Circulating Tumor DNA Analysis for Patients with Oncogene-Addicted NSCLC With Isolated Central Nervous System Progression

Abstract

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Discovery of Targetable Genetic Alterations in NSCLC Patients with Different Metastatic Patterns Using a MassARRAY-Based Circulating Tumor DNA Assay

“…50.0% of oligo–brain metastatic patients, and the VAF was lower compared to patients with multi-brain metastases. This finding is consistent with previous studies using NGS-based assays analyzing 37 genes [ 37 ], where 52.0% of oligo–brain metastatic patients had detectable mutations in ctDNA, and the median VAF was lower in patients with oligo–brain metastatic disease compared to patients with multi-brain metastases [ 37 ]. Similar obstacles have been also described for primary brain tumors, where somatic alterations in the plasma were also detected in only 50.0% of patients [ 36 ].…”

ALK Inhibitors in ALK-positive NSCLC with Central Nervous System Metastases

“…Another situation that could be encountered is the development of isolated CNS progression, a frequent phenomenon with crizotinib, that could also occur with ngALKi. 17 For example, in the ASCEND-4 study evaluating first-line ceritinib versus chemotherapy, 48% of patients failing ceritinib developed isolated CNS progression. 7 Isolated CNS progression occurs as either a consequence of resistance alterations or insufficient drug penetration.…”

“…In the latter case, there may be a retention of sensitising alterations. 17 The distinction between these two causes of isolated CNS progression would better guide the treatment sequence between alternate second-generation drugs and third-generation drugs or the use of local therapies, such as cranial irradiation. However, performing a molecular profile in patients with isolated CNS progression is challenging, as it should be performed in CSF rather than in plasma.…”

“…Plasma circulating tumour DNA is negative in ≥50% of cases of isolated CNS progression, depending on the performance of the technique. 17 In the absence of resistance alterations, an insufficient drug concentration in the brain might be responsible. However, currently there are only scarce data in Figure 1: Most common treatment sequences and outcomes based on clinical trials 4,6,8,9,12,14 Intracranial…”

“…In isolated CNS progression, a positive liquid biopsy might predict subsequent extra-CNS progression, but these data should be validated in prospective studies. 17 Due to the availability and performance of ngALKi, patients can have long-term survival despite the presence of brain metastases. 20,21 We hope to witness even more rapid improvement in their management as other promising options are being investigated.…”