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Chao-Chi Ho
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P1.03 - Biology (ID 161)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.03-21 - Epigenome-Wide Association Study of Cancer Associated Fibroblasts-Induced Oncogenic Transformation of Lung Epithelial Cells (ID 2602)
09:45 - 18:00 | Author(s): Chao-Chi Ho
- Abstract
Background
Cancer-associated fibroblasts (CAFs) provide a microenvironment suitable for tumor development. CAFs have been shown to hold the capacity to facilitate carcinogenesis, drug resistance, tumor recurrence and metastasis through the signaling networks. Most studies investigating the impact of CAFs have focused on the cancer cells. The issue that how CAFs could induce carcinogenesis in the adjacent normal tissues, including genetic and epigenetic changes; however, attracts less attention. We aimed to characterize CAF-driven molecular changes in non-tumorous epithelial cells by genome/epigenome-wide study.
Method
We primary cultured CAFs from NSCLC patients and co-cultured CAFs with normal human epithelial cells (BEAS2B). We performed in vitro soft agar assay and processed the established cocultured clones onto the methylome and transcriptome high-throughput platforms.
Result
We found that the CAF-BEAS2B coculture could form colonieson the soft agar while CAFs or BEAS2B alone could not. Following isolation, the cells of cocultured clones developed more colonies than the parental BEAS2B by colony formation assay. The absence of CAF marker CD90 staining indicated no CAF contamination in the cocultured clones. In addition, DNA methylation profiling integrated with gene expression identified clusters (eg. ROBO1) that could discriminate cocultured clones from parental BEAS2B cells. The results of this study showed that CAFs could induce normal epithelial cells to undergo oncogenic transformation via DNA methylation regulation, suggesting the pro-tumorigenic potency of CAFs.
Conclusion
Exploring the molecular interaction between CAFs and surrounding normal cells could help clarify the role of CAFs predisposed in the microenvironment in transforming normal cells epigenetically.
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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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P2.01-39 - Serial Plasma ctDNA Tests Identify Genomic Alterations for Early Prediction of Osimertinib Treatment Outcome in T790M+ NSCLC (ID 2396)
10:15 - 18:15 | Author(s): Chao-Chi Ho
- Abstract
Background
Recent advances in detection of genomic DNA from plasma samples allow us to follow the alteration of shedding tumor DNA in plasma before and after systemic treatment with multiple biopsies. Osimertinib is the standard of care for NSCLC patients with T790M mutations. We plan to use serial plasma cfDNA genomic alteration to predict osimertinib efficacy and search for possible resistance mechanisms.
Method
We prospectively collected plasma from patients of EGFR mutation-positive NSCLC who harbored acquired EGFR T790M mutation following prior EGFR-TKI therapy. Plasma samples were collected before starting osimertinib treatment, 4 weeks following osimertinib treatment and upon disease progression. ctDNA were detected by Guardant360 gene panel test.
Result
Fifteen patients (median age 62 [range 48-77], 53% men, 53% exon 19 deletion and 47% exon 21 L858R mutation) received osimertinib treatment. Acquired T790M mutation was diagnosed by using plasma sample only (Cobas® or digital PCR) (n = 11), tissue or pleural effusion only (n = 2), and both tissue and plasma samples (n = 2). Before starting osimertinib treatment, activating mutations were detected in plasma in all patients, T790M was detected in 93% (n = 14) and TP53 mutation was detected in 47% (n = 7) of the patients by using Guardant360. After osimertinib treatment, 11 out of the 14 patients had non-detectable plasma T790M at the 4th week. Follow-up CT at least 8 weeks following osimertinib treatment of the 11 patients disclosed decreased tumor size (6 confirmed PR, 1 unconfirmed PR and 5 SD by RECIST criteria). The remaining 3 patients who had detectable plasma T790M (n = 2) or increased activating mutation allele frequency (n = 1) at the 4th week had progressive disease within 16 weeks. The first patient had initial PR but later developed C797S on progression. The second patient developed new liver tumor following prior stable disease. This patient had baseline TP53 and CDKN2A mutations detected in the plasma, and allele frequencies decreased at the 4th week and increased on progression. The last patient had rapid progression on osimertinib treatment, and alterations in PTEN and TP53 were detected on baseline and increased at the 4th week and on progression. In that patient, T790M mutation was not detectable at the 4th week but activating mutation increased in allele frequency at the 4th week and on progression. Regarding patients with baseline TP53 mutation, 4 (57%) patients who had non-detectable plasma TP53 mutation at the 4th week achieved disease control, and 2 (29%) patients had detectable or increased TP53 mutation allele frequency had PD within 16 weeks.
Conclusion
4 week plasma ctDNA following osimertinib treatment may predict early progression within 16 weeks.
