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Lu Zhang
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OA03 - Systemic Therapies for SCLC: Novel Targets and Patients' Selection (ID 121)
- Event: WCLC 2019
- Type: Oral Session
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Now Available
- Moderators:Christine Lee Hann, Makoto Nishio
- Coordinates: 9/08/2019, 13:30 - 15:00, Hilton Head (1978)
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OA03.05 - Characterization of Genomic Alterations in Chinese LCNEC and SCLC via Comprehensive Genomic Profiling (Now Available) (ID 1486)
13:30 - 15:00 | Author(s): Lu Zhang
- Abstract
- Presentation
Background
LCNEC and SCLC are aggressive neuroendocrine carcinomas with overlap in clinical, histopathologic, morphologic and genomic features. Differential molecular features between the two subtypes have not been well elucidated, contributing the uncertainty for optimal clinical strategy for each subtype. Here we interrogated the genomic characteristics in LCNEC as compared to SCLC along with their histologically related subtypes: carcinoids and atypical carcinoids via comprehensive genomic profiling.
Method
FFPE samples from 31 LCNECs, 35 SCLCs, 14 carcinoids and 22 atypical carcinoids were sequenced in a CLIA-certified sequencing laboratory using 520-cancer-related gene panel, with an average sequencing depth of 1385X.
Result
Comparative mutational analysis revealed that both LCNEC and SCLC sub-cohorts displayed higher rate of TP53 alterations than that of carcinoid (p<0.001, p<0.001). SCLC patients harbored more RB1 and PIK3CA mutations than LCNECs (p<0.001, p=0.014) and carcinoids (p<0.001, p=0.018). In addition, mutation frequencies of LRP1B, FAT1, PRKDC, PIK3CA, NOTCH1, SPTA1 and EPHA3 in SCLC were significantly higher than that in carcinoid. Mutations in TP53 and RB1 occurred concurrently in 83% (29/35) SCLC patients, whereas in only 32.3% (10/31) LCNECs.（Fig.1） We further investigated the distribution of mutations across KEGG pathways and found that mutation frequencies in both HIF-1 and Notch signaling pathways were lower in LCNEC than SCLC (p=0.032, p=0.025). Copy number variation (CNV) analysis revealed that LCNEC and SCLC had comparable CNVs which were significantly higher than carcinoid (p<0.001, p<0.001) and atypical carcinoid (p=0.010, p=0.028). TMB analysis also revealed a comparable TMB status of LCNEC (12.7/Mb) and SCLC (11.9/Mb), and relatively lower TMB in both carcinoid (2.4/Mb, p<0.001, p<0.001) and atypical carcinoid (5.6/Mb, p=0.003, p=0.009) than LCNEC and SCLC.
Conclusion
We demonstrated the differential genomic characteristics in the four subtypes of neuroendocrine carcinomas. Compared with SCLC, LCNEC has lower mutation frequencies in RB1, PIK3CA, as well as HIF-1 and Notch signaling pathways. In addition, LCNEC and SCLC had comparable CNV and TMB status, which significantly higher than that of carcinoids and atypical carcinoid.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-50 - Impact of Concomitant HER2 Alterations in Mediating Clinical Outcomes of EGFR-Mutant Patients to Different Generation of EGFR-TKIs (Now Available) (ID 1161)
09:45 - 18:00 | Author(s): Lu Zhang
- Abstract
Background
The 2nd generation EGFR-TKI are selective and potent irreversible pan-HER inhibitors. Given their effect on HER2 besides EGFR, we investigated the role of HER2 co-alterations in mediating the clinical outcomes of EGFR-mutant non-small cell lung cancers to 2nd generation or other generation EGFR-TKIs.
Method
Plasma/tissue samples from advanced NSCLC before and after 1L EGFR-TKI treatment were sequenced using 168-/520-cancer-related gene panels, respectively. Clinical records of 94 EGFR-mutant pts (92 adenocarcinomas and 2 adenosquamous cell carcinomas) after 1st/3rd (n=73) or 2nd generation (afatinib, n=16; dacomitinib, n=5) EGFR-TKI treatment were collected for clinical outcomes evaluation. Event-time distributions were estimated using Kaplan-Meier and compared with long-rank test.
Result
Among the 94 pts identified as EGFR-positive at baseline, 8 (8.5%) had concurrent HER2 gain-of-function alterations (amplification or active mutation). Survival analysis showed that for those with concomitant EGFR and HER2 alterations at baseline, pts achieved favorable PFS (23.2 vs 5.6 months, p=0.04) to 2nd generation (n=2) than to 1st/3rd generation EGFR-TKI (n=6) as 1L treatment. And for those receiving 1L 1st/3rd generation EGFR-TKI (n=73), the presence of baseline HER2 alterations (n=6) was associated with shorter PFS (5.6 vs 9.8 months, p=0.16) and OS (15.7 vs 21.0 months, p=0.06) than absence of HER2 (n=67), although the difference was not significant due to a small sample size. In addition, we found all the samples (n=21) obtained from pts after 2nd generation EGFR-TKI resistance were HER2-negative, but pts progressed on 1st or 3rd generation EGFR-TKI with HER2 as the only resistance mechanism were observed in our study cohort.
Conclusion
Our findings suggested that, for EGFR-mutant pts combined with HER2 alterations at baseline or those resistant to 1L treatment of 1st/3rd EGFR-TKI due to HER2 alterations only，2nd EGFR-TKI might be a better choice.Our findings suggested that, for EGFR-mutant pts combined with HER2 alterations at baseline or those resistant to 1L treatment of 1st/3rd EGFR-TKI due to HER2 alterations only，2nd EGFR-TKI might be a better choice.
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P2.09 - Pathology (ID 174)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.09-11 - Genomic Profiling of Pulmonary Lymphoepithelioma-Like Carcinoma (PLELC) (ID 1520)
10:15 - 18:15 | Author(s): Lu Zhang
- Abstract
Background
PLELC, a rare and distinct type of primary lung cancer, is characterized by Epstein-Barr virus (EBV) infection. Histologically, it resembles undifferentiated nasopharyngeal carcinomas (NPC). Only a few hundred cases have been reported since its discovery. Due to the extreme rareness, its genomic landscape remains elusive.
Method
Tissue samples of 27 PLELC patients (13 males and 14 females) with various stages (Ib to IV) were subjected to targeted sequencing using a panel consisting of 520 cancer-related genes, spanning 1.6Mb of human genome.
Result
Collectively, we identified 184 somatic mutations spanning 109 genes, including 107 SNVs, 12 insertions or deletions (INDELs) and 65 copy-number amplifications (CNAs). Approximately, 50% of patients had CNAs. One patient had no mutation detected from this panel. Except for 2 patients, 1 with HER2 amplification and another with KRAS mutation, no other classic NSCLC driver genes were detected. The most frequently mutated genes were CCND1, TP53, DAXX and NFkBIA, occurring in 30%, 26%, 22% and 22% of patients, respectively. Interestingly, 78% (21/27) patients had mutations in epigenetic regulators. Of the 184 mutations identified, 51 occurred in epigenetics-related genes. Pathway analysis also revealed an enrichment of genes participating in chromatin remodeling and organization. Next, we compared the genomic profile of PLELC with lung adenocarcinoma and EBV positive NPC. The frequency of TP53 mutations was significantly higher in lung adenocarcinoma (68% vs 26%, p=0.021). Comparing to NPC, PLELC had significantly more mutations in epigenetic regulators. TMB analysis revealed a median TMB of 1.6/Mb, significantly lowered than lung adenocarcinomas (p<0.01). We also assessed PD-L1expression and revealed that 67% had an overexpression of PD-L1. Interestingly,TP53-mutant patients were more likely to associated low PD-L1 expression (p<0.01).
Conclusion
In this study, we elucidated a distinct genomic landscape associated with PLELC with no classic NSCLC driver mutation but an enrichment of mutations in epigenetic regulators. The observation of high expression of PD-L1 and lack of canonical druggable driver mutation raises the potential of immunocheckpoint blockade therapy for PLELC.
