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Poster Session (ID 8)
- Event: ACLC 2018
- Type: Poster Session
- Presentations: 2
- Coordinates: 11/07/2018, 00:00 - 00:00, Poster Hall
P101 - Intratumor Heterogeneity Comparison Among Different Subtypes of (ID 206)
00:00 - 00:00 | Author(s): L. Chang
Intratumor heterogeneity (ITH) can lead to therapeutic failure, drug resistance, and poor survival. Understanding of ITH among different non-small cell lung cancer (NSCLC) subtypes is necessary. Circulating tumor DNA (ctDNA) released by tumor cell into the blood, can originate from any subclonal population within the tumor and therefore has great potential for presenting ITH. Whether ctDNA profile could represent these ITH is still an open question.
We performed 181 multi-region tumor tissues sequencing and matched ctDNA sequencing from 32 operative NSCLC to compare ITH among different NSCLC subtypes, including EGFR-mutant lung adenocarcinoma (LUAD), KRAS-mutant LUAD, EGFR&KRAS-wild-type LUAD, and lung squamous cell carcinoma (LUSC), and examine potential value of ctDNA for ITH analysis. If the somatic genetic alteration is shared by all the tissue regions, it is defined as trunk mutation. Otherwise, it is called branch mutation. ITH is evaluated by ITH index (ITHi). The ITHi will be higher, if the tumor has less trunk mutations.
EGFR-mutant LUAD showed significantly higher ITHi than KRAS-mutant LUAD/wild-type LUAD (P=0.03) and numerically higher ITH than LUSC. For trunk mutations, driver mutations were identified at a higher proportion than passenger mutations (60% vs. 40%, P=0.0023) in overall, especially in EGFR-mutant LUAD (86% vs. 14%, P=0.0004), while it was opposite in KRAS-mutant LUAD (40% vs. 60% , P=0.18). For branch mutations, the proportions of driver mutations and passenger mutations were similar for each NSCLC subtype. Additionally, for driver mutations, the proportions of oncogenes and tumor suppressor genes (TSGs) seemed to be similar both in the trunk (58% and 42%) and branch (49% and 51%) in general. However, oncogenes showed a higher proportion in EGFR-mutant LUAD, while TSG alterations had a strong enrichment in LUSC in trunk. ctDNA analysis showed unsatisfactory detections of tumor-derived trunk and branch mutations (43% vs. 23%;, P=4.53e-6) among all NSCLC subtypes. LUSC and EGFR&KRAS-wild-type LUAD had higher proportions for tumor-derived trunk mutations (81% and 53%) than those in EGFR-mutant LUAD (30%) and KRAS-mutant LUAD (22%), while the detections for tumor-derived branch mutations in ctDNA were extremely poor (from 13% to 25%) among all above NSCLC subtypes.
EGFR-mutant LUAD has the highest ITHi than other NSCLC subtypes, offering further understanding of tumorigenesis mechanisms among different NSCLC subtypes. Besides, ctDNA analysis shows unsatisfactory detections of tumor-derived mutations among all NSCLC subtypes, thus it maybe not an appropriate method to reflect ITH.
P102 - The Correlations of Tumor Mutational Burden Among Single-region Tissue, Multi-region Tissues And Blood in NSCLC (ID 208)
00:00 - 00:00 | Author(s): L. Chang
Tumor mutational burden (TMB) is emerging as a practical biomarker for response to immune checkpoint inhibitors (ICIs). Non-small cell lung cancer (NSCLC) patients with high-level tissue TMB (tTMB) or blood TMB (bTMB) are associated with better efficacy of ICIs. However, the correlations of single-region tTMB, multi-region tTMB and bTMB remain to be determined. Moreover, whether intratumor heterogeneity (ITH) has impact on TMB should be clarified.
We collected multi-region tumor tissues with matched blood from 32 operative NSCLC and explored the correlations among one-region tTMB, multi-region tTMB and bTMB through a 1021-gene panel sequencing. One-region tTMB was defined as the number of somatic non-synonymous mutations from single region. multi-region tTMB was calculated with non-repetitive mutations from all regions. bTMB was analyzed with tumor-derived mutations from ctDNA. TMB of >9 mutations/Mb was classified as high, using the top quartile threshold of 2000 samples from database of Geneplus. Besides, we used TMB fold-change, computed by the mean tTMB of single, double, and triple regions through a random iterated algorithm, to evaluate the influence of the enrolled region numbers on tTMB and explored the impact of ITH on tTMB.
Both of single-region tTMB and bTMB showed strong correlations with multi-region tTMB, while the former correlated better (Pearson r=0.94, P=2E-84, Pearson r=0.47, P=0.0067). It showed extremely high specificity (100%) but relatively low sensitivity (43%) when using bTMB define TMB-high patients, while most false-negative predictions were in early-stage patients. The classification accuracy was higher in late-stage patients (83%) than in early-stage patients (70%).Compared to single region, we found significantly enhanced tTMB fold-change if taking multi-regions for consideration. However, it showed insignificant tTMB fold-change increase if the included regions' number more than three. Moreover, the tTMB fold-change increased more sharply in ITH-high group compared with the ITH-low group significantly (fold-change 2.32 vs. 1.02, P=8.879e-05). The conversion rate of tTMB level status (conversion of tTMB-low to tTMB-high) in the ITH-high group was numerically higher than that in the ITH-low group (16.67% vs. 3.84%).
Single-region tTMB has stronger correlation with multi-region tTMB compared with bTMB, revealing the limitation of TMB analysis using ctDNA. ITH has an impact on tTMB, especially in high-level ITH patients, thus firstly demonstrating tTMB heterogeneity and providing an explanation for why some low-TMB patients evaluated by a single region biopsy still achieve benefit from ICIs.