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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)
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): Curtis Gumbs
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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