Detection of actionable mutations in circulating tumor DNA for non-small cell lung cancer patients

Abstract

Liquid biopsy approaches, especially the detection of circulating tumor DNA (ctDNA), are emerging as sensitive and reliable surrogates for tumor tissue-based routine diagnostic testing. Here, we retrospectively analyzed serially collected plasma samples of non-small cell lung cancer (NSCLC) patients obtained at first diagnosis to evaluate the added value of ctDNA analysis for detecting therapeutically relevant variants and determining the consequent clinical implications. One hundred eighty plasma samples from consecutively recruited NSCLC patients were included. Circulating cell-free DNA (ccfDNA) was extracted and analyzed with the UltraSEEK Lung Panel v2 on the MassARRAY System. Tumor tissue next-generation sequencing (NGS) data, performed as routine molecular testing in the clinical setting, were retrieved from the national pathology registry for 132 patients. Here we show that in 82% of the patients, mutations are concordantly detected in tumor tissue and plasma. More mutations are reported with tumor tissue-based NGS in nineteen patients, while in four patients additional mutations are detected in plasma. Tissue-based molecular tumor profiling identifies 60 patients eligible for targeted treatment including fifteen (8%) harboring fusions currently not covered by UltraSEEK. Based on ctDNA analysis, 41 patients (23%) are identified as eligible for BRAFV600-, EGFR-, or KRASG12C-targeted therapies. In the absence of tumor tissue NGS data (n = 48), five therapeutically relevant mutations are detected. Molecular tumor profiling of ctDNA identifies therapeutically relevant mutations at a comparable rate to tumor tissue-based NGS and might therefore serve as an alternative or complementary test for the detection of actionable variants in plasma. van der Leest, Rozendal et al. identify therapeutically relevant mutations in circulating tumor DNA profiles at baseline for patients with non-small cell lung cancer. They detect more circulating tumor DNA mutations using both plasma and tumor tissue compared to tissue detection of mutations alone. Being able to identify cancer mutations to direct treatment strategies has become very important in improving outcomes of patients with non-small cell lung cancer. With the detection of cancer DNA in the blood, referred to as liquid biopsy, an alternative to invasive tissue-based diagnostics now exists. We tested how sensitive the UltraSEEK Lung Panel (a method which evaluates a panel of genes) was in the detection of mutations in blood affecting treatment decisions for patients with non-small cell lung cancer. The same mutations were detected using tissue and this blood-based method in 82% of the patients. Moreover, in a similar number of patients, the most favorable treatment advice was based on tissue and blood information. This study showed that blood testing is suitable for the detection of mutations and has the potential to improve diagnostics for lung cancer patients.

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