclusion:
PDL1 gene amplification is synergistically regulating PD-L1 protein expression. In addition, JAK2 amplification upregulates PD-L1 expression, following the concept of cooperative oncogenic effects of genes within the PDJ amplicon. PDL1, JAK2 and PTEN CNAs analysis may be relevant for anti-PD-1/PD-L1 patient selection.
