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Sangmin Chang
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MA19 - Genomic Markers of IO Response (ID 922)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Immunooncology
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 15:15 - 16:45, Room 201 BD
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MA19.04 - The Clinical Implication of Frameshift Indel Mutation Burden in Non-Small Cell Lung Cancer (NSCLC) (ID 12592)
15:35 - 15:40 | Author(s): Sangmin Chang
- Abstract
- Presentation
Background
Tumor mutational burden (TMB) has been proposed as a potential predictive marker for immune checkpoint inhibitor (ICI) response in many cancers, including NSCLC. Recently, research has revealed frameshift indel (fsindel) of all mutations to be significantly associated with ICI response in melanoma patients. However, little is currently known regarding its clinical implication in NSCLC patients treated with PD1/PD-L1 inhibitors (ICIs).
a9ded1e5ce5d75814730bb4caaf49419 Method
Next generation sequencing of 324 genes (FoundationOneTM) was used to derive fsindel burden and TMB. A total of 128 patient data with NSCLC treated with ICIs were analyzed from Northwestern University (N=68) and the University of Miami (N=60). A total of 128 patients were divided into two groups with 0 fsindel (FS-) and more than 1 fsindel (FS+). Progression free survival (PFS) and overall survival (OS) were compared between FS+ and FS- groups. PFS and OS outcomes of TMB high group (H-TMB, upper¼) and TMB low group (L-TMB, lower¼) were also compared.
4c3880bb027f159e801041b1021e88e8 Result
Among 128 patients, 51.6% belonged to FS+ group (N=66). Between FS-/FS+ groups, there were no significant differences in mean age (66.2/66.0) and performance status (0.9/0.9). Lines of ICIs used in the FS-/FS+ groups were 1st (19/19%), 2nd (47/56%), 3rd (24/11%), and 4th line or more (10/14%). FS+ group had significantly longer PFS compared with FS- group (median 6.2/2.7 months, P=0.02, Figure 1). No significant difference in OS was seen between the two groups (median 16.8/11.2 months, P=0.70). In contrast, however, H-TMB did not show any significant difference in PFS (median 5.6/4.0 months, P=0.14) and OS (median 15.8/15.1 months, P=0.69) compared to L-TMB.
8eea62084ca7e541d918e823422bd82e Conclusion
This is the first report to illustrate an association between fsindel and outcome in patients with NSLC treated with ICIs. Our findings suggest its potential role as a predictive marker for immunotherapy.
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P1.04 - Immunooncology (Not CME Accredited Session) (ID 936)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.04-01 - Impact of Chromatin Remodeling Genes Including SMARCA2 and PBRM1 on Neoantigen and Immune Landscape of NSCLC (ID 12593)
16:45 - 18:00 | Author(s): Sangmin Chang
- Abstract
Background
Epigenetic changes in tumors and their microenvironment immune cells have been the recent focus of cancer research. Aberrations in SWI/SNF complexes within the chromatin remodeling machine may play a major role in carcinogenesis. However, little is known about their impact on neoantigen and the immune landscape of NSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients were divided into two groups; Mut group (at least one mutation in 27 SWI/SNF complex subunit genes including SMARCA2 and PBRM1) and NoMut group (no SWI/SNF mutations). We analyzed genomic, transcriptomic data from the TCGA database including patients with adenocarcinoma (ADC, n=515) and squamous cell carcinoma (SQCC, n=501) of lung cancer. The tumor immune landscape was analyzed using the signatures derived from 812 ‘immune metagenes’ (Angelova, M. et al, 2015). We analyzed neoantigen burden and immune landscape between two groups. RNA expression of the above genes were compared. Patients were also divided by the expression levels of the above genes (1st quartile vs 4th quartile).
4c3880bb027f159e801041b1021e88e8 Result
Mut group (142 samples, 14%) showed significant higher neoantigen burden compared with NoMut group in ADC and SQCC (mean 32.17/15.22 and 34.75/19.83 mutation/mbp, respectively, both P<0.01). In addition, the Mut group demonstrated higher infiltration of activated CD8 T cells compared with the NoMut group in ADC (39%/25%, P<0.01). However, there was no significant difference between two groups in SQCC (32%/27%, P=0.42).
For two representative genes (SMARCA2 and PBRM1), lower expression of the two genes were associated with higher infiltration of activate CD8 T-cells in ADC (60%/6% and 37%/17%, respectively, both P<0.01) and SQCC (40%/21% and 43%/17%, respectively, both P<0.01). However, there was no difference in neoantigen burden with respect to gene expression in either ADC or SQCC.
8eea62084ca7e541d918e823422bd82e Conclusion
Mutation or low expression of chromatin remodeling genes including SMARCA2 and PBRM1 were associated with higher neoantigen burden and higher tumor infiltration of activated CD8 T-cells in human NSCLC.
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P1.04-25 - The Implication of Frameshift Mutation Burden in Neoantigen and Immune Cell Landscape in Non-Small Cell Lung Cancer (NSCLC) (ID 11995)
16:45 - 18:00 | Author(s): Sangmin Chang
- Abstract
Background
Recent research has shown an association between enrichment of insertion and deletion (indel) mutations and tumor-specific neoantigens, which in turn correlated with T-cell activation in renal cell carcinomas. Furthermore, frameshift indel (fsindel) mutation counts were significantly associated with clinical response to immune checkpoint inhibitors (ICIs) in melanoma patients. However, little is currently known about such associations in NSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Method
Neoantigen counts were based on CloudNeo, a cloud pipeline used for identifying patient-specific neoantigens. The immune cell signatures of 31 distinct immune cell types of samples were derived from RNA-sequencing of 812 immune metagenes obtained from The Cancer Genome Atlas. 511 lung adenocarcinoma (ADC) and 471 squamous cell carcinoma (SqCC) patient samples were divided into 4 quartiles (Q1-Q4) according to number of fsindel mutations in order to compare neoantigen counts and immune cell infiltration. Fsindel mutations were identified from mutation annotations generated by the Genomic Data Commons’ MuTect2 somatic variation calling workflow.
4c3880bb027f159e801041b1021e88e8 Result
8eea62084ca7e541d918e823422bd82e Conclusion
The range of fsindel count of ADC and SqCC were 0-139 and 0-150, respectively, while the median fsindel count was 7 and 8, respectively. Neoantigen count showed a significant positive association with fsindel in both ADC and SqCC (p<0.0001, p<0.01 respectively). Furthermore, a higher number of fsindels was associated with significantly increased activated CD4 and CD8 T-cell infiltration in ADC (Figure 1. p<0.001, p<0.01, respectively), while a similar trend was observed in SqCC for CD4 and CD8 T-cells, although not significant (Figure 1. p=0.056, p=0.341, respectively).
We report for the first time the association between fsindels and higher neoantigen burden and infiltration of activated CD4 and CD8 T-cells in human NSCLC. As the presence of immune cells has been shown to be an important factor in determining response to ICIs, our findings suggest that fsindels could potentially be used as a predictive marker for immunotherapy.
6f8b794f3246b0c1e1780bb4d4d5dc53
