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Yan Ding
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MA26 - New Therapies and Emerging Data in ALK, EGFR and ROS1 (ID 930)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 13:30 - 15:00, Room 201 BD
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MA26.01 - Accumulation of Concomitant Mutations Involved in Drug Resistance in the Sequential ALK TKI Treatments of ALK-Positive NSCLC (ID 12550)
13:30 - 13:35 | Author(s): Yan Ding
- Abstract
- Presentation
Background
ALK tyrosine kinase inhibitors (TKIs), including crizotinib and several next-generation TKIs, have shown promising clinical outcomes for ALK-positive lung cancer patients. However, distinct resistant-mechanisms have been suggested for different ALK fusion variants in response to various TKIs. The genomic alterations associated with these heterogeneous resistant-mechanisms have not been adequately investigated, especially for patients received sequential ALK TKI treatments.
a9ded1e5ce5d75814730bb4caaf49419 Method
The distribution of ALK fusion variants in 475 ALK-positive lung cancer patients (cohort I) out of 11842 lung cancer patients (4%) tested by next-generation sequencing were analyzed. In addition, mutation profiles of 416 cancer-relevant genes in the post-ALK TKI treatment tumor samples from 52 non-small cell lung cancer (NSCLC) patients (cohort II) who represent the similar distribution of ALK fusion variants as in cohort I were analyzed. Thirty-five patients received crizotinib treatment only (crizotinib group), whereas the other 17 patients were treated with multiple lines of ALK TKIs (multi-TKI group), including lorlatinib, alectinib, ceritinib and brigatinib.
4c3880bb027f159e801041b1021e88e8 Result
EML4-ALK v3 and v1 are the two most common ALK fusion variants in both cohorts. In cohort II, 18 different ALK activating mutations were found in 17 patients (49%) of the crizotinib group and 10 patients (59%) of the multi-TKI group, although with different mutation patterns. In the multi-TKI group, G1202R was the most frequent ALK activating mutation found in 35% of the patients, while L1196M (14%) and G1269A (11%) were more common in the crizotinib cohort. Of note, there was a significant enrichment of concomitant ALK activating mutations in the multi-TKI group (p=0.031), as well as a trend of increased number of patients carrying activation of ALK by-pass/downstream pathways (p=0.056) in this group compared with the crizotinib group, resulting in a significantly higher recurrence of dual activation of ALK and ALK by-pass/downstream pathways in the multi-TKI group (29%) than that in the crizotinib group (6%) (p=0.031). Patients with concomitant TP53 mutation had significantly shorter progression free survival (PFS) compared with TP53 wildtype patients upon crizotinib treatment (median PFS: 8 vs 13 months, HR 1.494, p=0.019) regardless of fusion variant types.
8eea62084ca7e541d918e823422bd82e Conclusion
Significantly higher frequency of concomitant mutations, including concomitant ALK activating mutations, and dual activation of ALK and ALK by-pass/downstream pathways, was observed after multiple lines of ALK TKI treatments, indicating the diversity and complexity of resistance-mechanisms in response to next-generation ALK TKIs. Concomitant TP53 mutation might serve as a prognosis biomarker for worse clinical outcomes treated with crizotinib.
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P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.01-108 - Temporal Heterogeneity of Resistant Mutations in Sequential ALK TKI Treated Lung Cancer Revealed by NGS-Based Liquid Biopsy (ID 13488)
16:45 - 18:00 | Author(s): Yan Ding
- Abstract
Background
Crizotinib and several next-generation ALK TKIs have been widely applied in the treatment of ALK-positive lung cancer patients. However, drug resistance is eventually developed to these ALK TKIs via heterogeneous resistance mechanisms, which is needed to be further explored. Due to the invasiveness and feasibility of repetitive tissue biopsies, liquid biopsy has become a promising alternative for dynamically monitoring tumor genomic evolution and guides decision-making for treatment adjustment.
a9ded1e5ce5d75814730bb4caaf49419 Method
Primary tumor sample of a 71-year-old male patient diagnosed with stage IV lung adenocarcinoma was subjected for targeted next-generation sequencing (NGS) for identification of driver mutations. Mutation profiles of circulating tumor DNA (ctDNA) from seven sequential plasma samples during the treatment course of crizotinib, brigatinib, and lorlatinib were closely monitored.
4c3880bb027f159e801041b1021e88e8 Result
The dynamic mutation profiles during the disease course were represented in the Figure. As EML4-ALK v1 fusion was detected in the primary tumor, the patient was administrated with crizotinib and reached a progression-free survival (PFS) of 11 months when ALK G1269A was identified upon progression. As a result, brigatinib, a second generation ALK TKI overcoming G1269A-driven resistance, was applied. Dynamic monitoring of patient’s ctDNA during brigatinib treatment showed a dramatic drop of G1269A mutant allele frequency (MAF) to undetectable level, whereas a novel F1174L became the dominant clone. The disease progressed after 9-month of brigatinib treatment, and the patient was switched to lorlatinib. A third mutation E1210K quickly overtook F1174L as the dominant clone with the accumulation of more concomitant mutations towards the end of the treatment (8 different mutations) with a PFS of 9 months. Interestingly, brigatinib-sensitive G1269A came back after 6-month of lorlatinib treatment.
8eea62084ca7e541d918e823422bd82e Conclusion
Temporal heterogeneity of ALK activating mutations was observed along the treatment course of different TIKs via NGS-based liquid biopsy, which could provide guidance for stepwise treatment strategy for better patient care.
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P2.01-52 - Identification of Leptomeningeal Metastasis-Specific Exosomal miRNA Signatures in Cerebrospinal Fluids of NSCLC Patients (ID 13074)
16:45 - 18:00 | Author(s): Yan Ding
- Abstract
Background
Leptomeningeal metastasis (LM) is a devastating complication with poor prognosis in non-small-cell lung cancer (NSCLC) patients. The confirmed diagnosis of LM usually involves neurological evaluation, MRI imaging, and cytopathology analysis of limited tumor cells from cerebrospinal fluid (CSF). Exosomes are extracellular vesicles in body fluids enriched with microRNAs (miRNAs), which have been implicated to participate in brain metastasis. Here, we aimed to identify LM-specific exosomal miRNA signatures in NSCLC patients to elucidate their potential role in LM mechanism and to predict LM via liquid biopsy.
a9ded1e5ce5d75814730bb4caaf49419 Method
Exosomes prepared from CSF and plasma samples of 39 advanced NSCLC patients with (LM+) or without (LM-) LM as well as 12 non-cancer individuals (NC) were underwent small RNA next-generation sequencing. For patients in the LM+ group, paired plasma samples were taken before (PLM+pre) and upon (PLM+post) LM diagnosis. Exosomal miRNA profiles were subjected for differential expression analysis, pathway enrichment analysis, and signature discovery.
4c3880bb027f159e801041b1021e88e8 Result
Unsupervised hierarchical clustering of the miRNA expression profiles clearly separated CSF samples into LM+ and LM free groups (LM- and NC). Interestingly, these samples were stratified based on their LM status only, regardless of their intraparenchymal metastasis status. In total, 247 (185 up and 62 down-regulated) miRNAs were identified differentially presented in the LM+ CSF exosome samples compared to the LM- and NC groups. Top altered miRNAs include dramatically up-regulated miR-200 family and down-regulated miR-144/451 cluster. Predicted gene targets of these top-regulated miRNAs were significantly enriched in Ras/MAPK/PI3K-AKT signaling, endocytosis pathways, and so on. Promisingly, a signature of five CSF exosomal miRNAs (let-7e-5p, miR-28-3p, miR-375, miR-200a-3p, and miR-486-5p) was identified for classification of LM+ patients with 100% sensitivity and 100% specificity. Due to the higher background complexity, we only identified one miRNA (miR-24-3p) was significantly up-regulated and one miRNA (miR-92b-5p) was significantly down-regulated in LM+ patients’ plasma-derived exosomes (PLM+pre and PLM+post) compared with the LM free group (PLM- and PNC). However, a combined signature of seven miRNAs (miR-24-3p, miR-223-3p, miR-340-5p, miR-27a-3p, miR-423-5p, miR-2110 and miR-342-5p) from PLM+pre samples was identified for the prediction of future LM with 81% sensitivity and 76% specificity.
8eea62084ca7e541d918e823422bd82e Conclusion
NSCLC patients with LM present a remarkably distinct CSF exosomal miRNA signature, which may involve in the progression of LM, and can be used as diagnostic biomarkers for LM. Furthermore, the identification miRNA signature in the pre-LM plasma samples suggests the potential use of liquid biopsy to predict LM for better patient care.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P2.03 - Biology (Not CME Accredited Session) (ID 952)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.03-12 - EGFR and ERBB2 Germline Mutations in Chinese Lung Cancer Patients and Their Roles in Genetic Susceptibility to Cancer (ID 12560)
16:45 - 18:00 | Author(s): Yan Ding
- Abstract
Background
Inherited genetic determinants of lung cancer risk remains relatively elusive. Rare germline mutations in EGFR and ERBB2 have previously been reported in lung cancer patients, which may be associated with the genetic susceptibility to lung cancer.
a9ded1e5ce5d75814730bb4caaf49419 Method
We retrospectively analyzed the next-generation sequencing (NGS) results targeting 416 cancer-relevant genes, including the whole exons of EGFR and ERBB2, in a cohort of 9091 Chinese lung cancer patients.
4c3880bb027f159e801041b1021e88e8 Result
Of the 9091 Chinese lung cancer patients, nine germline mutations from 12 patients were identified within or adjacent to the kinase domain of EGFR: K757R (two patients), D1014N (two patients), I646S, G724S, V786M, T790M, L792F, R831H, and L844V, and one germline mutation was identified adjacent to the kinase domain of ERBB2: V1128I. The incidence of EGFR T790M germline mutation is much lower compared with the reported frequency in the Caucasian patients. Somatic mutations detected in the 12 patients carrying rare EGFR/ERBB2 germline mutations were most commonly EGFR exon19 deletion, L858R, and G719S mutations, and rare EGFR: S768I mutation and a novel D770delinsDNPH indel mutation. The superior response to afatinib of the patient carrying only EGFR L844V germline mutation suggests that this germline mutation might be sensitive to TKI treatment.
8eea62084ca7e541d918e823422bd82e Conclusion
Here we indentified eight novel EGFR germline mutations and the ERBB2: V1128I germline mutation were linked to the genetic susceptibility of lung cancer in Chinese population.
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P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.13-07 - CUX1-ALK: A Novel ALK Rearrangement That Responds to Crizotinib in Non-Small-Cell Lung Cancer (ID 12736)
16:45 - 18:00 | Author(s): Yan Ding
- Abstract
Background
Lung cancer is the leading cause of cancer-related deaths worldwide. ALK rearrangement has been identified in 3% to 5% non-small-cell lung cancer (NSCLC) patients. The most common ALK rearrangement is EML4-ALK. Other rare ALK arrangements, such as KIF5IB-ALK and KLC-ALK, have also been identified that might be potential therapeutic targets, although the efficacy of ALK inhibitors on the majority of these rare ALK rearrangements has not been assessed in clinic.
a9ded1e5ce5d75814730bb4caaf49419 Method
In this study, using comprehensive next-generation sequencing targeting 416 pan-cancer genes and introns of 16 genes frequently rearranged in cancer, we identified a novel CUX1-ALK fusion gene in a lung adenocarcinoma patient. The exact CUX1-ALK fusion transcript was determined via RNA-seq, and confirmed by RT-PCR. The oncogenic ability of CUX1-ALK fusion gene was further validated in 293T cells for the activation of ALK self-phosphorylation and downstream signaling pathways.
4c3880bb027f159e801041b1021e88e8 Result
After the detection of CUX1-ALK fusion gene, RNA-seq analysis of FFPE sections from the primary tumor specimen was applied to reveal a 97 nt fragment from CUX1 intron 8 inserted before the 53 nt position in ALK exon 20. Expression of the CUX1-ALK fusion protein in 293T cells confirmed the self-phosphorylation of the fusion protein and the activation of ALK downstream signaling pathways, including MAPK, JAK-STAT, and PI3K/AKT signaling pathways, which all could be inhibited by the addition of crizotinib. Furthermore, the patient showed a superior response to crizotinib with a progression-free survival of 20 months.
8eea62084ca7e541d918e823422bd82e Conclusion
This study provides the novel finding of CUX1-ALK fusion gene from NSCLC patient which could provide personalized treatment solutions for the maximum benefit to NSCLC patients.
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