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H. Brunnström
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MA12 - Miscellaneous Biology/Pathology (ID 476)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:B. Dome, W.D. Travis
- Coordinates: 12/06/2016, 14:20 - 15:50, Schubert 1
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MA12.01 - Next Generation Sequencing Based Clinical Framework for Analyses of Treatment Predictive Mutations and Gene Fusions in Lung Cancer (ID 4108)
14:20 - 14:26 | Author(s): H. Brunnström
- Abstract
- Presentation
Background:
The use of new, emerging techniques in the search of tailored patient therapies is rapidly becoming a reality. Here we describe the optimization and implementation of next generation sequencing for treatment predictive mutation screening in parallel with gene fusion status of ALK, RET and ROS1 in non-small cell lung cancer (NSCLC) patients.
Methods:
The Illumina TruSight tumor 26-gene NGS panel was validated in 81 clinical routine FFPE or cytology specimens and implemented in 533 diagnostic NSCLCs during one year of clinical analysis. In parallel, a RNA-based NanoString method was evaluated in 169 cases for gene fusion status of ALK, RET and ROS1.
Results:
We have successfully established a streamlined workflow with a 5-day turnaround time from specimen arrival to mutation report. The concordance in the validation cohort was 99% for comparable variants. In the 533 diagnostic samples, 1-2 variants were detected in 79% of the cases. Most frequently mutated genes included TP53, KRAS, EGFR, STK11, and BRAF, all with differences in mutational patterns between histological subgroups. The RNA-based NanoString assay was successfully established and validated. The success rate in the 169 cases was 80% and 10 gene fusions were found (five ALK fusions, three RET fusions and two ROS1 fusions) all in adenocarcinomas. Integration of mutation and gene fusion status revealed that 68% of adenocarcinomas, 13% of SqCCs and 56% of NSCLC-NOS harbored ≥1 actionable alteration ALK, RET, ROS1, EGFR, KRAS, PIK3CA, BRAF, NRAS, MAP2K1, ERBB2 or AKT1. Specifically, in 13.2% of the adenocarcinomas where no EGFR or ALK alteration was detected emerging targeted therapy may be considered in addition to the 15.3% of patients that was eligible for EGFR or ALK inhibitors. The corresponding proportions for SqCCs were 5.5% in addition to the 2.2%, and for NSCLC-NOS 2.5% in addition to the 11.2% eligible for EGFR or ALK inhibitors.
Conclusion:
Next generation sequencing in combination with the NanoString technology is time- and cost efficient in the diagnostic routine for treatment predictive mutation screening and gene fusion status detection. The techniques represent valuable tools for pinpointing patients eligible to standard targeted therapies in addition to new emerging therapies.
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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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P1.02-063 - Mutation Profiling by Targeted Next-Generation Sequencing of an Unselected NSCLC Cohort (ID 4147)
14:30 - 14:30 | Author(s): H. Brunnström
- Abstract
Background:
Non-small cell lung cancer (NSCLC) is a heterogeneous disease, with a wide diversity when it comes to molecular variations. In the non-squamous subset a large variety of altered driver genes have been identified.
Methods:
The mutational status was evaluated in a consecutive Swedish NSCLC cohort consisting of 354 patients, who underwent surgical resection between 2006 and 2010. DNA was prepared from either fresh frozen or formalin fixed paraffin embedded tissue (FFPE) and used for library preparation using a Haloplex gene panel and subsequently sequenced on an Illumina Hiseq instrument. The gene panel covers all exons of 82 genes, previously identified in NSCLC. The panel design utilizes two strand capture and reduced target fragment length compatible with degraded FFPE samples (Moens et al., J Mol Diagn, 2015).
Results:
All previously known hotspot alterations in the driver genes KRAS, EGFR, HER2 (exon 20 insertions), NRAS, BRAF, MET (exon 14-skipping) and PIK3CA (exon 9 and 20) were analyzed in the 252 non-squamous cases, see figure. KRAS mutations were found in 98 patients (39%) whereas EGFR alterations were present in 33 (13%). The prevalence of KRAS mutations is higher than normally reported and could be due to the large fraction of smokers included in this cohort. The EGFR prevalence is a bit higher than previously demonstrated (Sandelin et al. Anitcancer Res, 2015). Mutations in the other driver genes were detected at low frequencies (HER2(3%), BRAF(2%), NRAS(1%), MET(1%) and PIK3CA(1%)). Figure 1
Conclusion:
The preliminary analysis of mutational status in this large unselected Swedish NSCLC cohort reveals mutation frequencies in the common driver genes resembling previous reports on western populations with a high smoking rate. Ongoing analysis of the remaining genes will be used for pathway analysis and could provide a more complete picture of the lung cancer pathogenesis.
