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X. Niu
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-056 - Tumor Heterogeneity in Lesion Specific Response Creates ROS1 Fusion Mediating Resistance to Gefitinib in EGFR 19 Deletion Lung Adenocarcinoma (ID 6207)
14:30 - 15:45 | Author(s): X. Niu
- Abstract
Background:
Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer related death worldwide. In recent years molecular characterisation of NSCLC has led to the identification of several driver events including EGFR constitutive activation, ALK-rearrangement and ROS1 fusion. Whilst there are several mechanisms of EGFR-mutation stated in the literature, how genomic heterogeneity related with acquired EGFR resistance to second targeted agent affects response to subsequent therapy has not been noted.
Methods:
We studied EGFR-TKI, gefitinib, in an EGFR 19 deleted lung adenocarcinoma patient to assess whether tissue and liquid biopsy could be integrated with radiologic imagings to demonstrate the impact of individual actionable driver mutation on lesion specific response.
Results:
A 60-year old female, with no previous or family history of malignancy initially presented with EGFR 19 deletion mutation, ROS1 fusion negative and ALK rearrangement negative stage IV, T2aN3M1a lung adenocarcinoma detected in primary lung cancer tissue at the first diagnosis. Biopsy of this patient’s metastatic right cervical lymph node following prolonged response to gefitinb led to the loss of detection of EGFR mutation, and the novel mechanism of acquired resistance with EZR-ROS1 fusion where crizotinib was demonstrated to have good efficacy in all lesions, especially the enlarged lymphadenopathy, and also including diminishing efficacy on metastatic brain lesions. In circulating tumor DNA (ctDNA), mutant EGFR levels disappeared followed by gefitinib treatment, and a recognized EZR-ROS1 fusion was meanwhile identified before crizotinib therapy.
Conclusion:
This case displays tumor heterogeneity in action, where targeted therapy selects against primary drivers, allowing for the establishment of sub-colonies with new drivers within the specific lesion. Parallel analysis of tumor biopsies when disease progressed and ctDNA monitoring showed that lesion specific radiographic responses to subsequent targeted therapies could be driven by district resistant mechanism in the separate tumor lesions within the same patient. This demonstrates that the importance of molecular heterogeneity surveillance ensuing from acquired resistance in managing NSCLC, and the usage of liquid biopsies to allow for a holistic viewpoint of the molecular landscape of this heterogeneous disease.
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P3.02a - Poster Session with Presenters Present (ID 470)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02a-030 - ROS1 Fusion Chinese Lung Adenocarcinoma Patients Treated with Crizotinib Detected Using Next-Generation Genotyping from ctDNA (ID 6163)
14:30 - 15:45 | Author(s): X. Niu
- Abstract
Background:
Chromosomal rearrangements involving the c-ros oncogene 1 (ROS1) have been described as a subset of non-small cell lung cancer (NSCLC). Recently Crizotinib has exhibited marked therapeutic efficacy in the treatment of the ROS1 fusion NSCLC. However, resistance often occurs and repeated biopsy is necessary for tumor genotyping and underlying resistant mechanism. Circulating tumor DNA (ctDNA) represents a promising way to assess tumor genetic profile non-invasively. This study aims to assess whether liquid biopsies accurately screen disease diagnosis and reflect the response to Crizotinib treatment through analysis of ctDNA for ROS1 fusions in patients with lung adenocarcinoma, and to elucidate the underlying mechanisms of ROS1 targeted drug resistance.
Methods:
Twelve plasma samples were collected from a cohort of 4 patients with ROS1 fusion advanced stage lung adenocarcinoma, confirmed by fluorescent in situ hybridization (FISH) in tissue. A prospective-retrospective analysis on ctDNA was further performed from archived plasma samples using our ctDNA panel with concurrent CT or MRI imaging at the baseline and 8-week intervals during responsive Crizotinib treatment, and at progressive disease.
Results:
All patients showed detectable levels of ROS1 fusion in ctDNA at baseline. Upon treatment with Crizotinib, response rate is inversely correlated with levels of ROS1 fusion. One patient with progressive disease, patient 1, exhibited a detectable CD74-ROS1 fusion with 13.5% concentration at baseline; it was undetectable at partial response and re-elevated to 8.2% accompanied by an acquired G2032R mutation when disease progressed.
Conclusion:
Our ctDNA panel could be applied clinically to detect ROS1 fusion from plasma for accurate screening and convenient monitoring where detection correlates with disease status, and could distinguish mutations associated with Crizotinib induced resistance in patients with NSCLC, thus facilitating personalized cancer therapy.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-041 - Genome-Wide Screen of DNA Methylation Changes Reveals GABBR2 as a Novel Potential Target for EGFR 19 Deletion Adenocarcinoma with Erlotinib (ID 6219)
14:30 - 15:45 | Author(s): X. Niu
- Abstract
Background:
Lung cancer is the leading cause of cancer related death around the world. The last decade has witnessed the rapid development of epidermal growth factor receptor (EGFR) directly targeted therapies that have significantly changed the treatment of non-small-cell lung cancer (NSCLC). However, the challenge of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) has been an issue when talking with activating EGFR mutations, which makes it crucial to elucidate the mechanism of EGFR-TKI targeted drug resistance.
Methods:
Methyl-sensitive cut counting sequencing (MSCC), one of the most commonly used whole-genome DNA methylation sequencing technology, was applied to investigate the changes of paired tissue DNA methylation before and after TKI (erlotinib) treatment lasting two cycles with partial response (PR) for stage IIIa (N2) lung adenocarcinoma patients (N=2) with activating EGFR 19 deletion. Sequenom EpiTYPER assay method was further analyzed to double confirm the changed methylated candidate genes in these two patients, through comparing the methylated changes in paired tissues before and after TKI treatment. Western blotting, cell cycle and apoptosis analysis by the up/down regulation of a candidate gene (GABBR2) were performed in three lung adenocarcinoma cell lines, A549 (EGFR wild type), HCC4006 (EGFR 19 deletion, DelL747-E749) and HCC827 (EGFR 19 deletion, DelE746-A750), to elucidate the mechanism of GABBR2 gene in the regulation of EGFR-TKI treatment.
Results:
Sixty aberrant methylated genes were firstly discovered using MSCC method in these two patients harboring EGFR 19 del mutation treated with erlotinib. Two aberrant methylated genes, CBFA2T3 and GABBR2, were clearly validated by the Sequenom EpiTYPER assay subsequently. GABBR2 was significantly down regulated in HCC4006 and HCC827 cells harboring EGFR 19 mutations but remained conservative in A549 cells with EGFR wild-type after erlotinib treatment by Western blotting. The phenomenon was in line with the obvious apoptosis of HCC4006 and HCC827 cell lines after erlotinib treatment, but not in A549 cells. GABBR2 was further induced down regulation after erlotinib exposure through apoptosis method silenced by siRNA using RNAi technology. Meanwhile, GABBR2 gene was demonstrated up regulation rescued the apoptosis significantly, when overexpressing GABBR2 in HCC827 cell lines along with erlotinib treatment.
Conclusion:
Genome-wide screen of DNA methylation changes demonstrated that GABBR2 gene might be as a novel potential treatment target for stage IIIa (N2) EGFR 19 deletion adenocarcinoma with erlotinib treatment. Our research provides a new theoretical basis for the epigenetic study of EGFR mutated lung adenocarcinoma treatment.
