Abstract
With the rapid development of targeted therapies for the treatment of cancer, methods for predicting response and outcome are in high demand. Non-small cell lung cancer driven by genomic rearrangements of the anaplastic lymphoma kinase (ALK) gene can be successfully treated with ALK-targeted therapy. Unfortunately, a subset of patients does not respond, and all patients ultimately acquire resistance, highlighting the need for better clinical tools to manage these patients. Here, we performed targeted next-generation sequencing on plasma circulating tumor DNA (ctDNA) from 24 patients to assess the clinical utility of ctDNA genomic profiling. Patients with detectable ctDNA prior to treatment had worse progression-free survival (PFS) than those without (median 8.7 vs. 15.2 months, p = 0.028). In addition, the presence of ctDNA within two months after treatment initiation predicted inferior PFS (median 4.6 vs. 14.5 months, p = 0.028). Longitudinal monitoring of ctDNA with droplet digital PCR during treatment reflected the radiological response and revealed potential acquired resistance mutations. Interestingly, an increase in the ctDNA concentration was evident prior to the determination of progressive disease by conventional radiological imaging, with a median lead time of 69 days (range 30–113). Genomic profiling of ctDNA is a promising tool for predicting outcome and monitoring response to targeted therapy.
Highlights
Targeted therapies are becoming standard treatment for multiple cancer types, and several targeted therapy options are available for the treatment of non-small cell lung cancer (NSCLC)
It is recommended that all NSCLC patients with an adenocarcinoma component are tested for anaplastic lymphoma kinase (ALK) rearrangements in their diagnostic biopsy, and several ALK tyrosine kinase inhibitor (TKI) are approved for the treatment of ALK-positive patients [1,2]
Commercial CAPP-Seq assay, we demonstrated that circulating tumor DNA (ctDNA) analyses prior to and early following ALK-TKI treatment initiation may predict clinical outcome and that longitudinal levels of tumor-derived single-nucleotide variant (SNV) in the plasma follow clinical response patterns
Summary
Targeted therapies are becoming standard treatment for multiple cancer types, and several targeted therapy options are available for the treatment of non-small cell lung cancer (NSCLC). Rearrangements of the anaplastic lymphoma kinase (ALK) gene are found in a subset of NSCLC patients and drive tumor growth. The tumor cells are susceptible to targeted therapy using small tyrosine kinase inhibitors (TKIs). It is recommended that all NSCLC patients with an adenocarcinoma component are tested for ALK rearrangements in their diagnostic biopsy, and several ALK TKIs are approved for the treatment of ALK-positive patients [1,2]. Not all patients respond to the treatment, and all patients eventually acquire resistance and experience disease progression. The mechanisms of resistance to ALK TKIs have been thoroughly investigated in the last few years [3,4].
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