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D.L. Aisner
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-057 - Comparison of Molecular Testing Modalities for Detection of ROS1 Rearrangements in a Cohort of Positive Patient Samples (ID 10110)
09:30 - 09:30 | Author(s): D.L. Aisner
- Abstract
Background:
Targeting oncogenic gene fusions with small molecules has proven to be a highly successful treatment strategy in lung cancer. For ALK and ROS1 rearrangement/fusion positive cases, fusion directed therapy is now considered standard of care for advanced disease. Consequently, the accurate clinical detection of rearrangements/fusions is of critical clinical importance. Multiple distinct methodologies are employed in the clinical setting for rearrangement/fusion detection. In this study, we compare the performance of several of these methodologies on a large cohort of ROS1 rearrangement/fusion-positive patient samples.
Method:
Eighteen ROS1 rearrangement/fusion-positive clinical samples were assessed by at least two of the following molecular testing methodologies: break-apart fluorescence in situ hybridization (FISH), DNA-based hybrid capture library preparation followed by next-generation sequencing (NGS), and RNA-based anchored multiplex PCR library preparation followed by NGS.
Result:
None of the testing methodologies demonstrated 100% sensitivity in detection of ROS1 rearrangements/fusions. FISH results were negative in 2/18 tested clinical samples. One of these demonstrated an atypical staining pattern, suggestive of a complex rearrangement. The other occurred in a case of GOPC-ROS1 fusion in which the genes are in close proximity on chromosome 6. The DNA-based NGS assay was negative in 3/11 tested clinical samples. This assay suffered from poor bait coverage in intronic regions containing repetitive sequences, and false negatives were likely due to this deficiency. The RNA-based NGS assay did not identify ROS1 fusions in 3/15 tested clinical samples. However, this assay is highly reliant on RNA quality, and missed calls were associated with metrics derived from the assay suggestive of degraded RNA (and thus the results would have been deemed uninformative). Additionally, we report cases in which the detected fusion at the transcript level (via RNA-based NGS) occurred between exons not predicted by proximal exons bordering the detected genomic breakpoint (via DNA-based NGS), likely due to exon removal via mRNA splicing. For these cases, the detected genomic DNA breakpoint may have resulted in a non-call due to the prediction of an out-of-frame fusion transcript.
Conclusion:
Rearrangement/fusion detection in the clinical setting is complex and all methodologies have inherent limitations that users must be aware of. Consequently, careful scrutiny of negative results must be performed, particularly in cases negative for other known oncogenic drivers (pan-negative cases). Ideally, orthogonal rearrangement/fusion testing methodologies should be employed for such cases.
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P3.03 - Chemotherapy/Targeted Therapy (ID 719)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.03-007 - LCMC2: Expanded Profiling of Lung Adenocarcinomas Identifies ROS1 and RET Rearrangements and TP53 Mutations as a Negative Prognostic Factor (ID 8338)
09:30 - 09:30 | Author(s): D.L. Aisner
- Abstract
Background:
The Lung Cancers Mutation Consortium (LCMC) is a multi-institutional effort where 16 sites identify oncogenic drivers and pool data to assess the impact of targeted therapies in patients with lung adenocarcinomas. We now report the results of the second patient cohort (LCMC2) with an expanded multiplex molecular panel to include RET and ROS1 and tumor suppressors.
Method:
904 patients with centrally confirmed stage IV lung adenocarcinomas who were candidates for therapy had at least one of 14 oncogenic drivers assessed in a CLIA-compliant laboratory using genotyping, FISH, massively parallel sequencing (NGS), and immunohistochemistry (IHC) analyses.
Result:
Among 423 patients tested for all 14 targets, we found a driver in 65%. Mutated KRAS was found in 31%, sensitizing EGFR in 14%, MET amplification in 5%, ALK rearrangements in 4%, BRAF V600E in 3%, and HER2 in 3%. Rearrangements in RET and ROS1 were each found in 2% (CI 1 to 3%). Using IHC, PTEN loss was found in 8% (CI 6 to 11%) and MET expression in 58% (CI 55 to 61%). Use of targeted therapies in patients with EGFR, HER2, or BRAF mutations, ALK, ROS1, or RET rearrangements, and MET amplification was associated with a gain in overall survival of 1.5 years relative to those with the same drivers not receiving targeted therapy and a gain of 1 year relative to those without an actionable driver. Current and former cigarette smokers derived a survival benefit from targeted therapies similar to never smokers (p=0.975). Among 154 patients who had all drivers assessed and NGS testing in addition, any TP53 mutation was associated with poorer survival among those with EGFR, ALK, or ROS1 (p=0.014). STK11 was detected in 11%, all in patients with KRAS mutations.
Conclusion:
Using an expanded testing panel, LCMC2 demonstrates the survival benefit of matching targeted treatments to oncogenic drivers in patients with lung adenocarcinomas, identifies additional prognostic factors, and supports the performance of multiplex molecular testing on specimens from all individuals with lung adenocarcinomas irrespective of clinical characteristics. We detected either MET amplifications or HER2 mutations in 7%, together more than the 4% with ALK. A targeted drug is available in the United States for 35% of patients with lung adenocarcinomas. The routine use of massively parallel sequencing (NGS) detects both targetable drivers and tumor suppressor genes that have significance for therapy selection and prognosis. Supported by Free to Breathe
