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Longitudinal Tracking of ALK-Rearranged NSCLC From Plasma Using Circulating Tumor RNA and Circulating Tumor DNA
Simon Heeke1, Saumil Gandhi2, Hai T Tran1
1Department of Thoracic Head & Neck Medical Oncology, UT MD Anderson Cancer Center, Houston, Texas.
Background:
Although the administration of tyrosine-kinase inhibitors in ALK-rearranged NSCLC has revolutionized precision medicine, the detection of gene rearrangements from liquid biopsies remains challenging. RNA-based detection has revealed promising sensitivity for rearrangement detection and thus we hypothesize that a liquid biopsy assay analyzing circulating tumor RNA (ctRNA) in addition to circulating tumor DNA (ctDNA) will improve detection. Furthermore, we hypothesize that the detection of gene fusions at baseline will correlate with clinical outcomes.
Methods:
We retrospectively analyzed 86 plasma samples from 33 patients enrolled in the BRIGHTSTAR clinical trial assessing local consolidative therapy (LCT) and brigatinib in patients with stage IV or recurrent NSCLC and confirmed ALK rearrangement (NCT03707938) using a targeted next-generation sequencing assay that analyzes ctDNA to detect gene rearrangements and mutations in 80 genes and ctRNA to detect gene arrangements in 36 genes.
Results:
ALK rearrangements were detected in 15 of 28 patients (54%) at baseline, of which eight were detected in both ctDNA and ctRNA. ALK rearrangements were detected in two patients pre-LCT, exclusively in ctRNA, but cleared completely post-LCT. The detection of ALK fusion at baseline was associated with significantly worse progression-free survival (p = 0.033). Plasma cell-free DNA concentrations for patients with detectable ALK rearrangements at baseline were significantly higher than for those without detectable gene fusions (12.3 ng/mL versus 20.2 ng/mL, p = 0.0046).
Conclusions:
The inclusion of ctRNA in liquid biopsies increased detection of ALK rearrangements and detection at baseline was associated with significantly worse progression-free survival highlighting the added benefit of ctRNA.
Insights
Adding circulating tumor RNA (ctRNA) to liquid biopsies improves detection of ALK rearrangements in non-small cell lung cancer. Baseline ALK fusion detection correlates with worse progression-free survival, highlighting ctRNA
Area of Science:
- Oncology
- Molecular Diagnostics
- Genomics
Background:
- Tyrosine-kinase inhibitors have advanced precision medicine for ALK-rearranged NSCLC.
- Detecting gene rearrangements from liquid biopsies remains a challenge.
- RNA-based detection shows promise for improved sensitivity.
Purpose of the Study:
- To evaluate if a liquid biopsy assay combining circulating tumor DNA (ctDNA) and ctRNA improves ALK rearrangement detection.
- To determine if baseline gene fusion detection correlates with clinical outcomes in ALK-rearranged NSCLC.
Main Methods:
- Retrospective analysis of 86 plasma samples from 33 patients with ALK-rearranged NSCLC.
- Utilized a targeted next-generation sequencing assay analyzing ctDNA (80 genes) and ctRNA (36 genes).
- Assessed samples from the BRIGHTSTAR clinical trial (NCT03707938).
Main Results:
- ALK rearrangements detected in 54% (15/28) of patients at baseline.
- ctRNA detected ALK rearrangements exclusively in two patients pre-LCT.
- Baseline ALK fusion detection was linked to significantly worse progression-free survival (p=0.033).
Conclusions:
- Incorporating ctRNA into liquid biopsies enhances ALK rearrangement detection rates.
- Baseline ALK fusion detection is a significant negative prognostic indicator for progression-free survival.
- ctRNA analysis offers added value in the liquid biopsy approach for ALK-rearranged NSCLC.
