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Evaristo Maiello
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-26 - ALK Fusion Variant Detection by Targeted RNA-Seq in TKIs Treated ALK-Positive Lung Adenocarcinoma (ID 1860)
09:45 - 18:00 | Author(s): Evaristo Maiello
- Abstract
Background
Clinical outcomes of ALK positive (ALK+) Non-Small-Cell Lung Cancer (NSCLC) and the identification of the most effective anaplastic lymphoma kinase inhibitor (ALKi) according to the specific ALK fusion variants are not well assessed. We retrospectively characterized fusion variant distribution in a cohort of ALK+ lung adenocarcinomas (ADC) with paired clinical data about treatments and outcomes.
Method
Diagnostic tumor tissue from advanced ALK+ (by FISH and/or IHC) ADC diagnosed from 2010 to 2018 and treated with single or multiple ALKis were collected (expanded cohort from Gobbini et al. Lung Cancer, 2017). The OncomineTM Solid Tumor Fusion Transcript Kit on an Ion PGM™ system and the Ion Reporter™ software were used to identify targeted ALK fusion gene products (ThermoFisher).
Result
Specific fusion variant transcripts were found in 34/55 (62%) of collected samples. As expected, EML4-ALK fusion transcripts were the most common (31/34 samples, 91%), but HIP-ALK transcripts were also detected (3/34 - 9%). Among EML4-ALK fusions the following variants were detected: V1 (n=11); V2 (n=2); V3a/b (n=12 ) V5a/b (n=5 ) and E6A19 (n=1). Patient median age was 60 year [range 36-85], 22 were male and 12 female. Three patients were current, 11 former and 20 never smokers. Crizotinib, alectinib, ceritinib, brigatinib and lorlatinib were the ALKis used. Independently of the therapy line, 12 patients received crizotinib only, while 22 patients received crizotinib followed by one or two other ALKis. Regardless of the type of transcript, those patients who received more than one ALKi had a better median overall survival compared to those receiving crizotinib only, as expected (74 vs 21 months, HR: 5.31; 95%CI: 1.464-19.26, log rank p=0.0006). Furthermore, a significant difference in the mean duration of the different ALKi treatment was found according to the ALK variants (Chi-square p<0.0001), suggesting a private ALKi efficacy profile for specific fusion variants. Finally, the 3 HIP-ALK cases showed a better outcome with respect the EML4-ALK variants (not reached vs 51 months).
Conclusion
Our analysis suggests that different ALK fusion variant might affect ALKi treatment duration in ALK+ lung ADC.
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P2.14 - Targeted Therapy (ID 183)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.14-14 - Comparison of Molecular Testing Modalities for Detection of NRG1 Rearrangements in Invasive Mucinous Adenocarcinoma (ID 2179)
10:15 - 18:15 | Author(s): Evaristo Maiello
- Abstract
Background
The NRG1 (Neureguline-1) fusion gene has been recently described as a new molecular feature of non small cell lung cancer (NSCLC), strictly related to invasive mucinous adenocarcinoma (IMA) subtype. Despite of NRG1 fusion partners, all Nrg1 chimeric ligands were predicted to retain the EGF-like domain of the wild-type NRG1 III-β3 isoform that produces oncogenic signals through ErbB2-ErbB3 heterodimers and leads to phosphorylation of ErbB3. To date, the NRG1 fusions were quite exclusively identified by RNA sequencing and only in few cases confirmed by fluorescent in situ hybridization (FISH) analysis, mainly due to the cellular features of IMA subtypes that produce interference in fluorescent signals detection. An accurate detection of NRG1 rearrangement/fusions in clinical tumor samples is actually demanded. In this study we compared the performance of two molecular testing approaches to detect NRG1 breaks in paraffin embedded formalin fixed (FFPE) IMA lung tissues.
Method
A total of 19 lung FFPE IMAs were screened by immunohistochemistry (IHC) to evaluate the expression of phosphorylated-ErbB3 (pErbB3) receptor. Samples positive for pErbB3 staining were tested by using by break-apart FISH to detect putative NRG1 rearrangements and RNA-targeted next generation sequencing (NGS) to identify fusion variants.
Result
Eleven cases showed an increased expression of pErbB3 in cancer cells compared to the adjacent non-involving bronchial epithelium which demonstrated a basal level staining of the protein. pErbB3 positive cases were investigated by FISH and showed <15% of rearranged nuclei (range 17-47%, mean 29%). In addition to the canonical signal split pattern, the FISH NRG1 assay reveals that cells also showed rearrangement patterns in form of isolated 3’ signals, thus indicating a strength analogy with ALK and ROS1 fusions, where a 5’ gene deletion was frequently observed. CD74-NRG1 fusion variant was identified by NGS analysis in four cases, whereas in three cases a 3’/5’ NRG1 imbalance was detected. For both approaches, we identified assay characteristics that likely contributed to false-negative results.
Conclusion
Our investigations confirm the usefulness of IHC/FISH combined approach for NRG1 broken tumors identification, but also highlight the crucial role of NGS to identify NRG1 functional chimeric transcripts. Such combined molecular testing should enhance the selection of NRG1-positive patients to include in clinical trials with specific compounds designed to inhibit the RTK downstream signal.
