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Quan Lin
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P86 - Targeted Therapy - Clinically Focused - New Target (ID 263)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P86.20 - The Prevalence of NTRK1 Fusion in a Chinese Lung Cancer Cohort (ID 3601)
00:00 - 00:00 | Author(s): Quan Lin
- Abstract
Introduction
At present, several neurotrophin receptor kinase (NTRK) inhibitors have been marketed and achieved marked efficacy in TRK fusion positive cancers, including lung cancers. However, there are few investigations on the molecular characteristics of NTRK fusion in Chinese lung cancers. We herein retrospectively explore the prevalence of NTRK1 fusion in a large Chinese lung cancer population and estimate the proportion of patients with NTRK1 fusion who may benefit in clinic.
Methods
A total of 12,565 Chinese lung cancer patients, including 8,167 adenocarcinoma patients, was used for the investigation of NTRK1 fusion, especially NTRK1 fusions with critical kinase domains. From 2017 to 2019, these patients’ ctDNA or tumor specimens were performed with targeted sequencing that including NTRK1 fusion testing. Concomitant drive mutations were also analyzed.
Results
NTRK1 fusions were identified in a total of 11 patients (11/12565, 0.088%), including 7 adenocarcinoma patients (7/8167, 0.086%). The median age of these patients was 62 years old, ranging from 46 to 74. Eight fusion partners were identified, seven of which had critical kinase domains, exception NTRK1-CDH7. The partners TPM3, TPR, IRF2BP2 and LMNA have been reported in lung cancer. Here, we found three fusion forms of TPM3-NTRK1 (3 pts); One form of TPR-NTRK1 (2 pts), IRF2BP2-NTRK1 (1 pt) and LMNA-NTRK1 (1 pt), respectively. Interestingly, we here identified another three novel partners of NTRK1: DPP10, FRMPD1 and KMT2C, and all of these novel fusions harbored critical kinase domains of NTRK1. According to clinical results of LOXO-101, NTRK1 fusion with critical kinase domain had a good response to this inhibitor. Therefore, in our cohort, it is likely that 0.08% (10/12565) of lung cancer patients would benefit clinically from NTRK inhibitors. We then analyzed the concomitant driver mutations, seven of the ten NTRK functional fusion cases (70%) owned tumor suppressor gene TP53 co-mutations. Five of the ten (50%) patients had actionable EGFR co-mutations, EGFR L858R in 4 pts and G719C in 1 pt. Mis-match repair genes (MLH3, MSH2, MSH6), BRAF V600E and PIK3CA E545Q co-mutated with NTRK1 fusion in 3 patients, 2 patients and 1 patient respectively. EGFR sensitive mutations (L858R/G719C) and TP53 hotspot mutations easily co-mutated in the same NTRK1 functional fusions patients (4 pts) and all of these patients were previously treatment with EGFR TKIs. Meaningfully, one NTRK1 fusion patient, without the treatment of EGFR TKIs, was with co-mutations of EGFR L858R and BRAF V600E. Previous clinical investigations or experiments have confirmed that gene fusion could mediate the resistance of EGFR-TKI, and the combination of EGFR TKIs and gene fusion inhibitors may be an effective treatment for these patients.
Conclusion
Here, we identified 10 cases (in 12,565 cases, 0.08%) with functional NTRK1 fusions in a Chinese lung cancer cohort; these patients may be benefit from NTRK inhibitors in clinic. Three novel partners (DPP10-, FRMPD1- and KMT2C-) were found in our cohort. Half of the NTRK1 fusion patients were co-mutated with EGFR activating mutations, which meaning that understanding of gene fusion mediating EGFR-TKI resistance is helpful to the development of follow-up treatment strategies.
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P88 - Targeted Therapy - Clinically Focused - ROS1 (ID 265)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P88.05 - A Recommended one-step Targeted Sequencing Technology for Identification of a Dual CD74-ROS1 in NSCLC (ID 3630)
00:00 - 00:00 | Presenting Author(s): Quan Lin
- Abstract
Introduction
ROS1 rearrangements define a distinct molecular subtype of non-small-cell lung cancer (approximately 2% of NSCLC), which can be effectively treated with a tyrosine kinase inhibitor (TKI) targeting ROS1/MET/ALK rearrangements such as crizotinib. The coexistence of two variants of ROS1 fusion has been described, however, dual-ROS1 fusions detected simultaneously in one patient with NSCLC is still rare. Herein we present a dual CD74-ROS1 (CD74-E6 and ROS1-E32/34) fusions in a patient with lung adenocarcinoma using one-step targeted sequencing technology who responded well to crizotinib.
Methods
We retrospectively reviewed genomic profiles of 180 NSCLC patients using a targeted panel across 51 cancer-related genes . A dual ROS1 fusions: CD74-ROS1 (C6:R32, 21.64%) and CD74-ROS1 (C6:R34, 28.24%) was identified in this cohort and the break-apart FISH analysis showed clear separation of green (5’) and red (3’) signals corresponding to the ROS1 gene. 51 genes panel is based on the one-step targeted sequencing technology, which can achieve high coverage depth at relatively low cost for its amplicon-based protocol. To validate the reliability of this dual fusions detected, the hybridization capture-based assay and paired-end RNA sequencing were performed. The hybridization capture-based assay detected neither of the dual fusions using a targeted DNA panel which included ROS1 and CD74 genes for the fusions. The average distinct coverage of this sample is 1565× and the total mapping reads are 141892 for ROS1 intron31-35 region in hybridization capture-based assay. Both CD74-ROS1 (C6:R32) and CD74-ROS1 (C6:R34) were observed in RNAseq assay using Collibri stranded RNA-Seq kit and VAHTS® Universal V6 kit.
Results
Based on reliable results, especially coverage reads number of CD74-ROS1 (C6:R32) and CD74-ROS1 (C6:R34), this finding may be due to the alternative splicing of ROS1 RNA. RNA splicing plays an essential role in the process of gene regulation, which allows for the exon composition of spliced mRNA to vary significantly[4]. However, because of lack of DNA sequence of the fusion gene, we can be unable to determine whether one of the dual-ROS1 fusion is a resulting variant from different genomic rearrangement or just a splice variant in mRNA of CD74-ROS1. In addition, the break-apart FISH is the most commonly used diagnostic method for detecting ROS1 fusion genes to date. However, FISH can’t identify the coexistence of divergent variants of fusion genes.
Conclusion
For this dual ROS1 fusion pattern, one-step targeted sequencing technology may be a more efficient diagnostic method than FISH, the hybridization capture-based assay and RNA-Seq. Our results are also given demonstrated the one-step targeted sequencing technology is as a potential effective tool for dual fusions detection. Although ROS1 gene fusion is found in about 1-2% of NSCLC, data on dual ROS1 fusions remain scarce because of the low occurrence rate. The mechanism of this phenomenon and the possible difference in response to ROS1 inhibitors and the clinical behavior of patients with dual-ROS1 fusions has yet to be investigated.
