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Ying Jin
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OA15 - Targeted Agents and Immunotherapy for Small Cell Lung Cancer (ID 152)
- Event: WCLC 2019
- Type: Oral Session
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Now Available
- Moderators:Raffaele Califano, Charles M Rudin
- Coordinates: 9/10/2019, 14:30 - 16:00, Hilton Head (1978)
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OA15.04 - Genomic and TCR Intratumor Heterogeneity of Small-Cell Lung Cancer by Multiregion Sequencing: An Association with Survival (Now Available) (ID 1458)
14:30 - 16:00 | Author(s): Ying Jin
- Abstract
- Presentation
Background
Small cell lung cancer (SCLC) is an aggressive cancer. Although sensitive to initial therapy, recurrence is almost inevitable. The molecular mechanisms underlying recurrence are unknown. We have previously demonstrated that complex genomic and T cell receptor (TCR) intratumor heterogeneity (ITH) was associated with increased risks of relapse in non-small cell lung cancers (NSCLC). Genomic ITH and TCR architecture of SCLC and its clinical impact have not been well studied, largely due to lack of tumor specimens as surgery is rarely used to treat SCLC.
Method
We performed multiregion whole-exome sequencing and TCR sequencing of 49 tumor samples from 18 resected limited-stage SCLCs to delineate the immunogenomic ITH of SCLC. We compared the results to those in NSCLC and assessed the association of genomic and TCR attributes with patient’s survival.
Result
On average, 544 mutations/sample were detected. The median proportion of trunk mutations (mutations identified in all regions within the same tumors) was 80.4% versus 70% in NSCLC (TRACERx, Jamal-Hanjani, NEJM, 2017, p=0.08) and all TP53 and RB1 mutations were trunk mutations, suggesting these mutations were early events during carcinogenesis of this cohort of SCLCs. A higher non-synonymous tumor mutational burden (TMB) was associated with a higher T cell density (infiltration) in the tumor (r=0.46, p=0.005). Compared to the TCR repertoire of NSCLC (Reuben, WCLC, 2017), these SCLC tumors demonstrated significantly lower T-cell density (0.05 versus 0.24, p<0.0001), richness (diversity, 1,043 versus 3,666, p<0.0001) and clonality (reactivity, average 0.02 versus 0.15, p<0.0001) despite similar non-synonymous TMB (average 187 in SCLC versus 176 mutations/sample in NSCLC). Only 0.2% to 14.6% of T cells were detectable across all regions from the same tumors, suggesting substantial TCR ITH. Jaccard index (JI), a parameter quantifying TCR ITH was significantly lower in SCLC than in NSCLC (0.06 versus 0.1, p<0.0001) implying higher level of TCR ITH in SCLC than NSCLC. Interestingly, higher T-cell density, richness or clonality appeared to be associated with lower risk of recurrence numerically. Furthermore, higher TCR JI (less degree of ITH) was associated with significantly longer overall survival (HR=0.15, p=0.04).
Conclusion
Limited-stage SCLC tumors have distinct TCR repertoire and genomic ITH architecture. Overall, SCLC may have a more pronounced immunosuppressive microenvironment and higher level of TCR repertoire ITH than NSCLC. Nevertheless, higher degree of T cell infiltration and clonal expansion as well as more homogeneous T cell response may be associated with more favorable clinical outcome in patients with limited-stage SCLC.
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-17 - Genomic Evolution During TKI Treatment in Non-Small Cell Lung Cancer Patients With or Without Acquired T790M Mutation (ID 2988)
09:45 - 18:00 | Author(s): Ying Jin
- Abstract
Background
EGFR-mutant non-small-cell lung cancer (NSCLC) patients inevitably develop drug resistance when treated with EGFR tyrosine kinase inhibitors (TKIs). Clonal and clinical analyses of genetic alterations at baseline and progressive disease (PD), as well as differences between acquired T790M and T790M-negative patients in drug-resistant mechanisms, have not been systematically studied.
Method
We performed targeted sequencing of pre-treatment and PD tumor samples from 54 EGFR-mutant NSCLC patients. Ten additional patients were sequenced using whole exome sequencing to infer the clonal evolution patterns.
Result
We observed new co-occurring alterations and pathways limiting EGFR-inhibitor response, including 9p34.3/19p13.3 (NOTCH1/STK11) co-deletion and TGF-beta pathway alterations. Besides acquired T790M mutation, chromosomal instability (CIN) related genes including AURKA and TP53 alterations were the most frequently acquired events. CIN significantly increased with TKI treatment in T790M-negative patients. Transcriptional regulators including HNF1A, ATRX and NKX2-1 acquired alterations were enriched in T790M-positive patients, and diverse oncogenic pathway alterations were more common in T790M-negative patients. T790M-positive patients had improved PFS compared to T790M-negative patients. We further identified subgroups within T790M-positive or T790M-negative patients with distinct PFS. Clonal evolution analysis indicated progression of T790M-positive patients depends on competition between T790M and non-T790M resistant subclones.
Conclusion
Our study is the first attempt to identify co-occurring copy number events to stratify patients resistant to TKI treatment. Besides acquired T790M mutation, chromosomal instability (CIN) related genes were identified as the most frequently acquired events. Clonal evolution analysis indicated indicate that higher competitive advantage of T790M was associated with improved PFS.
