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H. Tu
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JCES01 - Joint IASLC - Chinese Society for Clinical Oncology - Chinese Alliance Against Lung Cancer Session (ID 413)
- Event: WCLC 2016
- Type: Joint Chinese / English Session
- Track:
- Presentations: 1
- Moderators:F.R. Hirsch, C. Bai
- Coordinates: 12/04/2016, 08:00 - 11:45, Stolz 1
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JCES01.18 - Dual Positive PD-L1 and CD8+ TIL Represents a Predominant Subtype in NSCLC and Correlates with Augmented Immunogenicity (ID 7060)
08:00 - 11:45 | Author(s): H. Tu
- Abstract
Background:
Recent studies have identified that the degree of tumor infiltrating lymphocyte (TIL) infiltration and PD-L1 expression in the tumor microenvironment (TME) are significantly correlated with the clinical outcomes of anti-PD-1/PD-L1 therapies. Here we conducted this study to verify the distribution of PD-L1/CD8[+] TIL expression and its clinical significance in non-small cell carcinoma (NSCLC). Potential mechanism predicted for PD-1 blockade was explored in depth as well.
Methods:
Immunohistochemistry was performed to detect PD-L1 and CD8 expression in NSCLC. The Kaplan–Meier (KM) survival curve was used to estimate disease free survival (DFS) and overall survival (OS). Gene Set Enrichment Analysis (GSEA) was used to determine potentially relevant gene expression signatures.
Results:
288 cases with stage I-IIIA NSCLC were evaluated for PD-L1 and CD8+ TIL staining. Dual positive PD-L1 and CD8 (PD-L1+/CD8+) represents a predominant subtype in NSCLC, accounting for 36.5% (105/288), followed by PD-L1-/CD8- (24.3%, 70/288), PD-L1-/CD8+ (26.0%, 75/288) and PD-L1+/CD8- (13.2%, 38/288). Survival analysis of DFS (p=0.031) and OS (p=0.002) showed a significant difference between four subgroups. Furthermore, we analyzed the correlation between expression types of PDL1/CD8 and mutation burden and angtigen presentation. We can identified dual positive PD-L1 and CD8 was significant with increased mutation burden (p<0.001), high frequency of mismatch repair (MMR) related gene mutation. More interestingly, tumor with dual positive PD-L1 and CD8 manifested a remarkable activated angtigen presentation and T cell receptor signature compared with other subgroups.
Conclusion:
Dual positive PD-L1 and CD8 was identified as a predominant subtype in NSCLC and correlates with increased immunogenicity. These findings provide the evidence that combined analysis of PD-L1 and CD8 in NSCLC may be a promising way to predict PD-1 blockade immunotherapy.
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-043 - Peripheral Blood CD45RA+ CCR7+ Naive T Cells Were Correlated with Prognosis in Non-Small Cell Lung Cancer Patients (ID 5999)
14:30 - 15:45 | Author(s): H. Tu
- Abstract
Background:
CD45RA+ CCR7+ naive T cells were reported to generate effectors possessed the high potent cytotoxic activity and low level of "exhaustion" T cells in vitro. However the relationship between frequency of naïve T cells in peripheral blood and prognosis in non-small cell lung cancer (NSCLC) is not clear. In order to elucidate this relationship, we first analyzed the frequency of CD45RA+ CCR7+ naïve T cell in peripheral blood of healthy population and patients with NSCLC.
Methods:
The frequency of CD45RA+ CCR7+ naïve T cells was calculated by flow cytometry from healthy volunteers and NSCLC patients. The correlation of naive T cell frequency and overall survival (OS) of NSCLC patients who were treated with tyrosine kinase inhibitors (TKIs) or chemotherapy was statistically analyzed.
Results:
105 healthy volunteers (age rank 23-85year-old) and 137 NSCLC patients (age rank 33-86year-old) were enrolled in our study from 2013 October 1st to 2015 December 1st. Our results showed that the frequency of peripheral blood naïve T cells in NSCLC patients’ (Mean=17.8±5.7%) was significantly lower than that in healthy subjects’ (Mean=31.2±5.2%) (p<0.05). The frequency of naïve T cell was negatively correlated with the frequency of PD-1+CD8+ T cells (R[2]=0.1111, p<0.001) in peripheral blood of NSCLC patients, whereas, which was positively associated with the immune activity of CD8+ T cells and with the frequency of lymphoid stem cells or lymphoid progenitor cells in peripheral bloods (R[2]=0.1521, p<0.001). In the patients who were treated with TKIs，mOS in the group of high frequency of naïve T cells (>17.8%) was not reached, while that of group with low frequency (17.8%) was 19.0m (HR=0.3057, 95% CI 0.1127- 0.8291, p=0.0199). In patients who were administered chemotherapy, the mOS in the naïve T cells low frequency group was 12.0m, but in the high frequency group the median OS was undefined (HR=0.3286, 95% CI 0.1100 0.9817, p=0.0463).
Conclusion:
Our study shows that the CD45RA+ CCR7+ naïve T cells in peripheral blood closely related with immune response, and the frequency of naïve T cells in peripheral blood is positively associated with prognosis of NSCLC, which can be worked as a valuable prognostic factor for NSCLC patients.
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P3.02a - Poster Session with Presenters Present (ID 470)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02a-020 - Clinical Failure to Crizotinib in Patients with Anaplastic Lymphoma Kinase-Positive Advanced Non-Small-Cell Lung Cancers (ID 4523)
14:30 - 15:45 | Author(s): H. Tu
- Abstract
Background:
Crizotinib, as the standard treatment for use in first-line treatment of anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC), showed superiority over platinum-based chemotherapy in advanced ALK-positive lung adenocarcinoma.Undoubtedly, the resistance to crizotinib is a current bottleneck which limits its clinical application. However, there are few reports about clinical failure to crizotinib, especially the correlation between the failure patterns of crizotinib and survival benefit.
Methods:
Totally,171 ALK-positive NSCLC patients treated with crizotinib were reviewed at the Guangdong General Hospital in China from October 2010 to July 2016.The status of ALK rearrangement was assessed by Lysis ALK Break Apart fluorescence in situ hybridization,reverse transcription polymerase chain reaction, or Ventana ALK immunohistochemistry.Chi-square test and Kapla-Meier survival curve were used to analyze the results statistically.
Results:
Among enrolled patients,47.5%(81/171) gained secondary resistance,10.5%(18/171) had primary resistance and 4 patients stopped taking crizotinib because of the occurrence of unacceptable toxicities including anasarca,ventricular tachycardia and hepatic insufficiency. Moreover,49 patients had no progression,in which 2 patients had taken crizotinib more than 5 years uninterruptedly.In the patients with secondary resistance (n=81),46 were male and 63 were never smokers.Brain metastases occurred in 27.1%(22/81) at the baseline,half of which(11/22) still had brain progression after the treatment of crizotinib.On the contrary,21 patients without brain metastases at the baseline were evaluated at disease progression because of brain metastases.We classified patients with secondary resistance into several categories according to the failure patterns of crizotinib, such as dramatic,gradual and local progression.There were 47(58.0%), 2(2.5%) and 32(39.5%) patients for dramatic, gradual and local progression respectively.The patients with dramatic progression had an inferior progression-free survival with crizotinib to those with gradual and local progression (9.8 vs 11.9 months),which did not achieve statistical significance.The post progression survival(PPS) of dramatic progression group is 10.4 months.The PPS of other group is 20.5 months comparatively.Patients with dramatic progression showed shorter overall survival when compared with other patients (26.7 vs 41.0 months, P=0.042).
Conclusion:
Dramatic progression was prevalent in ALK-positive lung adenocarcinoma beyond failure to crizotinib, and predicted poor overall survival.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-059 - The Role of Epidermal Growth Factor Receptor in the Onset of Skeletal Related Events in Non-Small Cell Lung Cancer (ID 6042)
14:30 - 15:45 | Author(s): H. Tu
- Abstract
Background:
Bone metastasis is frequent in non-small cell lung cancer (NSCLC) patients, and subsequent skeletal related events (SREs) adversely deteriorate life quality and survival. Patients harboring sensitive epidermal growth factor receptor (EGFR) mutation experience a prolonged life expectancy. However, it is unclear whether survival enhancement in NSCLC patients with sensitive EGFR mutation may encounter an increase in the onset of SREs or not. Also, it is still unknown whether time to SREs is impacted by EGFR mutation status. In this study, we evaluated the impact of EGFR mutation status and other clinic-pathological variables on the incidence of SREs and on survival outcomes of SREs in stage IV NSCLC patients.
Methods:
We conducted a retrospective study of medical records from patients who were diagnosed stage IV NSCLC in a single institute. EGFR mutation status, and other clinical-pathological variables, bone metastasis outcomes and survival data were collected and statistically analyzed.
Results:
410 patients with evident bone metastasis were enrolled in the study. 49.0% patients were detected with sensitive EGFR mutation, and 29.0% were prophylactically administered bisphosphonate. 42.7% experienced at least one SRE, the most common type of which was palliative radiotherapy. Patient harboring sensitive EGFR mutation hold a lower incidence of SREs than patients who were detected with wild type EGFR (37.3% vs 47.8%, p=0.031), and patients who received bisphosphonate confronted a lower incidence of SRE comparing with patients who didn’t receive bisphosphonate prophylactically (36.1% vs 45.4%, p=0.087). Median time from bone metastasis to first SRE was two months longer in patients with EGFR mutation, comparing to patients with wild type EGFR, with a marginal significance (5.0m vs 3.0m, p=0.08). The administration of bisphosphonate delayed the median time to first SRE for 5 months (7.0m vs 2.0m, p=0.037). In multivariate analysis using a Cox proportion model, wild type EGFR (HR=1.559, 95%CI 1.081-2.249), multiple bone lesions (HR= 1.991, 95%CI 1.217-3.258), mixed type bone lesions (HR=2.144, 95%CI 1.085-4.238) were independent risk factors of survival post first SRE, while a smoking history (HR=1.428, p=0.053) was shown marginally significant with an impaired survival post first SRE.
Conclusion:
This retrospective study shows that EGFR mutation has a propensity to impact the onset of SRE and prolong survival post first SRE in patients with stage IV NSCLC. For patients with higher risks to experience SREs, bisphosphonate is an alternative to impede the process.
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P3.02b-095 - Tracing Spatiotemporal T790M Heterogeneity in Patients with EGFR-Mutant Advanced NSCLC after Acquired Resistance to EGFR TKIs (ID 6057)
14:30 - 15:45 | Author(s): H. Tu
- Abstract
Background:
With the marketing of osimertinib, epidermal growth factor receptor (EGFR) T790M mutation has become a clinically significant biomarker for advanced EGFR-mutant non-small-cell lung cancer (NSCLC) after acquired resistance to previous EGFR TKIs. However, T790M status might vary spatiotemporally and consequently hinder the initiation and clinical efficacy of third generation EGFR TKIs. Till now, the spatiotemporal traces of T790M under treatment pressure have not been fully elucidated.
Methods:
We retrospectively reviewed T790M status and clinical courses of 93 patients who underwent multiple (≥2) rebiopsies after acquired resistance to first or second generation EGFR TKIs from 2010 to 2015 in Guangdong General Hospital. Patients underwent synchronous rebiopsies at the same lesion or paired tissue and plasma rebiopsies were enrolled to evaluate the spatial T790M heterogeneity. Patients received heterochronous rebiopsies at the same lesion or different lesions were enrolled to evaluate the temporal and spatiotemporal T790M heterogeneity respectively.Tissue EGFR detection was performed by SNAPSHOT or Amplification Refractory Mutation System (ARMS). Plasma EGFR was detected by ARMS.
Results:
A total of 99 evaluations were performed with 6 of 93 enrolled patients underwent both synchronous and heterochronous rebiopsies. Among 20 patients who underwent synchronous rebiopsies at the same lesion, 13 revealed T790M heterogeneity. Among 17 patients who had paired tissue and plasma rebiopsies, 8 showed T790M heterogeneity. Spatial T790M heterogeneity ratio was 57% (21/37) in general. 33% (10/30) patients who received heterochronous rebiopsies at the same lesion revealed temporal T790M heterogeneity. Spatiotemporal T790M heterogeneity was observed in 53% (17/32) of patients who received heterochronous multiple sites rebiopsies. Of abovementioned patients with heterochronous T790M heterogeneity, T790M status in 67% (18/27) switched from negative to positive after chemotherapy or continuation of EGFR TKIs and in 33% (9/27) switched from positive to negative after chemotherapy or combined regimens of chemotherapy and EGFR TKIs.
Conclusion:
T790M status could vary spatiotemporally at a ratio of 33-57% in patients with acquired resistance to previous EGFR TKIs. Repeated rebiopsies both at the same lesion and various lesions might be valued particularly in T790M-negative cases in this subset of patients.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-060 - Dual Positive PD-L1 and CD8+ TIL Represents a Predominant Subtype in NSCLC and Correlates with Augmented Immunogenicity (ID 4502)
14:30 - 15:45 | Author(s): H. Tu
- Abstract
Background:
Recent studies have identified that the degree of tumor infiltrating lymphocyte (TIL) infiltration and PD-L1 expression in the tumor microenvironment (TME) are significantly correlated with the clinical outcomes of anti-PD-1/PD-L1 therapies. Here we conducted this study to verify the distribution of PD-L1/CD8[+] TIL expression and its clinical significance in non-small cell carcinoma (NSCLC). Potential mechanism predicted for PD-1 blockade was explored in depth as well.
Methods:
Immunohistochemistry was performed to detect PD-L1 and CD8 expression in NSCLC. The Kaplan–Meier (KM) survival curve was used to estimate disease free survival (DFS) and overall survival (OS). Gene Set Enrichment Analysis (GSEA) was used to determine potentially relevant gene expression signatures.
Results:
288 cases with stage I-IIIA NSCLC were evaluated for PD-L1 and CD8+ TIL staining. Dual positive PD-L1 and CD8 (PD-L1+/CD8+) represents a predominant subtype in NSCLC, accounting for 36.5% (105/288), followed by PD-L1-/CD8- (24.3%, 70/288), PD-L1-/CD8+ (26.0%, 75/288) and PD-L1+/CD8- (13.2%, 38/288). Survival analysis of DFS (p=0.031) and OS (p=0.002) showed a significant difference between four subgroups. Furthermore, we analyzed the correlation between expression types of PDL1/CD8 and mutation burden and angtigen presentation. We can identified dual positive PD-L1 and CD8 was significant with increased mutation burden (p<0.001), high frequency of mismatch repair (MMR) related gene mutation. More interestingly, tumor with dual positive PD-L1 and CD8 manifested a remarkable activated angtigen presentation and T cell receptor signature compared with other subgroups. Figure 1
Conclusion:
Dual positive PD-L1 and CD8 was identified as a predominant subtype in NSCLC and correlates with increased immunogenicity. These findings provide the evidence that combined analysis of PD-L1 and CD8 in NSCLC may be a promising way to predict PD-1 blockade immunotherapy.
