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Haiyan Tu
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-88 - Molecular Alterations in Cerebrospinal Fluid Predict Clinical Outcomes of Central Nervous System Metastases in Lung Cancer (ID 1511)
10:15 - 18:15 | Author(s): Haiyan Tu
- Abstract
Background
Cerebrospinal fluid (CSF) has been proven as good media for genetic profiling of central nervous system (CNS) metastases. However, the association of genetic alterations in CSF and clinical outcomes remains elusive.
Method
A total of 94 lung cancer patients with CNS metastases underwent lumbar puncture. Circulating tumor DNA were extracted from CSF and profiled by next-generation sequencing. The effect of genetic alterations in CSF on survival and treatment outcomes were evaluated.
Result
The most common genes seen in CSF were EGFR, TP53, MET, CDKN2A, MYC, NTRK1 and CDK6. Kaplan-Meier survival analysis indicated that CDK4, CDK6, FGFR1, MET and MYC alterations, which were also characterized by more copy number changes, were associated with poor survival. Multivariate analysis found only MET (HR, 2.01; 95% CI, 1.15 to 3.52) and MYC alterations (HR, 2.31; 95% CI, 1.27 to 4.21) were correlated to poor OS. Forty-two patients harbored high n-CNVs (defined as the number of genes with copy number variations >2) while 50 patients carried low n-CNVs (defined as the number of genes with copy number variations <=2). Median overall survival (OS) of patients with high n-CNVs in CSF was 14.9 months (95% CI, 9.2 to 25.8 months), significantly shorter than those with low n-CNVs (21.6 months, 95% CI, 17.9 months to not reached (NR); HR, 1.9; 95% CI, 1.11 to 3.24; P=0.016). Patients with high n-CNVs and MET and MYC CNVs (copy number variations) were associated with the poorest OS. Osimertinib significantly prolonged OS only among patients with high n-CNVs (with vs. without osimertinib, 25.8 vs. 9.2 months; P=0.004). Among T790M negative patients, high n-CNVs seemed to positively associate with better response to osimertinib (OS with vs. without osimertinib, 23 vs. 7.8 months; P=0.058). Further analysis indicated that EGFR and FGFR1 CNV were the most significant factors associated with OS benefit from osimertinib among the high n-CNVs group (P=0.014; P=0.02). TP53_LOH and Wnt pathway alterations were significantly more prevalent in the high n-CNVs group than in the low n-CNVs group (P=0.016, P=0.006). With regard to clinical characteristics, higher performance status score (HR, 2.06; 95% CI, 1.38 to 3.07; P=0.0004) and occurrence of extracranial metastases (HR, 3.21; 95% CI, 1.25 to 8.24; P=0.015) suggested poor OS.
Conclusion
While genetic profiles in CSF, like high n-CNVs as well as MET and MYC CNV were related to poor prognosis, patients with high n-CNVs, especially those with EGFR or FGFR1 CNV might benefit more from osimertinib, further supporting CSF as liquid biopsy of CNS metastases in lung cancer.
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P2.17 - Treatment of Early Stage/Localized Disease (ID 189)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.17-16 - Genomic Heterogeneity and Evolutionary Trajectory in Multifocal Synchronous Lung Cancer (ID 2082)
10:15 - 18:15 | Author(s): Haiyan Tu
- Abstract
Background
Multifocal synchronous lung cancer (MSLC) presented as coexistence of multiple tumor lesions that share an identical germline genetic background and environmental exposure in individual patients. Along with the improved resolution of cross-sectional imaging, multiple types of ground glass opacities (GGOs) have been detected in increasing frequency as well as solid nodules even in an unique patient. However the molecular origins and relationships among the synchronous lesions remain unclear.
Method
10 treatment-naive MSLC patients were retrospectively collected while 25 tissue samples were performed whole exosome sequencing. In addition, we constructed phylogenetic trees to estimate the ancestral relationships of individual foci.
Result
79 somatic mutations in average were identified in MSLC tissues. The most significant mutated gene EGFR has been detected in 10 samples from 7 patients in our cohort. Tumor mutation burden as was significantly higher in IAC lesions than AIS/MIA ones. The mutation spectra of single-nucleotide variations (SNVs) were fairly consistent across the same histologic type even from different patients. Compared to AIS/MIA, IAC samples displayed a preponderance of A>T/T>A transition (Ti) while less frequency of A>C/T>G transversion (Tv). However few share mutations were located by pair of lesions in individual patients. Distinct genomic profiles suggested all were primary tumours. WNT pathway was enriched in AIS/MIA lesions exclusively while IAC appeared TGFβ/TP53 pathway mutation associated with cell proliferation and apoptosis.
Conclusion
Even in the same individual patient different lung cancer lesions may be driven by distinct genomic profiles so that each presented its own evolutionary trajectory. A deeper understanding of tumorigenesis is still in need to improve the diagnosis and treatment of MSLC.
